Max J. Hilz, M.D., Ph.D.

Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel
Burlina, Alessandro P; Sims, Katherine B; Politei, Juan M; Bennett, Gary J; Baron, Ralf; Sommer, Claudia; Moller, Anette Torvin; Hilz, Max J
2011 ;11:61-61, BMC neurology
BACKGROUND: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. METHODS: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. RESULTS: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. CONCLUSIONS: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate
— id: 137993, year: 2011, vol: 11, page: 61, stat: Journal Article,

Awareness of Fabry disease among rheumatologists--current status and perspectives
Cimaz, Rolando; Guillaume, Severine; Hilz, Max J; Horneff, Gerd; Manger, Bernhard; Thorne, J Carter; Moller, Anette Torvin; Wulffraat, Nico M; Roth, Johannes
2011 Apr;30(4):467-475, Clinical rheumatology
Fabry disease is an inherited disorder of lipid metabolism caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Burning peripheral pain with triggered crises of excruciating pain and gastrointestinal dysmotility point to Fabry small fiber neuropathy; angiokeratoma, corneal deposits, and hypohidrosis are other common early manifestations. Progressive dysfunction of the kidneys, heart, and/or brain develops in adulthood. Diagnosis is often delayed which is of great concern, as therapeutic outcomes with enzyme replacement therapy are generally more favorable in early stages of Fabry disease. Results of a survey among 360 rheumatologists and pediatricians clinically managing patients with rheumatologic conditions demonstrate that Fabry manifestations are generally poorly recognized and that awareness of appropriate diagnostic tests is low. To raise awareness about the musculoskeletal aspects of Fabry disease among rheumatologists, the International Musculoskeletal Working Group on Lysosomal Storage Disorders has reviewed the current knowledge. We propose a diagnostic algorithm with burning pain in hands and feet and triggered attacks of excruciating pain as keystones. Evidence of autonomic nerve dysfunction and simple temperature sensitivity testing can provide important diagnostic clues. Multi-systemic involvement should be explored by taking a detailed medical history, including family history, and performing a thorough physical examination and appropriate laboratory workup. Confirmatory tests include the alpha-Gal A enzyme activity assay (males) and genetic testing (females). We propose that medical specialists use our diagnostic algorithm when evaluating individuals with peripheral neuropathic pain
— id: 134187, year: 2011, vol: 30, page: 467, stat: Journal Article,

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome
Freeman R; Wieling W; Axelrod FB; Benditt DG; Benarroch E; Biaggioni I; Cheshire WP; Chelimsky T; Cortelli P; Gibbons CH; Goldstein DS; Hainsworth R; Hilz MJ; Jacob G; Kaufmann H; Jordan J; Lipsitz LA; Levine BD; Low PA; Mathias C; Raj SR; Robertson D; Sandroni P; Schondorff R; Stewart JM; van Dijk JG
2011 Apr 26;161(1-2):46-48, Autonomic neuroscience
— id: 126645, year: 2011, vol: 161, page: 46, stat: Journal Article,

Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome
Freeman, Roy; Wieling, Wouter; Axelrod, Felicia B; Benditt, David G; Benarroch, Eduardo; Biaggioni, Italo; Cheshire, William P; Chelimsky, Thomas; Cortelli, Pietro; Gibbons, Christopher H; Goldstein, David S; Hainsworth, Roger; Hilz, Max J; Jacob, Giris; Kaufmann, Horacio; Jordan, Jens; Lipsitz, Lewis A; Levine, Benjamin D; Low, Phillip A; Mathias, Christopher; Raj, Satish R; Robertson, David; Sandroni, Paola; Schatz, Irwin; Schondorff, Ron; Stewart, Julian M; van Dijk, J Gert
2011 Apr;21(2):69-72, Clinical autonomic research
— id: 146236, year: 2011, vol: 21, page: 69, stat: Journal Article,

Frequency analysis unveils cardiac autonomic dysfunction after mild traumatic brain injury
Hilz, Max J; Defina, Philip A; Anders, Stefan; Koehn, Julia; Lang, Christoph J; Pauli, Elisabeth; Flanagan, Steven R; Schwab, Stefan; Marthol, Harald
2011 Sep;28(9):1727-1738, Journal of neurotrauma
Abstract Long-term mortality is increased after mild traumatic brain injury (mTBI). Central cardiovascular-autonomic dysregulation resulting from subtle, trauma-induced brain lesions might contribute to cardiovascular events and fatalities. We investigated whether there is cardiovascular-autonomic dysregulation after mTBI. In 20 mTBI patients (37+/-13 years, 5-43 months post-injury) and 20 healthy persons (26+/-9 years), we monitored respiration, RR intervals (RRI), blood pressures (BP), while supine and upon standing. We calculated the root mean square successive RRI differences (RMSSD) reflecting cardiovagal modulation, the ratio of maximal and minimal RRIs around the 30th and 15th RRI upon standing (30:15 ratio) reflecting baroreflex sensitivity (BRS), spectral powers of parasympathetic high-frequency (HF: 0.15-0.5 Hz) RRI oscillations, of mainly sympathetic low-frequency (LF: 0.04-0.15 Hz) RRI oscillations, of sympathetic LF-BP oscillations, RRI-LF/HF-ratios reflecting sympathovagal balance, and the gain between BP and RRI oscillations as additional BRS index (BRS(gain)). We compared supine and standing parameters of patients and controls (repeated measures analysis of variance; significance: p<0.05). While supine, patients had lower RRIs (874.2+/-157.8 vs. 1024.3+/-165.4 ms), RMSSDs (30.1+/-23.6 vs. 56.3+/-31.4 ms), RRI-HF powers (298.1+/-309.8 vs. 1507.2+/-1591.4 ms(2)), and BRS(gain) (8.1+/-4.4 vs. 12.5+/-8.1 ms.mmHg(-1)), but higher RRI-LF/HF-ratios (3.0+/-1.9 vs. 1.2+/-0.7) than controls. Upon standing, RMSSDs and RRI-HF-powers decreased significantly in controls, but not in patients; patients had lower RRI-30:15-ratios (1.3+/-0.3 vs. 1.6+/-0.3) and RRI-LF-powers (2450.0+/-2110.3 vs. 4805.9+/-3453.5 ms(2)) than controls. While supine, mTBI patients had reduced cardiovagal modulation and BRS. Upon standing, their BRS was still reduced, and patients did not withdraw parasympathetic or augment sympathetic modulation adequately. Impaired autonomic modulation probably contributes to cardiovascular irregularities post-mTBI
— id: 138015, year: 2011, vol: 28, page: 1727, stat: Journal Article,

Metronomic breathing shows altered parasympathetic baroreflex function in untreated Fabry patients and baroreflex improvement after enzyme replacement therapy
Hilz, Max J; Koehn, Julia; Kolodny, Edwin H; Brys, Miroslaw; Moeller, Sebastian; Stemper, Brigitte
2011 Dec;29(12):2387-2394, Journal of hypertension
OBJECTIVE: In untreated Fabry patients without overt autonomic dysfunction and normal baroreflex sensitivity (BRS) at rest, BRS is impaired during orthostatic, sympathetic challenge but normalizes after enzyme-replacement therapy (ERT) (Hilz et al., J Hypertens 2010; 28:1438-1448). This study evaluated BRS during parasympathetic challenge with six cycles per minute metronomic deep breathing (MDB) in Fabry patients before and after ERT. METHODS: In 22 Fabry patients (28 +/- 8years), we monitored RR-intervals (RRIs), SBP, and respiratory frequency during spontaneous breathing (spont_breath) and MDB, before and after 18 (11 patients) or 23 months (11 patients) of biweekly ERT (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) RRI fluctuations, parasympathetic high-frequency (0.15-0.5 Hz) RRI fluctuations, sympathetically mediated low-frequency powers of SBP and high-frequency powers of SBP. We calculated BRS (ms/mmHg) during spont_breath and MDB as low-frequency-high-frequency alpha index (coherence >0.5). We compared parameters during spont_breath and MDB within and between patients before and after ERT and 15 age-matched (27 +/- 5years) healthy men (RANOVA and posthoc analysis; significance: P < 0.05). RESULTS: During spont_breath and MDB, parameters were similar between groups. Within the three groups, RRIs were lower, whereas RRI low-frequency powers and SBP low-frequency powers were higher during MDB than during spont_breath. BRS was similar during MBD and spont_breath in untreated patients (P > 0.05), but increased significantly with MDB in patients after ERT (P = 0.048) and in controls (P = 0.035). CONCLUSION: In untreated Fabry patients, MDB uncovers impaired BRS. After 18 or 23 months of ERT, MDB-induced BRS increase is similar in Fabry patients and controls, demonstrating that ERT not only restores sympathetic but also parasympathetic baroreflex activation
— id: 141327, year: 2011, vol: 29, page: 2387, stat: Journal Article,

High NIHSS Values Predict Impairment of Cardiovascular Autonomic Control
Hilz, Max Josef; Moeller, Sebastian; Akhundova, Aynur; Marthol, Harald; Pauli, Elisabeth; De Fina, Philipp; Schwab, Stefan
2011 Jun;42(6):1528-1533, Stroke
BACKGROUND AND PURPOSE: Stroke is frequently associated with autonomic dysfunction, which causes secondary cardiovascular complications. Early diagnosis of autonomic imbalance prevents complications, but it is only available at specialized centers. Widely available surrogate markers are needed. This study tested whether stroke severity, as assessed by National Institutes of Health Stroke Scale (NIHSS) scores, correlates with autonomic dysfunction and thus predicts risk of autonomic complications. METHODS: In 50 ischemic stroke patients, we assessed NIHSS scores and parameters of autonomic cardiovascular modulation within 24 hours after stroke onset and compared data with that of 32 healthy controls. We correlated NIHSS scores with parameters of total autonomic modulation (total powers of R-R interval [RRI] modulation; RRI standard deviation [RRI-SD], RRI coefficient of variation), parasympathetic modulation (square root of the mean squared differences of successive RRIs, RRI-high-frequency-powers), sympathetic modulation (normalized RRI-low-frequency-powers, blood pressure-low-frequency-powers), the index of sympatho-vagal balance (RRI-LF/HF-ratios), and baroreflex sensitivity. RESULTS: Patients had significantly higher blood pressure and respiration, but lower RRIs, RRI-SDs, RRI coefficient of variation, square root of the mean squared differences of successive RRIs, RRI-low-frequency-powers, RRI-high-frequency-powers, RRI-total powers, and baroreflex sensitivity than did controls. NIHSS scores correlated significantly with normalized RRI-low-frequency-powers and RRI-LF/HF-ratios, and indirectly with RRIs, RRI-SDs, square root of the mean squared differences of successive RRIs, RRI-high-frequency-powers, normalized RRI-high-frequency-powers, RRI-total-powers, and baroreflex sensitivity. Spearman-Rho values ranged from 0.29 to 0.47. CONCLUSIONS: Increasing stroke severity was associated with progressive loss of overall autonomic modulation, decline in parasympathetic tone, and baroreflex sensitivity, as well as progressive shift toward sympathetic dominance. All autonomic changes put patients with more severe stroke at increasing risk of cardiovascular complications and poor outcome. NIHSS scores are suited to predict risk of autonomic dysregulation and can be used as premonitory signs of autonomic failure
— id: 134185, year: 2011, vol: 42, page: 1528, stat: Journal Article,

Neuroimaging supports central pathology in familial dysautonomia
Axelrod, Felicia B; Hilz, Max J; Berlin, Dena; Yau, Po Lai; Javier, David; Sweat, Victoria; Bruehl, Hannah; Convit, Antonio
2010 Feb;257(2):198-206, Journal of neurology
Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits
— id: 104788, year: 2010, vol: 257, page: 198, stat: Journal Article,

Neurological complications in Fabry disease
Duetsch, M.; Hilz, M. J.
2010 DEC ;31:S243-S250, Revue de Medecine Interne
In Fabry disease, deficiency of a-galactosidase A results in the accumulation of glycosphingolipids in body fluids and tissues including corneas, blood vessels, kidneys and also structures of the central and peripheral nervous system. Many patients show cardiovascular and cerebrovascular dysfunction. Cerebrovascular dysfunction is particularly associated with a high risk of strokes and of mortality even at a young age. The prevalence and severity of cerebrovascular complications increase with patients'age. Clinical data as well as histologic and neurophysiologic studies showed predominantly small fiber dysfunction in patients with Fabry disease. We recently performed quantitative sensory testing in patients with Fabry disease and found reduced cold and heat-pain detection thresholds, while nerve conduction velocities were only mildly reduced. From our findings, we concluded that small fiber dysfunction is more prominent than large fiber dysfunction in Fabry patients. Clinically, small fiber dysfunction contributes to recurrent episodes of burning and lancinating pain and paresthesias in the distal extremities. Such episodes can be typically triggered by changes of the environmental temperature, particularly by warming. Moreover, dysfunction of small thinly-myelinated and unmyelianated nerve fibers accounts for altered sympathetic and parasympathetic modulation. Sympathetic dysfunction explains the hypohidrosis and a subsequent poor exercise and heat tolerance. Enzyme replacement therapy (ERT) with recombinant human a galactosidase A is available. We could demonstrate improvement of small fiber neuropathy and neuropathic pain after 18-23 months of ERT, which probably resulted from glycosphingolipid clearing from perineurial cells, axons and Schwann cells or from blood vessels supplying the nerves. (C) 2010 Societe nationale francaise de medecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved
— id: 120553, year: 2010, vol: 31, page: S243, stat: Journal Article,

Supine squatting supports cardiovascular recovery of familial dysautonomia patients
Ehmann E.C.; Marthol H.; Baltadzhieva R.; Mller S.; Axelrod F.B.; Hilz M.J.
2010 ;17:550-550, European journal of neurology
Background: Familial Dysautonomia (FD) is associated with severe orthostatic hypotension (OH) which improves with reclining, squatting or abdominal compression. Combined reclining and splanchnic compression (supinesquatting) might promote cardiovascular recovery. Objective: To evaluate recovery-times of blood pressure (BP) and superior-mesenteric-artery (SMA) blood-flow upon supine positioning after OH, without and with supinesquatting. Methods: In 11 FDs (18+/-4 years) and 12 age-matched controls, we recorded heart rate (HR) BP, cross-sectional SMA-area and SMA-mean velocity (SMA-Vel) using Doppler-ultrasound. We assessed SMA-blood-flow (SMABF) as SMA-Vel X SMA-area, and SMA-resistance as MBP/SMA-BF-ratio. We determined parameters during 5minutes supine position, at 90degree head-up tilt (standing), upon return to supine without, and in a second trial with supine-squatting. BP-recovery-times were defined as times from tilting-back until BP returned to baseline values minus 2SD. Results: In FDs, BP during standing (95.0+/-26.0mmHg) was lower than supine BP (147.0+/-17.3mmHg, p<0.05). In controls, standing did not change BP.Without squatting, BP recovery-times were longer in FDs than controls (85.4+/-60.9s vs. 12.6+/-27.3s; p<0.05). With squatting, recovery-times of patients (36.6+/-49.5s) and controls (26.0+/-44.8s) were similar. Upon standing, both groups decreased SMA-Area, SMA-Vel, SMA-BF (p<0.05). FDs had slightly lower SMAVel and significantly lower SMA-BF with than without supine-squatting. Only controls increased their SMAresistance upon standing. SMA-resistance decreased upon return to supine without squatting in both groups but increased in FDs during supine squatting. Conclusion: Supine-squatting shortens recovery-times after OH, very likely because of increased SMA-resistance, reduced splanchnic pooling and increased blood redistribution to heart and brain
— id: 113824, year: 2010, vol: 17, page: 550, stat: Journal Article,

A validated disease severity scoring system for Fabry disease
Giannini, Edward H; Mehta, Atul B; Hilz, Max J; Beck, Michael; Bichet, Daniel G; Brady, Roscoe O; West, Michael; Germain, Dominique P; Wanner, Christoph; Waldek, Stephen; Clarke, Joe T R; Mengel, Eugen; Strotmann, Jorg M; Warnock, David G; Linhart, Ales
2010 Mar;99(3):283-290, Molecular genetics & metabolism
Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument's total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument's domains was estimated and the DS3's quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R(2)=0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts
— id: 108305, year: 2010, vol: 99, page: 283, stat: Journal Article,

Autonomic Dysfunction in Fabry Disease
Hilz, Max J.
2010 JUN ;32(8):S93-S93, Clinical therapeutics
— id: 112191, year: 2010, vol: 32, page: S93, stat: Journal Article,

ENZYME REPLACEMENT THERAPY FOR FABRY DISEASE: A SYSTEMATIC REVIEW OF AVAILABLE EVIDENCE
Hilz, Max J.; Tylki-Szyman'ska, Anna; Schaefer, Roland M.
2010 JUN ;32(8):S113-S114, Clinical therapeutics
— id: 112193, year: 2010, vol: 32, page: S113, stat: Journal Article,

Enzyme replacement therapy improves cardiovascular responses to orthostatic challenge in Fabry patients
Hilz, Max J; Marthol, Harald; Schwab, Stefan; Kolodny, Edwin H; Brys, Miroslaw; Stemper, Brigitte
2010 Jul;28(7):1438-1448, Journal of hypertension
OBJECTIVE: Fabry patients have autonomic dysfunction but usually do not present clinically overt signs of orthostatic dysregulation. This study evaluated orthostatic regulation and baroreflex sensitivity (BRS) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy (ERT). METHODS: In 22 Fabry patients (aged 28W8 years), we assessed electrocardiographic RR intervals (RRIs), SBP, DBP and respiratory frequency, in supine and standing position, before and after 18 (11 patients) or 23 months (11 patients) of biweekly alpha-galactosidase A infusions (1.0 mg/kg agalsidase beta). We determined spectral powers of mainly sympathetically mediated low-frequency (0.04-0.15 Hz) and parasympathetically mediated high-frequency (0.15-0.5 Hz) RRI fluctuations, and sympathetic low-frequency powers of blood pressure fluctuations. We normalized RRI powers by relating low-frequency and high-frequency powers to total powers (low-frequency + high-frequency powers), assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance. As a measure of BRS, we used the alpha-index, obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP (coherence>0.5). We compared parameters in supine and standing position of untreated and treated patients with those of 15 healthy age-matched (27+/-5 years) men (repeated-measure analysis of variance, significance at P<0.05). RESULTS: Supine biosignals were similar in all groups. Upon standing, RRIs were lower in controls and patients after ERT than in patients before ERT (P<0.05); normalized RRI high-frequency powers as well as BRS decreased, whereas DBP, low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only (P<0.05). CONCLUSION: Reduced increase in heart rate, blood pressure and sympathetic activation, and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon standing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function, which, in turn, is an established parameter of improved disease prognosis
— id: 138172, year: 2010, vol: 28, page: 1438, stat: Journal Article,

Sympathetic cardiovascular hyperactivity precedes brain death
Marthol, Harald; Intravooth, Tassanai; Bardutzky, Jurgen; De Fina, Philip; Schwab, Stefan; Hilz, Max J
2010 Dec;20(6):363-369, Clinical autonomic research
OBJECTIVE: The time preceding brain death is associated with complex dysregulation including autonomic dysfunction that may compromise organ perfusion, thus inducing final organ failure. In this study, we assessed autonomic function in patients prior to brain death. METHODS: In 5 patients (2 women, median 60 years, age range 52-75 years) with fatal cerebral hemorrhage or stroke and negative prognosis, we monitored RR-intervals (RRI), systolic and diastolic blood pressure (BP), and oxygen saturation. Adjustment of mechanical ventilation remained constant. We assessed autonomic function from spectral powers of RRI and BP in the mainly sympathetic low- (LF, 0.04-0.15 Hz) and parasympathetic high-frequencies (HF, 0.15-0.5 Hz), and calculated the RRI-LF/HF-ratio as index of sympathovagal balance. Three patients required norepinephrine (0.5-1.6 mg/h) for up to 72 h to maintain organ perfusion. Norepinephrine was reduced to 0.2-0.5 mg/h within 2 h before brain death was diagnosed according to the criteria of the German Medical Association. Wilcoxon test compared average values of ten 2-min epochs determined 2-3 h (measurement 1) and 1 h (measurement 2) before brain death. RESULTS: We found higher systolic (127.3 +/- 15.9 vs. 159.4 +/- 44.8 mmHg) and diastolic BP (60.1 +/- 15.6 vs. 74.0 +/- 15.2 mmHg), RRI-LF/HF-ratio (1.2 +/- 1.6 vs. 3.9 +/- 4.0), and BP-LF-powers (2.7 +/- 4.8 vs. 23.1 +/- 28.3 mmHg(2)) during measurement 2 than during measurement 1 (p < 0.05). CONCLUSIONS: The increase in BPs, in sympathetically mediated BP-LF-powers, and in the RRI-LF/HF-ratio suggests prominent sympathetic activity shortly before brain death. Prefinal sympathetic hyperactivity might cause final organ failure with catecholamine-induced tissue damage which impedes post-mortem organ transplantation
— id: 133829, year: 2010, vol: 20, page: 363, stat: Journal Article,

Respiratory alterations during sleep in familial dysautonomia
Moeller S.; Axelrod F.B.; Rapoport D.M.; Ayappa I.; Buechner S.; Sczepanska H.; Dimitrov N.; Hilz M.J.
2010 ;17:549-549, European journal of neurology
Introduction: Sudden death during sleep is a risk in familial dysautonomia (FD). Respiratory abnormalities might contribute to fatalities. Objective: This study was performed to assess respiratory abnormalities in FD during sleep. Methods: In 11 FD patients (5 females, 28+/-11 years) and 11 age- and sex-matched controls (6 females, 28+/-11 years), we recorded polysomnographic signals during one night, and assessed sleep latency, REMlatency, sleep stages, number of sleep cycles and apnoeas.Apnoea responses were classified as oxygen desaturation (<=4% SatO2-decrease within 30sec) or arousals (<=3sec abrupt shift in electroencephalographic frequencies to alpha- or theta-activity or frequencies >16Hz). Chi²-test compared numbers of patients and controls with apnoea, desaturation or arousal. U-test assessed differences in frequencies of individual apnoeas, desaturations or arousals between patients and controls (significance: p<0.05). Results: 10 patients and 4 controls had apnoeas (p<0.05). 9 patients and 1 control developed deoxygenation (p<0.05); 3 patients and 1 control had arousals. Apnoea frequency (median, 25^th percentile; 75^th percentile, range) was higher in patients (8; 5; 18; 0-28) than in controls (0; 0; 1; 0-2; p<0.05). Apnoea-induced desaturations also were more frequent in patients (6; 2; 10; 0-26) than in controls (0; 0; 0; 0-1; p<0.05) while arousal frequency was similar in patients (0; 0; 1; 0-2) and controls (0, 0, 0, 0-1). Conclusion: High frequency of sleep apnoeas and deoxygenation in FD patients may cause fatalities, as deoxygenation which induces hypoventilation, arterial hypotension, and bradyarrhythmia in FD patients (Bernardi et al. Am J Respir Crit Care Med. 2003;167:141-9)
— id: 113823, year: 2010, vol: 17, page: 549, stat: Journal Article,

A VALIDATED DISEASE SEVERITY SCORING SYSTEM FOR FABRY DISEASE
Wanner, Christoph; Giannini, Edward H.; Mehta, Atul B.; Hilz, Max J.; Beck, Michael; Bichet, Daniel G.; Brady, Roscoe O.; West, Michael; Germain, Dominique P.; Waldek, Stephen; Clarke, Joe T. R.; Mengel, Eugen; Strotmann, Joerg M.; Warnock, David G.; Linhart, Ales
2010 JUN ;32(8):S108-S109, Clinical therapeutics
— id: 112192, year: 2010, vol: 32, page: S108, stat: Journal Article,

C-fiber axon reflex flare size correlates with epidermal nerve fiber density in human skin biopsies
Bickel, Andreas; Heyer, Gisela; Senger, Christine; Maihoefner, Christian; Heuss, Dieter; Hilz, Max J; Namer, Barbara
2009 Dec;14(4):294-299, Journal of the peripheral nervous system
The size of the neurogenic axon reflex flare (ARFS) has been proposed to serve as a non-invasive measure of C-fiber neuropathies. This idea is based on the observation that ARFS is often reduced in patients with small-fiber neuropathies. In this study, we compared ARFS and electrically evoked axon reflex sweating with intraepidermal nerve fiber density (IENF) in patients with peripheral neuropathy in order to validate these methods against an objective standard method of diagnosing small-fiber neuropathy. ARFS was significantly correlated with IENF, while axon reflex sweating was not correlated to IENF. We conclude that measurement of ARFS is a potential objective non-invasive diagnostic tool for analysis of C-fiber function in patients with small-fiber neuropathies
— id: 108304, year: 2009, vol: 14, page: 294, stat: Journal Article,

Stress, sex, music :
Hilz, Max J
[S.l. : s.n.], 2009,
Dr. Max J. Hilz discusses the imbalance of the autonomic nervous system and its recovery process when dealing with stress; the fight and flight response; increased death rate in persons with a history of mild traumatic brain injury and dieing from stress; causes for sudden cardiac death; stress related diseases; sex therapy and evaluating stress in relationship due to premature ejaculation and erectile dysfunction; how music affects and improves stress by playing brief music examples that cause positive and negative responses; discussion of study showing anticipatory stress and how relaxation helps reduce this stress; video footage showing Dr. Hilz's Autogenic Training relaxation technique by hypnotizing a patient with a severe stress disorder; an experiment showing the correlation between sweaty hands and stress; and Dr. Hilz's plans to open an anti-stress and longevity center in New York which will assist patients with stress prevention
— id: 2310, year: 2009, vol: , page: , stat: ,

Orthostatic Challenge Reveals Subtle Sympathetic Cardiac Dysfunction in Patients with Mild Traumatic Brain Injury
Hilz, MJ; Anders, S; Aurnhammer, F; Marthol, H; Baltadhzieva, R; Schroeder, T; Rossmeissl, A; Flanagan, S
2009 ;72(11):A447-A447, Neurology
— id: 104737, year: 2009, vol: 72, page: A447, stat: Journal Article,

Patients with mild traumatic brain injury show subtle sympathetic cardiac dysfunction during orthostatic challenge
Hilz, MJ; Anders, S; Aurnhammer, F; Marthol, H; Baltadzhieva, R; Schroeder, T; Rossmeissl, A; Schwab, S; Flanagan, S; De Fina, P
2009 ;16(2):53-53, European journal of neurology
— id: 104738, year: 2009, vol: 16, page: 53, stat: Journal Article,

Ocular Pressure Test Shows Subtle Autonomic Cardiovascular Dysfunction in Patients with Mild Traumatic Brain Injury
Hilz, MJ; Aurnhammer, F; Anders, S; Marthol, H; Blaszczynska, P; Schroeder, T; Rossmeissl, A; Flanagan, S
2009 ;72(11):A406-A406, Neurology
— id: 104736, year: 2009, vol: 72, page: A406, stat: Journal Article,

Patients with mild traumatic brain injury have subtle autonomic cardiovascular dysfunction with ocular pressure test
Hilz, MJ; Aurnhammer, F; Anders, S; Marthol, H; Blaszczynska, P; Schroeder, T; Rossmeissl, A; Schwab, S; Flanagan, S; De Fina, P
2009 ;16(2):375-375, European journal of neurology
— id: 104739, year: 2009, vol: 16, page: 375, stat: Journal Article,

ENZYME REPLACEMENT THERAPY DECREASED FOREARM AND HAND COMPLIANCE IN FABRY DISEASE
Hilz, MJ; Kolodny, EH; Marthol, H
2009 JUL ;14(9):65-65, Journal of the peripheral nervous system
— id: 102290, year: 2009, vol: 14, page: 65, stat: Journal Article,

Sympathetic cardiovascular hyperactivity precedes brain death
Intravooth, T; Marthol, H; Hilz, MJ; De Fina, P; Schwab, S
2009 OCT ;285(5):S320-S320, Journal of the neurological sciences
— id: 106961, year: 2009, vol: 285, page: S320, stat: Journal Article,

Relation between ictal asystole and cardiac sympathetic dysfunction shown by MIBG-SPECT
Kerling, F; Dutsch, M; Linke, R; Kuwert, T; Stefan, H; Hilz, M J
2009 Aug;120(2):123-129, Acta neurologica Scandinavica
OBJECTIVE: Tachyarrhythmias are common during epileptic seizures while bradyarrhythmias or asystoles are less frequent. Ictal asystole might be related to epilepsy-induced cardiac sympathetic denervation. METHODS: To evaluate cardiac post-ganglionic denervation in epilepsy patients with ictal asystoles we assessed I123-meta-iodobenzylguanidine (MIBG) as a marker of post-ganglionic cardiac norepinephrine-uptake, using single photon emission computed tomography (MIBG-SPECT). RESULTS: In five of 844 patients with presurgical video-electroencephalography-monitoring, we recorded ictal asystoles during nine of 37 seizures. Asystole patients underwent cardiologic examination (Holter-electrocardiogram, echocardiogram) and cardiac MIBG-SPECT. We compared cardiac MIBG uptake in the asystole patients to the uptake in 18 temporal lobe epilepsy (TLE) patients without bradyarrhythmias and in 14 controls without cardiac or neurological disease. As the cardiological examinations were unremarkable in all subjects, the heart/mediastinum-MIBG-uptake ratios (H/M-ratios) differed significantly between the three groups (P = 0.004). H/M-ratios were lower in asystole TLE patients (mean +/- SD: 1.58 +/- 0.3) than in patients without asystole (1.81 +/- 0.18; P = 0.037) or controls (1.96 +/- 0.16). CONCLUSIONS: Pronounced reduction in cardiac MIBG uptake of asystole patients indicates post-ganglionic cardiac catecholamine disturbance. Impaired sympathetic cardiac innervation limits adjustment and heart rate modulation, and may increase the risk of asystole and ultimately sudden unexpected death in epilepsy (SUDEP)
— id: 104789, year: 2009, vol: 120, page: 123, stat: Journal Article,

Early administration of low molecular weight heparin after spontaneous intracerebral hemorrhage. A safety analysis
Kiphuth, Ines C; Staykov, Dimitre; Kohrmann, Martin; Struffert, Tobias; Richter, Gregor; Bardutzky, Jurgen; Kollmar, Rainer; Maurer, Mathias; Schellinger, Peter D; Hilz, Max-Josef; Doerfler, Arnd; Schwab, Stefan; Huttner, Hagen B
2009 ;27(2):146-150, Cerebrovascular diseases
BACKGROUND: Venous thromboembolism (VTE) is a common complication after stroke. Application of low molecular weight heparins (LMWH) has been proven to be beneficial for the prevention of VTE in ischemic stroke patients. However, there is no consensus whether and how to administer LMWH for prevention of thrombotic complications after acute spontaneous intracerebral hemorrhage (sICH), the main concern being possible hematoma growth. The objective of this study was to assess the safety of early subcutaneous LMWH in patients with sICH with respect to hemorrhage enlargement. METHODS: A total of 97 patients with sICH were analyzed. LMWH (either enoxaparin-natrium or dalteparin-natrium) were initiated within 36 h after admission in all patients without clinical evidence of hemorrhage enlargement or an absence of evidence of hematoma growth on CT. Hematoma growth (significant when >33%, moderate when >20%) was assessed on follow-up CT between days 5 and 11. RESULTS: None of the patients showed a significant hemorrhage growth. Between days 2 and 10, 2 patients experienced a moderate hematoma enlargement of 22.4 and 20.9%. None of the included patients developed a fatal lung embolism. CONCLUSIONS: Early application of subcutaneous LMWH for prevention of venous thromboembolism seems to be safe, and probably does not increase the risk of hematoma growth in patients with sICH
— id: 104790, year: 2009, vol: 27, page: 146, stat: Journal Article,

Enzyme replacement therapy for Fabry disease: a systematic review of available evidence
Schaefer, Roland M; Tylki-Szymanska, Anna; Hilz, Max J
2009 Nov 12;69(16):2179-205, Drugs
Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable
— id: 108306, year: 2009, vol: 69, page: 2179, stat: Journal Article,

Acute effects of sildenafil on flow mediated dilatation and cardiovascular autonomic nerve function in type 2 diabetic patients
Stirban, Alin; Laude, Dominique; Elghozi, Jean-Luc; Sander, Denise; Agelink, Marcus W; Hilz, Max J; Ziegler, Dan
2009 Feb;25(2):136-143, Diabetes/metabolism research & reviews
BACKGROUND: Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study. METHODS: A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured. RESULTS: Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo. CONCLUSIONS: Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS
— id: 96623, year: 2009, vol: 25, page: 136, stat: Journal Article,

A simple deep breathing test reveals altered cerebral autoregulation in type 2 diabetic patients
Brown, C M; Marthol, H; Zikeli, U; Ziegler, D; Hilz, M J
2008 May;51(5):756-761, Diabetologia
AIMS/HYPOTHESIS: Patients with diabetes mellitus have an increased risk of stroke and other cerebrovascular complications. The purpose of this study was to evaluate the autoregulation of cerebral blood flow in diabetic patients using a simple method that could easily be applied to the clinical routine screening of diabetic patients. METHODS: We studied ten patients with type 2 diabetes mellitus and 11 healthy volunteer control participants. Continuous and non-invasive measurements of blood pressure and cerebral blood flow velocity were performed during deep breathing at 0.1 Hz (six breaths per minute). Cerebral autoregulation was assessed from the phase shift angle between breathing-induced 0.1 Hz oscillations in mean blood pressure and cerebral blood flow velocity. RESULTS: The controls and patients all showed positive phase shift angles between breathing-induced 0.1 Hz blood pressure and cerebral blood flow velocity oscillations. However, the phase shift angle was significantly reduced (p < 0.05) in the patients (48 +/- 9 degrees ) compared with the controls (80 +/- 12 degrees ). The gain between 0.1 Hz oscillations in blood pressure and cerebral blood flow velocity did not differ significantly between the patients and controls. CONCLUSIONS/INTERPRETATION: The reduced phase shift angle between oscillations in mean blood pressure and cerebral blood flow velocity during deep breathing suggests altered cerebral autoregulation in patients with diabetes and might contribute to an increased risk of cerebrovascular disorders
— id: 104792, year: 2008, vol: 51, page: 756, stat: Journal Article,

Stroke-induced sudden-autonomic death: areas of fatality beyond the insula
Hilz, Max J; Schwab, Stefan
2008 Sep;39(9):2421-2422, Stroke
— id: 96624, year: 2008, vol: 39, page: 2421, stat: Journal Article,

Enzyme replacement therapy improves skin blood flow control in Fabry patients
Hilz, MJ; Kolodny, EH; Marthol, H
2008 AUG ;15(3):49-49, European journal of neurology
— id: 98134, year: 2008, vol: 15, page: 49, stat: Journal Article,

Enzyme replacement therapy lowers forearm and hand compliance in Fabry patients
Hilz, MJ; Kolodny, EH; Marthol, H
2008 AUG ;15(3):48-49, European journal of neurology
— id: 98133, year: 2008, vol: 15, page: 48, stat: Journal Article,

"Right middle cerebral artery stroke blunts cardiovascular responses to music, left middle cerebral artery stroke reduces blood pressure response to pleasant music"
Hilz, MJ; Nath, J; Gryc, T; Wong, S; Lee, MHM; Marthol, H; Stemper, B
2008 ;70(11):A371-A371, Neurology
— id: 104740, year: 2008, vol: 70, page: A371, stat: Journal Article,

Cyclophosphamide for anti-GAD antibody-positive refractory status epilepticus
Kanter, Ines C; Huttner, Hagen B; Staykov, Dimitre; Biermann, Teresa; Struffert, Tobias; Kerling, Frank; Hilz, Max-Josef; Schellinger, Peter D; Schwab, Stefan; Bardutzky, Jurgen
2008 May;49(5):914-920, Epilepsia
Glutamic acid decarboxylase (GAD) is the enzyme which catalyzes the production of gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS). There is increasing evidence that severe GAD autoimmunity may be associated with refractory epilepsy. Immunomodulation and GABAergic drugs have been suggested as treatment options. We report here for the first time on a patient with sudden onset of refractory status epilepticus in the presence of strong intrathecal anti-GAD antibody synthesis who was successfully treated with cyclophosphamide, and give an overview of available data on epilepsy associated with GAD autoimmunity
— id: 104794, year: 2008, vol: 49, page: 914, stat: Journal Article,

In vivo detection of hepatitis C virus (HCV) RNA in the brain in a case of encephalitis: evidence for HCV neuroinvasion
Seifert, F; Struffert, T; Hildebrandt, M; Blumcke, I; Bruck, W; Staykov, D; Huttner, H B; Hilz, M-J; Schwab, S; Bardutzky, J
2008 Mar;15(3):214-218, European journal of neurology
We report here a 27-year-old woman who presented with encephalitis of unknown origin. Magnetic resonance imaging (MRI) of the brain revealed leukoencephalopathy, cerebrospinal fluid showed signs of inflammation. Serum and brain biopsy tissue was tested positive for hepatitis C virus (HCV). Neuropathological investigation supported the hypothesis of viral encephalitis. C3, C4 and cryoglobulins as well as cerebral MR-angiography were normal. Neurological complications of HCV infection other than hepatic encephalopathy are generally attributed to parainfectious phenomena. This is the first case of HCV-RNA detection in vivo in human brain in literature and it raises the possibility that HCV is able to induce encephalitis caused by neurotrophism. This is supported by the fact that there is a growing body of literature on HCV-induced cerebral dysfunction and laboratory findings indicating HCV neuroinvasion
— id: 104793, year: 2008, vol: 15, page: 214, stat: Journal Article,

Advanced electrocardiographic predictors of mortality in familial dysautonomia
Solaimanzadeh, I; Schlegel, T T; Feiveson, A H; Greco, E C; DePalma, J L; Starc, V; Marthol, H; Tutaj, M; Buechner, S; Axelrod, F B; Hilz, M J
2008 Dec 15;144(1-2):76-82, Autonomic neuroscience
OBJECTIVE: To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD). METHODS: Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG. RESULTS: Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease. CONCLUSION: Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea
— id: 104791, year: 2008, vol: 144, page: 76, stat: Journal Article,

Effects of vagus nerve stimulation on cardiovascular regulation in patients with epilepsy
Stemper, B; Devinsky, O; Haendl, T; Welsch, G; Hilz, M J
2008 Apr;117(4):231-236, Acta neurologica Scandinavica
OBJECTIVE: To evaluate the impact of vagus nerve stimulation (VNS) on heart rate and blood pressure (BP) modulation in epilepsy patients. MATERIAL AND METHODS: Twenty-one epilepsy patients with VNS were tested during on (60 s) and off (5 min) phases. We monitored BP, RR intervals (RRI) and respiration. Spectral analysis was performed in low- (LF: 0.04-0.15 Hz) and high-frequency bands (HF: 0.15-0.5 Hz). For coherences above 0.5, we calculated the LF transfer function between systolic BP and RRI, and the HF transfer function gain and phase between RRI and respiration. Differences between the on and off phases were evaluated using Wilcoxon test. RESULTS: VNS did not change RRI and BP values. The LF power of BP and the LF and HF power of RRI increased significantly. There was a slight change in the RRI/BP LF gain and the RRI/respiration HF gain (ns). The HF phase between RRI and respiration decreased significantly. CONCLUSIONS: Our findings show that VNS influences both sympathetic and parasympathetic cardiovascular modulation. However, our results also show that VNS does not negatively influence autonomic cardiovascular regulation
— id: 104796, year: 2008, vol: 117, page: 231, stat: Journal Article,

Cardiovascular autonomic function in poststroke patients
Dutsch, M; Burger, M; Dorfler, C; Schwab, S; Hilz, M J
2007 Dec 11;69(24):2249-2255, Neurology
BACKGROUND: Autonomic dysregulation is frequent in acute ischemic stroke. Several studies concluded that imbalance between sympathetic and parasympathetic cardiovascular function predisposes to malignant cardiac arrhythmia. However, there are few data on cardiovascular autonomic function in post-acute stroke patients. OBJECTIVE: To study cardiovascular autonomic function 18 to 43 months after lacunar stroke. Patients and METHODS: We continuously monitored R-R intervals (RR(int)), mean blood pressure (BP(mean)), and respiration in 15 patients (8 women, aged 43 to 73 years) after right-sided stroke, in 13 patients (7 women, aged 50 to 75 years) after left-sided stroke, and in 21 age- and sex-matched controls at rest. We used autoregressive spectral analysis to assess sympathetic and parasympathetic modulation as powers of RR(int) and BP(mean) oscillations in the low-frequency (LF: 0.04 to 0.15 Hz) and high-frequency bands (HF: 0.15 to 0.5 Hz). RESULTS: Mean values of RR(int), BP(mean), and respiratory frequency did not differ between patients after right- or left-sided stroke and controls (p > 0.05). Patients after right-sided stroke showed a trend toward elevated LF power of RR(int) as compared with patients after left-sided stroke and controls (p < 0.10). HF powers of RR(int) were reduced in patients after right- and left-sided stroke as compared with controls (p < 0.05). LF/HF ratio of RR(int) was elevated in patients after right-sided stroke as compared with patients after left-sided stroke and controls (p < 0.05). CONCLUSION: Irrespective of the side of the ischemia, post-acute stroke patients showed a parasympathetic cardiac deficit. Additionally, sympathetic cardiovascular modulation was increased in patients after right-sided stroke. Post-acute stroke patients might be at an increased risk for cardiac arrhythmia after unopposed sympathetic stimulation
— id: 104795, year: 2007, vol: 69, page: 2249, stat: Journal Article,

Peripheral nervous system involvement in Fabry disease: role in morbidity and mortality
Hilz, Max J
2007 ;29 Suppl A:S11-S12, Clinical therapeutics
— id: 96625, year: 2007, vol: 29 Suppl A, page: S11, stat: Journal Article,

Paradoxical cardiovascular activation during emotional stimulation in patients with right ventromedial prefrontal lesions
Hilz, MJ; Devinsky, O; Szczepanska, H; Borod, JC; Marthol, H; Tutaj, M
2007 MAR 20 ;68(12):A362-A362, Neurology
— id: 104245, year: 2007, vol: 68, page: A362, stat: Journal Article,

Right ventromedial prefrontal lesions result in paradoxical cardiovascular activation with emotional stimuli (vol 129, pg 343, 2006)
Hilz, MJ; Devinsky, O; Szczepanska, H; Borod, JC; Marthol, H; Tutaj, M
2007 MAR ;130(12):879-879, Brain
— id: 104246, year: 2007, vol: 130, page: 879, stat: Journal Article,

Pharmacologic autonomic blockade during sinusoidal baroreceptor stimulation revealed sympathetic modulation and absence of parasympathetic modulation of cerebral blood flow velocity
Hilz, MJ; Riss, S; Tillmann, A; Wasmeier, G; Stemper, B; Marthol, H
2007 AUG ;14(3):28-28, European journal of neurology
— id: 98157, year: 2007, vol: 14, page: 28, stat: Journal Article,

Acute onset of fatal vegetative symptoms: unusual presentation of adult Alexander disease
Huttner, H B; Richter, G; Hildebrandt, M; Blumcke, I; Fritscher, T; Bruck, W; Gartner, J; Seifert, F; Staykov, D; Hilz, M-J; Schwab, S; Bardutzky, J
2007 Nov;14(11):1251-1255, European journal of neurology
Since genetic analysis of the GFAP gene for the diagnosis of adult Alexander disease (AD) has been established in 2001, several cases of both sporadic and familial cases of AD have been described. Except for one patient, all subjects revealed glial fibrillary acidic protein (GFAP) mutations, and clinical progression of symptoms, mainly bulbar and pseudobulbar, were moderate. Here we report on a patient with acute onset of vegetative symptoms, rapid progression, and death within 2 months. Although histology and final magnetic resonance imaging (MRI) were characteristic of AD, sequencing of the encoding GFAP gene revealed no mutation. We believe that this case report expands the so far known clinical spectrum and MRI dynamics of adult AD, and suggest that analysis of the coding part of GFAP may be inconclusive in rare cases. In such patients, only histology may lead to definitive diagnosis
— id: 104797, year: 2007, vol: 14, page: 1251, stat: Journal Article,

Hereditary sensory neuropathy type IV. Two case reports
Kohl, B; Hulsemann, W; Habenicht, R; Hilz, MJ; Stemper, B; Pust, B
2007 ;155(3):281-286, Monatsschrift Kinderheilkunde
We report on two schoolboys suffering from hereditary sensory neuropathy type IV (HSAN IV). HSAN IV is also referred to in English-speaking countries as CIPA, which stands for congenital insensitivity to pain and anhidrosis. Thus, this term names the cardinal symptoms of this extremely rare disease. In our article, in addition to symptoms and diagnostic procedures we illustrate the clinical course in both our patients, focusing on complications requiring reconstructive surgery of the hands and feet. $$:
— id: 104741, year: 2007, vol: 155, page: 281, stat: Journal Article,

Bruxism and autonomic activity - Response
Marthol, H; Reich, S; Jacke, J; Lechner, KH; Wichmann, M; Hilz, MJ
2007 FEB ;17(1):51-51, Clinical autonomic research
— id: 98054, year: 2007, vol: 17, page: 51, stat: Journal Article,

Cardiovascular and cerebrovascular responses to lower body negative pressure in type 2 diabetic patients
Marthol, Harald; Zikeli, Udo; Brown, Clive Martin; Tutaj, Marcin; Hilz, Max Josef
2007 Jan 31;252(2):99-105, Journal of the neurological sciences
In diabetic patients, vascular disease and autonomic dysfunction might compromise cerebral autoregulation and contribute to orthostatic intolerance. The aim of our study was to determine whether impaired cerebral autoregulation contributes to orthostatic intolerance during lower body negative pressure in diabetic patients. Thirteen patients with early-stage type 2 diabetes were studied. We continuously recorded RR-interval, mean blood pressure and mean middle cerebral artery blood flow velocity at rest and during lower body negative pressure applied at -20 and -40 mm Hg. Spectral powers of RR-interval, blood pressure and cerebral blood flow velocity were analyzed in the sympathetically mediated low (LF: 0.04-0.15 Hz) and the high (HF: 0.15-0.5 Hz) frequency ranges. Cerebral autoregulation was assessed from the transfer function gain and phase shift between LF oscillations of blood pressure and cerebral blood flow velocity. In the diabetic patients, lower body negative pressure decreased the RR-interval, i.e. increased heart rate, while blood pressure and cerebral blood flow velocity decreased. Transfer function gain and phase shift remained stable. Lower body negative pressure did not induce the normal increase in sympathetically mediated LF-powers of blood pressure and cerebral blood flow velocity in our patients indicating sympathetic dysfunction. The stable phase shift, however, suggests intact cerebral autoregulation. The dying back pathology in diabetic neuropathy may explain an earlier and greater impairment of peripheral vasomotor than cerebrovascular control, thus maintaining cerebral blood flow constant and protecting patients from symptoms of presyncope
— id: 104799, year: 2007, vol: 252, page: 99, stat: Journal Article,

Bilateral striatal hyperintensities on diffusion weighted MRI in acute methanol poisoning
Peters, A S; Schwarze, B; Tomandl, B; Probst-Cousin, S; Lang, C J G; Hilz, M-J
2007 Sep;14(9):e1-e2, European journal of neurology
— id: 104798, year: 2007, vol: 14, page: e1, stat: Journal Article,

Differential impairment of the sudomotor and nociceptor axon-reflex in diabetic peripheral neuropathy
Berghoff, Martin; Kilo, Sonja; Hilz, Max J; Freeman, Roy
2006 Apr;33(4):494-499, Muscle & nerve
It is not known whether C-fiber functional subclasses are differentially affected by diabetes mellitus or whether the patterns of C-fiber dysfunction are different between type 1 and type 2 diabetes. We therefore examined efferent sympathetic sudomotor and primary afferent nociceptor C-fiber function in diabetic patients. Acetylcholine (10%) was used to evoke C-fiber (axon-reflex)-mediated responses. The nociceptor (flare) response was measured using a laser Doppler device. The sudomotor response was quantified with silastic imprints. The nociceptor C-fiber-mediated flare response was reduced in type 2 diabetic patients (P < 0.008) but was similar to controls in type 1 diabetic patients. The sympathetic C-fiber-mediated responses, including sweat volume (P < 0.05) and the number of activated sweat glands (P = 0.003), were increased in patients with type 1 diabetes. There also was a trend toward a larger axon-reflex sweat area in patients with type 1 diabetes (P = 0.09). No differences in these sweat responses were found in patients with type 2 diabetes compared to controls. These findings suggest that the functional abnormalities in diabetic peripheral neuropathy are not homogeneous and that C-fiber subclasses are differentially affected in type 1 and 2 diabetes mellitus
— id: 68218, year: 2006, vol: 33, page: 494, stat: Journal Article,

Impaired baroreflex function in temporal lobe epilepsy
Dutsch, Mathias; Hilz, Max J; Devinsky, Orrin
2006 Oct;253(10):1300-1308, Journal of neurology
Changes of cardiovascular function are frequent in temporal lobe epilepsy (TLE). The baroreflex - the most important reflex for cardiovascular stability - has not been studied systematically in TLE. We evaluated cardiovascular variability and baroreflex function in TLE.In 22 TLE patients and 20 controls, we continuously monitored heart rate (HR) and blood pressure (BP). Time-domain parameters were derived from recordings at rest and from standard cardiovascular reflex tests. Spectral analysis determined sympathetic and parasympathetic modulation of HR and BP in the low (LF-power) and high frequency range (HF-power). We calculated the relative LF- and HF-powers of HR in relation to the sum of LF- and HF-powers. LF/HF-ratio of HR was assessed as a parameter of sympatheticovagal balance. LF-transfer function gain between BP and HR determined baroreflex function.Time-domain parameters did not differ between TLE patients and controls. Spectral analysis showed decreased absolute LF- and HF-powers but increased relative LF-power and LF/HF-ratio of HR in TLE. LF-transfer function gain between BP and HR was reduced in TLE (p<0.05).The reduction of absolute LF- and HF-powers indicates decreased total autonomic variability in TLE. However, increased relative LF-power and LF/HF-ratio of HR in TLE show a relative increase of sympathetic tone. Most importantly, we demonstrate an impaired baroreflex function in TLE. These cardiovascular autonomic abnormalities may contribute to cardiac arrhythmia in TLE
— id: 96627, year: 2006, vol: 253, page: 1300, stat: Journal Article,

Right ventromedial prefrontal lesions result in paradoxical cardiovascular activation with emotional stimuli
Hilz, Max J; Devinsky, Orrin; Szczepanska, Hanna; Borod, Joan C; Marthol, Harald; Tutaj, Marcin
2006 Dec;129(Pt 12):3343-3355, Brain
Ventromedial prefrontal cortex (VMPFC) lesions can alter emotional and autonomic responses. In animals, VMPFC activation results in cardiovascular sympathetic inhibition. In humans, VMPFC modulates emotional processing and autonomic response to arousal (e.g. accompanying decision-making). The specific role of the left or right VMPFC in mediating somatic responses to non-arousing, daily-life pleasant or unpleasant stimuli is unclear. To further evaluate VMPFC interaction with autonomic processing of non-stressful emotional stimuli and assess the effects of stimulus valence, we studied patients with unilateral VMPFC lesions and assessed autonomic modulation at rest and during physical challenge, and heart rate (HR) and blood pressure (BP) responses to non-stressful neutral, pleasant and unpleasant visual stimulation (VES) via emotionally laden slides. In 6 patients (54.0 +/- 7.2 years) with left-sided VMPFC lesions (VMPFC-L), 7 patients (43.3 +/- 11.6 years) with right-sided VMPFC lesions (VMPFC-R) and 13 healthy volunteers (44.7 +/- 11.6 years), we monitored HR as R-R interval (RRI), BP, respiration, end-tidal carbon dioxide levels, and oxygen saturation at rest, during autonomic challenge by metronomic breathing, a Valsalva manoeuvre and active standing, and in response to non-stressful pleasant, unpleasant and neutral VES. Pleasantness versus unpleasantness of slides was rated on a 7-point Likert scale. At rest, during physical autonomic challenge, and during neutral VES, parameters did not differ between the patient groups and volunteers. During VES, Likert scores also were similar across the three groups. During pleasant and unpleasant VES, HR decreased (i.e. RRI increased) significantly whereas BP remained unchanged in volunteers. In VMPFC-L patients, HR decrease was insignificant with pleasant and unpleasant VES. BP slightly increased (P = 0.06) with pleasant VES but was stable with unpleasant VES. In contrast, VMPFC-R patients had significant increases in HR and BP during pleasant and not quite significant HR increases (P = 0.06) with only slight BP increase during unpleasant VES. Other biosignals remained unchanged during VES in all groups. Our results show that VMPFC has no major influence on autonomic modulation at rest and during non-emotional, physical stimulation. The paradoxical HR and BP responses in VMPFC-R patients suggest hemispheric specialization for VMPFC interaction with predominant parasympathetic activation by the left, but sympathetic inhibition by the right VMPFC. Valence of non-stressful stimuli has a limited effect with more prominent left VMPFC modulation of pleasant and more right VMPFC modulation of unpleasant stimuli. The paradoxical sympathetic disinhibition in VMPFC-R patients may increase their risk of sympathetic hyperexcitability with negative consequences such as anxiety, hypertension or cardiac arrhythmias
— id: 96626, year: 2006, vol: 129, page: 3343, stat: Journal Article,

ANS changes during sleep
Hilz, MJ
2006 SEP ;13(2):300-301, European journal of neurology
— id: 98065, year: 2006, vol: 13, page: 300, stat: Journal Article,

Quantitative studies of autonomic function
Hilz, MJ; Dutsch, M
2006 JAN ;33(1):6-20, Muscle & nerve
Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various. approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity
— id: 61373, year: 2006, vol: 33, page: 6, stat: Journal Article,

Partial adrenoreceptor blockade demonstrates sympathetic modulation of cerebral blood flow velocity
Hilz, MJ; Riss, S; Tillmann, A; Wasmeier, G; Stemper, B; Marthol, H
2006 ;66(5):263-263, Neurology
— id: 104742, year: 2006, vol: 66, page: 263, stat: Journal Article,

EFNS guidelines on the diagnosis and management of orthostatic hypotension
Lahrmann, H; Cortelli, P; Hilz, M; Mathias, CJ; Struhal, W; Tassinari, M
2006 SEP ;13(9):930-936, European journal of neurology
Orthostatic (postural) hypotension (OH) is a common, yet under diagnosed disorder. It may contribute to disability and even death. It can be the initial sign, and lead to incapacitating symptoms in primary and secondary autonomic disorders. These range from visual disturbances and dizziness to loss of consciousness (syncope) after postural change. Evidence based guidelines for the diagnostic workup and the therapeutic management (non-pharmacological and pharmacological) are provided based on the EFNS guidance regulations. The final literature research was performed in March 2005. For diagnosis of OH, a structured history taking and measurement of blood pressure (BP) and heart rate in supine and upright position are necessary. OH is defined as fall in systolic BP below 20 mmHg and diastolic BP below 10 mmHg of baseline within 3 min in upright position. Passive head-up tilt testing is recommended if the active standing test is negative, especially if the history is suggestive of OH, or in patients with motor impairment. The management initially consists of education, advice and training on various factors that influence blood pressure. Increased water and salt ingestion effectively improves OH. Physical measures include leg crossing, squatting, elastic abdominal binders and stockings, and careful exercise. Fludrocortisone is a valuable starter drug. Second line drugs include sympathomimetics, such as midodrine, ephedrine, or dihydroxyphenylserine. Supine hypertension has to be considered
— id: 68339, year: 2006, vol: 13, page: 930, stat: Journal Article,

Altered cerebral regulation in type 2 diabetic patients with cardiac autonomic neuropathy
Marthol, H; Brown, C M; Zikeli, U; Ziegler, D; Dimitrov, N; Baltadzhieva, R; Hilz, M J
2006 Oct;49(10):2481-2487, Diabetologia
AIMS/HYPOTHESIS: Assessment of cerebral regulation in diabetic patients is often problematic because of the presence of cardiac autonomic neuropathy. We evaluated the technique of oscillatory neck suction at 0.1 Hz to quantify cerebral regulation in diabetic patients and healthy control subjects. SUBJECTS AND METHODS: In nine type 2 diabetic patients with cardiac autonomic neuropathy and 11 age-matched controls, we measured blood pressure and cerebral blood flow velocity responses to application of 0.1 Hz neck suction. We determined spectral powers and calculated the transfer function gain and phase shift between 0.1 Hz blood pressure and cerebral blood flow velocity oscillations as parameters of cerebral regulation. RESULTS: In the patients and control subjects, neck suction did not significantly influence mean values of the RR interval, blood pressure and cerebral blood flow velocity. The powers of 0.1 Hz blood pressure and cerebral blood flow velocity oscillations increased in the control subjects, but remained stable in the patients. Transfer function gain remained stable in both groups. Phase shift decreased in the patients, but remained stable in control subjects. CONCLUSIONS/INTERPRETATION: The absence of an increase in the power of 0.1 Hz blood pressure and cerebral blood flow velocity oscillations confirmed autonomic neuropathy in the diabetic patients. Gain analysis did not show altered cerebral regulation. The decrease in phase shift in the patients indicates a more passive transmission of neck suction-induced blood pressure fluctuations onto the cerebrovascular circulation, i.e. altered cerebral regulation, in the patients, and is therefore suited to identifying subtle impairment of cerebral regulation in these patients
— id: 68216, year: 2006, vol: 49, page: 2481, stat: Journal Article,

Enhanced sympathetic cardiac modulation in bruxism patients
Marthol, Harald; Reich, Sven; Jacke, Julia; Lechner, Karl-Heinz; Wichmann, Manfred; Hilz, Max Josef
2006 Aug;16(4):276-280, Clinical autonomic research
Sleep bruxism, an oral parafunction including teeth clenching and grinding, might be related to increased stress. To evaluate sympathetic cardiac activity in bruxism patients, we monitored cardiac autonomic modulation using spectral analysis of heart rate variability and compared results to those of age-matched healthy volunteers. In bruxism patients, sympathetic cardiac activity was higher than in volunteers. The increased sympathetic tone suggests increased stress and might be related to occlusal disharmonies
— id: 68217, year: 2006, vol: 16, page: 276, stat: Journal Article,

Deep brain stimulation improves orthostatic regulation of patients with Parkinson disease
Stemper, B; Beric, A; Welsch, G; Haendl, T; Sterio, D; Hilz, M J
2006 Nov 28;67(10):1781-1785, Neurology
OBJECTIVE: To evaluate whether subthalamic nucleus (STN) stimulation has an effect on the orthostatic regulation of patients with Parkinson disease (PD), we studied cardiovascular regulation during on and off phases of STN stimulation. METHODS: We examined 14 patients with PD (mean age 58.1 +/- 5.8 years, 4 women, 10 men) with bilateral STN stimulators. Patients underwent 3 minutes of head-up tilt (HUT) testing during STN stimulation and after 90 minutes interruption of stimulation. We monitored arterial blood pressure (BP), RR intervals (RRI), respiration, and skin blood flow (SBF). Baroreflex sensitivity (BRS) was assessed as the square root of the ratio of low-frequency power of RRI to the low-frequency power of systolic BP for coherences above 0.5. RESULTS: During the on phase of the STN stimulation, HUT induced no BP decrease, a significant tachycardia, and a significant decrease of SBF. During the off phase of stimulation, HUT resulted in significant decreases in BPsys and RRI and only a slight SBF decrease. HUT induced no change of BRS during stimulation, but lowered BRS when the stimulator was off (p < 0.05). CONCLUSIONS: STN stimulation of patients with PD increases peripheral vasoconstriction and BRS and stabilizes BP, thereby improving postural hypotension in patients with PD. The results indicate that STN stimulation not only alleviates motor deficits but also influences autonomic regulation in patients with PD
— id: 104800, year: 2006, vol: 67, page: 1781, stat: Journal Article,

Effect of physical countermaneuvers on orthostatic hypotension in familial dysautonomia
Tutaj, Marcin; Marthol, Harald; Berlin, Dena; Brown, Clive M; Axelrod, Felicia B; Hilz, Max J
2006 Jan;253(1):65-72, Journal of neurology
Familial dysautonomia (FD) patients frequently experience debilitating orthostatic hypotension. Since physical countermaneuvers can increase blood pressure (BP) in other groups of patients with orthostatic hypotension, we evaluated the effectiveness of countermaneuvers in FD patients. In 17 FD patients (26.4 +/- 12.4 years, eight female), we monitored heart rate (HR), blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR) and calf volume while supine, during standing and during application of four countermaneuvers: bending forward, squatting, leg crossing, and abdominal compression using an inflatable belt. Countermaneuvers were initiated after standing up,when systolic BP had fallen by 40mmHg or diastolic BP by 30mmHg or presyncope had occurred. During active standing, blood pressure and TPR decreased, calf volume increased but CO remained stable.Mean BP increased significantly during bending forward (by 20.0 (17 - 28.5) mmHg; P = 0.005) (median (25(th) - 75(th) quartile)), squatting (by 50.8 (33.5 - 56) mmHg; P = 0.002), and abdominal compression (by 5.8 (-1 - 34.7) mmHg; P = 0.04) - but not during leg-crossing. Squatting and abdominal compression also induced a significant increase in CO (by 18.1 (-1.3 - 47.9) % during squatting (P = 0.02) and by 7.6 (0.4 - 19.6) % during abdominal compression (P=0.014)). HR did not change significantly during the countermaneuvers. TPR increased significantly only during squatting (by 37.2 (11.8 - 48.2) %; P = 0.01). However, orthopedic problems or ataxia prevented several patients from performing some of the countermaneuvers. Additionally, many patients required assistance with the maneuvers. Squatting, bending forward and abdominal compression can improve orthostatic BP in FD patients, which is achieved mainly by an increased cardiac output. Squatting has the greatest effect on orthostatic blood pressure in FD patients. Suitability and effectiveness of a specific countermaneuver depends on the orthopedic or neurological complications of each FD patient and must be individually tested before a therapeutic recommendation can be given
— id: 68219, year: 2006, vol: 253, page: 65, stat: Journal Article,

[Methods of quantitative evaluation of the autonomic nerve system]
Hilz, Max J; Dutsch, M
2005 Jun;76(6):767-778, Nervenarzt
Dysfunction of the autonomic nervous system is a frequent finding in many neurological and internal diseases. The quantitative assessment of cardiovascular and sudomotor function is important for diagnosing the autonomic impairment. In this review article, we focus on standard tests that allow evaluation of cardiovascular and sudomotor autonomic functions and describe methods of quantitative assessment that are better suited for research
— id: 68221, year: 2005, vol: 76, page: 767, stat: Journal Article,

Quantitative studies of autonomic function
Hilz, Max J; Dutsch, Matthias
2005 Jun;62(16):1814-1825, Muscle & nerve
Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity. Muscle Nerve, 2005
— id: 56049, year: 2005, vol: 62, page: 1814, stat: Journal Article,

Cold pressor testing shows increased sympathetic cardiovascular activation in patients after left-sided lacunar stroke
Hilz, MJ; Burger, M; Dorfler, C; Neundorfer, B; Dutsch, M
2005 ;64(6):A170-A170, Neurology
— id: 104743, year: 2005, vol: 64, page: A170, stat: Journal Article,

Enhanced external counterpulsation does not compromise cerebral autoregulation
Marthol, H; Werner, D; Brown, C M; Hecht, M; Daniel, W G; Hilz, M J
2005 Jan;111(1):34-41, Acta neurologica Scandinavica
OBJECTIVES: Enhanced external counterpulsation (EECP) rhythmically augments blood pressure (BP) by diastolic lower-body compression. Recently, we showed decreased mean cerebral blood flow velocity (CBFVmean) in young healthy persons during EECP, but unchanged CBFVmean in atherosclerotic patients. In this study, we assessed EECP effects on dynamic cerebral autoregulation (CA). MATERIAL& METHODS: In 23 healthy persons and 15 atherosclerotic patients we monitored heart rate (HR), mean BP (BPmean) and CBFVmean before and during 5 min EECP. We analyzed spectral powers of HR, BPmean and CBFVmean in the low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency ranges to determine CA from the LF-transfer function gain and phase shift between BPmean and CBFVmean oscillations. RESULTS: EECP increased HR and BPmean, while transfer function gain and phase shift remained stable. CONCLUSIONS: Stable gain and phase values suggest that EECP does not compromise CA and, therefore, does not seem to bear cerebrovascular risks
— id: 68223, year: 2005, vol: 111, page: 34, stat: Journal Article,

Impairment of parasympathetic baroreflex responses in migraine patients
Sanya, E O; Brown, C M; von Wilmowsky, C; Neundorfer, B; Hilz, M J
2005 Feb;111(2):102-107, Acta neurologica Scandinavica
OBJECTIVES: The aim of this study was to assess baroreflex regulation of the heart rate and blood vessels in migraine patients in comparison with healthy controls. METHODS: In 30 migraine patients who were in a headache-free phase, aged 34 +/- 2 years, and 30 healthy controls, aged 34 +/- 3 years, we applied oscillatory neck suction at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was paced at 0.25 Hz. Electrocardiographic RR-intervals, blood pressure and respiration were continuously recorded. Responses to the baroreflex stimulations were assessed as the changes in power of the RR-interval and blood pressure fluctuations at the relevant stimulating frequency from the baseline values. RESULTS: Systolic and diastolic blood pressure responses to the 0.1 Hz neck suction pressure were not significantly different between the patients and controls. The RR-interval oscillatory response to 0.2 Hz neck suction was significantly less (P < 0.05) in the migraine patients (4.45 +/- 0.27 ln ms2) compared with the controls (5.48 +/- 0.36 ln ms2). CONCLUSION: These results suggest that baroreflex-mediated cardiovagal responses are reduced in migraine patients. However, the sympathetic-mediated baroreflex control of the blood vessels is intact in the migraine patients. The autonomic nervous system may have a role in the pathophysiology of migraine
— id: 68222, year: 2005, vol: 111, page: 102, stat: Journal Article,

Abnormal heart rate and blood pressure responses to baroreflex stimulation in multiple sclerosis patients
Sanya, Emmanuel O; Tutaj, Marcin; Brown, Clive M; Goel, Nursel; Neundorfer, Bernhard; Hilz, Max J
2005 Jun;15(3):213-218, Clinical autonomic research
Cardiovascular autonomic neuropathy has been previously reported in patients with multiple sclerosis (MS) using standard reflex tests. However, no study has separately evaluated both parasympathetic and sympathetic cardiovascular autonomic regulation. We therefore assessed the baroreflex-mediated vagal and sympathetic control of the heart rate and sympathetic control of the blood vessels in MS patients using sinusoidal neck stimulation.We studied 13 multiple sclerosis patients aged 28-58 years and 18 healthy controls aged 26-58 years. The carotid baroreflex was stimulated by sinusoidal neck suction (0 to -30 mmHg) at 0.1 Hz to assess the autonomic control of the heart and blood vessels, and at 0.2 Hz to assess the vagal control of the heart. Continuous recordings were made of blood pressure, electrocardiographic RR-interval and respiration, with breathing paced at 0.25 Hz. Spectral analysis was used to evaluate the magnitude of the low frequency (LF, 0.03-0.14 Hz) and high frequency (HF, 0.15-0.50 Hz) oscillations in RR-interval and blood pressure in response to the sinusoidal baroreceptor stimulation. Responses to the applied stimulus were assessed as the change in the spectral power of the RR-interval and blood pressure fluctuations at the stimulating frequency from the baseline values.The increase in the power of 0.1 Hz RR-interval oscillations during the 0.1 Hz neck suction was significantly smaller (p<0.01) in the MS patients (4.47+/-0.27 to 5.62+/-0.25 ln ms(2)) than in the controls (4.12+/-0.37 to 6.82+/-0.33 ln ms(2)). The increase in the power of 0.1 Hz systolic BP oscillations during 0.1 Hz neck suction was also significantly smaller (p<0.01) in the MS patients (0.99+/-0.19 to 1.96+/-0.39 mmHg(2)) than in the healthy controls (1.27+/-0.34 to 9.01+/-4.10 mmHg(2)). Neck suction at 0.2 Hz induced RR-interval oscillations at 0.2 Hz that were significantly smaller (p<0.05) in the patients (3.22+/-0.45 ln ms(2)) than in the controls (5.27+/-0.29 ln ms(2)). These results indicate that in MS patients, baroreflex dysfunction is not only restricted to the cardiovagal limb of the baroreflex, but that the sympathetic modulation of the blood vessels is also affected
— id: 68220, year: 2005, vol: 15, page: 213, stat: Journal Article,

Abnormal baroreflex responses in multiple sclerosis - Reply
Sanya, EO; Tutaj, M; Brown, CM; Goel, N; Neundorfer, B; Hilz, MJ
2005 ;15(6):420-420, Clinical autonomic research
— id: 104744, year: 2005, vol: 15, page: 420, stat: Journal Article,

Sudomotor function in familial dysautonomia
Bickel, A; Axelrod, F B; Marthol, H; Schmelz, M; Hilz, M J
2004 Feb;75(2):275-279, Journal of neurology neurosurgery & psychiatry
BACKGROUND: Patients with familial dysautonomia (FD) manifest episodic hyperhidrosis despite the reduction of sudomotor fibres and sweat glands associated with this autonomic neuropathy. We assessed peripheral sudomotor nerve fibre and sweat gland function to determine if this symptom was due to peripheral denervation hypersensitivity. METHODS: In 14 FD patients and 11 healthy controls, direct and axon reflex mediated sweat responses were determined by measuring transepidermal water loss (TEWL) after application of acetylcholine via a microdialysis membrane, a novel method to evaluate sudomotor function in neuropathy patients. Results were compared with data from conventional quantitative sudomotor axon reflex testing (QSART). Using microdialysis, interstitial fluid was analysed for plasma proteins to evaluate protein extravasation induced by acetylcholine as an additional parameter of C-fibre function. RESULTS: Although reduced axon reflex sweating was expected in FD patients, neither direct or axon reflex mediated sweat responses, nor acetylcholine induced protein extravasation differed between control and patient groups. However, the baseline resting sweat rate was higher in FD patients than controls (p<0.05). TEWL and QSART test results correlated (r = 0.64, p = 0.01), proving the reliability of TEWL methodology in evaluating sudomotor function. CONCLUSION: The finding of normal direct and axon reflex mediated sweat output in FD patients supports our hypothesis that, in a disorder with severe sympathetic nerve fibre reduction, sudomotor fibres, but not the sweat gland itself, exhibit chemical hypersensitivity. This might explain excessive episodic hyperhidrosis in situations with increased central sympathetic outflow
— id: 68228, year: 2004, vol: 75, page: 275, stat: Journal Article,

Cerebral autoregulation is compromised during simulated fluctuations in gravitational stress
Brown, Clive M; Dutsch, Matthias; Ohring, Susanne; Neundorfer, Bernhard; Hilz, Max J
2004 Mar;91(2-3):279-286, European journal of applied physiology
Gravity places considerable stress on the cardiovascular system but cerebral autoregulation usually protects the cerebral blood vessels from fluctuations in blood pressure. However, in conditions such as those encountered on board a high-performance aircraft, the gravitational stress is constantly changing and might compromise cerebral autoregulation. In this study we assessed the effect of oscillating orthostatic stress on cerebral autoregulation. Sixteen (eight male) healthy subjects [aged 27 (1) years] were exposed to steady-state lower body negative pressure (LBNP) at -15 and -40 mmHg and then to oscillating LBNP at the same pressures. The oscillatory LBNP was applied at 0.1 and 0.2 Hz. We made continuous recordings of RR-interval, blood pressure, cerebral blood flow velocity (CBFV), respiratory frequency and end-tidal CO(2). Oscillations in mean arterial pressure (MAP) and CBFV were assessed by autoregressive spectral analysis. Respiration was paced at 0.25 Hz to avoid interference from breathing. Steady-state LBNP at -40 mmHg significantly increased low-frequency (LF, 0.03-0.14 Hz) powers of MAP ( P<0.01) but not of CBFV. Oscillatory 0.1 Hz LBNP (0 to -40 mmHg) significantly increased the LF power of MAP to a similar level as steady-state LBNP but also resulted in a significant increase in the LF power of CBFV ( P<0.01). Oscillatory LBNP at 0.2 Hz induced oscillations in MAP and CBFV at 0.2 Hz. Cross-spectral analysis showed that the transfer of LBNP-induced oscillations in MAP onto the CBFV was significantly greater at 0.2 Hz than at 0.1 Hz ( P<0.01). These results show that the ability of the cerebral vessels to modulate fluctuations in blood pressure is compromised during oscillatory compared with constant gravitational stress. Furthermore, this effect seems to be more pronounced at higher frequencies of oscillatory stress
— id: 68230, year: 2004, vol: 91, page: 279, stat: Journal Article,

Cerebral autoregulation improves in epilepsy patients after temporal lobe surgery
Dutsch, Matthias; Devinsky, Orrin; Doyle, Werner; Marthol, Harald; Hilz, Max J
2004 Oct;251(10):1190-1197, Journal of neurology
Patients with temporal lobe epilepsy (TLE) often show increased cardiovascular sympathetic modulation during the interictal period, that decreases after epilepsy surgery. In this study, we evaluated whether temporal lobectomy changes autonomic modulation of cerebral blood flow velocity (CBFV) and cerebral autoregulation. We studied 16 TLE patients 3-4 months before and after surgery. We monitored heart rate (HR), blood pressure (BP), respiration, transcutaneous oxygen saturation (sat-O(2)), end-expiratory carbon dioxide partial pressure (pCO(2)) and middle cerebral artery CBFV. Spectral analysis was used to determine sympathetic and parasympathetic modulation of HR, BP and CBFV as powers of signal oscillations in the low frequency (LF) ranges from 0.04-0.15Hz (LF-power) and in the high frequency ranges from (HF) 0.15-0.5Hz (HF-power). LF-transfer function gain and phase shift between BP and CBFV were calculated as parameters of cerebral autoregulation. After surgery, HR, BP(mean), CBFV(mean), respiration, sat-O(2), pCO(2) and HF powers remained unchanged. LF-powers of HR, BP, CBFV and LF-transfer function gain had decreased while the phase angle had increased (p<0.05). The reduction of LF powers and LF-gain and the higher phase angle showed reduced sympathetic modulation and improved cerebral autoregulation. The enhanced cerebrovascular stability after surgery may improve autonomic balance in epilepsy patients
— id: 60149, year: 2004, vol: 251, page: 1190, stat: Journal Article,

Pupillography refines the diagnosis of diabetic autonomic neuropathy
Dutsch, Matthias; Marthol, Harald; Michelson, Georg; Neundorfer, Bernhard; Hilz, Max Josef
2004 Jul 15;222(1-2):75-81, Journal of the neurological sciences
Although diabetic autonomic neuropathy involves most organs, diagnosis is largely based on cardiovascular tests. Light reflex pupillography (LRP) non-invasively evaluates pupillary autonomic function. We tested whether LRP demonstrates autonomic pupillary dysfunction in diabetics independently from cardiac autonomic neuropathy (CAN) or peripheral neuropathy (PN). In 36 type-II diabetics (39-84 years) and 36 controls (35-78 years), we performed LRP. We determined diameter (PD), early and late re-dilation velocities (DV) as sympathetic parameters and reflex amplitude (RA) and constriction velocity (CV) as parasympathetic pupillary indices. We assessed the frequency of CAN using heart rate variability tests and evaluated the frequency of PN using neurological examination, nerve conduction studies, thermal and vibratory threshold determination. Twenty-eight (77.8%) patients had abnormal pupillography results, but only 20 patients (56%) had signs of PN or CAN. In nine patients with PN, only pupillography identified autonomic neuropathy. Four patients had pupillary dysfunction but no CAN or PN. In comparison to controls, patients had reduced PD, late DV, RA and CV indicating sympathetic and parasympathetic dysfunction. The incidence and severity of pupillary abnormalities did not differ between patients with and without CAN or PN. LRP demonstrates sympathetic and parasympathetic pupillary dysfunction independently from PN or CAN and thus refines the diagnosis of autonomic neuropathy in type-II diabetics
— id: 68225, year: 2004, vol: 222, page: 75, stat: Journal Article,

Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy
Hilz, M J; Brys, M; Marthol, H; Stemper, B; Dutsch, M
2004 May 13;62(7):1066-1072, Neurology
BACKGROUND: Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. Recently, enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A has become available. OBJECTIVE: To evaluate whether ERT improves Fabry neuropathy. METHODS: In 22 Fabry patients (age 27.9 +/- 8.0 years) undergoing ERT with recombinant human alpha-galactosidase A (agalsidase beta) for 18 (n = 11) or 23 (n = 11) months and in 25 control subjects (age 29.0 +/- 10.4 years), the authors performed quantitative sensory testing using the 4, 2, and 1 stepping algorithm (CASE IV). Detection thresholds of vibration (VDT) on the first toe were assessed; cold detection thresholds (CDT), heat-pain onset (HP 0.5), and intermediate heat-pain (HP 5.0) assessments were made on the dorsum of the feet. Patient values above mean + 2.5 SD of control values were considered abnormal. RESULTS: Before ERT, VDT, CDT, HP 0.5, and HP 5.0 were higher in patients than control subjects (p < 0.05). Following ERT, patients developed lower thresholds than prior to ERT for VDT (15.5 +/- 3.5 vs 14.3 +/- 4.1; p < 0.05), HP 0.5 (22.3 +/- 6.7 vs 19.4 +/- 1.3; p < 0.01), and HP 5.0 (27.3 +/- 5.6 vs 22.5 +/- 2.3; p < 0.01). Moreover, fewer patients had abnormal results of VDT (2 vs 4), CDT (7 vs 12), HP 0.5 (0 vs 9), and HP 5.0 (4 vs 20) after than before ERT. CONCLUSIONS: ERT therapy with agalsidase beta significantly improves function of C-, Adelta-, and Abeta-nerve fibers and intradermal vibration receptors in Fabry neuropathy. Lack of recovery in some patients with abnormal cold or heat-pain perception suggests the need for early ERT, prior to irreversible nerve fiber loss
— id: 46022, year: 2004, vol: 62, page: 1066, stat: Journal Article,

Enhanced external counterpulsation improves skin oxygenation and perfusion
Hilz, M J; Werner, D; Marthol, H; Flachskampf, F A; Daniel, W G
2004 Jun;34(6):385-391, European journal of clinical investigation
BACKGROUND: Enhanced external counterpulsation (EECP) augments diastolic and reduces systolic blood pressures. Enhanced external counterpulsation has been shown to improve blood flow in various organ systems. Beneficial effects on skin perfusion might allow EECP to be used in patients with skin malperfusion problems. This study was performed to assess acute effects of EECP on superficial skin blood flow, transdermal oxygen and carbon dioxide pressures. MATERIALS AND METHODS: We monitored heart rate, blood pressure, transdermal blood flow as well as oxygen and carbon dioxide pressures in 23 young, healthy persons (28 +/- 4 years) and 15 older patients (64 +/- 7 years) with coronary artery disease before, during and 3 min after 5 min EECP. Friedman test was used to compare the results of 90-s epochs before, during and after EECP. Significance was set at P < 0.05. RESULTS: Enhanced external counterpulsation increased heart rate and mean blood pressure. During EECP, transdermal oxygen pressure and concentration of moving blood cells increased while transdermal carbon dioxide pressure and velocity of moving blood cells decreased significantly in both groups. After EECP, transdermal carbon dioxide pressure was still reduced while the other parameters returned to baseline values. CONCLUSIONS: Improved skin oxygenation and carbon dioxide clearance during EECP seem to result from the increased concentration and reduced flow velocity, i.e. prolonged contact time, of erythrocytes. The increased concentration of moving blood cells and the decreased velocity of moving blood cells at both tested skin sites indicate peripheral vasodilatation
— id: 68226, year: 2004, vol: 34, page: 385, stat: Journal Article,

Assessing function and pathology in familial dysautonomia: assessment of temperature perception, sweating and cutaneous innervation
Hilz, Max J; Axelrod, Felicia B; Bickel, Andreas; Stemper, Brigitte; Brys, Miroslaw; Wendelschafer-Crabb, Gwen; Kennedy, William R
2004 Oct;127(Pt 9):2090-2098, Brain
This study was performed to assess cutaneous nerve fibre loss in conjunction with temperature and sweating dysfunction in familial dysautonomia (FD). In ten FD patients, we determined warm and cold thresholds at the calf and shoulder, and sweating in response to acetylcholine iontophoresis over the calf and forearm. Punch skin biopsies from calf and back were immunostained and imaged to assess nerve fibre density and neuropeptide content. Mean temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. The average density of epidermal nerve fibres was greatly diminished in the calf and back. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis. The few sweat glands present within the biopsies had had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene related peptide-ir (CGRP-ir) were virtually absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Temperature perception was more impaired than sweating. Epidermal nerve fibre density was found to be profoundly reduced in FD. Decreased SP and CGRP-ir nerves suggest that the FD gene mutation causes secondary neurotransmitter depletions. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration
— id: 46110, year: 2004, vol: 127, page: 2090, stat: Journal Article,

Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease
Hilz, Max Josef; Kolodny, Edwin H; Brys, Miroslaw; Stemper, Brigitte; Haendl, Thomas; Marthol, Harald
2004 Jun;251(5):564-570, Journal of neurology
In Fabry disease, there is glycosphingolipid storage in vascular endothelial and smooth muscle cells and neurons of the autonomic nervous system. Vascular or autonomic dysfunction is likely to compromise cerebral blood flow velocities and cerebral autoregulation. This study was performed to evaluate cerebral blood flow velocities and cerebral autoregulation in Fabry patients. In 22 Fabry patients and 24 controls, we monitored resting respiratory frequency, electrocardiographic RR-intervals, blood pressure, and cerebral blood flow velocities (CBFV) in the middle cerebral artery using transcranial Doppler sonography. We assessed the Resistance Index, Pulsatility Index, Cerebrovascular Resistance, and spectral powers of oscillations in RR-intervals, mean blood pressure and mean CBFV in the high (0.15-0.5 Hz) and sympathetically mediated low frequency (0.04-0.15 Hz) ranges using autoregressive analysis. Cerebral autoregulation was determined from the transfer function gain between the low frequency oscillations in mean blood pressure and mean CBFV. Mean CBFV (P < 0.05) and the powers of mean blood pressure (P < 0.01) and mean CBFV oscillations (P < 0.05) in the low frequency range were lower,while RR-intervals, Resistance Index (P < 0.01), Pulsatility Index, Cerebrovascular Resistance (P < 0.05), and the transfer function gain between low frequency oscillations in mean blood pressure and mean CBFV (P < 0.01) were higher in patients than in controls. Mean blood pressure, respiratory frequency and spectral powers of RR-intervals did not differ between the two groups (P > 0.05). The decrease of CBFV might result from downstream stenoses of resistance vessels and dilatation of the insonated segment of the middle cerebral artery due to reduced sympathetic tone and vessel wall pathology with decreased elasticity. The augmented gain between blood pressure and CBFV oscillations indicates inability to dampen blood pressure fluctuations by cerebral autoregulation. Both, reduced CBFV and impaired cerebral autoregulation, are likely to be involved in the increased risk of stroke in patients with Fabry disease
— id: 46144, year: 2004, vol: 251, page: 564, stat: Journal Article,

Principles of spectral analysis of heart rate variability
Hilz, MJ
2004 ;11(1-2):346-346, European journal of neurology
— id: 104745, year: 2004, vol: 11, page: 346, stat: Journal Article,

[Female sexual dysfunction: a systematic overview of classification, pathophysiology, diagnosis and treatment]
Marthol, H; Hilz, M J
2004 Apr;72(3):121-135, Fortschritte der neurologie-psychiatrie
Sexual dysfunction is defined as 'disturbances in sexual desire and in the psychophysiological changes that characterize the sexual response cycle and cause marked distress and interpersonal difficulty'. The female sexual response cycle consists of three phases: desire, arousal, and orgasm. Various organs of the external and internal genitalia, e.g. vagina, clitoris, labia minora, vestibular bulbs, pelvic floor muscles and uterus, contribute to female sexual function. During sexual arousal, genital blood flow and sensation are increased. The vaginal canal is moistened (lubrication). During orgasm, there is rhythmical contraction of the uterus and pelvic floor muscles. Within the central nervous system, hypothalamic, limbic-hippocampal structures play a central role for sexual arousal. Sexual arousal largely depends on the sympathetic nervous system. Moreover, nonadrenergic/noncholinergic neurotransmitters (NANC), e.g. vasoactive intestinal polypeptide (VIP) and nitric oxide (NO), are involved in smooth muscle relaxation and enhancement of genital blood flow. Furthermore, various hormones may influence female sexual function. Estrogen has a significant role in maintaining vaginal mucosal epithelium as well as sensory thresholds and genital blood flow. Androgens primarily affect sexual desire, arousal, orgasm and the overall sense of well-being. The internationally accepted classification of female sexual dysfunction consists of hypoactive sexual desire disorders, sexual aversion disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Vascular insufficiency, e.g. due to atherosclerosis, and neurologic diseases, e.g. diabetic neuropathy, are major causes of sexual dysfunction. Additionally, sexual dysfunction may be due to changes in hormonal levels, medications with sexual side effects or of psychological origin. For the diagnosis of female sexual dysfunction, a detailed history should be taken initially, followed by a physical examination and laboratory studies. Physiologic monitoring of parameters of arousal potentially allows to diagnose organic diseases. Recordings at baseline and following sexual stimulation are recommended to determine pathologic changes that occur with arousal. Duplex Doppler sonography, photoplethysmography or the measurement of vaginal and minor labial oxygen tension may help to evaluate genital blood flow. Moreover, measurements of vaginal pH and compliance should be performed. Neurophysiological examination, e.g. measurement of the bulbocavernosus reflex and pudendal evoked potentials, genital sympathetic skin response (SSR), warm, cold and vibratory perception thresholds as well as testing of the pressure and touch sensitivity of the external genitalia, should be performed to evaluate neurogenic etiologies. Medical management of female sexual dysfunction so far is primarily based on hormone replacement therapy. Application of estrogen results in decreased pain and burning during intercourse. The efficacy of various other medications, e.g. sildenafil, L-arginine, yohimbine, phentolamine, apomorphine and prostaglandin E1, in the treatment of female sexual dysfunction is still under investigation
— id: 46239, year: 2004, vol: 72, page: 121, stat: Journal Article,

Sympathetic and parasympathetic baroreflex dysfunction in familial dysautonomia
Stemper, B; Bernardi, L; Axelrod, F B; Welsch, G; Passino, C; Hilz, M J
2004 Oct 26;63(8):1427-1431, Neurology
OBJECTIVE: To assess the possible abnormalities in the baroreflex modulation of both the heart and the arterial vasculature, in order to better evaluate the role of baroreflex abnormalities in the generation of the cardiovascular symptoms and complications affecting the familial dysautonomia (FD) patient. METHODS: Twenty-one FD patients and 22 controls underwent 3 minutes of passive head-up tilt (HUT) and baroreceptor stimulation by means of sinusoidal neck suction (NS; 0 to -30 mm Hg; 0.1 Hz [LF] and 0.2 Hz [HF]). Respiration was maintained constant during NS at 15 breaths/minute. The authors monitored RR-intervals (RRI), blood pressure (BP) (Colin), and respiration. NS induced changes of RRI and BP were determined by spectral analysis. RESULTS: HUT showed orthostatic hypotension without compensatory tachycardia in FD patients but not in controls. LF-NS increased LF power of RRI and BP and HF-NS increased HF power of RRI in controls, but not in FD patients. CONCLUSIONS: Familial dysautonomia patients have a widespread baroreflex abnormality, involving both the efferent sympathetic arm on the resistance vessels, and the sympathetic and parasympathetic efferent arms on the heart. Therefore, the abnormalities in the control of blood pressure-i.e., supine hypertension, orthostatic hypotension, blood pressure lability-and heart rate-i.e., bradyarrhythmias-are likely due to baroreflex abnormalities
— id: 68224, year: 2004, vol: 63, page: 1427, stat: Journal Article,

Dynamic cerebral autoregulation is impaired in glaucoma
Tutaj, Marcin; Brown, Clive M; Brys, Miroslaw; Marthol, Harald; Hecht, Martin J; Dutsch, Matthias; Michelson, Georg; Hilz, Max J
2004 May 15;220(1-2):49-54, Journal of the neurological sciences
OBJECTIVES: Autonomic and endothelial dysfunction is likely to contribute to the pathophysiology of normal pressure glaucoma (NPG) and primary open angle glaucoma (POAG). Although there is evidence of vasomotor dysregulation with decreased peripheral and ocular blood flow, cerebral autoregulation (CA) has not yet been evaluated. The aim of our study was to assess dynamic CA in patients with NPG and POAG. MATERIALS AND METHODS: In 10 NPG patients, 11 POAG patients and 11 controls, we assessed the response of cerebral blood flow velocity (CBFV) to oscillations in mean arterial pressure (MAP) induced by deep breathing at 0.1 Hz. CA was assessed from the autoregressive cross-spectral gain between 0.1 Hz oscillations in MAP and CBFV. RESULTS: 0.1 Hz spectral powers of MAP did not differ between NPG, POAG and controls; 0.1 Hz CBFV power was higher in patients with NPG (5.68+/-1.2 cm(2) s(-2)) and POAG (6.79+/-2.1 cm(2) s(-2)) than in controls (2.40+/-0.4 cm(2) s(-2)). Furthermore, the MAP-CBFV gain was higher in NPG (2.44+/-0.5 arbitrary units [a.u.]) and POAG (1.99+/-0.2 a.u.) than in controls (1.21+/-0.1 a.u.). CONCLUSION: Enhanced transmission of oscillations in MAP onto CBFV in NPG and POAG indicates impaired cerebral autoregulation and might contribute to an increased risk of cerebrovascular disorders in these diseases
— id: 68227, year: 2004, vol: 220, page: 49, stat: Journal Article,

Inherited autonomic neuropathies
Axelrod, Felicia B; Hilz, Max J
2003 Mar-Apr;23(4):381-390, Seminars in neurology
Inherited autonomic neuropathies are a rare group of disorders associated with sensory dysfunction. As a group they are termed the 'hereditary sensory and autonomic neuropathies' (HSAN). Classification of the various autonomic and sensory disorders is ongoing. In addition to the numerical classification of four distinct forms proposed by Dyck and Ohta (1975), additional entities have been described. The best known and most intensively studied of the HSANs are familial dysautonomia (Riley-Day syndrome or HSAN type III) and congenital insensitivity to pain with anhidrosis (HSAN type IV). Diagnosis of the HSANs depends primarily on clinical examinations and specific sensory and autonomic assessments. Pathologic examinations are helpful in confirming the diagnosis and in differentiating between the different disorders. In recent years identification of specific genetic mutations for some disorders has aided diagnosis. Replacement or definitive therapies are not available for any of the disorders so that treatment remains supportive and directed toward specific symptoms
— id: 46215, year: 2003, vol: 23, page: 381, stat: Journal Article,

Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia
Bernardi, Luciano; Hilz, Max; Stemper, Brigitte; Passino, Claudio; Welsch, Goetz; Axelrod, Felicia B
2003 Jan 15;167(2):141-149, American journal of respiratory & critical care medicine
Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD
— id: 37074, year: 2003, vol: 167, page: 141, stat: Journal Article,

Effects of lower body negative pressure on cardiac and vascular responses to carotid baroreflex stimulation
Brown, C M; Hecht, M J; Neundorfer, B; Hilz, M J
2003 ;52(5):637-645, Physiological research
The aim of this study was to assess carotid baroreflex responses during graded lower body negative pressure (LBNP). In 12 healthy subjects (age 29+/-4 years) we applied sinusoidal neck suction (0 to -30 mmHg) at 0.1 Hz to examine the sympathetic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Responses to neck suction were determined as the change in spectral power of RR-interval and blood pressure from baseline values. Measurements were carried out during progressive applications (0 to -50 mmHg) of LBNP. Responses to 0.1 and 0.2 Hz carotid baroreceptor stimulations during low levels of LBNP (-10 mmHg) were not significantly different from those measured during baseline. At higher levels of LBNP, blood pressure responses to 0.1 Hz neck suction were significantly enhanced, but with no significant change in the RR-interval response. LBNP at all levels had no effect on the RR-interval response to 0.2 Hz neck suction. The unchanged responses of RR-interval and blood pressure to neck suction during low level LBNP at -10 mmHg suggest no effect of cardiopulmonary receptor unloading on the carotid arterial baroreflex, since this LBNP level is considered to stimulate cardiopulmonary but not arterial baroreflexes. Enhanced blood pressure responses to neck suction during higher levels of LBNP are not necessarily the result of a reflex interaction but may serve to protect the circulation from fluctuations in blood pressure while standing
— id: 68232, year: 2003, vol: 52, page: 637, stat: Journal Article,

Effects of age on the cardiac and vascular limbs of the arterial baroreflex
Brown, C M; Hecht, M J; Weih, A; Neundorfer, B; Hilz, M J
2003 Jan;33(1):10-16, European journal of clinical investigation
BACKGROUND: Healthy ageing has several effects on the autonomic control of the circulation. Several studies have shown that baroreflex-mediated vagal control of the heart deteriorates with age, but so far there is little information regarding the effect of ageing on sympathetically mediated baroreflex responses. The aim of this study was to assess the effects of ageing on baroreflex control of the heart and blood vessels. MATERIALS AND METHODS: In 40 healthy volunteers, aged 20-87 years, we applied oscillatory neck suction at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was maintained at 0.25 Hz. Blood pressure, electrocardiographic RR intervals and respiration were recorded continuously. Spectral analysis was used to evaluate the magnitude of the low-frequency (0.03-0.14 Hz) and high-frequency (0.15-0.50 Hz) oscillations in the RR interval and blood pressure. Responses to neck suction were assessed as the change in power of the RR interval and blood pressure fluctuations at the stimulation frequency from baseline values. RESULTS: Resting low- and high-frequency powers of the RR interval decreased significantly with age (P < 0.01). However, the low-frequency power of systolic blood pressure did not correlate with age. Spontaneous baroreflex sensitivity (alpha-index) showed a significant inverse correlation with age (r = -0.46, P < 0.05). Responses of the RR interval and systolic blood pressure to 0.1 Hz neck suction stimulation were not related to age, however, the RR interval response to 0.2 Hz neck suction declined significantly with age (r = -0.61, P < 0.01). CONCLUSIONS: These results confirm an age-related decrease in cardiovagal baroreflex responses. However, sympathetically mediated baroreflex control of the blood vessels is preserved with age
— id: 37004, year: 2003, vol: 33, page: 10, stat: Journal Article,

Assessment of cerebrovascular and cardiovascular responses to lower body negative pressure as a test of cerebral autoregulation
Brown, Clive M; Dutsch, Matthias; Hecht, Martin J; Neundorfer, Bernhard; Hilz, Max J
2003 Apr 15;208(1-2):71-78, Journal of the neurological sciences
The aim of this study was to determine whether lower body negative pressure (LBNP), combined with noninvasive methods of assessing changes in systemic and cerebral vascular resistance, is suitable as a method for assessing cerebral autoregulation.In 13 subjects we continuously assessed heart rate, blood pressure, cerebral blood flow velocity (CBFV) and cardiac output during graded levels of LBNP from 0 to -50 mm Hg. With increasing levels of LBNP, cardiac output declined significantly (to 55.8+/-4.5% of baseline value) but there was no overall change in mean arterial pressure. CBFV also fell at higher levels of LBNP (to 81.4+/-3.2% of baseline) but the percentage CBFV change was significantly less than that in cardiac output (P<0.01). The maximum increase in cerebrovascular resistance (pulsatility ratio) was significantly less than that in total peripheral resistance (17+/-6% vs. 105+/-16%, P<0.01). Spectral analysis showed that the power of low-frequency oscillations in mean arterial pressure, but not CBFV, increased significantly at the -50 mm Hg level of LBNP.These results show that, even during high levels of orthostatic stress, cerebral autoregulation is preserved and continues to protect the cerebral circulation from changes in the systemic circulation. Furthermore, assessment of cardiovascular and cerebrovascular parameters during LBNP may provide a useful clinical test of cerebral autoregulation
— id: 36998, year: 2003, vol: 208, page: 71, stat: Journal Article,

Effect of cold face stimulation on cerebral blood flow in humans
Brown, Clive M; Sanya, Emmanuel O; Hilz, Max J
2003 Jun 30;61(1):81-86, Brain research bulletin
BACKGROUND AND PURPOSE: In humans, activation of the diving reflex by a cold stimulus to the face results in bradycardia, peripheral vasoconstriction and an increase in blood pressure. However, responses of the cerebral blood flow have not yet been evaluated. We undertook this study to assess the effect of cold face stimulation on the cerebral circulation in humans. METHODS: Seventeen healthy volunteers, aged 27+/-5 years were evaluated during application of a cold stimulus (0 degrees C) to the forehead for 60s. We continuously monitored mean arterial pressure (MAP), mean flow velocity (MFV) of the middle cerebral artery, cardiac output, skin blood flow, heart rate and end-tidal CO2. Total peripheral resistance (TPR) was calculated as MAP divided by cardiac output. Cerebrovascular resistance index (CVRi) was calculated as MAP divided by MFV. RESULTS: Cold face stimulation did not significantly affect cardiac output but resulted in significant decreases in heart rate and skin blood flow and an increase in MAP. MFV in the mid-cerebral artery showed a slight, but significant increase. The maximum increase in CVRi (14.2+/-11.4%) was significantly (P<0.01) less than the maximum increase in TPR (23.9+/-5.7%). End-tidal CO2 did not change significantly during the cold stimulation. CONCLUSIONS: In contrast to other sympathetic stimulations (e.g. lower body negative pressure), facial cooling results in an increase in cerebral blood flow. The amount of cerebral vasoconstriction was less than the amount of total peripheral vasoconstriction. These results suggest that although there is some constriction of the cerebral resistance vessels during cold face stimulation, cerebral perfusion was maintained, possibly by opposing parasympathetic activation
— id: 36993, year: 2003, vol: 61, page: 81, stat: Journal Article,

Orthostatic challenge reveals impaired vascular resistance control, but normal venous pooling and capillary filtration in familial dysautonomia
Brown, Clive M; Stemper, Brigitte; Welsch, Gotz; Brys, Miroslaw; Axelrod, Felicia B; Hilz, Max J
2003 Feb;104(2):163-169, Clinical science (London, 1979)
Patients with familial dysautonomia (FD) frequently have profound orthostatic hypotension without compensatory tachycardia. Although the aetiology is presumed to be sympathetic impairment, peripheral vascular responses to orthostasis have not been assessed. The aim of this study was to evaluate the control of vascular responses to postural stress in FD patients. Measurements of heart rate, blood pressure, cardiac stroke volume and cardiac output (CO), by impedance cardiography, and calf-volume changes, by impedance plethysmography, were taken from nine FD patients and 11 control subjects while supine and during head-up tilt. During leg lowering, we also assessed the venoarteriolar reflex by measuring skin red-cell flux. Head-up tilting for 10 min induced sustained decreases in mean arterial pressure in the FD patients, but not in the controls. Total peripheral resistance (TPR, i.e. mean arterial pressure/CO) increased significantly in the controls (39.8+/-6.8%), but not in the FD patients. Calf-volume changes during tilting, when normalized for the initial calf volume, did not differ significantly between the patients (4.62+/-1.99 ml.100 ml(-1)) and the controls (3.18+/-0.74 ml.100 ml(-1)). The vasoconstrictor response to limb lowering was present in the patients (47.7+/-9.0% decrease in skin red-cell flux), but was impaired as compared with the controls (80.7+/-3.4%) ( P <0.05). The impaired vasoconstriction during limb lowering and absent increase of TPR during tilting confirm that orthostatic hypotension in FD is due primarily to a lack of sympathetically mediated vasoconstriction without evidence of abnormally large shifts in blood volume towards the legs during orthostasis. This may be due, in part, to a preserved myogenic response to increased vascular pressure in the dependent vascular beds
— id: 37000, year: 2003, vol: 104, page: 163, stat: Journal Article,

Dynamic cerebral autoregulation remains stable during physical challenge in healthy persons
Brys, Miroslaw; Brown, Clive M; Marthol, Harald; Franta, Renate; Hilz, Max J
2003 Sep;285(3):H1048-H1054, American journal of physiology. Heart & circulatory physiology
The effects of physical activity on cerebral blood flow (CBF) and cerebral autoregulation (CA) have not yet been fully evaluated. There is controversy as to whether increasing heart rate (HR), blood pressure (BP), and sympathetic and metabolic activity with altered levels of CO2 might compromise CBF and CA. To evaluate these effects, we studied middle cerebral artery blood flow velocity (CBFV) and CA in 40 healthy young adults at rest and during increasing levels of physical exercise. We continuously monitored HR, BP, end-expiratory CO2, and CBFV with transcranial Doppler sonography at rest and during stepwise ergometric challenge at 50, 100, and 150 W. The modulation of BP and CBFV in the low-frequency (LF) range (0.04-0.14 Hz) was calculated with an autoregression algorithm. CA was evaluated by calculating the phase shift angle and gain between BP and CBFV oscillations in the LF range. The LF BP-CBFV gain was then normalized by conductance. Cerebrovascular resistance (CVR) was calculated as mean BP adjusted to brain level divided by mean CBFV. HR, BP, CO2, and CBFV increased significantly with exercise. Phase shift angle, absolute and normalized LF BP-CBFV gain, and CVR, however, remained stable. Stable phase shift, LF BP-CBFV gain, and CVR demonstrate that progressive physical exercise does not alter CA despite increasing HR, BP, and CO2. CA seems to compensate for the hemodynamic effects and increasing CO2 levels during exercise
— id: 36987, year: 2003, vol: 285, page: H1048, stat: Journal Article,

Hereditary dysautonomias: current knowledge and collaborations for the future
Cuajungco, Math P; Ando, Yukio; Axelrod, Felicia B; Biaggioni, Italo; Goldstein, David S; Guttmacher, Alan E; Gwinn-Hardy, Katrina; Hahn, Maureen K; Hilz, Max J; Jacob, Giris; Jens, Jordan; Kennedy, William R; Liggett, Stephen B; O'Connor, Daniel T; Peltzer, Sonia R; Robertson, David; Rubin, Berish Y; Scudder, Quandra; Smith, Linda J; Sonenshein, Gail E; Svejstrup, Jesper Q; Xu, Yang; Slaugenhaupt, Susan A
2003 Jun;13(3):180-195, Clinical autonomic research
The hereditary dysautonomias (H-Dys) are a large group of disorders that affect the autonomic nervous system. Research in the field of H-Dys is very challenging, because the disorders involve interdisciplinary, integrative, and 'mind-body' connections. Recently, medical scientists, NIH/NINDS representatives, and several patient support groups gathered for the first time in order to discuss recent findings and future directions in the H-Dys field. The H-Dys workshop was instrumental in promoting interactions between basic science and clinical investigators. It also allowed attendees to have an opportunity to meet each other, understand the similarities between the various forms of dysautonomia, and experience the unique perspective offered by patients and their families. Future advances in H-Dys research will depend on a novel multi-system approach by investigators from different medical disciplines, and it is hoped that towards a common goal, novel 'bench-to-bedside' therapeutics will be developed to improve the lives of, or even cure, patients suffering from dysautonomic syndromes
— id: 36990, year: 2003, vol: 13, page: 180, stat: Journal Article,

Polyneuropathie erkennen und behandeln. Mit Fingerspitzengefuhl zur richtigen Diagnose
Hecht M; Heuss D; Hilz MJ
2003 ;2:81-85, MMW Fortschritte der Medizin
— id: 37075, year: 2003, vol: 2, page: 81, stat: Journal Article,

[Diagnosis and treatment of polyneuropathy: what can the family doctor do?]
Hecht, M; Heuss, D; Hilz, M J
2003 May 26;145 Suppl 2:81-85, MMW Fortschritte der Medizin
Polyneuropathies are common disorders of the peripheral nervous system. Early diagnosis and therapy enables to stop the progression of the polyneuropathy and to ameliorate polyneuropathic symptoms in most cases. Clinical examination is sufficient to diagnose polyneuropathy. However, to reveal the etiology of a polyneuropathy additional diagnostic procedures are necessary. The general practitioner should recognize the signs and symptoms of a polyneuropathy and start necessary investigations. If the etiology of the polyneuropathy is revealed specific therapy can be started. Furthermore, polyneuropathic symptoms can be ameliorated independently of the underlying cause
— id: 68229, year: 2003, vol: 145 Suppl 2, page: 81, stat: Journal Article,

Increased hypoxic blood pressure response in patients with amyotrophic lateral sclerosis
Hecht, Martin J; Brown, Clive M; Mittelhamm, Felix; Werner, Dierk; Heuss, Dieter; Neundorfer, Bernhard; Hilz, Max-Josef
2003 Sep 15;213(1-2):47-53, Journal of the neurological sciences
OBJECTIVES: There is evidence of impaired cardiovascular autonomic control and reduced baroreflex sensitivity in patients with amyotrophic lateral sclerosis (ALS). A compromised baroreflex-chemoreflex interaction might result in inadequate responses to chemoreflex activation with progressive hypercapnia and hypoxia and contribute to early fatalities. This study was performed to assess cardiovascular and ventilatory responses to hypercapnic and hypoxic stimulation in ALS patients with impaired baroreflex function. PATIENTS AND METHODS: In 15 ALS patients with previously demonstrated baroreflex dysfunction and in 15 age-matched controls, we compared electrocardiographic RR-interval (RRI), systolic blood pressure (SBP) and minute ventilation (VE) during normal ventilation and during selective progressive hypoxia and hypercapnia. RESULTS: Ventilatory and RRI responses to hypoxic and hypercapnic stimulation as well as SBP responses to hypercapnia did not differ between patients and controls. In contrast, hypoxia induced a significant SBP increase in patients only. CONCLUSIONS: The normal ventilatory and RRI responses to chemoreflex activation suggest intact afferent chemoreflex function. The hypertensive response to hypoxia might be due to a compromised interaction with the baroreflex. Avoiding hypoxic episodes might reduce the risk of cardiovascular crisis in ALS patients
— id: 36988, year: 2003, vol: 213, page: 47, stat: Journal Article,

Burden of care in amyotrophic lateral sclerosis
Hecht, Martin J; Graesel, Elmar; Tigges, Sebastian; Hillemacher, Thomas; Winterholler, Martin; Hilz, Max-Josef; Heuss, Dieter; Neundorfer, Bernhard
2003 Jun;17(4):327-333, Palliative medicine
OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal disease with unique demands on patients and carers. PATIENTS AND METHODS: The total burden of care and burden components in 37 ALS carers were measured using validated questionnaires. Furthermore, influencing factors (functional impairment of the patient, additional carers, participation in support groups) were assessed. RESULTS: The mean total burden of care for ALS was low compared with dementia, mixed neuropsychiatric and internal diseases, but was correlated with functional impairment (P = 0.003). The main burden components were 'personal and social restrictions' and 'physical and emotional problems'. Problem behaviour of the patients was low in general, but was higher in carers participating in support groups (P = 0.002). Carers supported by additional carers had higher strain. CONCLUSION: The low burden of ALS carers may be caused by the low incidence of problem behaviour in ALS patients. However, if problem behaviour exists, carers participate more often in support groups, indicating the need for assistance. The burden of care increases with the functional impairment. Support for the carers has to start sooner
— id: 36989, year: 2003, vol: 17, page: 327, stat: Journal Article,

Delayed cerebrovascular autoregulatory response to ergometer exercise in normotensive elderly humans
Heckmann, Josef G; Brown, Clive M; Cheregi, Michaela; Hilz, Max J; Neundorfer, Bernhard
2003 ;16(4):423-429, Cerebrovascular diseases
BACKGROUND: Relatively little is known about physiological cerebrovascular haemodynamics during physical stress in elderly healthy individuals. The aim of this study was to determine the effect of ergometer stress on cerebrovascular haemodynamics in elderly healthy individuals in comparison with young healthy individuals, using non-invasive methods. METHODS: Continuous middle cerebral artery blood flow velocity (CBFV; transcranial Doppler ultrasound), beat-to-beat blood pressure, heart rate and transcutaneous pCO(2) were measured in response to 3 min ergometer exercise stress in 18 elderly healthy subjects (mean age +/- SD 66.5 +/- 5.8 years) and 18 healthy young subjects (mean age +/- SD 29.4 +/- 4.7 years). Pulsatility index (PI) was used as a parameter for cerebrovascular resistance. The subjects were in a supine position with an elevated trunk and performed exercise by pedalling on an ergometer, generating 75-100 W. Statistical analysis was carried out using MANOVA, a general linear model with repeated measures. RESULTS: In both groups, blood pressure increased significantly (p < 0.001) with time during exercise, with no significant differences between the groups or regarding interaction (time sequence/group factor). Heart rate increased significantly with time during exercise (p < 0.001) and was significantly more prominent (p = 0.002) and prolonged (p < 0.001) in the young group. pCO(2) did not differ with time or between the groups and with regard to interaction. Mean CBFV (MFV) increased significantly during time (p < 0.001). Between the groups, there was no significant difference (p = 0.836), but with regard to interaction (time sequence/group factor), there was a significant delay in MFV increase in the group of young subjects (p = 0.002). The PI, a measure of cerebrovascular resistance, increased significantly with time without significant differences between the groups (p = 0.061), but was significantly delayed in the elderly regarding the interaction time sequence/group factor (p < 0.001). CONCLUSION: The cerebrovascular changes during ergometer exercise may reflect the combined activation of the cerebrovascular autoregulative mechanisms (predominantly neurogenic and myogenic). In healthy normotensive elderly subjects, cerebral autoregulatory capacity is retained but delayed in response to ergometer stress compared with young healthy subjects. We speculate that these findings may contribute to a higher risk of cerebral hypoperfusion in the elderly
— id: 68233, year: 2003, vol: 16, page: 423, stat: Journal Article,

[Erectile dysfunction--value of neurophysiologic diagnostic procedures]
Hilz, M J; Marthol, H
2003 Oct;42(10):1345-1350, Urologe. Ausg. A.
Neurogenic, particularly autonomic disorders, frequently contribute to the etiology and pathophysiology of erectile dysfunction. Parasympathetic and sympathetic outflow mediates erection. Noncholinergic, nonadrenergic neurotransmitters induce activation of cyclic monophosphates, leading to relaxation of smooth muscles of the corpora cavernosa and by this to tumescence and rigidity, i.e. erection. The diagnosis of neurologic causes of erectile dysfunction requires a detailed history and neurologic examination. Conventional neurophysiological procedures evaluate the function of rapidly conducting, thickly myelinated nerve fibers only. Therefore, techniques such as sphincter ani externus electromyography, latency measurements of the pudendal nerve or bulbocavernosus reflex studies frequently do not contribute to the diagnostic process. The evaluation of small nerve fibers that are essential for erection, for example by means of psychophysical quantitative thermotesting, might improve the diagnosis of neurogenic causes of erectile dysfunction. In addition, the assessment of heart rate variability at rest, during metronomic breathing, Valsalva maneuver, and active standing might be helpful to identify an autonomic neuropathy as the cause of erectile dysfunction
— id: 68231, year: 2003, vol: 42, page: 1345, stat: Journal Article,

Outcome of epilepsy surgery correlates with sympathetic modulation and neuroimaging of the heart
Hilz, Max J; Platsch, Gunther; Druschky, Katrin; Pauli, Elisabeth; Kuwert, Torsten; Stefan, Hermann; Neundorfer, Bernhard; Druschky, Achim
2003 Mar;216(1):153-162, Journal of the neurological sciences
Temporal lobe epilepsy (TLE) is frequently associated with sympathetic over-activity. Single photon emission computed tomography (SPECT) with 123iodine-meta-iodobenzylguanidine (MIBG), a norepinephrine analogue, showed reduced tracer uptake in cardiac sympathetic nerve endings, indicating myocardial catecholamine disturbance. We investigated whether outcome of epilepsy surgery correlates with cardiac autonomic function in TLE patients.We studied 16 TLE patients before and after epilepsy surgery. We recorded heart rate (HR) and determined sympathetic and parasympathetic cardiac modulation as powers of low (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.5 Hz) heart rate oscillations. The LF/HF-ratio was calculated as index of sympathovagal balance. Cardiac MIBG uptake was assessed with MIBG-SPECT and compared to control data.After surgery, eight patients were seizure-free and eight had persistent seizures. Sympathetic LF-power and LF/HF-ratio were higher in patients who had persistent seizures than in patients who became seizure-free. After surgery, both parameters decreased in seizure-free patients but increased in patients with persistent seizures. MIBG uptake was lower in patients than controls and even lower in the patient subgroup who had persistent seizures. In this subgroup, MIBG uptake further decreased after surgery (P<0.05).Sympathetic cardiac modulation decreased in TLE patients after successful surgery, but further increased if seizures persisted. Reduction of cardiac MIBG uptake progressed after surgery in patients with persistent seizures. Interference of epileptogenic discharges with autonomic neuronal transmission might account for sympathetic cardiac over-stimulation and reduced MIBG uptake. Both findings are possible risk factors for sudden unexplained death and might be relevant for risk stratification in epilepsy patients
— id: 46273, year: 2003, vol: 216, page: 153, stat: Journal Article,

Impact of urinary incontinence after stroke: results from a prospective population-based stroke register
Kolominsky-Rabas, Peter L; Hilz, Max-Josef; Neundoerfer, Bernhard; Heuschmann, Peter U
2003 ;22(4):322-327, Neurourology & urodynamics
AIM: The purpose of this study was to investigate, in a community-based population, the frequency of stroke-related urinary incontinence (
— id: 36992, year: 2003, vol: 22, page: 322, stat: Journal Article,

Clonidine improves postprandial baroreflex control in familial dysautonomia
Marthol, H; Tutaj, M; Brys, M; Brown, C M; Hecht, M J; Berlin, D; Axelrod, F B; Hilz, M J
2003 Oct;33(10):912-918, European journal of clinical investigation
BACKGROUND: Patients with familial dysautonomia (FD) frequently experience hypertensive crises after gastrostomy feeding. The central alpha2-agonist clonidine attenuates feeding-induced crises. The aim of this study was to assess the effect of clonidine on cardiovascular autonomic modulation and particularly baroreflex sensitivity in familial dysautonomia after gastrostomy feeding. MATERIAL AND METHODS: In nine patients, we monitored the RR-interval and systolic blood pressure at supine rest before (baseline 1) and after gastrostomy feeding (GF1). One day later, recordings were repeated after clonidine intake (baseline 2, GF2). We determined spectral powers of RR-interval and systolic blood pressure in the low- (LF) and high-frequency range (HF). Sympathovagal balance was determined from the LF/HF ratio of RR-interval. Baroreflex sensitivity was assessed from the alpha-index of systolic blood pressure and RR-interval. RESULTS: Gastrostomy feeding decreased RR-interval, while systolic blood pressure remained stable. Clonidine induced higher RR-intervals before and after gastrostomy feeding but decreased systolic blood pressure at baseline only. Gastrostomy feeding decreased HF-power of RR-interval significantly without clonidine, but only slightly after premedication. Clonidine increased the HF-power of RR-interval slightly at baseline and significantly after gastrostomy feeding. Gastrostomy feeding increased the LF/HF ratio without clonidine only. Clonidine decreased the LF/HF ratio at baseline and after gastrostomy feeding. Gastrostomy feeding did not change baroreflex sensitivity, but baroreflex sensitivity was higher at visit 2 than visit 1. CONCLUSIONS: In familial dysautonomia, clonidine augments baroreflex sensitivity and parasympathetic modulation. The resulting cardiovascular stabilization might attenuate feeding-induced crises
— id: 39055, year: 2003, vol: 33, page: 912, stat: Journal Article,

Impaired cardiovagal and vasomotor responses to baroreceptor stimulation in type II diabetes mellitus
Sanya, E O; Brown, C M; Dutsch, M; Zikeli, U; Neundorfer, B; Hilz, M J
2003 Jul;33(7):582-588, European journal of clinical investigation
BACKGROUND: In diabetic patients, impairment of the cardiovagal limb of the baroreflex has been well established. However, the role of sympathetic mediated baroreflex vasomotor control of the blood vessels is not well defined. We therefore assessed the vasomotor responses to sinusoidal baroreceptor stimulation in diabetic patients. MATERIALS AND METHODS: We studied 14 type II diabetic patients (age; 57 +/- 7 years) and 18 healthy controls (age; 59 +/- 11 years). Oscillatory neck suction was applied at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was paced at 0.25 Hz. Spectral analysis was used to evaluate the oscillatory responses of RR-interval and blood pressure. RESULTS: The diabetic patients showed a significantly lower RR-interval response (P < 0.05) to the 0.1 Hz neck suction (2.52 +/- 0.50-3.62 +/- 0.54 ln ms2) than the controls (4.23 +/- 0.31-6.74 +/- 0.36 ln ms2). The increase in power of 0.1 Hz systolic blood pressure oscillations during 0.1 Hz suction was also significantly smaller (P < 0.05) in the diabetics (1.17 +/- 0.44-1.69 +/- 0.44 mmHg2) than in the controls (1.60 +/- 0.29 mmHg2-5.87 +/- 1.25 mmHg2). The magnitude of the peak of the 0.2 Hz oscillation in the RR-interval in response to 0.2 Hz neck stimulation was significantly greater (P < 0.05) in the controls (3.42 +/- 0.46 ln ms2) than in the diabetics (1.58 +/- 0.44 ln ms2). CONCLUSION: In addition to cardiovagal dysfunction, baroreflex-mediated sympathetic modulation of the blood vessels is impaired in type II diabetic patients
— id: 36991, year: 2003, vol: 33, page: 582, stat: Journal Article,

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension
Singer, W; Opfer-Gehrking, T L; McPhee, B R; Hilz, M J; Bharucha, A E; Low, P A
2003 Sep;74(9):1294-1298, Journal of neurology neurosurgery & psychiatry
BACKGROUND: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. OBJECTIVE: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs. DESIGN: Prospective open label single dose trial. MATERIAL: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson's disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3). METHODS: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine. RESULTS: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms. CONCLUSIONS: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure
— id: 36986, year: 2003, vol: 74, page: 1294, stat: Journal Article,

Heart rate-dependent electrocardiogram abnormalities in patients with postural tachycardia syndrome
Singer, Wolfgang; Shen, Win K; Opfer-Gehrking, Tonette L; McPhee, Benjamin R; Hilz, Max J; Low, Phillip A
2003 Jan 31;103(1-2):106-113, Autonomic neuroscience
We recently published data suggesting the presence of an intrinsic sinus node abnormality in a subgroup of patients with the postural tachycardia syndrome (POTS). Based on the hypothesis that more widespread abnormalities of cardiac electrophysiologic properties may be present in POTS, we undertook a study to compare cardiac conduction and repolarization at different heart rate levels in patients with POTS and healthy controls. Eleven healthy controls and fourteen patients with POTS participated in the study. Acquisition of 12-lead electrocardiogram recordings were made during supine rest and during gradual head-up tilt. The heart rate of controls was titrated by isoproterenol infusion to match the heart rate of patients. Indices for cardiac conduction (PR interval, QRS duration, and R wave axis) and repolarization (QT interval, QTc interval, and T wave axis) were then compared at different heart rate levels. The PR interval decreased with increasing heart rate in controls more than in patients, resulting in a significantly longer PR interval in patients at the fastest heart rate level. The QT and QTc intervals were significantly shorter in POTS over the entire analyzed heart rate range. The T wave axis decreased with increasing heart rate in patients only. This resulted in a significantly lower T wave axis in patients at the fastest heart rate level. Our data suggest abnormalities of atrioventricular conduction and ventricular repolarization in patients with POTS. These findings may reflect intrinsic cardiac electrophysiologic abnormalities or may be secondary due to abnormalities of cardiac autonomic innervation
— id: 37002, year: 2003, vol: 103, page: 106, stat: Journal Article,

Terminal vessel hyperperfusion despite organ hypoperfusion in familial dysautonomia
Stemper, Brigitte; Axelrod, Felicia B; Marthol, Harald; Brown, Clive; Brys, Miroslav; Welsch, Goetz; Hilz, Max J
2003 Sep;105(3):295-301, Clinical science (London, 1979)
Patients with familial dysautonomia (FD) exhibit orthostatic hypotension as well as recumbent hypertension. In addition, during dysautonomic crises, patients have hypertensive blood pressure that is presumed to be secondary to episodic vasoconstriction, as well as swollen hands that are presumed to be secondary to vasodilatation. This discrepancy in vascular control is poorly understood, yet may provide insight into the pathophysiology of autonomic crises. To evaluate the pathological mechanisms of overall blood flow and end-organ perfusion, we assessed resting and post-ischaemic limb and skin blood flow in FD patients. In groups of 15 FD patients and 15 controls, we measured resting and post-ischaemic forearm blood flow using venous occlusion plethysmography, and superficial skin blood flow using laser Doppler flowmetry. At rest, arterial inflow was averaged from eight venous occlusion measurements and expressed as percentage volume change/min. Post-ischaemic plethysmographic inflow was determined from the peak influx during the first venous occlusion following 3 min of ischaemia. Transcutaneous forearm partial pressures of oxygen and carbon dioxide were monitored continuously. At rest, plethysmographic limb perfusion was lower in FD patients than in controls, while skin blood flow did not differ between the two groups. After ischaemia, hyperperfusion of the forearm and hand was less pronounced in FD patients than in controls, while skin blood flow was significantly higher in patients than in controls. Partial pressures of O(2) and CO(2) did not differ between the two groups. We conclude that the reduced overall limb perfusion in patients with FD is due to hypertension-induced structural changes to vessel walls, with an increase in resistance vessel rigidity. The exaggerated post-ischaemic skin perfusion in FD patients seems to be due to deficient sympathetic innervation of precapillary vessels and arteriovenous shunts and to denervation hypersensitivity of intradermal small nerve fibres. Both the reduced limb perfusion and the dysfunctional end-organ blood supply in FD patients are likely to be major contributors to the vasomotor instability observed in these subjects, particularly during periods of stress
— id: 36996, year: 2003, vol: 105, page: 295, stat: Journal Article,

Postischemic cutaneous hyperperfusion in the presence of forearm hypoperfusion suggests sympathetic vasomotor dysfunction in Fabry disease
Stemper, Brigitte; Hilz, Max J
2003 Aug;250(8):970-976, Journal of neurology
In Fabry disease, deficiency of alpha-galactosidase A induces glycolipid storage that accounts for neuropathy, renal failure, myocardial infarction and stroke. Vascular crises may be precipitated by stressful conditions. To evaluate pathomechanisms of overall organ versus microvessel perfusion in response to ischemic challenge, we assessed resting and postischemic forearm and skin blood flow in Fabry patients. In 14 Fabry patients and 15 healthy controls, we measured resting and postischemic forearm blood flow by means of venous occlusion plethysmography and superficial index finger skin blood flow using laser Doppler flowmetry. At rest, arterial inflow into the limb was averaged from eight venous occlusion measurements and expressed as % volume change/minute. Postischemic plethysmographic inflow was determined from the peak influx during the first venous occlusion following three minutes of ischemia. Transcutaneous oxygen and carbon dioxide partial pressures at the forearm were monitored continuously. At rest, plethysmographic forearm perfusion was 15% lower in patients than in controls (p < 0.05) while skin blood flow did not differ between patients and controls. After ischemia, forearm hyperperfusion was less pronounced in patients than in controls (p < 0.05), while skin perfusion almost doubled in patients but increased only slightly in controls. Transcutaneous oxygen and carbon dioxide pressures did not differ between both groups. We conclude that the reduced overall limb perfusion at rest and after ischemia is likely to be due to lipid deposition with increased rigidity, decreased distensibility and lowered diameter of the vasculature. The exaggerated skin perfusion after ischemia might be attributable to the small fiber neuropathy of Fabry patients with deficient vasoconstrictor tone and enhanced vasodilatation due to hypersensitivity of denervated intracutaneous nerve fibers towards ischemia
— id: 68234, year: 2003, vol: 250, page: 970, stat: Journal Article,

Changes of cerebral blood flow velocities during enhanced external counterpulsation
Werner, D; Marthol, H; Brown, C M; Daniel, W G; Hilz, M J
2003 Jun;107(6):405-411, Acta neurologica Scandinavica
OBJECTIVES: Intra-aortic counterpulsation is the most frequently used cardiac assist device. However, there are only few studies of the effects of counterpulsation on cerebral blood flow and these report conflicting outcomes. The new enhanced external counterpulsation (EECP) technique reproduces non-invasively the effects of intra-aortic counterpulsation. In this study, we evaluated effects of EECP on blood pressure (BP) and on cerebral flow velocity (CBFV). SUBJECTS AND METHODS: Twenty-three healthy controls and 15 atherosclerotic patients each underwent a 5-min session of EECP. Before, during and after EECP we monitored heart rate, beat-to-beat radial artery BP and CBFV. RESULTS: EECP induced a second increase in BP and CBFV during diastole with a significant increase of mean BP and a decrease of systolic BP in patients and controls. Mean CBFV increased in both groups during the first 5 s of EECP. After 3 min of EECP, diastolic CBFV was still higher than at baseline, but systolic CBVF was lower than at baseline; mean CBFV was as low as before EECP in the patients and lower than the baseline values in the controls. Three minutes after ending EECP, mean and systolic BP were lower in the patients than the corresponding baseline values. Otherwise, CBFV and BP values did not differ from baseline in patients and controls. CONCLUSION: Cerebral autoregulation ensures the constancy of cerebral blood flow even though EECP creates marked systemic changes. In the patients, the decrease of BP after EECP with maintained CBFV indicates an improved BPCBFV relation and a more economic autoregulation
— id: 36994, year: 2003, vol: 107, page: 405, stat: Journal Article,

Evaluation of nociceptive C-fiber function in diabetic peripheral neuropathy
Berghoff, M; Kilo, S; Hilz, MJ; Freeman, R
2002 ;58(7):A345-A345, Neurology
— id: 104746, year: 2002, vol: 58, page: A345, stat: Journal Article,

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation
Berghoff, Martin; Kathpal, Madeera; Kilo, Sonja; Hilz, Max J; Freeman, Roy
2002 Feb;92(2):780-788, Journal of applied physiology (Bethesda)
The relative contribution of endothelial vasodilating factors to acetylcholine (ACh)-mediated vasodilation in the forearm cutaneous microcirculation is unclear. The aims of this study were to investigate the contributions of prostanoids and cutaneous C fibers to basal cutaneous blood flow (CuBF) and ACh-mediated vasodilation. ACh was iontophoresed into the forearm, and cutaneous perfusion was measured by laser-Doppler flowmetry. To inhibit the production of prostanoids, four doses of acetylsalicylic acid (ASA; 81, 648, 972, and 1,944 mg) were administered orally. Cutaneous nerve fibers were blocked with topical anesthesia. Cyclooxygenase inhibition did not change basal CuBF or endothelium-mediated vasodilation to ACh. In contrast, ASA (972 and 1,944 mg) significantly reduced the C-fiber-mediated axon reflex in a dose-dependent fashion. Blockade of C-fiber function significantly reduced axon reflex-mediated vasodilation but did not affect basal CuBF or endothelium-dependent vasodilation. The findings suggest that prostanoids do not contribute significantly to basal CuBF or endothelium-dependent vasodilation in the forearm microcirculation. In contrast, prostanoids are mediators of the ACh-provoked axon reflex
— id: 37020, year: 2002, vol: 92, page: 780, stat: Journal Article,

Dermal microdialysis provides evidence for hypersensitivity to noradrenaline in patients with familial dysautonomia
Bickel, A; Axelrod, F B; Schmelz, M; Marthol, H; Hilz, M J
2002 Sep;73(3):299-302, Journal of neurology neurosurgery & psychiatry
OBJECTIVES: To use the technique of dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in patients with familial dysautonomia (FD) and in healthy controls. METHODS: In 14 patients with FD and 12 healthy controls, plasma extravasation, local laser Doppler blood flow, and skin blanching were observed before, during, and after application of 10(-6) M NA through a microdialysis membrane, located intradermally in the skin of the lower leg. RESULTS: Maximum local vasoconstriction measured by laser Doppler blood flow did not differ between patients with FD and controls. In contrast, patients with FD had an earlier onset of vasoconstriction (p = 0.02). Moreover, reaction to NA was more prominent and prolonged in FD, shown by a larger zone of skin blanching around the microdialysis membrane (p < 0.001) and delayed reduction of the protein content in the dialysate after termination of NA application (p = 0.03). CONCLUSION: These data support the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines. This may be one mechanism contributing to the major hypertension that frequently occurs during 'dysautonomic crises' in FD
— id: 37010, year: 2002, vol: 73, page: 299, stat: Journal Article,

Assessment of the neurogenic flare reaction in small-fiber neuropathies
Bickel, A; Kramer, H H; Hilz, M J; Birklein, F; Neundorfer, B; Schmelz, M
2002 Sep 24;59(6):917-919, Neurology
To improve sensitivity of the analysis of axon reflex flare reaction, the authors used a laser Doppler scanner and analyzed flare intensity and size induced by histamine iontophoresis simultaneously at the foot and thigh in patients with small-fiber neuropathy (n = 10) and controls (n = 9). Flare size, but not laser Doppler flux, clearly distinguished patients from controls at both locations (p < 0.01) and may be useful for evaluation of small-fiber neuropathies
— id: 37009, year: 2002, vol: 59, page: 917, stat: Journal Article,

Impaired cardiovascular responses to baroreflex stimulation in open-angle and normal-pressure glaucoma
Brown, Clive M; Dutsch, Matthias; Michelson, Georg; Neundorfer, Bernhard; Hilz, Max J
2002 Jun;102(6):623-630, Clinical science (London, 1979)
Autonomic neuropathy may contribute to the pathophysiology of both open-angle and normal-pressure glaucoma. However, autonomic function has not been studied extensively in these diseases. We evaluated baroreflex control of the heart and blood vessels in open-angle and normal-pressure glaucoma. We studied 14 patients with open-angle glaucoma, 15 with normal-pressure glaucoma and 17 controls. Sinusoidal neck suction (0 to -30 mmHg) was applied at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels, and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Baseline recordings showed no significant differences between the groups. The RR-interval response of the controls to neck suction at 0.1 Hz (3.88+/-0.32 to 6.65+/-0.44 lnms2) was significantly greater than that of the open-angle glaucoma patients (4.22+/-0.28 to 5.56+/-0.26 lnms2) and the normal-pressure glaucoma patients (4.53+/-0.27 to 5.53+/-0.37 lnms2) (P<0.05).The low-frequency power of diastolic blood pressure increased significantly in the controls (0.48+/-0.08 to 2.76+/-0.72 mmHg2; P<0.01) during 0.1 Hz neck suction, but did not change significantly in patients with either open-angle glaucoma or normal-pressure glaucoma. The RR-interval response in the control group (3.45+/-0.52 lnms2) to neck suction at 0.2 Hz was significantly greater than that of the normal-pressure glaucoma patients (1.84+/-0.32 lnms(2)) and the open-angle glaucoma patients (1.58+/-0.35 lnms2) (P<0.05). The decreased sympathetic and parasympathetic modulation during baroreceptor stimulation in patients with open-angle glaucoma and normal-pressure glaucoma suggests that autonomic dysfunction may contribute to the pathogenesis of both diseases
— id: 37015, year: 2002, vol: 102, page: 623, stat: Journal Article,

Pathophysiology and assessment of neuropathic pain in Fabry disease
Cleeland, CS; Hilz, MJ
2002 ;91(6):33-33, Acta paediatrica
— id: 104747, year: 2002, vol: 91, page: 33, stat: Journal Article,

Interictal cardiac autonomic dysfunction in temporal lobe epilepsy demonstrated by [I-123]metaiodobenzylguanidine-SPECT (vol 124, part 12, pg 2372, 2001)
Druschky, A; Hilz, MJ; Hopp, P; Platsch, G; Radespiel-Troger, M; Druschky, K; Kuwert, T; Stefan, H; Neundorfer, B
2002 ;125(6):219-219, Brain
— id: 104748, year: 2002, vol: 125, page: 219, stat: Journal Article,

Sympathetic and parasympathetic pupillary dysfunction in familial dysautonomia
Dutsch, M; Hilz, M J; Rauhut, U; Solomon, J; Neundorfer, B; Axelrod, F B
2002 Mar 15;195(1):77-83, Journal of the neurological sciences
Objective assessment of autonomic dysfunction in familial dysautonomia (FD) is largely based on the analysis of cardiovascular responses to challenge maneuvers such as orthostatic stress. Infrared pupillometry (IPM) provides an additional reliable method for cranial autonomic evaluation and has the advantage of requiring minimal cooperation.This study was performe to determine whether IPM contributes to the assessment of autonomic function in FD patients.In 14 FD patients and 14 healthy controls, we studied absolute and relative light reflex amplitude, pupillary constriction velocity (v(constr)), pupillary diameter, early and late pupillary re-dilatation velocity (v(dil 1), v(dil 2)) after dark adaptation. Prior to IPM, all patients had an ophthamological examination to evaluate refraction and corneal integrity.In comparison to controls, patients had a significant reduction of the parameters reflecting parasympathetic pupillary function (absolute light reflex amplitude 1.34plus minus0.21 vs. l.86plus minus0.14 mm, relative light reflex amplitude 22.74plus minus7.11% vs. 30.76plus minus3.57%, v(constr) 3.75plus minus1.09 vs. 5.80plus minus0.59 mm/s) and of the parameters reflecting sympathetic pupillary function (diameter 5.69plus minus0.66 vs. 6.35plus minus0.60 mm, v(dil 1) 1.29plus minus0.23 vs. 1.95plus minus0.23 mm/s, v(dil 2) 0.64plus minus0.13 vs. 0.72plus minus0.l2 mm/s; Mann--Whitney U-test: p<0.05).The non-invasive technique of IPM demonstrates dysfunction not only of the cranial parasympathetic, but also of the cranial sympathetic nervous system and, thus, further characterizes autonomic dysfunction in FD
— id: 25656, year: 2002, vol: 195, page: 77, stat: Journal Article,

Small fiber dysfunction predominates in Fabry neuropathy
Dutsch, M; Marthol, H; Stemper, B; Brys, M; Haendl, T; Hilz, M J
2002 Dec;19(6):575-586, Journal of clinical neurophysiology
Fabry disease is an X-linked recessive disease with a reduction of lysosomal alpha galactosidase A and consecutive storage of glycolipids e.g., in the brain, kidney, skin, and nerve fibers. Cardinal neurologic findings are hypohidrosis, painful episodes, and peripheral neuropathy. So far, the neurophysiological findings regarding the extent of large and small fiber dysfunction are contradictory. This study evaluated large and small nerve fiber function in a homogeneous group of Fabry patients. In 24 of 30 Fabry patients with creatinine below 194.7 mmol/L the authors assessed median, ulnar, and peroneal motor conduction velocity (MCV) and median, ulnar, and sural sensory conduction velocity (SCV) nerve conduction to study the function of thickly myelinated nerve fibers. In addition, the authors studied sympathetic skin responses (SSR) at both hands and feet in 24 patients. To evaluate A beta nerve fiber function, the authors determined vibratory detection thresholds (VDT) at the first toe in 30 patients. Function of A delta and C fibers was assessed by quantitative sensory testing of cold detection threshold (CDT) and heat-pain detection thresholds (HPDT). Nerve conduction studies showed significantly decreased amplitudes of MCVs and SCVs in Fabry patients as compared to controls. However, individual results of MCV and SCV studies were only mildly impaired. SSRs were present in all tested patients but SSR amplitudes were significantly decreased in Fabry patients in comparison to controls. VDT, CDT, and HPDT were significantly elevated in Fabry patients as compared to controls. However, only six patients had pathologic VDT, 19 had increased CDT, and 25 had elevated HPDT at a high level of stimulation. In Fabry patients, small fiber dysfunction is more prominent than large fiber dysfunction, confirming previous findings of sural nerve biopsies. The results suggest a higher vulnerability of small-diameter nerve fibers than of the thickly myelinated fibers
— id: 37005, year: 2002, vol: 19, page: 575, stat: Journal Article,

Hyperintense and hypointense MRI signals of the precentral gyrus and corticospinal tract in ALS: a follow-up examination including FLAIR images
Hecht, Martin J; Fellner, F; Fellner, C; Hilz, M J; Neundorfer, B; Heuss, D
2002 Jul 15;199(1-2):59-65, Journal of the neurological sciences
In amyotrophic lateral sclerosis (ALS) patients, hyperintense signals at the subcortical precentral gyrus in brain fluid attenuated inversion recovery (FLAIR) MR images have been found more frequently than in controls. Quantitative analysis has revealed a significant increase of the FLAIR-magnetic resonance imaging (MRI) signal at the subcortical precentral gyrus of ALS patients compared to healthy controls. In addition, hypointense signals at the rim of the precentral gyrus in FLAIR and T2-weighted images have been shown in ALS patients. In 17 ALS patients, we evaluated hyperintense signals in T2-, T1-, proton density-weighted and FLAIR MR images, and hypointense signals in T2-weighted and FLAIR images 15.7+/-3.0 months after the initial examination by visual scoring. In FLAIR images, a quantitative analysis was added. The visual scores of hyperintense signals along the corticospinal tract did not change significantly in all sequences. However, the quantitative evaluation of FLAIR images revealed a significant increase of the signal intensity at the subcortical precentral gyrus (p<0.005). In addition, the frequency of the visually evaluated hypointense signals at the precentral gyrus increased significantly (p<0.05). The change of MR results did not correlate with the change of clinical parameters. In ALS patients, the increase of the quantified MRI signal at the subcortical precentral gyrus in FLAIR images and the increase of hypointense signals at the rim of the precentral gyrus corroborate the hypothesis that these signals are related to the upper motor neuron degeneration in ALS. Their specificity and clinical relevance have to be clarified further
— id: 37013, year: 2002, vol: 199, page: 59, stat: Journal Article,

Subjective experience and coping in ALS
Hecht, Martin; Hillemacher, Thomas; Grasel, Elmar; Tigges, Sebastian; Winterholler, Martin; Heuss, Dieter; Hilz, Max-Josef; Neundorfer, Bernhard
2002 Dec;3(4):225-231, Amyotrophic lateral sclerosis & other motor neuron disorders
OBJECTIVE: Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease which has no known cure and limited symptomatic treatment. While coping strategies in more common diseases are widely assessed, coping is poorly understood in ALS. METHODS: We examined 41 ALS patients using a standardised interview, a validated coping self-rating questionnaire and a self-rating depression scale. The evaluation was repeated after six months. RESULTS: 'Loss of speech', 'loss of mobility' and 'the poor prognosis' were the most frequent answers in the standardised interview to questions regarding the worst aspect of the disease. Pain was seldom mentioned. 'Family members' were most helpful in coping with the disease, followed by 'unspecific mechanisms' and 'technical aids'. None of our patients expressed a wish for assisted suicide. In comparison with other fatal diseases, patients with ALS had similar rankings in the coping mechanism of 'rumination', but lower rankings in 'search for social integration', 'defence of fear', 'search for information and communication'. In contrast,* 'search for hold in the religion' was of high importance for our ALS patients. In the follow-up examination the importance of 'search for information and communication' increased. CONCLUSION: The results emphasise the importance of 'loss of speech' and the importance of the caring family as well as the availability of technical aids in ALS. Coping in ALS seems to be based mainly on 'rumination' and *'hold in the religion', but the increasing importance of 'search for information' indicates that the sustained offer of information is essential
— id: 36997, year: 2002, vol: 3, page: 225, stat: Journal Article,

Evaluation of peripheral and autonomic nerve function in Fabry disease
Hilz, M J
2002 ;91(439):38-42, Acta paediatrica. Supplement
The neurological manifestations of Fabry disease include severe episodes of lancinating pain and burning paraesthesias in the extremities, often triggered by changes in temperature. The preferential involvement of small nerve fibres and the accumulation of storage product in the central autonomic nervous system and autonomic ganglia means that standard neurophysiological procedures cannot adequately evaluate the peripheral and autonomic nervous systems of affected patients. This paper describes the various methods that have been developed to assess impairment of temperature perception, vibratory perception, sudomotor and sweat gland function, and limb and superficial skin blood flow and vasoreactivity. These methods, including thermal provocation tests, quantitative sudomotor axon reflex testing and venous occlussion plethsmography, have been used effectively in patients with Fabry disease to measure the extent of neurological dysfunction. CONCLUSIONS: Effective methods for measuring neurological involvement in patients with Fabry disease have been developed. These methods will be valuable in assessing the response of patients to enzyme replacement therapy
— id: 36999, year: 2002, vol: 91, page: 38, stat: Journal Article,

[Erectile dysfunction. An important manifestation of autonomic diabetic neuropathy]
Hilz, M J
2002 Nov 21;144(47):41-44, MMW Fortschritte der Medizin
In Germany, some 4-6 million men, including 1.2 million diabetics, suffer from erectile dysfunction (ED). Various other diseases including heart disease, hypertension, arteriosclerosis, hyperlipidemia, endocrine disorders, chronic renal insufficiency, prior radical prostatectomy, neurological diseases, trauma and the abuse of alcohol, tobacco, and side effects of medications, are frequently associated with ED. Medical history, clinical examination, routine blood chemistry and sexual hormone levels may help clarify the etiology of ED. Normally, relaxation of the smooth muscles of the corpus cavernosum--mediated by cGMP and cAMP--together with dilatation of penile arteries and occlusion of venous outflow, results in an erection. The oral type V phosphodiesterase inhibitor, Sildenafil, or prostaglandin E1 injection elevates the cGMP and cAMP levels, respectively. Other therapeutic options include mechanical aids, surgery, hormone replacement or sublingual apomorphine. Since 1998, Sildenafil, an effective, simple and safe oral treatment, has been available
— id: 37001, year: 2002, vol: 144, page: 41, stat: Journal Article,

Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia
Hilz, M J; Axelrod, F B; Braeske, K; Stemper, B
2002 Apr 15;196(1-2):81-89, Journal of the neurological sciences
In familial dysautonomia (FD), i.e. Riley-Day-syndrome, sympathetic cardiovascular function, as well as afferent temperature and pain mediating neurons, are significantly reduced. Thus, it was questioned if cold pressor test (CPT), which normally enhances sympathetic outflow and induces peripheral vasoconstriction by the activation of thermo- and nociceptive system activation, could be used to assess sympathetic function in FD.To evaluate whether CPT can be used to assess sympathetic activation in FD, we performed CPT in 15 FD patients and 18 controls. After a 35-min resting period, participants immersed their right hand and arm up to the elbow into 0-1 degrees C cold water while we monitored heart rate (HR), respiration, beat-to-beat radial artery blood pressure (BP), and laser Doppler skin blood flow (SBF) at the right index finger pulp. From these measurements, heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low and high frequency (LF, HF) power spectra of the electrocardiogram (ECG).All participants perceived cold stimulation and indicated discomfort. In controls, SBF decreased and HR and BP increased rapidly upon CPT. After 60 s, SBF indicated secondary vasodilatation in six controls, BP rise attenuated and HR returned to baseline in all controls. In the patients, SBF remained unchanged, HR and BP increased significantly, but after 50-60 s of CPT and changes were lower than in controls (p<0.05). RMSSD and CV decreased and LF increased significantly only in the controls.We conclude that CPT activates sympathetic HR and BP modulation despite impaired pain and temperature perception in FD patients. BP increase in the presence of almost unchanged SBF might be due to HR increase and to nociceptive arousal and emotionally induced catecholamine release as seen in emotional crises of FD patients. CPT assesses sympathetic cardiovascular responses independently from baroreflex function, which is compromised in FD
— id: 37017, year: 2002, vol: 196, page: 81, stat: Journal Article,

Transcranial Doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia
Hilz, M J; Axelrod, F B; Haertl, U; Brown, C M; Stemper, B
2002 May;72(5):657-660, Journal of neurology neurosurgery & psychiatry
OBJECTIVE: Cerebral autoregulation was assessed by transcranial Doppler sonography in 10 patients with familial dysautonomia and 10 age matched controls. METHODS: Blood pressure, heart rate, and middle cerebral artery blood flow velocity (CBFV) were simultaneously recorded when supine and during 180 seconds of head up tilt. Cerebrovascular resistance (CVR) was calculated from CBFV and mean blood pressure was adjusted to brain level. RESULTS: In the controls, mean blood pressure remained stable during tilt, but heart rate increased significantly. In the patients with familial dysautonomia, mean (SD) blood pressure decreased by 15.0 (10.8)% (p < 0.05). Heart rate remained unchanged. In controls, systolic and mean CBFV decreased by 9.1 (4.7)% and 9.4 (7.0)%, respectively, while diastolic CBFV remained stable. In the patients, diastolic and mean CBFV decreased continuously by 32.1 (13.9)% and by 14.8 (31.4)%. Supine CVR was 28% higher in patients than in controls and decreased significantly less during head up tilt. CONCLUSIONS: Tilt evokes orthostatic hypotension without compensatory tachycardia in patients with familial dysautonomia owing to decreased peripheral sympathetic innervation. High supine CVR values and relatively preserved CVR during tilt suggest preserved central sympathetic activation in familial dysautonomia, assuring adaptation of cerebrovascular autoregulation to chronic supine hypertension and orthostatic hypotension
— id: 37016, year: 2002, vol: 72, page: 657, stat: Journal Article,

Valsalva maneuver suggests increased rigidity of cerebral resistance vessels in familial dysautonomia
Hilz, M J; Axelrod, F B; Steingrueber, M; Stemper, B
2002 Oct;12(5):385-392, Clinical autonomic research
In familial dysautonomia (FD), cerebral autoregulation (CA) must adjust cerebral blood flow to extreme and rapid fluctuations in systemic blood pressure. Compromised CA during systemic blood pressure (BP) fluctuations might contribute to central autonomic dysfunction in FD.To evaluate CA during rapid BP changes, we monitored heart rate (HR), radial artery BP and middle cerebral artery blood flow velocity (CBFV), using transcranial Doppler sonography, in eight FD patients and twelve age-matched controls in supine position at baseline and during a Valsalva maneuver (VM, 40 mmHg expiratory pressure for 15 seconds). The best of four VM recordings was analyzed. We calculated two autoregulation parameters. CA(II) reflects BP related autoregulatory CBFV increase in late phase II of VM. CA(II) = [(CBFV(II late)-CBFV(II early))/CBFV(II early)]/[(BP(II late)-BP(II early))/BP(II early)]. CA(IV) reflects BP and HR related autoregulatory CBFV increase in phase IV of VM. CA(IV) = (CBFV(IV)/CBFV(I))/(BP(IV)/BP(I))/(HR(IV)/HR(I)). Baseline systemic BP, but not CBFV, was higher in the patients than the controls. During VM, both groups had similar CBFV and BP values, but CAIV and especially CA(II) were significantly lower in the patients than the controls. We have documented that FD patients maintain stable CBFV during rapid BP fluctuations associated with early and late phase II and phase IV of VM suggesting that small intracerebral vessels of FD patients are less responsive to rapid systemic blood pressure fluctuations. To compensate for decreased sympathetic vascular innervation, we propose that FD patients may alter the myogenic component of CA by vessel wall thickening resulting in increased rigidity of intracerebral resistance vessels. The resulting vasoconstriction would allow maintenance of normal baseline CBFV in spite of chronic recumbent hypertension
— id: 37007, year: 2002, vol: 12, page: 385, stat: Journal Article,

Decrease of sympathetic cardiovascular modulation after temporal lobe epilepsy surgery
Hilz, M J; Devinsky, O; Doyle, W; Mauerer, A; Dutsch, M
2002 May;125(Pt 5):985-995, Brain
In temporal lobe epilepsy (TLE), there is evidence of ictal and interictal autonomic dysregulation, predominantly with sympathetic overactivity. The effects of TLE surgery on autonomic cardiovascular control and on baroreflex sensitivity (BRS) have not been studied. To evaluate such effects, we monitored heart rate (HR), systolic blood pressure (BP(sys)) and respiration in 18 TLE patients 3-4 months before and after TLE surgery. We used Blackman-Tukey spectral analysis to assess sympathetic and parasympathetic modulation as powers of HR and BP(sys) oscillations in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.5 Hz) bands. BRS was determined as the LF transfer function gain between BP and HR. After surgery, HR, BP(sys), respiration and HF powers remained unchanged, while LF powers of HR (1.57 +/- 1.54 bpm(2)) and BP(sys) (2.19 +/- 1.34 mmHg(2)) and BRS (0.68 +/- 0.31 bpm/mmHg) were smaller than pre-surgical LF powers of HR (3.87 +/- 3.26 bpm(2)) and BP(sys) (4.80 +/- 3.84 mmHg(2)) and BRS (1.12 +/- 0.39 bpm/mmHg; P < 0.05). After TLE surgery, there is a reduction of sympathetic cardiovascular modulation and BRS that might result from decreased influences of interictal epileptogenic discharges on brain areas involved in cardiovascular autonomic control. TLE surgery seems to stabilize the cardiovascular control in epilepsy patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive bradycardiac counter-regulation, both of which might be relevant for the pathophysiology of sudden unexpected death in epilepsy patients (SUDEP). Thus, TLE surgery might contribute to reducing the risk of SUDEP
— id: 34409, year: 2002, vol: 125, page: 985, stat: Journal Article,

[Syncope - a systematic overview of classification, pathogenesis, diagnosis and management]
Hilz, M J; Marthol, H; Neundorfer, B
2002 Feb;70(2):95-107, Fortschritte der neurologie-psychiatrie
Syncope is defined as a temporary interruption of cerebral perfusion with a sudden and transient loss of consciousness and spontaneous recovery. Approximately one third of the population experiences syncope at least once during a lifetime.Presyncopal signs and symptoms, including weakness, headache, blurred vision, diaphoresis, nausea, and vomiting are sometimes present for seconds or minutes prior to loss of consciousness. After syncope, the patients may present with persisting drowsiness, headache, dizziness, nausea, but not usually confusion.Causes of syncope have been categorized as cardiovascular, non-cardiovascular, and unexplained. Cardiovascular causes can be subdivided into structural heart disease, coronary heart disease, and arrhythmia. Non-cardiovascular causes include neurological, metabolic, psychiatric and other disorders.Orthostatic hypotension - one of the most frequent causes of syncope - has manifold etiologies comprising various neurological and internal diseases. Orthostatic hypotension usually can be attributed to an impairment of peripheral vasoconstriction or to a reduction of the intravascular volume. Signs and symptoms, including the above prodromi are often present just after rising from a supine or sitting position. Frequently, blood pressure decreases significantly without an increase in heart rate. Autonomic cardiovascular modulation is often reduced.Many of the patients with 'unexplained' syncope experience neurally mediated (i. e. neurocardiogenic or vasovagal) syncope. In these patients, cardiovascular control may be stable for an extended period of time during orthostatic stress, then there is a sudden decrease in blood pressure and heart rate. Neurocardiogenic or neurally mediated syncope can be associated with painful or emotionally stressful situations such as anxiety or fear, with prolonged standing or specific trigger situations such as micturition, defecation, coughing or sneezing, visceral or carotid sinus stimulation, or with trigeminal or glossopharyngeal neuralgia. So far, the mechanisms of neurocardiogenic syncope are not completely understood.The passive 60 degrees to 70 degrees head-up tilt test is useful for the diagnosis of orthostatic and neurally mediated syncope. The sensitivity of the test can be improved by additional pharmacological provocation, e. g. by isoproterenol, or by increased orthostatic stress using lower body negative pressure stimulation.For the treatment of syncope one should first consider non-pharmacological options. Patients with orthostatic hypotension should avoid rapid changes of the body position from supine to standing, as well as high room temperature or other situations inducing peripheral vasodilatation. An increased intake of sodium and fluids, mild physical exercise or so-called postural counter-maneuvers can improve orthostatic tolerance.Among the drugs recommended for pharmacologic treatment are mineralocorticoids (e. g. fludrocortisone), vasoconstrictor agents (e. g. ephedrine, midodrine), adenosine receptor blockers (theophylline) and beta2-blockers (propanolol), anticholinergic agents, e. g. scopolamine or disopyramide, and negative cardiac inotropes, e. g. beta1-adrenergic blockers or disopyramide. Serotonin reuptake inhibitors (e. g. fluoxetine, sertraline), alpha2-adrenergic agonists (clonidine), central nervous system stimulants such as methylphenidate or phentermine are thought to be beneficial in specific cases. Cardiac pacemakers often seem to be recommended without adequate indication.The antidiuretic, V2-receptor specific, vasopressin analogue desmopressin increases the intravascular volume. Erythropoietin improves anemia and red blood cell decrease and augments blood pressure and cerebral oxygenation. In postprandial hypotension, octreotide, a somatostatin analogue, prostaglandin inhibitors such as indomethacin or ibuprofen, as well as metoclopramide or two cups of coffee per day might be beneficial
— id: 37019, year: 2002, vol: 70, page: 95, stat: Journal Article,

Assessment and evaluation of hereditary sensory and autonomic neuropathies with autonomic and neurophysiological examinations
Hilz, Max J
2002 May;12 Suppl 1(3):I33-I43, Clinical autonomic research
The five different types of the rare hereditary sensory and autonomic neuropathies (HSAN) are classified by their mode of inheritance, pathology, natural history, biochemical, neurophysiologic and autonomic abnormalities. Clinically, the different types of HSANs can be identified by a detailed history and examination and 'bedside' tests of sympathetic or parasympathetic function such as active standing, metronomic breathing or the Valsalva maneuver, sensory and motor nerve conduction studies, quantitative sensory testing of thermal and vibratory perception, and the analysis of sudomotor function by recordings of the sympathetic skin response (SSR) or the sweat output during quantitative sudomotor axon reflex testing (QSART). The slowly progressive, symmetrical HSAN type I manifests between the second and fourth decade with ulcers or mutilations of the lower extremities, low normal sensory and motor nerve conduction velocities, but abnormal warm, cold and heat pain perception and distal anhidrosis. In HSAN type II, symptoms occur already in infancy, trophic alterations affect fingers and toes. There are acral anhidrosis and various autonomic dysfunctions such as tonic pupils, eating and swallowing difficulties, constipation, episodic fever, profound hypotonia and episodes of apnea. Sensory perception is severely impaired and accounts for elevated vibratory but also thermal perception thresholds. Sensory nerve conduction is highly abnormal while motor nerve conduction studies are almost normal. Type III, the autosomal recessive familial dysautonomia (FD), is the most common of the HSANs. FD is characterized by pronounced autonomic, primarily sympathetic dysregulation with severe orthostatic hypotension, repeated episodes of autonomic crises with excessive arterial hypertension, profuse sweating, skin blotching, puffy hands and behavioral abnormalities. FD manifests only in children of Ashkenazi Jewish ancestry. Cardinal findings are diminished deep tendon reflexes, absence of overflow tears, absence of fungi-form papillae of the tongue and of axon flare response following intradermal histamine injection. Thermal and vibratory testing show pronounced impairment of temperature and pain but also of vibratory perception. Children with HSAN IV, 'congenital insensitivity to pain with anhidrosis' experience repeated episodes of high fevers during high environmental temperature due to anhidrosis. The anhidrosis of the hyperkeratotic skin accounts for absence of the SSR or lack of sweat output during QSART. The patients' insensitivity to superficial as well as deep, visceral pain can be demonstrated e. g. by quantitative heat pain testing. Patients develop severe mutilations e. g. of the tip of their tongue, they might have severe burn injuries and multiple, unnoticed fractures with neuropathic joints. Children with the very rare HSAN type V respond normally to tactile, vibratory or thermal stimuli, but have a selective loss of pain perception with otherwise normal neurological examination. Painful stimuli reveal no signs of discomfort
— id: 37011, year: 2002, vol: 12 Suppl 1, page: I33, stat: Journal Article,

Baroreflex stimulation shows impaired cardiovagal and preserved vasomotor function in early-stage amyotrophic lateral sclerosis
Hilz, Max J; Hecht, Martin J; Mittelhamm, Felix; Neundorfer, Bernhard; Brown, Clive M
2002 Sep;3(3):137-144, Amyotrophic lateral sclerosis & other motor neuron disorders
OBJECT: In ALS patients, autonomic nervous system dysfunction might account for an additional reduction of the quality and expectancy of life of individual patients and contribute to unexpected early fatalities. This study was undertaken to assess baroreflex-mediated vagal and sympathetic cardiovascular control of the heart and blood vessels in ALS patients. METHODS: In 12 early-stage ALS patients (age 54 +/- 4 years) and 12 controls (age 55 +/- 3 years) we assessed resting baroreflex sensitivity (BRS) by spectral analysis, then stimulated the carotid baroreflex by oscillating neck suction at 0.1 Hz to assess the autonomic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. RESULTS: Resting heart rate was significantly higher in the ALS patients than in the controls (P < 0.05), but resting baroreflex sensitivity did not differ significantly between the groups. Stimulation at 0.2 Hz induced an oscillation in R-R interval that was significantly smaller (P < 0.05) in ALS patients than in controls. R-R interval responses to 0.1 Hz stimulation were significantly (P < 0.01) reduced in ALS patients compared to controls. Responses of blood vessels to 0.1 Hz stimulation did not differ significantly between the groups. CONCLUSION: In early-stage ALS patients, BRS might be normal at rest. Only baroreflex activation reveals impaired cardiovagal responses while sympathetic vasomotor control is preserved. Treatment to restore sympathetic-parasympathetic balance to the heart could prevent early cardiovascular fatalities in some ALS patients
— id: 37003, year: 2002, vol: 3, page: 137, stat: Journal Article,

Enzyme replacement therapy improves cardiovascular control in Fabry patients during orthostatic stress
Hilz, MJ; Brys, MM; Haendl, T; Welsch, G; Franta, R; Stemper, B
2002 ;71(4):2413-2413, American journal of human genetics
— id: 104749, year: 2002, vol: 71, page: 2413, stat: Journal Article,

Stability of autonomic cardiovascular modulation and baroreflex function during Sildenafil use and physical challenge
Hilz, MJ; Stemper, B; Brys, M; Marthol, H; Franta, R; Axelrod, FB
2002 ;58(7):A348-A349, Neurology
— id: 104750, year: 2002, vol: 58, page: A348, stat: Journal Article,

Sex differences and lateral asymmetry in heart rate modulation in patients with temporal lobe epilepsy
Kirchner, A; Pauli, E; Hilz, M J; Neundorfer, B; Stefan, H
2002 Jul;73(1):73-75, Journal of neurology neurosurgery & psychiatry
This study was designed to study the influence of gender and lateral hemispheric asymmetry on heart rate modulation during temporal lobe seizures. Heart rate was recorded during complex partial seizures in 10 female and 11 male patients (12 with a right temporal lobe focus, nine with a left focus), with simultaneous video monitoring and bilateral subdural electrode placement. Heart rate changes were analysed during the seizure, at a time when the epileptic activity was restricted to one hemisphere. In this analysed interval, the heart rate of patients with a right temporal lobe focus showed a significant increase, from 73.5 to 91.0 beats/min (F = 10.7, df = 2.3/27, p < 0.001), while the heart rate of patients with a left sided focus only increased slightly, from 77.0 to 82.5 beats/min (NS). An effect of sex was demonstrated, in that the influence of focus laterality could only be shown in male patients (F = 14.24, df = 2.58/27, p < 0.001). These results confirm the right hemispheric lateralisation of sympathetic cardiac control in male patients
— id: 37014, year: 2002, vol: 73, page: 73, stat: Journal Article,

Reversible prolongation of motor conduction time after transcranial magnetic brain stimulation after neurogenic claudication in spinal stenosis
Lang, Eberhard; Hilz, Max Josef; Erxleben, Harald; Ernst, Mirko; Neundorfer, Bernhard; Liebig, Klaus
2002 Oct 15;27(20):2284-2290, Spine
STUDY DESIGN: A consecutive and controlled cohort study. OBJECTIVES: To assess the value of motor conduction time (MCT) between cortex and symptomatic leg muscles after transcranial magnetic brain stimulation as an indicator of reversible root ischemia in patients with neurogenic claudication in spinal stenosis. SUMMARY OF BACKGROUND DATA: Neurogenic claudication in spinal stenosis is thought to result from transient ischemia of active nerve root fibers. Subgroups of these patients have slowing of sensory or motor nerve root conduction during spinal claudication. MATERIAL AND METHODS: Forty-two patients with spinal claudication and radiologically confirmed signs of spinal stenosis were consecutively recruited. Motor conduction time was measured before and repetitively after challenge of walking on a treadmill (four stimuli per minute) until disappearance of the symptoms. Data of 30 patients (65 +/- 10 years) with a defined onset of motor-evoked potentials were compared with those of 12 control subjects (62 +/- 12 years). RESULTS: One minute after treadmill challenge, MCT increased in all 13 patients with signs of an exercise-dependent neurologic deficit by at least 1 msec (mean increase, 1.6 +/- 0.6 msec; < 0.001). Test-retest comparisons in six of these patients revealed good reproducibility of the MCT increase (coefficient of repeatability, 1.24 msec). In contrast, MCTs were unchanged or decreased in all 17 patients without exercise-dependent neurologic deficit ( < 0.01) and in the control subjects ( < 0.05). CONCLUSIONS: Measurements of MCT before and after treadmill challenge can demonstrate reversible root ischemia in patients with spinal claudication and exercise-dependent deficit of thickly myelinated nerve root fibers
— id: 37008, year: 2002, vol: 27, page: 2284, stat: Journal Article,

Transfer function analysis shows intact cerebral autoregulation in atherosclerotic patients during enhanced external counterpulsation
Marthol, HU; Werner, D; Brown, CM; Neundorfer, B; Daniel, WG; Hilz, MJ
2002 ;52(3):S53-S53, Annals of neurology
— id: 104751, year: 2002, vol: 52, page: S53, stat: Journal Article,

Evidence of an intrinsic sinus node abnormality in patients with postural tachycardia syndrome
Singer, Wolfgang; Shen, Win-Kuang; Opfer-Gehrking, Tonette L; McPhee, Benjamin R; Hilz, Max J; Low, Phillip A
2002 Mar;77(3):246-252, Mayo Clinic proceedings
OBJECTIVE: To determine whether an intrinsic sinus node abnormality is involved in the pathophysiology of the postural tachycardia syndrome (POTS). SUBJECTS, PATIENTS, AND METHODS: In this prospective study, we compared the relationship between P-wave axis (PWA) and heart rate (HR) in 11 healthy controls and 14 patients with POTS by obtaining 12-lead electrocardiographic recordings during supine rest and during gradual head-up tilt. The HR of controls was titrated with isoproterenol infusion to match the HR of patients. The PWA was compared at different HR levels, and the relationship between HR and PWA was assessed for patients and controls. Primary end points were the PWA-HR relationship in healthy controls, comparison of these data with data from patients with POTS as a group, and identification of a possible subgroup of patients with POTS with irregular PWA-HR relationship. RESULTS: The PWA increased with increasing HR following a similar logarithmic trendline in both groups. The PWA of patients was significantly lower at the lowest comparable HR level but not different at faster HR levels. Three patients (21%) had a clearly abnormal HR-PWA relationship with substantial shift toward lower PWA. CONCLUSIONS: Our data support the hypothesis of a primary sinus node abnormality in a subset of patients with POTS. The ability to identify patients with primary sinus node abnormality may have important therapeutic implications
— id: 37018, year: 2002, vol: 77, page: 246, stat: Journal Article,

Mononeuritis multiplex caused by Coxiella burnetii infection (Q fever)
Sommer, J B; Schoerner, C; Heckmann, J G; Neundoerfer, B; Hilz, M J
2002 Dec;106(6):371-373, Acta neurologica Scandinavica
After 1 week of flu-like illness, a 64-year-old man developed rapidly progressive mononeuritis multiplex involving the right arm and both legs. Serologic studies identified Coxiella burnetii as the cause of the febrile disease (Q fever). Fourteen days doxycycline treatment (200 mg daily) induced rapid and complete recovery. After 6 months, flu-like symptoms, weakness and hypalgesia of the right leg reappeared. Antibody titers again identified Q fever. Doxycycline was re-established and induced prompt recovery. Q fever has been associated with various neurologic complications such as meningoencephalitis, cerebellitis, optic neuritis or polyneuroradiculitis. This is the first report on Q fever related mononeuritis multiplex. Prolonged antibiotic treatment may be required to prevent relapsing infection from the resistant bacterium
— id: 37006, year: 2002, vol: 106, page: 371, stat: Journal Article,

Evaluation of cold face test bradycardia by means of spectral analysis
Stemper, B; Hilz, M J; Rauhut, U; Neundorfer, B
2002 Apr;12(2):78-83, Clinical autonomic research
The cold face test (CFT) is a non-invasive challenge maneuver of the autonomic nervous system which activates the peripheral sympathetic and the cardiac parasympathetic nervous system and induces peripheral vasoconstriction and bradycardia. The physiology of CFT-induced bradycardia is still controversial. The heart rate decrease might result from a direct central up-regulation of cardiovagal activity or might be a secondary effect of baroreceptor activation or of changes of respiration. The purpose of this study was to analyze the origin of CFT-induced bradycardia. To evaluate the influence of respiration on bradycardia during CFT, we studied cardiac responses in 10 healthy volunteers during CFT (0-1 degrees C cold compresses for 60 s) with three different respiratory patterns: one with spontaneous and two with paced respiration (6 and 15 cycles/minute). We continuously monitored heart rate (HR), blood pressure (BP) and respiration and determined heart rate variability by assessment of coefficient of variation (CV), standard deviation (SD) and the root mean square of successive differences (RMSSD) of HR as well as low (LF) and high (HF) frequency spectra power of HR and BP. When coherence was above 0.5, we calculated the transfer function gain between HR and respiration in the HF band, as an index of respiratory sinus arrhythmia, and between HR and BP in the LF band, as an index of baroreflex sensitivity. HR decreased and BP increased significantly during the three types of CFT. The decrease of HR and the increase of BP, of time and frequency domain parameters did not differ between the three breathing patterns. Respiration, and HF and LF power of respiration did not change during CFT. The gain of the HF-transfer function between HR and respiration and the LF-transfer function gain between HR and BP increased significantly during CFT, but the increase did not differ between the three breathing patterns. The increase of the gain of both transfer functions is most likely due to an increase of vagal traffic and together with the unchanged respiratory pattern suggests that CFT-induced bradycardia is not due to baroreflex or respiratory influences, but seems to result from central vagal activation
— id: 37012, year: 2002, vol: 12, page: 78, stat: Journal Article,

Multifocal motor neuropathy - state of diagnosis and therapy
Bickel, A; Neundorfer, B; Hecht, MJ; Hilz, MJ
2001 ;20(9):491-498, Nervenheilkunde
In the lost years, the multifocal motor neuropathy (MMN) has been characterized as an immunomediated neuropathy. Clinically MMN might be misdiagnosed as amyotrophic lateral sclerosis (ALS). The differential diagnosis, however, is important, as there is an effective therapy available for MMN-in contrast to ALS. The differentiation depends on the demonstration of characteristic focal conduction blocks in motor nerves in MMN. Other electrophysiological measurements such as peripheral nerve conduction studies and electromyography ore less useful. Another typical finding in MMN are high titers of specific anti-GM1-antibodies in the serum. This report summarizes diagnostic and differential diagnostic criteria and therapeutical options of MMN. $$:
— id: 104752, year: 2001, vol: 20, page: 491, stat: Journal Article,

Critical illness polyneuropathy: clinical findings and cell culture assay of neurotoxicity assessed by a prospective study
Druschky A; Herkert M; Radespiel-Troger M; Druschky K; Hund E; Becker CM; Hilz MJ; Erbguth F; Neundorfer B
2001 Apr;27(4):686-693, Intensive care medicine
OBJECTIVE: First, to evaluate the role of typical intensive care-related conditions like sepsis, prolonged ventilation, drug effects and metabolic disorders in the pathogenesis of critical illness polyneuropathy (CIP); second, to investigate the possible significance of patient serum neurotoxicity assessed by an in vitro cytotoxicity assay with respect to CIP development. DESIGN: Prospective study. SETTING: Neurological intensive care unit. PATIENTS AND PARTICIPANTS: Twenty-eight patients who were on mechanical respiratory support for at least 4 days during a 21-month study period. RESULTS: Diagnosis of CIP was established by clinical and electrophysiological examination in 16 (57%) of 28 patients. Patients were investigated on days 4, 8 and 14 of mechanical ventilation. Two of 16 CIP patients had clinical signs of polyneuropathy at initial examination. Factors that correlated significantly with the development of CIP were: the multiple organ failure score on day 8 of ventilation, the total duration of respiratory support, the presence of weaning problems and the manifestation of complicating sepsis and/or lung failure. The in vitro toxicity assay showed serum neurotoxicity in 12 of 16 CIP patients. Electrophysiological investigations yielded false positive results of the toxicity assay in six patients (not developing CIP) and false negative results in four patients (developing clinical and electrophysiological signs of CIP). Statistical analysis did not reveal a significant correlation between the diagnosis of CIP and the finding serum neurotoxicity. CONCLUSION: The results support the hypothesis of a multi-factorial aetiopathogenesis of CIP. We observed serum neurotoxicity in the majority of CIP patients, indicating the possible involvement of a so far unknown, low-molecular-weight neurotoxic agent in CIP pathogenesis
— id: 37026, year: 2001, vol: 27, page: 686, stat: Journal Article,

Interictal cardiac autonomic dysfunction in temporal lobe epilepsy demonstrated by [(123)I]metaiodobenzylguanidine-SPECT
Druschky A; Hilz MJ; Hopp P; Platsch G; Radespiel-Troger M; Druschky K; Kuwert T; Stefan H; Neundorfer B
2001 Dec;124(Pt 12):2372-2382, Brain
We studied the post-ganglionic cardiac sympathetic innervation in patients with chronic temporal lobe epilepsy (TLE) by means of [(123)I]metaiodobenzylguanidine-single photon computed tomography (MIBG-SPECT) and evaluated the effects of carbamazepine on cardiac sympathetic innervation. TLE is frequently associated with dysfunction of the autonomic nervous system. Autonomic dysregulation might contribute to unexplained sudden death in epilepsy. Anticonvulsive medication, particularly with carbamazepine, might also influence autonomic cardiovascular modulation. MIBG-SPECT allows the quantification of post-ganglionic cardiac sympathetic innervation, whereas measuring the variability of the heart rate provides only functional parameters of autonomic modulation. Antiepileptic drugs, especially carbamazepine (CBZ), can affect cardiovascular modulation. We determined the index of cardiac MIBG uptake (heart/mediastinum ratio) and heart rate variability (HRV) using time and frequency domain parameters of sympathetic and parasympathetic modulation in 12 women and 10 men (median age 34.5 years) with a history of TLE for 7-41 years (median 20 years). Myocardial perfusion scintigrams were examined to rule out deficiencies of MIBG uptake due to myocardial ischaemia. To assess the possible effects of CBZ on autonomic function, we compared MIBG uptake and HRV in 11 patients who had taken CBZ and 11 patients who had not taken CBZ, and in 16 healthy controls. In order to identify MIBG uptake defects due to myocardial ischaemia, all patients had a perfusion scintigram. Cardiac MIBG uptake was significantly less in the TLE patients (1.75) than in the controls (2.14; P = 0.001), but did not differ between subgroups with and without CBZ treatment. The perfusion scintigram was normal in all patients. Time domain analysis of HRV parameters suggested the predominance of parasympathetic cardiac activity in the TLE patients, but less parasympathetic modulation in the patients treated with CBZ than in those not treated with CBZ (P < 0.05), whereas frequency domain parameters showed no significant difference between the subgroups of patients or between patients and controls. MIBG-SPECT demonstrates altered post-ganglionic cardiac sympathetic innervation. This dysfunction might carry an increased risk of cardiac abnormalities
— id: 37022, year: 2001, vol: 124, page: 2372, stat: Journal Article,

[Diabetic autonomic neuropathy]
Dutsch M; Hilz MJ; Neundorfer B
2001 Sep;69(9):423-438, Fortschritte der neurologie-psychiatrie
Diabetic autonomic neuropathy is the most frequent autonomic neuropathy in western countries. Diabetic autonomic neuropathy affects almost every organ. Among the most common symptoms are cardiovascular disturbances such as reduced heart rate variability and pathologic orthostatic reaction. The diagnosis of diabetic autonomic neuropathy is mainly based on the analysis of cardiovascular challenge maneuvers. The following article describes epidemiology, clinical findings, diagnosis, pathogenesis, therapeutic options and prognosis in diabetic autonomic neuropathy
— id: 37024, year: 2001, vol: 69, page: 423, stat: Journal Article,

MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1- and proton-density-weighted images
Hecht MJ; Fellner F; Fellner C; Hilz MJ; Heuss D; Neundorfer B
2001 May 1;186(1-2):37-44, Journal of the neurological sciences
In some patients with amyotrophic lateral sclerosis (ALS), T2-weighted and proton-density-weighted magnetic resonance imaging (MRI) shows hyperintense or hypointense signals at the corticospinal tract. Fluid-attenuated inversion recovery (FLAIR) sequences increase the sensitivity of MRI to detect cortical and subcortical tissue changes. In 31 ALS patients and 33 controls, we studied the frequency and the extent of signal abnormalities in FLAIR images compared to T2-, T1- and proton-density-weighted images. Hyperintense signals at the corticospinal tract were significantly more frequent in FLAIR images than in all other tested sequences. In FLAIR images of ALS patients only, distinct hyperintense signals at the subcortical precentral gyrus (five patients), the centrum semiovale (eight patients), the crus cerebri (nine patients) and the pons (four patients) as well as mild hyperintense signals in the medulla oblongata (three patients) were seen. More frequently, but not exclusively in ALS patients, FLAIR images showed mild hyperintense signals at the subcortical precentral gyrus (15 patients vs. 1 control). Quantitative analysis confirmed the significant difference between ALS patients and controls at the subcortical precentral gyrus in FLAIR images. In T1-weighted images, the corticospinal tract at the capsula interna was hypointense in significantly more controls than ALS patients. Also this difference was confirmed in the quantitative analysis. Similar to previous results, MR image alterations did correlate poorly to clinical data of upper motor neuron affliction.MR images of the head, including FLAIR images, provide additional information regarding corticospinal tract involvement in ALS patients. Because of an overlap with physiological findings, they have to be interpreted cautiously, with the exception of hyperintense signals at the subcortical precentral gyrus
— id: 37025, year: 2001, vol: 186, page: 37, stat: Journal Article,

Neuropathy is a major contributing factor to diabetic erectile dysfunction
Hecht MJ; Neundorfer B; Kiesewetter F; Hilz MJ
2001 Sep;23(6):651-654, Neurological research
Erectile dysfunction (ED) in diabetes is multifactorial. So far, the impact of neuropathy has not been well determined. This study was performed to assess the frequency of abnormal neurophysiological tests in patients with ED due to diabetes compared to patients with ED due to nondiabetic neuropathies in order to estimate the contribution of neuropathy in diabetic ED. Forty-nine men with ED were studied. We classified ED as 'diabetic', 'neuropathic' or 'ED of other origin'. 26.6% of the men fulfilled the criteria of diabetic ED, 42.9% had neuropathic ED. In every patient history taking, a questionnaire focusing on autonomic symptoms other than ED, clinical examination, nerve conduction studies (NCS), sphincter ani electromyography (EMG), heart rate variability testing (HRV) and quantitative sensory testing (QST) was performed. Vascular function was assessed by the intracavernosal prostaglandin E1 (PGE1) injection test. The frequency of abnormal results in diabetic and neuropathic patients was compared. Vascular function was abnormal in only one patient with diabetic ED and three patients with neuropathic ED. Both groups had similar frequencies of autonomic symptoms other than ED (64% in diabetic vs. 64% in neuropathic patients), abnormal EMG (33% vs. 40%) and abnormal QST (vibratory perception 83% vs. 84%, cold perception 9% vs. 19%, warm perception 42% vs. 43%). Abnormal clinical findings (50% vs. 33%), NCS (75% vs. 50%) and HRV (39% vs. 25%) were slightly, but not significantly more frequent in men with diabetic ED than neuropathic ED. The tests indicating neuropathy showed abnormalities in men with diabetic ED as frequently as in men with neuropathic ED. Some tests even suggested neuropathy more often in diabetic than in neuropathic ED. The findings support the hypothesis that neuropathy contributes significantly to the pathophysiology of ED in diabetes mellitus
— id: 37023, year: 2001, vol: 23, page: 651, stat: Journal Article,

Electrodiagnostic examination of Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy
Hecht, MJ; Bickel, A; Neundorfer, B; Hilz, MJ
2001 ;20(9):486-490, Nervenheilkunde
Guilloin-Barre syndrome (GBS) is the most common cause of acute generalised neuropathy. In Europe, 70% of the GBS patients develop an acute inflammatory demyelinating polyneuropathy (AIDP). Demyelinisation of the nerves accounts for a slowing down in nerve conduction, characterized by prolonged distal motor latencies, decreased nerve conduction velocities, potential dispersion and prolonged F-wave-latency, as well as conduction blocking, characterized by conduction blocks, decreased amplitudes of compound muscle action potentials and diminished recruitment of motor units in the electromyography. Demyelinisation often occurs in distal and proximal nerve regions. Sensory nerve abnormalities are less frequent and occur later in the course of the disease. Acute motor axonal neuropathy (AMAN) and acute motor-sensory axonal neuropathy (AMSAN) are characterized by decreased potential amplitudes and, later in the course of the dis-ease, signs of acute denervation in EMG. In contrast, in chronic demyelinating polyneuropathy (CIDP) there are frequently generalised demyelinations as well as secondary axonal alterations. In the early phase of the disease, electrophysiologic signs may be discrete. According to the American Academy of Electrodiagnostic Medicine (AAEM) the presence of demyelinating nerve conduction study abnormalities in at least two nerves in regions not typical for compressive mononeuropathies, preferably in both an arm and a leg, or a limb and the face are very suspicious for Guillairi-Barre syndrome. For a more precise staging of the course of the disease, the criteria of the Dutch Guillain-Barre study group (for GBS) and the criteria of Alsbury and Cornbloth (for CIDP) are more appropriate. $$:
— id: 104753, year: 2001, vol: 20, page: 486, stat: Journal Article,

[Cerebrovascular circulation from a clinical view. Historical review, physiology, pathophysiology, diagnostic and therapeutic aspects]
Heckmann JG; Erbguth FJ; Hilz MJ; Lang CJ; Neundorfer B
2001 Oct 15;96(10):583-592, Medizinische klinik
Strokes have been known since ancient times. Today, stroke is the second most frequent cause of death and the most frequent cause of invalidity. In about 80% of cases, stroke is caused by cerebral ischemia and in about 20% by intracerebral hemorrhage, subarachnoidal hemorrhage, venous thrombosis and other cerebrovascular diseases. The brain is one of the most richly perfused tissues and depends fundamentally on the supply of oxygen and glucose. In order to assure adequate cerebral blood flow, the brain is capable of autoregulation through the interaction of diverse autoregulatory mechanisms (myogenic, neurogenic and metabolic factors, blood viscosity, renin-angiotensin-system and endothelium). Reduction of cerebral blood flow below the threshold of about 25 ml/100 g x min leads to an impairment of the functional metabolism and later to impairment of the structural metabolism. Pathophysiologically, a large number of isolated pathobiochemical processes (loss of energy, lactate acidosis, excitating amino acid release, ion balance disorders, calcium overload, free radical release, etc.) start to interfere with each other. Delayed edema and inflammation lead to secondary brain damage. Apoptosis is probably induced by ischemia and can cause secondary deterioration. The basic principles in the treatment of ischemia are firstly the rapid restoration of cerebral blood flow (lysis, carotid endarterectomy) and secondly--following infarction--a limitation of brain damage (preservation of ischemic but not necrotic brain tissue, prevention of secondary complications). Stroke treatment requires profound diagnostic and therapeutic expertise and interdisciplinary cooperation of neuroradiologists, neurosurgeons, vascular surgeons and cardiologists. Stroke can best be managed in special 'stroke units', which have now been established in nearly all parts of Germany. Beside acute management of stroke and neurological rehabilitative treatment, emphasis has to be laid on primary (public information, education, treatment of risk factors) and secondary prophylaxis (treatment with antiaggregants, anticoagulants, a. o.)
— id: 37021, year: 2001, vol: 96, page: 583, stat: Journal Article,

Hemispheric influence on autonomic modulation and baroreflex sensitivity
Hilz MJ; Dutsch M; Perrine K; Nelson PK; Rauhut U; Devinsky O
2001 May;49(5):575-584, Annals of neurology
Several studies suggest hemispheric lateralization of autonomic cardiovascular control. There is controversy regarding which hemisphere dominates sympathetic or parasympathetic activity. Hemispheric influences on baroreflex sensitivity (BRS) have not yet been evaluated. To determine hemispheric autonomic control in epilepsy patients, we assessed cardiovascular and baroreflex modulation before and during hemispheric inactivation. For 15 patients with drug-refractory epilepsy, we analyzed autonomic heart rate (HR) and blood pressure (BP) modulation and BRS before and during left and right intracarotid amobarbital procedure (IAP). After Blackman-Tukey spectral analysis, we calculated the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.5 Hz) power of HR and BP as well as BRS as the LF transfer function gain between BP and HR. Right hemispheric inactivation induced a significant decrease of BP and an increase of HF power of HR and BP (p < 0.05). Left inactivation increased HR, BP, and LF power of both signals and decreased BRS by nearly 30% (p < 0.05). The results confirm previous IAP studies showing sympathetic lateralization in the right hemisphere and, moreover, demonstrate parasympathetic predominance and up-regulation of BRS in the left hemisphere. In epilepsy patients, unilateral electrical activity might derange autonomic balance between both hemispheres and contribute to cardiovascular dysregulation and sudden fatalities
— id: 20660, year: 2001, vol: 49, page: 575, stat: Journal Article,

Effect of vagus nerve stimulation on baroreflex sensitivity and respiratory sinus arrhythmia in patients with epilepsy
Hilz, MJ; Stemper, B; Haendl, T; Welsch, G; Devinsky, O
2001 APR 24 ;56(8):A424-A425, Neurology
— id: 104271, year: 2001, vol: 56, page: A424, stat: Journal Article,

Influence of posture on the Valsalva manoeuvre
Singer W; OpferGgehrking TL; McPhee BR; Hilz MJ; Low PA
2001 Apr;100(4):433-440, Clinical science (London, 1979)
The objective of the present study was to evaluate the influence of posture on the responses of blood pressure (BP) and heart rate (HR) to the Valsalva manoeuvre (VM). Neurohumoral activation, as well as changes in intravascular and intracardiac volumes and pressures, are well known effects of orthostatic stress. These changes are likely to have significant effects on cardiovascular reflexes, such as the response to the VM. However, the influence of posture on the VM has not been intensively evaluated, except for a few studies involving small sex- and age-selected case series. We therefore investigated the effects of posture on the VM in a larger non-selected group of healthy control subjects. In 19 healthy volunteers (ten female/nine male; age range 20-72 years, mean age 43 years), two reproducible VMs (40 mmHg; 15 s) were performed after 10 min of supine rest, 10 min of sitting and 10 min of standing. HR and BP were monitored continuously. End-diastolic volume, total peripheral resistance and cardiac output were calculated at baseline for each position. We found that assuming an upright position resulted in increases in total peripheral resistance and HR, accompanied by decreases in end-diastolic volume and cardiac output. The fall in BP during early phase II and the BP overshoot during phase IV were clearly more pronounced with increasing orthostatic stress, whereas the rise in BP during late phase II remained unchanged; pulse pressure was more compressed during phase II, but higher during phase IV. The Valsalva ratio was not significantly affected, but baroreflex gain (calculated from early phase II) was significantly decreased in the upright position. While a reduced late phase II was observed on one occasion in each of the lying and sitting positions, three abnormal responses were observed during standing. We conclude that posture has a significant influence on BP responses to the VM, probably resulting from changes in the intrathoracic blood volume. Standing results in a lower rate of 'flat-top' responses, but also seems to reduce the specificity of this test. Sympathetic activation in the upright position seems to blunt baroreflexes, leading to similar HR responses in spite of larger changes in BP
— id: 37027, year: 2001, vol: 100, page: 433, stat: Journal Article,

Impaired cardiovascular responses during hypoxic chemoreceptor stimulation in familial dysautonomia
Stemper, B; Hilz, MJ; Bernardi, L; Welsch, G; Passino, C; Axelrod, FB
2001 ;56(8):A426-A426, Neurology
— id: 104754, year: 2001, vol: 56, page: A426, stat: Journal Article,

Ictal SPECT during autonomic crisis in familial dysautonomia
Axelrod FB; Zupanc M; Hilz MJ; Kramer EL
2000 Jul 12;55(1):122-125, Neurology
The authors report results of SPECT cerebral perfusion studies in two patients with familial dysautonomia (FD) during dysautonomic crises and when clinically stable. SPECT imaging studies used 99mTc ethylene cysteine dimer. During dysautonomic crises, regions in the temporoparietal and frontal lobes had increased uptake. Uptake in these areas was less during asymptomatic periods. Episodic asymmetric cerebral perfusion during crises especially affecting the frontal and temporal lobes is suggestive of ictal activity
— id: 11600, year: 2000, vol: 55, page: 122, stat: Journal Article,

The quantitative sudomotor axon reflex testing (QSART)
Bickel, A; Hilz, MJ
2000 ;19(5):259-263, Nervenheilkunde
For the examination of peripheral sudomotor function, quantitative sudomotor axon reflex testing (QSART) was established and evaluated recently. Based on on axon reflex, on indirect sweet response from eccrine sweat glands is evoked after application of acetylcholine to the skin. Using on appropriate setting, a dynamic and quantitative measurement of sweat response is possible. This method is especially useful for sensitive evaluation of autonomic disturbances, that con occur during the course of peripheral neuropathies. As non-invasive, technical simple method, it con easily be used for follow-up examinations. $$:
— id: 104755, year: 2000, vol: 19, page: 259, stat: Journal Article,

Differentiation of Parkinson's disease and multiple system atrophy in early disease stages by means of I-123-MIBG-SPECT
Druschky A; Hilz MJ; Platsch G; Radespiel-Troger M; Druschky K; Kuwert T; Neundorfer B
2000 Apr 1;175(1):3-12, Journal of the neurological sciences
BACKGROUND: Differential diagnosis between idiopathic Parkinson's disease (PD) and multiple system atrophy (MSA) is often difficult in early disease stages. Since MSA is misdiagnosed as PD in more than 20% of the early stages, there is need for methods refining the differentiation of the two disease entities. In PD postganglionic involvement of the autonomic nervous system (ANS) predominates whereas in MSA the ANS is mainly affected in its preganglionic structures. The functional integrity of postganglionic cardiac sympathetic neurons can be investigated using I-123-metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT). OBJECTIVES: We investigated whether I-123-MIBG-SPECT allows to differentiate between early stages of PD and MSA in patients not yet requiring L-dopa therapy. METHODS: Thirty patients (10 PD and 20 MSA patients) underwent MIBG-SPECT and evaluation of heart rate variability (HRV). Patients on any medication interfering with MIBG-accumulation were excluded from the study. Cardiac perfusion was evaluated by myocardial scintigraphy. RESULTS: The median cardiac MIBG uptake was significantly decreased in PD as well as MSA patients compared to controls (P<0.001). However, in the PD group MIBG uptake was significantly lower than in MSA (P=0.03). Even in PD patients without clinical signs of autonomic failure, MIBG uptake was significantly lower than in MSA patients (P=0.03). Analysis of heart rate parameters did not differentiate between PD and MSA patients. The median coefficient of variation was significantly smaller in PD and MSA patients compared to control subjects. CONCLUSIONS: Our study shows that MIBG-SPECT identifies autonomic cardiac dysfunction in very early stages of both, PD and MSA. More importantly, the technique facilitates differentiation of MSA and PD in the early stages. The different pathology with prominent peripheral, postganglionic sympathetic dysfunction in PD and primarily central and preganglionic lesions in MSA accounts for a lower MIBG uptake in PD compared to MSA patients
— id: 37036, year: 2000, vol: 175, page: 3, stat: Journal Article,

Brain stem diagnostics: blink reflex, masseter reflex, masseter inhibitory reflex
Erxleben, H; Hilz, MJ
2000 ;19(5):252-258, Nervenheilkunde
The blink reflex, the masseter reflex and the masseter inhibitory reflex ore sensitive tests to detect brain stem lesions and lesions of the peripheral facial and trigeminus nerve. The combined evaluation of the three brain stem reflexes seems particularly useful since all three reflexes ore mediated via different pathways. This allows further a more specific analysis of the structures or anatomical localisations involved in a specific dysfunction. They ore especially useful for follow-up examinations. $$:
— id: 104756, year: 2000, vol: 19, page: 252, stat: Journal Article,

Differentiation of occlusion versus pseudoocclusion of the internal carotid artery - are ultrasound techniques sufficient?
Hecht, M; Hilz, MJ
2000 ;19(5):220-+, Nervenheilkunde
The differentiation of occlusion versus pseudoocclusion of the internal carotid artery (ACI) has important impact on therapeutical considerations. Until now angiography is thought to be the 'gold standard' in the differential-diagnosis of occlusion and pseudoocclusion. However, colour doppler imaging and power doppler imaging ore the methods of choice for non-invasive diagnosis of extracroniell ACI-occlusion. The additional use of echo-contrast agents (e.g. Levovist(R)) improves the sensitivity of colour doppler imaging and the specificity of power doppler imaging. The combined use of various ultrasound techniques is highly sensitiv and specific for the differentiation of ACI-occlusian from pseudoocclusion and allows often for avoiding invasive techniques as angiography. Sensitivity and specificity of sonography ore dependent on the experience of the examiner. Besides the use of adequate diagnostic techniques it is important that the examination is done by a sonographist, who has wide experience in the field of carotid artery ultrasonography. $$:
— id: 104757, year: 2000, vol: 19, page: 220, stat: Journal Article,

Somatosensible evoked potentials following stimulation of the trigeminal nerve in diagnostics of brainstem lesions
Hecht, M; Hilz, MJ; Neundorfer, B
2000 ;19(5):247-+, Nervenheilkunde
Somatosensible evoked potentials (SEP) following stimulation of the trigeminal nerve provide additional diagnostic information in brainstem lesions. After stimulation of the upper and lower lip (separately or simultaneously) the afferent impulses reach the Nd. sensorius principalis nervi trigemini in the pens via the Gasseri ganglion. From there the impulses ore transmitted by the lemniscus trigeminalis to the thalamus and terminate in the postcentral gyrus (area 3b). The latency of the P19-peak is the most important parameter. Separate stimulation of the upper and lower lip allows for detection of even discrete lesions in the trigerminal system. By combining trigeminal SEP with other techniques such as auditory evoked potentials or blink reflex the exact localisation of brainstem lesions may be identified. Trigeminal SEP show in 41-100% of multiple sclerosis patients additional, clinically inapparent, foci. Also in ischemic brainstem lesions trigeminal SEP may provide additional information. In trigeminal neuralgia as well as in neurinoma of the acoustical nerve affection of the brainstem may be recognised by trigeminal SEP. $$:
— id: 104758, year: 2000, vol: 19, page: 247, stat: Journal Article,

Oral mucosal blood flow following dry ice stimulation in humans
Heckmann JG; Hilz MJ; Hummel T; Popp M; Marthol H; Neundorfer B; Heckmann SM
2000 Oct;10(5):317-321, Clinical autonomic research
The aim of the current pilot study was to establish a procedure that would allow the investigation of microcirculatory changes in the oral cavity. The authors studied the effects of painful stimulation using dry ice (CO2). To investigate potential regional differences in the change of blood flow, recordings were made for the tongue and at the mucosa of the hard palate, lip, and oral vestibule. The authors investigated 26 patients divided into groups of younger subjects (10 men, 3 women; age range 21-31 y) and older patients (2 men, 11 women; age range 54-74 y). Mucosal blood flow (mBF) was obtained at the hard palate, at the tip of the tongue, on the midline of the oral vestibule, and at the lip. Measurements were made during rest and for 2 minutes after application of dry ice for a 10-second duration, using a pencil-shaped apparatus. Blood pressure, heart rate, cutaneous blood flow, transcutaneous partial pressure of carbon dioxiode (PCO2) and partial pressure of oxygen (PO2) were recorded. Mucosal blood flow increased at all sites in response to application of dry ice (p <0.001), with peak flow at 0.5 minute to 1.5 minutes after onset of stimulation. During the 1.5 minutes to 2 minutes, blood flow decreased at all measurement sites with a tendency to return to baseline. Heart rate, blood pressure, pCO2, PO2, and cutaneous blood flow did not show significant changes. Overall, responses in older patients showed more variance when compared with younger patients. Stimulation by dry ice appears to be an effective, noninvasive, and tolerable means to investigate mucosal blood flow at different mucosal sites. Preliminary data indicate different levels of responsiveness to painful cold stimulation at different sites on the oral and perioral mucosa; particularly, mucosal blood flow response at the tongue was least pronounced. Therefore, assessment of stimulated mucosal blood flow appears to be a promising tool to investigate the pathophysiology of a number of neurologic symptoms, eg, the burning mouth syndrome
— id: 37028, year: 2000, vol: 10, page: 317, stat: Journal Article,

Transcranial doppler sonography-ergometer test for the non-invasive assessment of cerebrovascular autoregulation in humans
Heckmann JG; Hilz MJ; Muck-Weymann M; Neundorfer B
2000 Aug 1;177(1):41-47, Journal of the neurological sciences
Cerebrovascular hemodynamics during physical stress have been sparsely investigated, mostly through risky invasive techniques. The aim of this study was to determine the effect of ergometer stress on cerebrovascular hemodynamics in humans using the non-invasive and thus clinically-applicable method of transcranial Doppler sonography (TCD) combined with simultaneous non-invasive measurements of cardiovascular parameters. In eighteen healthy subjects (six women, twelve men; 29.3+/-4.6 years old) left midcerebral artery blood flow velocities (CBFVs) were continuously monitored using TCD during 3 min at rest, 3 min during ergometry and 3 min recovery. Simultaneously, systolic, diastolic, mean CBFVs, pulsatility index (PI), heart rate, beat-to-beat blood pressure (BP) and transcutaneous p(CO(2)) were measured. The subjects were supine with elevated trunk. Ergometry was performed by pedalling a Muhe-ergometer. In eight volunteers, the procedure was repeated within the next day to test the repeatability of the results. Heart rate increased significantly during ergometry (from 65.2+/-11 to 105. 3+/-12.3/min; P<0.05). The systolic BP increased significantly slightly later during ergometry (from 118.9+/-8.6 to 141.6+17.9 mmHg; P<0.05). Transcutaneous p(CO(2)) was initially within physiological ranges, but increased significantly after a delay during the 3rd min of cycling (from 39.7+/-3.7 to 41.1+/-4.7 mmHg; P<0.05). MFV started to rise significantly after 1 min of the exercise period (from 59.6+10.9 to 68.3+13.9 cm/s; P<0.05). PI increased immediately and significantly at the start of exercise (PI at rest 0.93+0.11; PI ergometry 1.1+0.13; P<0.05). The results were found to be reproducible in the eight volunteers. The cerebrovascular changes during ergometer exercise may reflect the combined activation of the cerebrovascular autoregulative mechanisms (neurogenic, myogenic and metabolic). The TCD-ergometer test presented here is non-invasive and would seem to present a low risk for patients who are judged fit enough for mild exercise. The test may contribute to the detection of cerebrovascular abnormalities in various diseases
— id: 37032, year: 2000, vol: 177, page: 41, stat: Journal Article,

Functional transcranial Doppler sonography
Heckmann, JG; Hilz, MJ; Muck-Weymann, M; Neundorfer, B
2000 ;19(5):242-246, Nervenheilkunde
Functional transcranial Doppler sonography (fTCD) examines cerebral hemodynamics at rest and during diverse activation manoeuvres. In the fTCD during visual activation the posterior cerebral artery (PCA) is insonoted. Further fTCD methods for the evaluation of the posterior circulation are the simultaneous insonation of the middle cerebral artery (MCA) and the PCA or direct insonation of the basilar artery (BA) during vestibular stimulation using caloric irrigation. The fTCD during tilt-table-test with heed-up tilt is meanwhile a very established method for autonomic testing. The fTCD during head-down tilt is still experimental for testing cerebrovascular autoregulation in healthy volunteers. The autoregulative stimulus is the rapid cephal blood influx which probably activates the myogenic mechanism of cerebrovascular autoregulation. The fTCD during ergometry examines cerebrovascular changes during physical stress. The cerebrovascular changes reflect the complex coactivation of diverse autoregulative mechanisms (neurogenic, metabolic, myogenic). In patients with defined cerebrovascular disturbances (chronic tension type headache, migraine) abnormal findings were detected. FTCD is a new method which enables noninvasive and with exact time correlation changes analysis of cerebrovascular hemodynamics during diverse activation procedures. Clinical applications can be seen in patients with cerebrovascular or autonomic diseases and in testing of cerebrovoscular autoregulation following pharmocological treatment (e.g. antihypertensive drugs). $$:
— id: 104759, year: 2000, vol: 19, page: 242, stat: Journal Article,

Erectile dysfunction--diagnostic approach and treatment options
Hilz MJ
2000 ;53(6):234-236, Supplements to Clinical neurophysiology
— id: 36995, year: 2000, vol: 53, page: 234, stat: Journal Article,

Quantitative sensory testing of thermal and vibratory perception in familial dysautonomia
Hilz MJ; Axelrod FB
2000 Aug;10(4):177-183, Clinical autonomic research
Familial dysautonomia (FD) is an inherited disorder that is known to affect both sensory and autonomic functions as a result of incomplete neuronal development and progressive loss but the degree to which patients are affected differs greatly. To determine if quantitative vibration and thermal testing refined the assessment of severity, 23 familial dysautonomia patients were evaluated by clinical examination, measurements of median, peroneal and sural nerve conduction velocities (NCV), and assessment of vibration thresholds at two body sites and of warm and cold perception thresholds at 6 body sites using the method of limits. Data from 80 age-matched normal individuals provided control data for vibration and temperature thresholds. All familial dysautonomia patients had abnormal thermal thresholds. Vibration perception was abnormal in 20 patients. NCVs were slowed in 8 of 16 patients who agreed to be tested. Abnormalities in thermal thresholds are consistent with the reduction of small nerve fibers in familial dysautonomia Abnormal vibration thresholds might be due to disturbed conduction of vibratory impulse trains and reflect the degree to which the disorder is progressive. Vibration and thermal sensation testing were better accepted and provided more information than NCV regarding severity of disease
— id: 37030, year: 2000, vol: 10, page: 177, stat: Journal Article,

Abnormal vasoreaction to arousal stimuli--an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry
Hilz MJ; Hecht MJ; Berghoff M; Singer W; Neundoerfer B
2000 Jul;17(4):419-425, Journal of clinical neurophysiology
Early diagnosis of diabetic autonomic neuropathy contributes to the prevention of serious complications and improves the prognosis of patients with diabetes. Common tests of peripheral autonomic function are the quantitative sudomotor axon reflex test or the sympathetic skin response (SSR). Quantitative sudomotor axon reflex test is quantifiable but technically demanding. Sympathetic skin response cannot be quantified easily. To study whether measurement of skin vasomotion is suited to assess early sympathetic peripheral neuropathy, we monitored skin blood flow at the index finger pulp using laser Doppler flowmetry before and after electrical stimulation. We assured that the stimulus was sufficient to elicit an efferent sympathetic response by monitoring palmar SSR ipsilateral to the flow measurement. In 21 diabetic patients with at least stage one polyneuropathy and 21 age-matched controls, SSR was recorded from one palm and sole following electrical stimulation at the contralateral wrist. Sympathetic skin response was present at the palms in all patients and controls and absent at the sole of two patients only. Eight patients (38.9%) had abnormal SSR, with absent plantar responses in two patients, prolonged plantar latencies in six patients, and prolonged volar SSR latencies in two patients. Skin blood flow responses were more often abnormal (46.1%) than SSR (P < 0.05), responses were delayed in two patients and absent in another 8 patients. Skin blood flow retest reliability was high with a repeatability coefficient of 10.64% in controls and 12.34 % in patients. Skin blood flow monitoring after sympathetic stimulation provides a reproducible parameter of sympathetic vasomotor control and complements the diagnostic value of SSR testing
— id: 37031, year: 2000, vol: 17, page: 419, stat: Journal Article,

[Diabetic somatic polyneuropathy. Pathogenesis, clinical manifestations and therapeutic concepts]
Hilz MJ; Marthol H; Neundorfer B
2000 Jun;68(6):278-288, Fortschritte der neurologie-psychiatrie
Diabetic polyneuropathy is the most frequent neuropathy in western countries. In Germany, there are 3.5 to 4 million diabetic patients. Diagnosis should rule out other polyneuropathies and assess two out of the five diagnostic criteria: neuropathic symptoms, neuropathic deficits, pathological nerve conduction studies, pathological quantitative sensory testing and pathological quantitative autonomic testing. So far, the pathophysiology of diabetic neuropathy remains to be fully understood. Among the various pathophysiological concepts are the Sorbitol-Myo-Inositol hypothesis attributing Myo-Inositol depletion to the accumulation of Sorbitol and Fructose, the concept of deficiency of essential fatty acids with reduced availability of gamma-linolenic-acid and prostanoids, the pseudohypoxia- and hypoxia-hypothesis attributing endothelial and axonal dysfunction and structural lesions to increased oxidative stress and free radical production. Obviously, the hyperglycemia induced generation of advanced glycation end products (AGEs) also contributes to structural dysfunctions and lesions. Elevated levels of circulating immune complexes and activated T-lymphocytes as well the identification of autoantibodies against vagus nerve or sympathetic ganglia support the concept of an immune mediated neuropathy. The reduction of neurotrophic factors such as nerve growth factor, neurotrophin-3 or insulin-like growth factors also seems to further diabetic neuropathy. The symmetrical, distally pronounced and predominantly sensory neuropathy is far more frequent than the symmetrical neuropathy with predominant motor weakness or the asymmetrical neuropathy. The painless neuropathy manifests with impaired light touch sensation, position sense, vibratory perception and diminished or absent ankle deep tendon reflexes. The painful sensory diabetic neuropathy primarily affects small nerve fibers and accounts for decreased temperature perception and paresthesias. The proximal, diabetic amyotrophy evolves subacutely or acutely, induces motor weakness of the proximal thigh and buttock muscles and is painful. Cranial nerve III-neuropathy is also painful and has an acute onset. Truncal radiculopathy follows the distribution of truncal roots and frequently causes intense pain. Autonomic neuropathy occurs with and without somatic neuropathy. The most important therapy is to attempt optimal blood glucose control, to reduce body weight and hyperlipidemia. Symptomatic therapy includes alpha-lipoic acid treatment, as the antioxidant seems to improve neuropathic symptoms. Aldose reductase inhibitors might reduce sorbitol and fructose production and normalize myo-inositol levels. However, there are no aldose reductase inhibitors available in Europe as yet. Evening primrose oil, containing gamma-linolenic acid, might improve nerve conduction velocities, temperature perception, muscle strength, tendon reflexes and sensory function. Substitution of nerve growth factor showed promising results in pilot studies but failed in a large-scale multicenter study. Symptomatic pain treatment can be achieved with tricyclic antidepressants, selective serotonin reuptake inhibitors, anticonvulsants such as carbamazepine, gabapentin or lamotrigine, or anti-arrhythmic drugs such as mexiletine. Topical capsaicin application should reduce neuropathic pain but also induces local discomfort in the beginning of therapy. Vasoactive substances, so far have not proven to be of major benefit in diabetic neuropathy. Physical therapy and thorough footcare are of primary importance and allow prevention of secondary complications such as foot amputations
— id: 37034, year: 2000, vol: 68, page: 278, stat: Journal Article,

[Mechanisms of cerebral autoregulation, assessment and interpretation by means of transcranial doppler sonography]
Hilz MJ; Stemper B; Heckmann JG; Neundorfer B
2000 Sep;68(9):398-412, Fortschritte der neurologie-psychiatrie
Cerebrovascular autoregulation assures constancy of cerebral perfusion despite blood pressure changes, as long as mean blood pressure remains in a range between 50-170 mmHg. Static and dynamic myogenic mechanisms dampen sudden blood pressure changes. Neurogenic influences of sympathetic, noradrenergic fibers modulate primarily proximal, large diameter segments of cerebral arteries, but also small 15-20 microns diameter vessels. Parasympathetic, vasodilating impulses are of less influence. Monoaminergic brainstem centers such as the dorsal raphe nucleus, locus coeruleus or nucleus reticularis pontis oralis also influence vessel tone. Metabolic, local parenchymal and endothelial substances have major impact on cerebral vessel tone. Particularly important are nitric oxide, calcitonin gene related peptide, substance P, endothelin, potassium channels and autocoids such as histamine, bradykinin, arachidonic acid, prostanoids, leucotrienes, free radicals or serotonin. The clinical examination of autoregulation is mostly based on brief blood pressure changes induced by drugs such as angiotensin, phenylephrine or sodium nitroprusside, or by challenge maneuvers. Frequently, blood pressure is challenged by a tilt-table maneuver, the 'leg-cuff'-method according to Aaslid, or a Valsalva maneuver. The analysis of coherence and phase relation between spontaneous or metronomic breathing modulation of blood pressure and brain perfusion also assesses autoregulatory function. Cerebral blood flow is determined by means of transcranial Doppler sonography, mostly of the proximal segment of the mid-cerebral artery. There is some controversy whether a decrease of cerebral blood flow velocity measured at this segment indicates vasodilatation at the insonated segment or reflects blood flow reduction due to decreased perfusion of down-stream vessel segments. Various clinical and animal studies are presented demonstrating diameter constancy of the insonated mid-cerebral artery segment and thus indicating that slowing of mid cerebral artery blood flow velocity as assessed by transcranial Doppler sonography is due to a decrease of down-stream perfusion. Direct, intraoperative measurements of vessel diameter confirm this conclusion
— id: 37029, year: 2000, vol: 68, page: 398, stat: Journal Article,

Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients
Hilz MJ; Stemper B; Kolodny EH
2000 Feb;84(2-3):361-365, Pain
In Fabry disease, an X-linked alpha-galactosidase A deficiency, painful crises and limb paresthesias are possibly linked to thermal exposure. Small nerve fiber function has not yet been tested after cold challenge. In two Fabry patients (15 and 17 years old), their heterozygote mother, their healthy sister, and eight controls, we determined warm and cold perception thresholds at the dorsal foot and the lower medial calf (method of limits, Somedic-Thermotest), before and 1, 5, 10 and 15 min after 30 s immersion of one leg into 5 degrees C water. Discomfort was rated from 0 to 10. At baseline, thermal thresholds of all participants were normal. In contrast to controls, the patients tolerated 30 s cold stimulation only with interruptions. The mother aborted stimulation after 6 s because of pain. The patients and their mother reported intense burning pain and numbness during and after stimulation. After cold exposure, thermal sensation was highly abnormal for 20 min in one and 80 min in the other brother. In controls, thermal thresholds were somewhat elevated after stimulation but normalized within 10.0+/-4.6 min. Discomfort during cold exposure was rated 8-10 by the patients and their mother, but 3-5 by the healthy persons.We assume that glycolipid accumulation in cutaneous and vasa nervorum vessels as well as small nerve axons accounts for skin and small fiber malperfusion during cold induced vasoconstriction. Transitory ischemia initiated burning pain and prolonged small fiber dysfunction
— id: 37038, year: 2000, vol: 84, page: 361, stat: Journal Article,

[Physiology and methods for studying the baroreceptor reflex]
Hilz MJ; Stemper B; Neundorfer B
2000 Jan;68(1):37-47, Fortschritte der neurologie-psychiatrie
The baroreflex is of major importance for the moment-to-moment maintenance of arterial pressure particularly during orthostatic stress. Blood pressure increase stimulates the receptors e.g. in the carotid sinuses and the aortic arch, and rapidly increases the receptor discharge rate. Blood pressure decrease induces arrest of impulse transmission to the nucleus of the solitary tract. The impulses are modulated by the nucleus ambiguous, the rostral ventrolateral medulla, the dorsal nucleus of the vagus nerve, parabrachial and paraventricular nuclei and other central structures. Blood pressure increase induces an increase of cardiovagal activity resulting in cardiodeceleration and a decrease of sympathetic peripheral vasoconstrictor outflow. The receptor firing rates show adaptation and resetting to longer lasting blood pressure changes, hysteresis, i.e. firing rates that are higher with rapid blood pressure increase than during the return to baseline pressure. The receptors interact with respiration, chemoreceptor stimulation, central stimuli, exercise and sleep, etc. Baroreceptor function and interaction e.g. with chemoreceptors is compromised in diseases such as diabetic autonomic neuropathy. Guillain-Barre syndrome, arterial hypertension, heart failure and probably in most stroke patients. Fatal complications may result from baroreceptor malfunction. Subtle analysis of the baroreflex is therefore crucial for a refined pathophysiological understanding of these diseases. Pharmacological testing and 'neck chamber' negative pressure stimulation of the receptors are as useful as the non-invasive computerized analysis of the interaction of spontaneous blood pressure and heart rate fluctuations
— id: 37037, year: 2000, vol: 68, page: 37, stat: Journal Article,

Introduction to this special issue
Hilz, MJ
2000 ;19(5):3-3, Nervenheilkunde
— id: 104761, year: 2000, vol: 19, page: 3, stat: Journal Article,

Erectile dysfunction
Hilz, MJ; Hecht, M; Kolsch, C
2000 ;27(1):1-+, Aktuelle Neurologie
In Germany, 4-6 million men suffer from erectile dysfunction. Psychogenic, vascular, endocrine and metabolic disorders such as diabetes mellitus and neurogenic disturbances contribute to the etiology of erectile dysfunction. Erection depends on parasympathetic and - especially during emotional stimulation - on sympathetic outflow. The flaccid state is mediated via epinephrine and cotransmitters such as neuropeptide Y. Non-cholinergic, non-adrenergic neurotransmitters such as vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) are essential for the erection. NO, VIP, calcitonin gene related peptide (CGRP) and prostaglandin El activate guanylate and adenylate cyclases and thus elevate levels of cyclic guanosine and adenosine monophosphate. A secondary decrease of calcium levels induces relaxation of smooth muscles of vessel walls and corpus cavernosum trabeculae and leads to erection. Specific phosphodiesterases cleave the cyclic monophosphates and terminate smooth muscle relaxation and erection. Diagnosis of erectile dysfunction is based on an extended history, interdisciplinary clinical examination, assessment of standard laboratory parameters, testosterone and prolactin levels and penile artery Doppler sonography. Cavernosometry, cavernosography, angiography and neurophysiologic procedures such as sphincter ani externus electromyography or bulbocavernosus reflex latency measurements are of limited diagnostic value. Psychotherapy, use of vacuum devices, vascular surgery and - as an ultimate option - penile prostheses are among the therapeutic alternatives. Today, intracavernosal or intraurethral application of vasoactive substances such as prostaglandin El and oral phosphodiesterase inhibitors such as Sildenafil are the most important therapeutic approaches. In the majority of patients, erectile dysfunction is most likely not primarily a psychological disturbance. Particularly diabetic patients benefit from adequate diagnosis and consequent therapy. Their therapeutic compliance is likely to improve with adequate therapy of erectile dysfunction. This might promote the prevention of secondary complications of the underlying metabolic disease. $$:
— id: 104760, year: 2000, vol: 27, page: 1, stat: Journal Article,

Entrapment syndromes of the upper extremities
Hilz, MJ; Kolsch, C; Marthol, H; Neundorfer, B
2000 ;19(5):226-+, Nervenheilkunde
Entrapment syndromes ore due to chronic pressure induced lesions of peripheral nerves within an anatomical compartment of fixed size. Apart from the anatomical predisposition in a compartment, edema of surrounding tissue, endocrine, metabolic and traumatic factors, amyloid or mucopolysaccharid deposition contribute to the pathogenesis of entrapment syndromes. Hypesthesia, anesthesia, hypalgesia or hyperalgesia, paresthesia and dysesthesia in the skin areas supplied by the entrapped nerve, as well as motor weakness of muscles innervated by the nerve ore among the typical symptoms of on entrapment syndrome. Muscle atrophy can be seen in advanced stages. A detailed history, neurological and neurophysiolocial examination confirm the diagnosis. The carpal tunnel syndrome is the most frequent entrapment syndrome of the upper extremities. Entrapment of the ulnar nerve occurs in the ulnar groove at the elbow or at the cubital tunnel where the nerve posses The aponeurosis of origin of the flexor carpi ulnaris muscle. A more distal site of ulnar nerve entrapment is the Loge de Guyon. The various forms of thoracic outlet syndrome also induce tingling in the ulnar region of the hand. The anterior interosseus nerve syndrome and the pronator teres syndrome as well as the posterior interosseus nerve syndrome count among the less frequent entrapment syndromes. Therapeutical approaches depend on the anatomical structures, the pathogenesis and the severity of on entrapment. Conservative treatment is frequently sufficient to improve symptoms. Chronic and more advanced stages usually require surgery. $$:
— id: 104762, year: 2000, vol: 19, page: 226, stat: Journal Article,

Sympathetic skin response - technique of recording and aspects of clinical application
Horn, S; Hilz, MJ
2000 ;19(5):264-270, Nervenheilkunde
Spontaneous electrodermal activity can be derived from the palmar and plantar skin. These areas have a high density of sweet glands. Changes in potential at The sweat glands are considered to be the main cause for the measured electrodermal activity. A sympathetic skin response con be elicited by various arousal stimuli such as electrical, acoustic or emotional stimulation. SSR is used to diagnose autonomic sudomotor disorders of the peripheral and to some extent the central sympathetic nervous system. We describe the mechanisms of SSR generation, the technique of SSR recording and aspects of clinical application. $$:
— id: 104763, year: 2000, vol: 19, page: 264, stat: Journal Article,

Entrapment syndromes of the lower extremities
Neundorfer, B; Hilz, MJ
2000 ;19(5):237-+, Nervenheilkunde
An entrapment syndrome is defined as a chronic nerve irritation in fibro-osseous tunnel. The entrapment syndromes of the lower extremities ore the following. 1.) tarsaltunnel syndrome with compression of the tibial nerve posterior and inferior to the medial malleolus, 2.) Morton's syndrome with irritation of the 4(th) N. digitalis plantaris communis between the capitula of the 3(rd) and 4(th) metatarsal bones, 3.) saphenus neuropathy with compression of the saphenus nerve in the canalis adductorius Hunter, 4.) meralgia paraesthetica with irritation of the lateral cutaneaus nerve beneath the inguinal ligament, 5.) piriformis syndrome with compression of the sciatic nerve under the piriformis muscle, 6.) ilioinguinalis syndrome with lesion of this nerve passing the muscles of the abdominal well. The diagnosis con partially be ensured by electrodiagnostic methods. Therapeutically, infiltrations of local anaesthetic drugs can be performed or surgical exploration and decompression will be necessary. $$:
— id: 104764, year: 2000, vol: 19, page: 237, stat: Journal Article,

Peripheral neuropathy in chronic venous insufficiency
Reinhardt F; Wetzel T; Vetten S; Radespiel-Troger M; Hilz MJ; Heuss D; Neundorfer B
2000 Jun;23(6):883-887, Muscle & nerve
Chronic venous insufficiency (CVI) of the lower legs may cause tissue damage, but involvement of peripheral nerves is uncertain. We examined 30 patients with CVI and 20 healthy controls using motor and sensory nerve conduction studies, vibration testing and thermotesting, quantitative sudomotor axon-reflex test, and laser Doppler flowmetry. Subjects with possible confounding factors for peripheral neuropathies were excluded. Prolongation of distal motor latency of the peroneal nerve (median, 5.4 versus 4.5 ms; P = 0.02), increased limits for warm (9.60 degrees C versus 5.20 degrees C; P = 0.016) and cold detection (3.45 degrees C versus 1.55 degrees C; P = 0.016) and reduced vibration sense (2.8925 versus 1.1075; P < 0.008) were found. The results demonstrate a disturbance of A-alpha fibers, A-beta fibers, A-delta fibers, and thermoafferent-C fibers, possibly induced by ischemia due to venous microangiopathy and increased endoneurial pressure. Analogous to neuropathic ulcers in diabetes, the CVI-associated neuropathy may also be a cofactor in the development of venous ulcers
— id: 37035, year: 2000, vol: 23, page: 883, stat: Journal Article,

[Temporal lobe epilepsy: effect of focus side on the autonomic regulation of heart rate?]
Saleh Y; Kirchner A; Pauli E; Hilz MJ; Neundorfer B; Stefan H
2000 Jun;71(6):477-480, Nervenarzt
Epileptic activity can modulate reactions of the autonomic nervous system. Although there is some evidence of a differential left/right hemispheric influence on the cardiovascular system, diverse investigations have shown controversial results. In our study, complex partial seizures of patients with temporal lobe epilepsy were recorded using subdural electrodes, thus providing reliable information on the focus side. We analyzed the preictal and ictal heart rates of 27 patients, 16 revealing right and 11 revealing left temporal foci. During the seizures, both groups showed a significant increase in heart rate. Preictal tachycardia was only significant in the right focus group, whereas no significant change in heart rates could be detected in the left focus group. Our results confirm a right hemispheric lateralization of sympathetic cardiac control
— id: 37033, year: 2000, vol: 71, page: 477, stat: Journal Article,

Evidence of an intrinsic sinus node abnormality in patients with Postural Tachycardia Syndrome
Shen, WK; Singer, W; McPhee, BR; Opfer-Gehrking, TL; Hilz, MJ; Low, PA
2000 ;54(7):A160-A160, Neurology
— id: 104765, year: 2000, vol: 54, page: A160, stat: Journal Article,

Investigation of the neural and vascular control mechanisms of the cutaneous microcirculation
Berghoff, M; Kilo, S; Hilz, MJ; Freeman, R
1999 ;52(6):A341-A341, Neurology
— id: 104766, year: 1999, vol: 52, page: A341, stat: Journal Article,

Cardiac sympathetic denervation in early stages of amyotrophic lateral sclerosis demonstrated by 123I-MIBG-SPECT
Druschky A; Spitzer A; Platsch G; Claus D; Feistel H; Druschky K; Hilz MJ; Neundorfer B
1999 May;99(5):308-314, Acta neurologica Scandinavica
Involvement of the autonomic cardiac nervous system in early stages of amyotrophic lateral sclerosis (ALS) was evaluated in 40 patients. I-123-metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT) and heart rate variability (HRV) yielded information about sympathetic and parasympathetic innervation of the heart. MIBG-SPECT is a sensitive diagnostic method for demonstration of early cardiac sympathetic denervation. Both sympathetic and parasympathetic dysfunction was observed in 16 (40%) out of 40 patients. Mean cardiac MIBG uptake as demonstrated by the heart/mediastinum ratio was significantly reduced in all ALS patients in comparison with controls (P<0.01). The global MIBG-SPECT score was clearly abnormal in 29% and slightly abnormal in 22% of patients. HRV was diminished in 6 of 38 patients, 4 of whom having an abnormal MIBG-SPECT score as well. The presented results indicate that ALS patients with mild to moderate impairment may have evidence of postganglionic sympathetic adrenergic cardiac or cardiovagal denervation. To our knowledge, this is the first study indicating possible postganglionic sympathetic denervation in ALS. The original concept of ALS as an isolated degeneration of motor neurons seems to extend to a more widespread understanding of the disease which possibly represents different entities
— id: 37045, year: 1999, vol: 99, page: 308, stat: Journal Article,

Cardiac sympathetic denervation in Ross syndrome demonstrated by MIBG-SPECT
Druschky K; Hilz MJ; Koelsch C; Platsch G; Neundoerfer B
1999 May 28;76(2-3):184-187, Journal of the autonomic nervous system
We investigated cardiac sympathetic innervation by metaiodobenzylguanidine (MIBG) imaging in a patient with tonic pupils, loss of tendon reflexes, and segmental anhidrosis (Ross syndrome). Despite normal cardiovascular reflex tests, we observed a reduced global myocardial MIBG uptake as well as a regional uptake defect over the posterolateral cardiac territory indicating left ventricular peripheral sympathetic denervation. MIBG imaging seems to be a useful noninvasive diagnostic method for detection of early--possibly subclinical--cardiac autonomic impairment in Ross syndrome and provides further evidence of injury to postganglionic autonomic neurons as the underlying pathological mechanism of the disease
— id: 37043, year: 1999, vol: 76, page: 184, stat: Journal Article,

Transcranial Doppler sonography during acute 80 degrees head-down tilt (HDT) for the assessment of cerebral autoregulation in humans
Heckmann JG; Hilz MJ; Hagler H; Muck-Weymann M; Neundorfer B
1999 Jul;21(5):457-462, Neurological research
Cerebrovascular hemodynamics during postural changes have been sparsely investigated despite the fact that abnormal responses may contribute to the risk of stroke. The aim of this study was to determine the effect of acute 80 degrees head-down tilt (HDT) on cerebrovascular hemodynamics in humans using transcranial Doppler sonography (TCD). In 13 healthy volunteers (2 female, 11 male, age 19-37 years, mean age 26.8 years) left midcerebral artery blood flow velocities (CBFVs) were continuously monitored using TCD during 180 sec in horizontal position and during 60 sec of 80 degrees HDT. Simultaneously, systolic, diastolic, mean CBFVs, pulsatility index (PI), heart rate, beat-to-beat blood pressure (BP) and transcutaneous pCO2 were measured. In five volunteers, the procedure was repeated the next day to test the repeatability of the results. Mean BP increased slightly, but not significantly during tilt (from 80.5 +/- 7.7 mmHg to 85.9 +/- 14.1 mmHg; p > 0.05). Heart rate decreased significantly during the first 20 sec of HDT (from 66.8 +/- 9.9 min-1 to 60 +/- 11 min-1; p < 0.05). Transcutaneous pCO2 was within physiological ranges during the whole procedure (mean pCO2 minimum 39.5 +/- 2.9 mmHg, mean pCO2 maximum 42.2 +/- 3.3 mmHg). Mean CBFV did not change significantly during tilt (from 70.1 +/- 19.1 cm sec-1 to 66.6 +/- 14.1 cm sec-1; p > 0.05). PI, however, increased significantly with a more pronounced increase during the first 20 sec than the last 40 sec of tilt (PIsupine 0.92 +/- 0.11; PItilt(0-20 sec) 1.15 +/- 0.18; PItilt(21-60 sec) 1.03 +/- 0.16; p = 0.001; p = 0.017). The HDT results were found to be reproducible in the five volunteers. During 80 degrees-HDT mean BP and pCO2 did not change significantly. This observation combined with the significant decrease in heart rate during the first 20 sec of HDT, suggests that there is no sympathetic activation. The significant PI increase during HDT indicates a vasoconstriction of the cerebral resistance vessels. We assume that this vasoconstriction is due to the myogenic mechanism of cerebrovascular autoregulation triggered by a rapid, passive intracranial blood volume influx during HDT
— id: 37040, year: 1999, vol: 21, page: 457, stat: Journal Article,

Vestibular evoked blood flow response in the basilar artery
Heckmann JG; Leis S; Muck-Weymann M; Hilz MJ; Neundorfer B
1999 Jul;100(1):12-17, Acta neurologica Scandinavica
BACKGROUND AND PURPOSE: Monitoring of the basilar artery (BA) is difficult and has been sparsely performed. The aim of this study was to present physiological data of functional transcranial Doppler sonography (TCD) of the BA during caloric vestibular stimulation in healthy volunteers. METHODS: TCD of the BA was performed in 26 healthy volunteers (14 women, 12 men, age 25.1+/-3 years) during caloric vestibular stimulation. Vertigo was documented using electronystagmography (ENG) and a subjective vertigo scale ranging from 0 to 10 points. Simultaneously, capnogpraphy was performed. RESULTS: All subjects experienced vertigo, nausea and oszillopsia during vestibular irrigation. The average subjective vertigo was for a period of 106 s (+/-65.4); the average subjective estimated degree of vertigo was 6.7 points (+/-1.5). In all subjects, ENG demonstrated horizontal nystagm to the left non-irrigated side. In 14 subjects the subjective vertigo was rated by the individuals as extreme (point score > or =7) and in 12 subjects as low (point score <7). Mean flow velocity (MFV) in the BA increased significantly during vestibular irrigation, being more prominent in the initial irrigation and vertigo phase (5.8+/-5.9%, P<0.05) than in the second vertigo phase (2.2+/-8.8%, P<0.05). The calculated pulsatility index (PI), which indicates the condition of the small resistance vessels, decreased significantly (-4.9+/-8.1%; 4.3+/-8.9%, P<0.05) during both phases of vestibular activation. End tidal pCO2 did not change significantly (constant 5.4+/-0.4 Vol%), but respiration frequency was significantly increased during vestibular stimulation (12.3+/-3.8 min(-1) to 16.4+/-5.3 min(-1) and 16.3+/-4.8 min(-1), P<0.05) probably as a vegetative sign of vertigo. The observed MFV- and PI-changes were more prominent, although not quite significant, in the subgroup of subjects who experienced extreme subjective vertigo than in the subgroup who experienced low subjective vertigo. CONCLUSION: These observations indicate that MFV increase in the posterior circulation is due to activation of the vestibulocerebellum. In addition, it is possible that the previously elaborated MFV increase in the MCA might contribute to MFV increase in the BA via the posterior communicating artery. The difference in the 2 subgroups (extreme vertigo vs. low vertigo) may reflect the great variety of anatomical and physiological conditions of the peripheral vestibular organ, the brainstem anatomy and the corresponding blood supply. For clinical purposes this TCD-test may contribute to the investigation of the vasomotor reserve of the posterior circulation, e.g. in patients with vertebrobasilar ischemia, bilateral vestibular loss or local neurodegenerative disease
— id: 37042, year: 1999, vol: 100, page: 12, stat: Journal Article,

[Detection of patent foramen ovale. Transesophageal echocardiography and transcranial Doppler sonography with ultrasound contrast media are "supplementary, not competing, diagnostic methods"]
Heckmann JG; Niedermeier W; Brandt-Pohlmann M; Hilz MJ; Hecht M; Neundorfer B
1999 Jul 15;94(7):367-370, Medizinische klinik
BACKGROUND: The prevalence of patent foramen ovale (PFO) in healthy individuals is estimated to be about 25% and is elevated to 40% patients with stroke. To date transesophageal echocardiography (TEE) was considered to be the most sensitive method to detect PFO and was regarded as the gold standard. Transcranial Doppler sonography of the middle cerebral artery during contrast injection (c-TCD) has recently been proposed as an alternative method for the detection of PFO. We report our experience on 45 patients (age < 55 years) with stroke or transient ischemic attack (TIA) in whom both c-TCD and TEE were performed to detect PFO as a mechanism for embolic cerebral ischemia. PATIENTS AND METHODS: In 45 patients (21 women, 24 men, mean age 41.4 years ranging from 17 to 54 years) with cerebral ischemia, both standardized TEE and standardized c-TCD were performed separately. When any PFO was found by TEE and/or c-TCD, it was classified as positive. If c-TCD was positive but TEE negative, a second TEE was performed and vice versa. RESULTS: PFO was found epicritically in 26 patients (57.8%). First TEE detected PFO in 24 cases (sensitivity 92.3%). Separately performed c-TCD detected PFO in 22 cases of the PFO-positive cases (sensitivity 84.6%). However, c-TCD detected PFO in 2 cases, in which the first TEE had been negative, leading to a second TEE which confirmed PFO and demonstrated minimal shunt (7.7%). TEE detected PFO in 4 cases in which first c-TCD was negative. A second c-TCD confirmed in 2 of these 4 cases a positive right-to-left shunt. Neither method revealed false positive results (specifity 100%). The positive predictive value was 100% in both methods. The negative predictive value in TEE was 90.5% and in c-TCD was 82.6%. CONCLUSION: TEE and c-TCD are not concurrent diagnostic tools to detect PFO. Both supplement each other. If both methods are used in all PFO-suspected patients, PFO detection rate is higher than when using either method alone
— id: 37041, year: 1999, vol: 94, page: 367, stat: Journal Article,

Sympathetic skin response following thermal, electrical, acoustic, and inspiratory gasp stimulation in familial dysautonomia patients and healthy persons
Hilz MJ; Azelrod FB; Schweibold G; Kolodny EH
1999 Aug;9(4):165-177, Clinical autonomic research
To determine whether sympathetic skin response (SSR) testing evaluates afferent small or efferent sympathetic nerve fiber dysfunction, we studied SSR in patients with familial dysautonomia (FD) in whom both afferent small and efferent sympathetic fibers are largely reduced. We analyzed whether the response pattern to a combination of stimuli specific for large or small fiber activation allows differentiation between afferent and efferent small fiber dysfunction. In 52 volunteers and 13 FD patients, SSR was studied at palms and soles after warm, cold and heat as well as electrical, acoustic, and inspiratory gasp stimulation. In addition, thermal thresholds were assessed at four body sites using a Thermotest device (Somedic; Stockholm, Sweden). In volunteers, any stimulus induced reproducible SSRs. Only cold failed to evoke SSR in two volunteers. In all FD patients, electrical SSR was present, but amplitudes were reduced. Five patients had no acoustic SSR, four had no inspiratory SSR. Thermal SSR was absent in 10 patients with abnormal thermal perception and present in one patient with preserved thermal sensation. In two patients, thermal SSR was present only when skin areas with preserved temperature perception were stimulated. In patients with FD, preserved electrical SSR demonstrated the overall integrity of the SSR reflex but amplitude reduction suggested impaired sudomotor activation. SSR responses were dependent on the perception of the stimulus. In the presence of preserved electrical SSR, absent thermal SSR reflects afferent small fiber dysfunction. A combination of SSR stimulus types allows differentiation between afferent small or efferent sympathetic nerve fiber dysfunction
— id: 56486, year: 1999, vol: 9, page: 165, stat: Journal Article,

[Epilepsy and autonomic diseases]
Hilz MJ; Dutsch M; Kolsch C
1999 Feb;67(2):49-59, Fortschritte der neurologie-psychiatrie
This review article focuses on the functional anatomy of the central autonomic nervous system and the autonomic symptoms and dysfunctions occurring with epileptogenic activity involving areas of the central autonomic nervous system. Clinical experiences have demonstrated a close relation between epileptic and central autonomic activity. Autonomic symptoms are frequent signs of epileptic seizures and may cause dysfunctions in almost every organ system. Cardiorespiratory dysfunction has been described interictually. The increased frequency of sudden unexplained death in epilepsy patients may be related to disturbances in cardiac autonomic control. In contrast, electrical vagal stimulation reduces epileptogenic activity by influencing the central autonomic nervous system
— id: 37046, year: 1999, vol: 67, page: 49, stat: Journal Article,

Sympathetic skin response differentiates hereditary sensory autonomic neuropathies III and IV
Hilz MJ; Stemper B; Axelrod FB
1999 May 12;52(8):1652-1657, Neurology
OBJECTIVE: To evaluate whether sympathetic skin response (SSR) differs in patients with hereditary sensory autonomic neuropathy (HSAN) types III and IV. BACKGROUND: HSAN types III and IV are rare autosomal recessive disorders that cause many similar autonomic, sensory, and motor dysfunctions, but different sweating characteristics. HSAN III patients have preserved and at times, excessive sweating, whereas anhidrosis is characteristic of HSAN IV. SSR reflects the integrity of sympathetic sudomotor fibers and the activation of sweat glands through the change in skin resistance in response to an arousal stimulus. Therefore, SSR is a test method that might facilitate differential diagnosis of HSAN III and IV. METHODS: In 17 HSAN III patients (eight women, nine men; mean age, 20.65+/-5.45 years) and seven HSAN IV patients (five girls, two boys; mean age, 10.0+/-5.45 years) SSR was recorded from the palms and soles after repeated electrical, acoustic, and inspiratory gasp stimulations. In addition, all subjects underwent a neurologic examination; studies of median, peroneal motor, and sural nerve conduction velocities; and determination of vibratory and thermal perception thresholds. RESULTS: Although clinical differences were appreciated between the two types of HSANs, both HSANs had evidence of small-fiber involvement. Both HSANs had abnormal temperature and pain perception. In contrast, SSR was preserved in all HSAN III and absent in all HSAN IV patients. CONCLUSION: SSR provides another parameter to improve differentiation of HSAN III from HSAN IV, and also gives us additional information regarding sympathetic sudomotor fiber function in these developmental diseases
— id: 6114, year: 1999, vol: 52, page: 1652, stat: Journal Article,

Quantitative thermal perception testing in adults
Hilz MJ; Stemper B; Axelrod FB; Kolodny EH; Neundorfer B
1999 Sep;16(5):462-471, Journal of clinical neurophysiology
In 225 adults aged 18 to 80 years, normative warm and cold perception thresholds were assessed at the volar distal forearm, thenar eminence, lower medial calf, and lateral dorsal foot using the method of limits and a Thermotest (Somedic, Stockholm, Sweden). A 1.5-cm x 2.5-cm thermode, a 1 degrees C/s stimulus change rate, and a 32 degrees C baseline temperature were applied. Thresholds of five consecutive stimuli were averaged. At the thenar eminence a 3 degrees C/s stimulation was applied in addition to the 1 degree C/s stimulation. Effects of spatial summation were studied at the calf and forearm by additional testing with a 2.5-cm x 5.0-cm thermode. To evaluate the influence of skin temperature, thresholds were correlated with the pretest skin temperature at the tested sites. Reproducibility of stimulus perception was determined by comparing the lowest to the highest response to five consecutive stimuli. Results showed sufficient accuracy of thermal perception thresholds. Thresholds were higher with the 3 degrees C/s stimulation than with the 1 degree C/s stimulation. Thresholds were lower with the large than with the small probe. Skin temperature had only minimal influence on thresholds. The use of a 32 degrees C baseline temperature and a 1 degree C/s stimulus change rate is recommended. The large probe should be used at body sites where the entire thermode surface adjusts planely to the skin. Warming up the tested skin area is not necessary before thermotesting
— id: 37039, year: 1999, vol: 16, page: 462, stat: Journal Article,

Cold face test demonstrates parasympathetic cardiac dysfunction in familial dysautonomia
Hilz MJ; Stemper B; Sauer P; Haertl U; Singer W; Axelrod FB
1999 Jun;276(6 Pt 2):R1833-R1839, American journal of physiology
In familial dysautonomia (FD), i.e., Riley-Day syndrome, parasympathetic dysfunction has not been sufficiently evaluated. The cold face test is a noninvasive method of activating trigeminal brain stem cardiovagal and sympathetic pathways and can be performed in patients with limited cooperation. We performed cold face tests in 11 FD patients and 15 controls. For 60 s, cold compresses (0-1 degrees C) were applied to the cheeks and forehead while we monitored heart rate, respiration, beat-to-beat radial artery blood pressure, and laser-Doppler skin blood flow at the first toe pulp. From these measurements heart rate variability parameters were calculated: root mean square of successive differences (RMSSD), coefficient of variation (CV), low- and high-frequency (LF and HF, respectively) power spectra of the electrocardiogram, and the LF transfer function gain between blood pressure and heart rate. All patients perceived cold stimulation and acknowledged discomfort. In controls, heart rate and skin blood flow decreased significantly during cold face test; in patients, both parameters decreased only briefly and not significantly. In controls, blood pressure, RMSSD, CV, and heart rate HF-power spectra increased but remained unchanged in patients. Respiration, as well as heart rate LF power spectra, did not change in either group. In controls, LF transfer function gain between blood pressure and heart rate indicated that bradycardia was not secondary to blood pressure increase. We conclude that the cold face test demonstrated that patients with FD have a reduced cardiac parasympathetic response, which implies efferent parasympathetic dysfunction
— id: 37044, year: 1999, vol: 276, page: R1833, stat: Journal Article,

The contribution of sensory nerves to the cutaneous microcirculation in patients with type 1 and type 2 diabetes
Kilo, S; Berghoff, M; Hilz, MJ; Freeman, R
1999 ;52(6):A389-A389, Neurology
— id: 104767, year: 1999, vol: 52, page: A389, stat: Journal Article,

Disturbances of the vegetative nervous system
Neundorfer, B; Hilz, MJ
1999 ;26(2):49-54, Aktuelle Neurologie
The autonomic nervous system consists of two different components: the sympathetic and the parasympathetic nervous system, which are controlled by a central network in the brain and spinal cord. Therefore autonomic dysfunctions are caused by a variety of diseases of the CNS and PNS. Due to CNS diseases there are two general types of autonomic dysfunctions. Firstly deficiency syndromes caused by cell lesions and secondly pure dysfunctions without any structural lesions. Typical primary deficiency syndromes are MSA and Parkinson's disease; secondary deficiency syndromes are, for example, brain infarctions or syringomyelia. Typical examples of pure dysfunctions of the autonomic nervous system are side effects of drugs. Consecutive symptoms of an efferent autonomic denervation are pupillary dysfunction, trophic disturbances, anhidrosis and vasodysregulation; consecutive symptoms of an autonomic visceral denervation are cardioneuropathy, gastrointestinal disorders and urogenital disturbances. Diabetes mellitus is the most important etiology of autonomic peripheral neuropathy. $$:
— id: 104768, year: 1999, vol: 26, page: 49, stat: Journal Article,

Genetic heterogeneity in hereditary and autonomic sensory neuropathy type 4 (HSAN4)
Oddoux, C; Wang, J; Clayton, CM; Hilz, M; Cilio, R; Bertini, E; Mayaan, C; Blumenfeld, A; Axelrod, F; Ostrer, H
1999 OCT ;65(4):A482-A482, American journal of human genetics
— id: 53834, year: 1999, vol: 65, page: A482, stat: Journal Article,

Neurophysiologic findings in diabetic neuropathy: nerve conduction studies, electromyography, quantitative sensory testing
Hecht, M; Hilz, MJ
1998 ;17(10):430-436, Nervenheilkunde
Diabetic neuropathy is a mixed, but predominantly axonal neuropathy of all fiber types. Axonal damage accounts for fibrillations in needle electromyography (EMG). Nerve conduction studies show amplitude reduction of compound muscle action potentials and sensory nerve action potentials due to axonal damage. Peripheral nerve demyelination induces slight or moderate nerve conduction slowing. In early stages, distal foot muscles show fibrillations, sural nerve conduction is abnormal, peroneal nerve F-wave and H-reflex-latencies are prolonged. In advanced stages, EMG of proximal leg muscles or even arm muscles and upper extremity nerve conduction are abnormal. Diabetic radiculopathies and mononeuropathies are diagnosed by EMG. Mechanical ethiologies have to be ruled out by neuroimaging. Quantitative sensory testing (QST) is of high diagnostic value in diabetic neuropathy. Vibratory and thermal threshold evaluation unveil early neuropathy. Thermotesting is particularly valuable in the assessment of diabetic small fiber neuropathy and allows monitoring of the disease. $$:
— id: 104769, year: 1998, vol: 17, page: 430, stat: Journal Article,

Myogenic cerebrovascular autoregulation in migraine measured by stress transcranial Doppler sonography
Heckmann JG; Hilz MJ; Katalinic A; Marthol H; Muck-Weymann M; Neundorfer B
1998 Apr;18(3):133-137, Cephalalgia
BACKGROUND AND PURPOSE: Transcranial Doppler sonography (TCD) studies may help to elucidate the nature and role of vascular abnormalities in migraine. Our aim in this study was to evaluate cerebrovascular autoregulative response in migraine patients with and without aura to blood pressure increase using stress TCD. PATIENTS AND METHODS: Using transcranial Doppler ultrasound at rest and during ergometer stress (stress TCD), we studied the changes in mean flow velocities and resistance index (RI) in relation to physical stress in the middle cerebral artery. Fifteen migraine patients without aura, 15 migraine patients with aura, and 15 healthy control subjects were examined. Patients suffered from predominantly unilateral headache and were studied during an attack-free period. The Pourcelot's RI as a measure of cerebrovascular reactivity was calculated by dividing the difference between systolic and diastolic velocity by the systolic velocity. RESULTS: None of the subgroups showed any difference during ergometer exercise with regard to blood pressure, endtidal CO2, heart rate, or mean flow velocity. In all subgroups, sufficient physical stress was achieved. With respect to RI change, migraine patients without aura and healthy controls did not differ (p > 0.05). However, the RI change of migraine patients with aura was significantly lower than the RI change of migraine patients without aura or healthy subjects (p > 0.05). The discrimination analysis showed in addition that RI change (absolute and as a percentage) and mean flow velocity change (as a percentage) could be used as diagnostic variables to detect patients with aura symptoms. CONCLUSION: Differences exist in cerebrovascular reactivity in migraine patients with aura that may contribute to the neurologic disturbances in these patients during attack. We propose that there is disorder of myogenic cerebrovascular autoregulation in migraine patients with aura during headache-free intervals
— id: 37048, year: 1998, vol: 18, page: 133, stat: Journal Article,

[Transcranial Doppler exercise test in patients with chronic tension headache]
Heckmann JG; Muck-Weymann M; Katalinic A; Hilz MJ; Claus D; Neundorfer B
1998 Feb;69(2):131-136, Nervenarzt
In the etiopathology of tension type headache, vascular and autonomic disorders are discussed. Fifteen patients with chronic tension type headache according to the criteria of the IHS were investigated using the TCD-ergometer-test--a method used to evaluate the myogenic mechanism of cerebrovascular autoregulation--and the results were compared with the findings in fifteen healthy control subjects. The patients' Mean Flow Velocity (TAVmean) and Resistance Index (RI) at rest and after exercise were significantly decreased (p < 0.05). During exercise they normalized. The patients' endtidal pCO2 at rest and during exercise was significantly lower than the corresponding values of the control group (p < 0.05). Regarding blood pressure elevation and heart rate increase during exercise both groups did not differ significantly (p > 0.05). These findings suggest that patients with tension type headache have a diminished vascular tone in the cerebral vessels at rest which is normalised during exercise. The reduced endtidal pCO2 is considered as a physiological response to increase vascular tone via metabolic mechanism of cerebrovascular autoregulation. In conclusion it is suggested that therapeutic procedures which activate sympathetic autonomic nervous function to train cerebral vessels should be more carefully considered
— id: 37049, year: 1998, vol: 69, page: 131, stat: Journal Article,

Current diagnostic procedures for the detection of patent foramen ovale
Heckmann, JG; Hilz, MJ; Brandt-Pohlmann, M; Hecht, M; Neundorfer, B
1998 ;17(10):458-460, Nervenheilkunde
The prevalence of patent foramen ovale (PFO) in healthy individuals is estimated to be about 25% and is elevated to 60% in young patients with kryptogenetic stroke. Pathophysiologically during unvoluntary Valsalva manoeuvres a paradoxical embolism from the venous to the arterial system often occurs. To date, transesophageal echocardiography (TEE) was considered to be the most sensitive way to detect PFO. TEE, however, is semiinvasive, and there are a number of serious complications such as bleeding, hypoxia, bronchospasm, cardiac arrhythmias, bacteremia and sudden cardiac arrest. Transcranial Doppler sonography of the middle cerebral artery during contrast injection [Echovist (c-TCD)] has recently been proposed as an alternative method for the detection of PFO. In a PFO-positive case the typical Doppler wave spectrum is overlapped by high intensity transient signals (HITS) which are caused by the contrast bubbles in the blood stream. However, in the literature and in our own experience there are single cases with false negative results in TEE or in c-TCD. Both methods have a sensitivity of approximately 90% and a specifity of 100%. TEE and TCD-Echovist, used separately, have the small risk of false negative result. Combined use of both methods, however, increases the PFO detection rate. $$:
— id: 104770, year: 1998, vol: 17, page: 458, stat: Journal Article,

Normative values of vibratory perception in 530 children, juveniles and adults aged 3-79 years
Hilz MJ; Axelrod FB; Hermann K; Haertl U; Duetsch M; Neundorfer B
1998 Aug 14;159(2):219-225, Journal of the neurological sciences
Impaired vibratory perception is an early and frequent finding in various neuropathies. Quantitative vibratory threshold assessment refines the diagnosis of neuropathies but is based on psychophysical techniques requiring patient cooperation. Large, age and sex matched normative data bases are needed to better identify abnormal vibratory perception. In this study vibratory perception was tested at the second metacarpal bone and above the first metatarsal bone of 530 children, juveniles and adults aged 3.3-79.2 years. Thresholds assessed with a 128 Hz graded Rydel-Seiffer tuning fork, TF, were compared to three Vibrameter values, the vibration perception thresholds, VPT, determined with increasing vibration stimuli, the vibration disappearance threshold, VDT, determined with decreasing supraliminal stimuli, and the vibration threshold VT which equals the mean of VPT and VDT. The influence of gender, age, body height, weight and skin temperature at the tested site on thresholds was studied. Retest reliability was tested in 73 children aged 3.3-6.9 years and in 20 volunteers aged 5.2-66.1 years who were also tested for the influence of pretest skin warming on thresholds and for differences between results of the left and right body side. TF, VPT, VDT, VT were closely correlated with each other (Spearman: -0.67<Rs<-0.47; P<0.01). The skin temperature, body side, weight and height did not influence thresholds. In adults, thresholds increased with age and were higher in men above the age of 50 than in women of the same age. Thresholds at the feet were higher than at the hands (Wilcoxon: P<0.001). Retest reliability was high and did not depend on the retest interval. The study provides important normative data for the widespread use of quantitative vibration testing
— id: 7600, year: 1998, vol: 159, page: 219, stat: Journal Article,

[Autonomic disorders in polyneuropathies]
Hilz MJ; Dutsch M; Neundorfer B
1998 Sep 15;93(9):533-540, Medizinische klinik
BACKGROUND: Many polyneuropathies manifest autonomic disturbances. Diabetic neuropathy, the most frequent neuropathy in the western world, serves as model of the symptomatology of autonomic disturbances. DIABETIC NEUROPATHY: Clinical symptoms comprise pupillary and cardiovascular dysfunction such as orthostatic hypotonia and syncopes, thermoregulatory, gastrointestinal symptoms, disturbances in urogenital and respiratory function and unawareness of hypoglycemia. OTHER NEUROPATHIES: This article also describes autonomic symptoms in alcoholic neuropathy, in Guillain-Barre syndrome, in paraneoplastic polyneuropathies, in toxic neuropathies, in acute and subacute autonomic neuropathy, in amyloidosis, in porphyria, in familiar dysautonomia, in HIV infection and in botulism
— id: 37047, year: 1998, vol: 93, page: 533, stat: Journal Article,

Highly abnormal thermotests in familial dysautonomia suggest increased cardiac autonomic risk
Hilz MJ; Kolodny EH; Neuner I; Stemper B; Axelrod FB
1998 Sep;65(3):338-343, Journal of neurology neurosurgery & psychiatry
OBJECTIVE: Patients with familial dysautonomia have an increased risk of sudden death. In some patients with familial dysautonomia, sympathetic cardiac dysfunction is indicated by prolongation of corrected QT (QTc) interval, especially during stress tests. As many patients do not tolerate physical stress, additional indices are needed to predict autonomic risk. In familial dysautonomia there is a reduction of both sympathetic neurons and peripheral small nerve fibres which mediate temperature perception. Consequently, quantitative thermal perception test results might correlate with QTc values. If this assumption is correct, quantitative thermotesting could contribute to predicting increased autonomic risk. METHODS: To test this hypothesis, QTc intervals were determined in 12 male and eight female patients with familial dysautonomia, aged 10 to 41 years (mean 21.7 (SD 10.1) years), in supine and erect positions and postexercise and correlated with warm and cold perception thresholds assessed at six body sites using a Thermotest. RESULTS: Due to orthostatic presyncope, six patients were unable to undergo erect and postexercise QTc interval assessment. The QTc interval was prolonged (>440 ms) in two patients when supine and in two additional patients when erect and postexercise. Supine QTc intervals correlated significantly with thermal threshold values at the six body sites and with the number of sites with abnormal thermal perception (Spearman's rank correlation p<0.05). Abnormal Thermotest results were more frequent in the four patients with QTc prolongation and the six patients with intolerance to stress tests. CONCLUSION: The results suggest that impaired thermal perception correlates with cardiac sympathetic dysfunction in patients with familial dysautonomia. Thus thermotesting may provide an alternative, albeit indirect, means of assessing sympathetic dysfunction in autonomic disorders
— id: 7601, year: 1998, vol: 65, page: 338, stat: Journal Article,

Quantitative thermal perception testing in 225 children and juveniles
Hilz MJ; Stemper B; Schweibold G; Neuner I; Grahmann F; Kolodny EH
1998 Nov;15(6):529-534, Journal of clinical neurophysiology
Quantitative Thermotesting evaluates peripheral small nerve fiber function. The method of limits is a widely used algorithm of perception threshold determination. Normative data are needed to apply the method of limits in children and juveniles. In 225 healthy boys and girls, aged 7 to 17.9 years, warm and cold perception thresholds were established with the method of limits at the volar distal forearm, the thenar eminence, the lower medial calf, the lateral dorsal foot, and the cheek. A 1 degree C/s stimulus velocity, a 32 degrees C thermode baseline, and a 1.5-cm x 2.5-cm Thermotest stimulator were used. Accuracy of stimulus perception was studied by comparing the lowest to the highest response of five consecutive stimuli. The influence of different stimulator sizes on thresholds was tested at the lower calf and distal forearm with an additional 2.5-cm x 5.0-cm thermode. To determine the impact of the pretest skin temperature on thresholds, skin temperature was correlated with thresholds. Results showed good intratrial reproducibility of thresholds. The large thermode yielded lower thresholds than the small probe. Skin temperature had only minor influence on thresholds. The large probe should be used at body sites where it adjusts planely
— id: 6043, year: 1998, vol: 15, page: 529, stat: Journal Article,

Hemispheric inactivation during intracarotid amobarbital test suggests right hemispheric lateralization of sympathetic cardiac control
Hilz, MJ; Devinsky, O; Duetsch, M; Perrine, K; Rauhut, U; Nelson, PK
1998 SEP ;44(3):M35-M35, Annals of neurology
— id: 104276, year: 1998, vol: 44, page: M35, stat: Journal Article,

Transcranial Doppler sonography during acute 80-degree head-down tilt for the assessment of cerebral autoregulation humans
Hilz, MJ; Russo, H; Hagler, H; Muck-Weymann, M; Neundorfer, B
1998 ;44(3):T162-T162, Annals of neurology
— id: 104772, year: 1998, vol: 44, page: T162, stat: Journal Article,

Staging of diabetic polyneuropathy
Hilz, MJ; Stemper, B
1998 ;17(10):424-429, Nervenheilkunde
Uniform criteria are necessary for the diagnosis and staging of diabetic neuropathy. In 1988 the San Antonio Consensus Conference on Diabetic Neuropathy recommended the assessment of five diagnostic categories: neuropathic symptoms, neuropathic deficits, pathologic nerve conduction studies, pathologic quantitative sensory examinations and pathologic quantitative autonomic examination. The 'Rochester Diabetic Neuropathy Study' (RDNS)-group recommended to base the diagnosis of diabetic neuropathy on pathologic findings in at least two of these five categories. We review present the minimal diagnostic criteria required to define abnormality for each of these categories. Clinical parameters as well as various scores, e.g. the Neuropathy Impairment Score, Neuropathy Dis ability Score, and Neuropathy Symptom Score are discussed. An easily applicable tool to stage polyneuropathy is the Erlangen Neuropathy Assessment Questionnaire. $$:
— id: 104771, year: 1998, vol: 17, page: 424, stat: Journal Article,

Impaired endothelium dependent with preserved non-endothelium dependent cutaneous microvascular function in patients with insulin dependent diabetes mellitus
Kilo, S; Khalil, LA; Veves, A; Hilz, MJ; Freeman, R
1998 ;50(4):S55005-S55005, Neurology
— id: 104773, year: 1998, vol: 50, page: S55005, stat: Journal Article,

Ludwig Robert Muller (1870-1962)--a pioneer of autonomic nervous system research
Neundorfer B; Hilz MJ
1998 Feb;8(1):1-5, Clinical autonomic research
Ludwig Robert Muller, MD, professor of internal medicine, born in 1870 in Augsburg, Bavaria, studied medicine from 1890 to 1893 in various European cities and specialized in pathology and bacteriology. In 1895, he joined A. Strumpell, one of Germany's outstanding internists and neurologists, in Erlangen, Germany. Henceforth, Muller focused on the autonomic nervous system. In his 1898 Habilitation, a thesis required to join the academic faculty, which he entitled Anatomy and pathology of the lower spinal cord, he presented studies on the autonomic innervation of the bladder and colon. Based on animal studies, he continued to publish essential findings on the autonomic innervation of heart, lungs, and gastrointestinal tract. Muller was the first to report afferent pathways from internal organs to the brain. His book The vegetative nervous system was first published in 1920. In 1931, he wrote the book Lebensnerven und Lebenstriebe (Life nerves and life instincts). Many of his papers dealt with the regulation of thirst, hunger and sleep. He was Chairman of Internal Medicine in Wurzburg, Germany, from 1914 to 1920, and also in Erlangen as Strumpell's successor from 1920 to 1936. The broad scope of Muller's publications makes him one of the important pioneers of autonomic nervous system research
— id: 37050, year: 1998, vol: 8, page: 1, stat: Journal Article,

Diabetic autonomic neuropathy: cardiovascular and peripheral autonomic findings
Stemper, B; Hilz, MJ
1998 ;17(10):437-443, Nervenheilkunde
Dysfunction of autonomic nervous system affects up to 30% of patients with diabetes mellitus after 10 to 15 years. The autonomic neuropathy, especially cardiovascular autonomic neuropathy has a broad influence on the course and the prognosis of patients. Non-invasive cardiovascular reflex tests and tests of sudomotor control allow to diagnose autonomic dysfunction before the patients develop a symptomatic autonomic neuropathy. There is evidence that deterioration of autonomic dysfunction can be prevented and autonomic function even improves with good metabolic control e.g. by means of insulin infusion systems. This manuscript describes cardio-vascular and sudomotor function tests as well as two batteries of tests used for evaluation and classification of cardiovascular autonomic neuropathy. $$:
— id: 104774, year: 1998, vol: 17, page: 437, stat: Journal Article,

Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter
Weiser M; Hilz MJ; Bronfin L; Axelrod FB
1998 Feb;8(1):13-23, Clinical autonomic research
Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation
— id: 7846, year: 1998, vol: 8, page: 13, stat: Journal Article,

Differentiation of carpal tunnel syndrome versus polyneuropathy in diabetic patients
Zahner, B; Hilz, MJ
1998 ;17(10):444-451, Nervenheilkunde
The additional occurring of entrapment syndromes in patients who suffer from diabetic neuropathy frequently causes diagnostic problems. The electrophysiological differentiation is often complicated. The following article gives a literature rewiew about the frequency of the combination of both diseases. Possible reasons for the frequent coincidence of these two diseases are explained. The electrophysiological techniques to differentiate whether a patient's symptoms are caused by a diabetic polyneuropathy or a carpal tunnel syndrome are shown. $$:
— id: 104775, year: 1998, vol: 17, page: 444, stat: Journal Article,

Therapy of diabetic polyneuropathy - present and future perspectives
Zahner, B; Hilz, MJ
1998 ;17(10):452-457, Nervenheilkunde
Up to now, treatment of diabetic polyneuropathy remains unsatisfactory. Nevertheless, new pathogenetic concepts about the possible reasons for the development of diabetic neuropathy create new therapeutic approaches to the disease. The following article reviews the therapeutic agents commonly used. Furthermore some new substances are reported which interfere in the pathogenetic pathway of diabetic neuropathy and might be beneficial for the patients suffering from this neuropathy in the future. $$:
— id: 104776, year: 1998, vol: 17, page: 452, stat: Journal Article,

Benign exertional headache/benign sexual headache: a disorder of myogenic cerebrovascular autoregulation?
Heckmann JG; Hilz MJ; Muck-Weymann M; Neundorfer B
1997 Oct;37(9):597-598, Headache
— id: 37051, year: 1997, vol: 37, page: 597, stat: Journal Article,

Effect of dopamine on middle cerebral artery blood flow: A single case study
Heckmann, JG; Erbguth, F; Huk, W; Hilz, MJ; Neundorfer, B
1997 ;5(3):107-110, Neurology, psychiatry, & brain research
We present a single case study on neurovascular dopamine effect in a patient with a circumscribed isolated hemodynamic relevant stenosis of the left intracranial internal carotid artery. After percutaneous transluminal angioplasty, angiography showed a restenosis and spasm. To improve cardiac output and to prevent hemodynamic reinfarction continously dopamine (4-7 mu g/kg body weight/min) was infused. Transcranial Doppler sonography (TCD) of the affected left middle cerebral artery (MCA) revealed a constant mean flow velocity (MFV) of 70 cm/sec despite hemodynamic changes due to dopamine. The Pulsatility Index (PI) was constantly low (0.4). suggesting a maximal vasodilation of the ipsilateral resistance vessels. In contrast, during dopamine infusion the MFV of the health!: right side increased from 42 cm/sec to 56 cm/sec and the PI decreased from 0.95 to 0.84. These recordings suggest that cerebral blood supply is augmented by dopamine infusion: firstly, due to an improved cardiac output and secondly, due to slight vasodilation of the cerebral resistance vessels. $$:
— id: 104778, year: 1997, vol: 5, page: 107, stat: Journal Article,

TCD during ergometer exercise - Method and case reports
Heckmann, JG; MuckWeymann, M; Grahmann, F; Claus, D; Hilz, MJ; Neundorfer, B
1997 ;24(2):79-83, Aktuelle Neurologie
TCD during ergometer exercise is a new method to evaluate the myogenic mechanism of cerebrovascular autoregulation. Twelve healthy subjects (4 f; 8 m; mean age 33.2 +/- 18.4 years) were investigated by TCD at rest and during ergometer exercise. The Resistance Index (RI) as a measure of vascular resistance was calculated by analysis of the Doppler wave spectrum. The increase of blood pressure (RRsyst. at rest = 118 +/- 7 mmHg; RRsyst. during exercise = 140 +/- 11 mmHg; p ? 0.0001) resulted in significant elevation of RI (RI at rest = 0.55 +/- 0.06; RI during exercise = 0.61 +/- 0.05; p = 0.0111). This phenomen is considered physiological and indicates an intact myogenic mechanism of cerebrovascular autoregulation. By measuring the end-tidal pCO(2) the metabolic autoregulative mechanism could be determined. In ten cases (patients with headache under exercise; patients with migraine and tension type headache; patients under medication of antiepileptic drugs and sympathetic blockers; patient with arterial hypertension; patient with polyneuropathy and autonomic disorder) we demonstrate the clinical relevance of the test. $$:
— id: 104777, year: 1997, vol: 24, page: 79, stat: Journal Article,

Paraneoplastic syndromes of the central and peripheral nervous system as well as the musculature
Neundorfer, B; Druschky, A; Hilz, MJ
1997 ;5(1):15-20, Neurology, psychiatry, & brain research
Paraneoplastic syndromes of the skeletal muscles as well as of the peripheral and central nervous system are relatively seldom. Typical, disorders are the dermatomyositis, the Lamwbert-Eaton-Syndrome, the subacute sensory neuropathy Denny-Brown, the paraneoplastic sensorimotor polyneuropathy. the subacute necrotizing myelopathy, the spinocerebellar degeneration, the subacute cerebellar degeneration and the encephalomyeloradiculitis with the subtypes bulbar encephalitis, limbic encephalitis and cerebellitis. In some of these disorders tissue-specific antibodies could be observed. This contributions gives an overview on 67 (out of 19.681) patients (0.34%) of our department, regarding the types of the p.s., the interval between the onset of p.s. and the diagnosis of the neoplasms. and the type of tumors accompanying the p.s. The hypotheses explaining the pathogenesis of the p.s., the epidemiology, symptomatology. diagnosis, differential diagnosis and therapeutic possibilities of the various p.s. are discussed and the own data compared with those of the literature. $$:
— id: 104779, year: 1997, vol: 5, page: 15, stat: Journal Article,

Late life polyneuropathy
Grahmann, F; Schober, S; Hilz, MJ; Neundorfer, B
1996 ;19(1):13-16, Age
A retrospective study over four years was performed reviewing the records of 1195 patients suffering from peripheral polyneuropathy without entrapment neuropathies, 613 patients over 60 years of age were compared with 582 patients under 60. Neurological diagnosis was made on the basis of personal and familyhistory, clinical examination, laboratory parameters, electrophysiology and in some cases by sural nerve biopsy, While diabetes was the most frequent etiology in both groups, it was more common in the old-age group (46.5% vs. 32.5%). Clinical manifestation of diabetic neuropathy did not differ. While alcoholism was not a major cause of late life polyneuropathy (2.62 vs. 15.5%), paraneoplastic neuropathy was somewhat more common in late life (3.42 vs, 2.4%) although this was not statistically significant. Paraproteinemic neuropathy as the only cause of neuropathy was found solely in the old-age group (0.8%). The percentage of cryptogenetic neuropathies was higher in late life (17.6% vs. 12.7%; p<0.05) with only the outpatients showing a statistically significant difference (p<0.05). From these findings, we concluded that there is a distinct etiological spectrum of neuropathies in late life, many with treatable causes, The higher percentage of cryptogenetic neuropathies in the elderly may be explained by a nonspecific neuropathy occurring in late life due to normal aging processes in the peripheral nerve. $$:
— id: 104780, year: 1996, vol: 19, page: 13, stat: Journal Article,

Quantitative thermal perception testing in preschool children
Hilz MJ; Glorius SE; Schweibold G; Neuner I; Stemper B; Axelrod FB
1996 Mar;19(3):381-383, Muscle & nerve
— id: 7002, year: 1996, vol: 19, page: 381, stat: Journal Article,

[Follow-up and prognosis of patients of a neurologic intensive care unit with special reference to age]
Neundorfer B; Hilz MJ; Wimbauer M
1996 Aug;64(8):285-291, Fortschritte der neurologie-psychiatrie
To evaluate risk factors effecting course and prognosis of neurological intensive care (ICU) patients with special respect to age, 422 patients (235 male, 187 female, mean age 56.7 years, standard deviation +/- 18.8 years) admitted to the ICU of the Department of Neurology, University Erlangen-Nurnberg, were retrospectively studied. The status at the time of ICU discharge was compared to that assessed 18-30 months later using the Barthel-Index, a five grade scale of independence, and the Glasgow Outcome Scale. At the time of reexamination, 203 of the 422 patients (48.2%) were still alive. The fatality rate increased with age. However, approximately 70% of the patients above the age of 70 years were still alive two years after ICU treatment with the majority of patients describing their life as satisfying. Multivariate analysis demonstrated that age by itself does not determine the course of disease. Age affects the prognosis only in combination with other variables such as preexisting diseases (e.g. stroke, carotid surgery, occlusive arterial disease), secondary complications (e. g. pneumonia), and specific ICU treatment (e.g. mechanical ventilation, nasogastric tube), and the patient's state at the time of ICU discharge (bedriddenness, aphasia, dementia)
— id: 37053, year: 1996, vol: 64, page: 285, stat: Journal Article,

Clinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination
Warner LE; Hilz MJ; Appel SH; Killian JM; Kolodry EH; Karpati G; Carpenter S; Watters GV; Wheeler C; Witt D; Bodell A; Nelis E; Van Broeckhoven C; Lupski JR
1996 Sep;17(3):451-460, Neuron
Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related 'myelinopathies' due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative)
— id: 37052, year: 1996, vol: 17, page: 451, stat: Journal Article,

[Improvement of temperature and vibration sense in chronic uremia after a single dialysis]
Hilz MJ; Claus D; Rosl G; Hofmann E; Braun J; Neundorfer B
1995 Jul;63(7):264-269, Fortschritte der neurologie-psychiatrie
Pathophysiology and pathoanatomy of uremic neuropathy are not yet well understood. A single hemodialysis positively increases nerve conduction velocities of uremic patients, thus demonstrating a functional A alpha-fiber improvement by detoxification. This study tested whether non-invasive Vibrameter and Thermotest studies show a similarly positive effect for A beta-, A delta- and C-fibers and whether the psychophysical techniques might substitute for nerve conduction studies. 20 uremic patients depending on chronic intermittent hemodialysis were examined shortly before and after a hemodialysis. Using a scaled 128 Hz tuning fork, a Vibrameter and a 'Marstock'-Thermotest, vibratory and warm and cold thresholds were assessed at both internal malleoli according to the method of limits. In addition, thermal thresholds were determined at the volar aspect of the non-shunted wrist. In nine patients the Vibrameter showed elevated thresholds before and after dialysis as did six patients with the tuning fork. Warm or cold thresholds were abnormal in four patients before treatment and in eight patients after dialysis. This was due to some patients reporting elevated thresholds after dialysis although they had had normal thresholds before the treatment. Still, the overall sum of abnormal thermal or vibratory thresholds at the different tested body sites had decreased after treatment. Moreover, mean values of thermal and vibratory thresholds of the 20 patients improved with dialysis (p < 0.05). Tuning fork results were too coarse and failed to show a dialysis effect.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 37054, year: 1995, vol: 63, page: 264, stat: Journal Article,

Thermal perception thresholds: influence of determination paradigm and reference temperature
Hilz MJ; Glorius S; Beric A
1995 Apr;129(2):135-140, Journal of the neurological sciences
The use of different paradigms and initial skin and thermode reference temperatures in quantitative thermal testing does not allow strict comparison of results generated from different laboratories. We tested (a) whether the reproducibility of the method of limits is higher for measurement of isolated warm and cold thresholds (WT, CT) as compared to difference limen (DL) thresholds, i.e. values derived from alternating warm and cold stimulation, and (b) whether WT-, CT- and DL-thresholds depend on the value of baseline skin and thermode temperatures. In 20 healthy volunteers WT-, CT-, and DL-thresholds were determined at the volar wrist using a Somedic-Thermotest. In condition A the baseline thermode temperature was set at 30 degrees C, and in conditions B and C at 35 degrees C; in condition C the tested skin area was also warmed to 35 degrees C prior to the test. The randomized tests were repeated within 1-8 days. WT-, CT-, and DL-values were reproducible, but DL-values were more widely spread than WT and CT. CT variability was lowest in condition A, and WT variability in condition C. We conclude that DL determination should be abandoned, since CT and WT better differentiate normal from abnormal thresholds than the coarse DL-values. We recommend the use of the lower baseline thermode temperature (30 degrees C) and elimination of warming of the tested skin area prior to the test
— id: 6642, year: 1995, vol: 129, page: 135, stat: Journal Article,

Thermal threshold determination in alcoholic polyneuropathy: an improvement of diagnosis
Hilz MJ; Zimmermann P; Claus D; Neundorfer B
1995 May;91(5):389-393, Acta neurologica Scandinavica
Reports on the incidence of alcoholic polyneuropathies are variable depending on diagnostic tools. In this study, 50 chronic alcoholics with positive MALT (Munich Alcoholism Test) and greater than seven years history of excessive alcohol abuse were examined neurologically. Tibial and peroneal motor and sural nerve conduction velocities (NCV) were studied. Warm and cold perception was evaluated in the area behind the internal malleolus using a Somedic-Thermotest. Thresholds were determined by the method of limits. The effect of a slow, medium and fast temperature change rate on thermal perception was tested. Thirty-eight patients (76%) showed signs of neuropathy. Thermal perception was more often abnormal (62%) than NCV (42%) and clinical examination (56%). A medium temperature change rate of 2.0-2.5 degrees C/s was the most sensitive index of small fiber neuropathy. Thermal threshold measurement proved to be a reliable, sensitive and easy to perform method that should become standard in the examination of polyneuropathies
— id: 57310, year: 1995, vol: 91, page: 389, stat: Journal Article,

Vibrameter testing facilitates the diagnosis of uremic and alcoholic polyneuropathy
Hilz MJ; Zimmermann P; Rosl G; Scheidler W; Braun J; Stemper B; Neundorfer B
1995 Dec;92(6):486-490, Acta neurologica Scandinavica
The diagnostic sensitivity of Vibrameter and tuning fork examination towards uremic and alcoholic neuropathy was tested in 75 patients. In 40 uremic and 35 alcoholic patients, we compared the sensitivity of neurological examination, nerve conduction studies (NCS) and vibration thresholds assessed at the malleoli by means of Vibrameter and scaled tuning fork. Vibrameter results were correlated with NCS. Polyneuropathy was diagnosed in 52 patients, but in 16 patients diagnosis depended upon inclusion of Vibrameter testing in the examination protocol. In uremic patients, Vibrameter (47.5%) showed abnormalities as often as NCS (45%), and more often than clinical (32.5%) or tuning fork examination (2.5%). In alcoholic patients, Vibrameter revealed abnormalities more often (60%) than NCS (34.3%) or tuning fork (14.3%). Correlations between NCS and vibratory thresholds were low (-0.52 < or = Rs < or = -0.35). Vibrameter studies are far more sensitive than tuning fork tests. The technique complements NCS and refines the diagnosis of uremic and alcoholic neuropathies
— id: 56821, year: 1995, vol: 92, page: 486, stat: Journal Article,

ISOFLURANE FOR 7 DAYS IN REFRACTORY STATUS EPILEPTICUS
HILZ, MJ; ERBGUTH, F; STEFAN, H; NEUNDORFER, B
1995 APR ;2(2):95-99, European journal of neurology
There is limited experience with continuous (>3 days) isoflurane anesthesia for status epilepticus (SE). We present a case with prolonged SE, probably due to thallium intoxication, in which isoflurane successfully suppressed seizure activity over 7 days without adverse effects. When isoflurane was discontinued, seizures returned despite high doses of barbiturates, and the patient died several months later. Early isoflurane anesthesia is an effective alternative therapy in prolonged convulsive SE resistant to common therapy and intravenous general anesthesia. However, its continuous application for several days requires familiarity with anesthesiologic principles, and scavenging of expiratory air
— id: 87239, year: 1995, vol: 2, page: 95, stat: Journal Article,

SYMPATHETIC SKIN-RESPONSE DIFFERENTIATES HEREDITARY SENSORY AND AUTONOMIC NEUROPATHIES TYPE-IV FROM TYPE-III
HILZ, MJ; STEMPER, B; BAER, R; KOLODNY, EH; AXELROD, FB
1995 AUG ;38(2):335-336, Annals of neurology
— id: 74954, year: 1995, vol: 38, page: 335, stat: Journal Article,

Is heat hypoalgesia a useful parameter in quantitative thermal testing of alcoholic polyneuropathy?
Hilz MJ; Claus D; Neundorfer B; Zimmermann P; Beric A
1994 Dec;17(12):1456-1460, Muscle & nerve
Detection of thermal hypoaesthesia, hyperalgesia, and paradoxical sensation significantly contribute to the diagnosis of polyneuropathy (PNP). There is controversy about the clinical usefulness of detected heat hypoalgesia. In 50 chronic alcoholic patients we compared the prevalence and diagnostic value of heat hypoalgesia (HPT) to that of cold (CT) and warm (WT) hypoaesthesia using a 'Marstock' thermotest. Clinical examination revealed PNP in 56%, cold hypoaesthesia was present in 62%, warm hypoaesthesia in 24%, paradoxical thermal sensation in 10%, cold and heat hyperalgesia in 12%, and heat hypoalgesia in 22%. Only 1 patient (2%) presented with heat hypoalgesia but normal warm and cold thresholds; he reported paradoxical thermal sensation and had PNP. One patient suffered first degree burn injury from heat pain examination. Heat hypoalgesia contributed least to the diagnosis of polyneuropathy (HPT versus CT: P < 0.001). In patients with sensory loss, testing heat hypoalgesia bears some risk of burn injury. In contrast to thermal hypoaesthesia and hyperalgesia, it does not significantly enrich the diagnostic workup of alcoholic polyneuropathies
— id: 12858, year: 1994, vol: 17, page: 1456, stat: Journal Article,

[The value of anamnesis and clinico-neurologic findings for neuromonitoring in anesthesia and intensive care]
Neundorfer B; Hilz MJ
1994 ;46(12):43-51, Klinische Anesthesiologie und Intensivtherapie
— id: 37055, year: 1994, vol: 46, page: 43, stat: Journal Article,

HEAT-PAIN DETERMINATION IN ALCOHOLICS - A SUPERFLUOUS TEST FOR ASSESSMENT OF POLYNEUROPATHIES
HILZ, MJ; CLAUS, D; ZIMMERMANN, P; NEUNDORFER, B
1993 ;43(4):A289-A289, Neurology
— id: 104781, year: 1993, vol: 43, page: A289, stat: Journal Article,

VISUAL-EVOKED POTENTIALS - INFLUENCES OF PRIMARY BRAIN-STEM LESIONS ON THE SCALP TOPOGRAPHY
HILZ, MJ; LITSCHER, G; PFURTSCHELLER, G; SCHWARZ, G; DRUSCHKY, KF; NEUNDORFER, B
1993 DEC ;24(4):258-262, EEG-EMG Zeitschrift fur Elektroenzephalographie, Elektromyographie und verwandte Gebiete
Visual evoked potentials were examined in 24 patients (mean age: 51.1 +/- 10.2 years) with primary brain stem lesion. Topographical recordings were performed within the first 3.1 +/- 2.7 days after onset of disease. The results showed an increase in the signal to noise ration-(SNR) parameter and the amplitude over the occipital region in patients with unfavourable outcome. These findings seem to indicate that the VEP topography probably can be used as an additional prognostic parameter in patients with primary brain stem lesions
— id: 52607, year: 1993, vol: 24, page: 258, stat: Journal Article,

[Clinical symptoms and therapy of status epilepticus]
Bauer J; Hilz MJ; Sappke U; Stefan H
1992 May;60(5):181-205, Fortschritte der neurologie-psychiatrie
The term 'status epilepticus' was first coined in 1824 by Calmeil as this condition had such a poor prognosis. Although still commonly misused today, from the beginning this term actually included all kinds of epileptic seizures, since there are as many types of status epileptici as there are seizure types. Status epileptici are usually triggered by a combination of factors including sleep deprivation, alcohol withdrawal, failure to take medication regularly and fever. In status epilepticus epileptic seizures and EEG discharges initially appear to be no different from isolated seizures. The longer the status epilepticus continues, however, the more atypical the seizures and EEG discharges become. Usually status epilepticus ends gradually. Irreversible damage or fatalities may occur especially in infants or under certain conditions (e.g. long status duration, protracted interval between seizure onset and medical treatment and symptomatic etiology). In most cases benzodiazepines and diphenylhydantoine are the preferred drugs used for treatment
— id: 37057, year: 1992, vol: 60, page: 181, stat: Journal Article,

Isoflurane anaesthesia in the treatment of convulsive status epilepticus. Case report
Hilz MJ; Bauer J; Claus D; Stefan H; Neundorfer B
1992 Mar;239(3):135-137, Journal of neurology
Status epilepticus may be resistant to intravenous anticonvulsive drugs. In these cases treatment with the inhalation anaesthetic agent isoflurane may be helpful in the further management. We describe a 35-year-old female patient who suffered from status epilepticus with partial seizures. In spite of therapy with benzodiazepine and phenytoin the status evolved into tonic clonic seizures. Treatment with thiopentone sodium did not stop seizure activity. Anaesthesia with isoflurane (dosage up to 1.5 vol.%) carried out twice within 72 h finally led to a termination of status epilepticus. From our own experience and reports in the literature we conclude that general anaesthesia with isoflurane can and should be used in the treatment of severe status epilepticus that does not respond to intravenous anticonvulsive agents
— id: 37058, year: 1992, vol: 239, page: 135, stat: Journal Article,

Influence of caffeine, sweating and local hyperemisation on "Marstock" thermotesting
Hilz MJ; Claus D; Balk M; Neundorfer B
1992 Jul;86(1):19-23, Acta neurologica Scandinavica
Marstock thermotesting evaluates A-delta- and C-fiber functions. To optimize this method, intraindividual variations of vasodilatation, blood flow and sympathetic activity probably biasing thermotest results were imitated by exogenous stimuli which strongly exaggerated these intraindividual variations. In 20 healthy subjects, warm (WT), cold (CT), and heat-pain (HT) thresholds were determined in the morning at the thenar (th), the volar wrist (wr), and behind the malleolus internus (mi). Thresholds at the thenar and the volar wrist were compared with those during severe sweating induced by Minor's test, and to those measured when sympathetic activity had been increased by the ingestion of a high dose of caffeine (0.5 g). Furthermore, the intraindividual variation of local capillary blood flow and vasodilatation was imitated by a rubefacient liniment (Forapin) applied to the three sites. After a local hyperemisation had been induced thermal thresholds were measured and compared to those measured without any stimulation. Local hyperemia did not influence thermal thresholds significantly. Sweating only lowered cold thresholds at the thenar significantly and only slightly raised warm and heat-pain thresholds at the thenar. Caffeine significantly lowered warm thresholds and raised heat-pain thresholds at the thenar. To conclude, the tested exogenous interferences do not disturb thermal perception markedly, especially when testing is not performed at the thenar, but at the volar wrist and when the testing-procedure and parameters are standardised
— id: 37056, year: 1992, vol: 86, page: 19, stat: Journal Article,

Air fluidization therapy of pressure sores due to Guillain-Barre and Cushing syndrome
Hilz MJ; Claus D; Druschky KF; Rechlin T
1992 ;18(1):62-63, Intensive care medicine
— id: 37059, year: 1992, vol: 18, page: 62, stat: Journal Article,

Blindness as an ictal phenomenon: investigations with EEG and SPECT in two patients suffering from epilepsy
Bauer J; Schuler P; Feistel H; Hilz MJ; Stefan H
1991 Feb;238(1):44-46, Journal of neurology
Blindness is a rare ictal phenomenon in epileptic seizures. It can occur as an aura, as the seizure itself, or postictally. We investigated two such patients, in one of whom blindness manifested as an aura prior to tonic clonic seizures; the interictal EEG exhibited a spike-wave focus bioccipitally. In the second patient blindness occurred postictally. An ictal SPECT, carried out at the onset of the seizure demonstrated marked hyperperfusion in both occipital regions
— id: 37061, year: 1991, vol: 238, page: 44, stat: Journal Article,

Continuous multivariable monitoring in neurological intensive care patients--preliminary reports on four cases
Hilz MJ; Litscher G; Weis M; Claus D; Druschky KF; Pfurtscheller G; Neundorfer B
1991 ;17(2):87-93, Intensive care medicine
Evoked potential monitoring is a standard examination method in neurological intensive therapy units. Previously, multimodality observation was only possible in follow-up examinations. First experience with a new bed-side system continuously monitoring 12 neurophysiological and clinical parameters is reported. It consists of a personal computer and various stimulation units. EEG activity, median nerve somatosensory evoked potentials (SEPs) and brainstem auditory evoked potential (BAEPs) are recorded. Additionally, EEG spectral band power, heart rate, heart rate variability, intracranial pressure, body temperature, expiratory PCO2, blood pressure and transcutaneously measured oxygenation can be monitored. This paper reports on 4 exemplary cases of the 33 patients we have monitored to date, illustrating the principles and main advantages of the system. The system was developed to support the observation of ICU patients as well as to aid therapeutic decisions. It supports the clinical determination of brain death by specifying the deterioration of various neurological systems
— id: 37062, year: 1991, vol: 17, page: 87, stat: Journal Article,

FORUM NEUROLOGICUM OF THE GERMAN-SOCIETY-FOR-NEUROLOGY - CONFERENCE OF THE DEUTSCHE-GESELLSCHAFT-FUR-NEUROLOGIE (ERLANGEN, SEPTEMBER 13-14, 1991)
HILZ, MJ
1991 ;18(6):R25-R29, Aktuelle Neurologie
— id: 104782, year: 1991, vol: 18, page: R25, stat: Journal Article,

[Successful treatment of the neuroleptic malignant syndrome using i.v. dantrolene sodium in the neurologic intensive care station]
Rechlin T; Hilz MJ; Claus D
1991 May;26(3):156-160, Anesthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie. AINS
The neuroleptic malignant syndrome (NMS) is one of the most dramatic psychiatric disorders every doctor in intensive care medicine can be confronted with. Two cases of successful treatment of NMS with intravenous application of dantrolene are presented. Although we used two very different doses, the treatment results were the same. Further studies will therefore be necessary to assess the optimal doses for this therapy
— id: 37060, year: 1991, vol: 26, page: 156, stat: Journal Article,

Thermal discrimination thresholds: a comparison of different methods
Claus D; Hilz MJ; Neundorfer B
1990 Jun;81(6):533-540, Acta neurologica Scandinavica
Thermal testing was carried out on 55 healthy subjects in order to establish normal results and reproducibility of warm and cold thresholds. Diurnal variations of thresholds were investigated in a further 30 normal subjects. Then the sensitivity of different testing procedures was investigated in 33 patients with diabetes mellitus, but without severe polyneuropathy. Forced choice testing takes 6 times longer than the method of limits, and the results are not considerably different. It is thought that the forced choice algorithm does not provide a method for clinical routine. Another new approach, the double random staircase method, may help to exclude bias without taking too much time
— id: 37064, year: 1990, vol: 81, page: 533, stat: Journal Article,

[Bilateral thalamic lesions in cerebral venous thrombosis]
Erbguth F; Druschky KF; Gmeiner HJ; Hilz MJ; Neundorfer B
1990 Feb;61(2):123-126, Nervenarzt
— id: 37066, year: 1990, vol: 61, page: 123, stat: Journal Article,

Zieve's syndrome and intracranial haemorrhage: coincidence or related disorders
Hilz MJ; Bauer J; Druschky KF; Huk WJ; Neundorfer B
1990 Apr;237(2):120-121, Journal of neurology
Zieve's syndrome (hyperlipidaemia, anaemia and fatty liver degeneration) may rarely occur with intracranial haemorrhage. Four patients suffering from both diseases are reported. Although it remains unclear whether there is a causal relationship between the two, it seems that hyperlipidaemia may be a major cause of intracranial bleeding. One reason for the small number of reported cases may be that hyperlipidaemic serum levels rapidly decrease after alcohol withdrawal
— id: 37065, year: 1990, vol: 237, page: 120, stat: Journal Article,

[Transcutaneous cardiac pacemaker for prevention and emergency therapy in neurologic intensive care patients]
Hilz MJ; Claus D; Bauer J; Neundorfer B
1990 Dec;61(12):744-748, Nervenarzt
In a number of neurological diseases, e.g. Guillain-Barre syndrome, patients are at high risk for a bradyarrhythmia or asystolia. Sometimes a cardiac pacemaker is needed for prophylaxis or for emergency therapy. The usual temporary insertion of a transvenous stimulating electrode has many disadvantages and a high incidence of complications. We report on our initial experience with the non-invasive technique of transcutaneous stimulation via superficial electrodes. The advantages of this method are discussed
— id: 37063, year: 1990, vol: 61, page: 744, stat: Journal Article,

[Wilson's disease--critical deterioration under high-dose parenteral penicillamine therapy]
Hilz MJ; Druschky KF; Bauer J; Neundorfer B; Schuierer G
1990 Jan 19;115(3):93-97, Deutsche medizinische Wochenschrift
A 31-year-old man with Wilson's disease, not treated for the past 4 1/2 years, was admitted to hospital with brain concussion after a fall. While receiving penicillamine, 1 g i.v. four times daily, the neurological signs worsened and akinesia, mutism, tachy- and bradyarrhythmias, as well as transitory respiratory insufficiency developed. Serum copper concentration on the sixth day of treatment was markedly decreased to 28 micrograms/dl, rising to 60 micrograms/dl on the ninth day. 24-hour urinary copper excretion was at first 4500-5000 micrograms. Only after drastic reduction of the penicillamine dosage to 600 mg three times daily was there any improvement and after 11 weeks the patient was again able to walk and was discharged. Marked, mainly hepatic, copper depletion from the high penicillamine dosage was the likely cause of the patient's initial deterioration. To avoid cerebral complications penicillamine should be administered in gradually increasing doses
— id: 37067, year: 1990, vol: 115, page: 93, stat: Journal Article,

Fatal complications after myelography with meglumine diatrizoate
Hilz MJ; Huk W; Schellmann B; Sorgel F; Druschky KF
1990 ;32(1):70-73, Neuroradiology
A case of inadvertent intrathecal injection of diatrizoate meglumine is presented. After myelography with 10 ml i.e. 6.5 g Angiografin, a 76-year-old man rapidly developed myoclonus, drowsiness and excessive metabolic acidosis. He died only a few hours later. Postmortem showed non-specific brain edema. RP-HPL-Chromatography confirmed high concentration of the contrast medium in CSF (6 mg/ml) which must have induced refractory central nervous dysregulation. The lethal effects of the misapplication of this agent on the nervous system are discussed
— id: 37068, year: 1990, vol: 32, page: 70, stat: Journal Article,

LANDRY-GUILLAIN-BARRE SYNDROME AFTER CARBON-MONOXIDE INTOXICATION
HILZ, MJ; NEUNDORFER, B; ENGELHARDT, A; CLAUS, D; GRAHMANN, F
1990 ;17(4):113-116, Aktuelle Neurologie
— id: 104783, year: 1990, vol: 17, page: 113, stat: Journal Article,

CT, MRI and SPECT neuroimaging in status epilepticus with simple partial and complex partial seizures: case report
Bauer J; Stefan H; Huk WJ; Feistel H; Hilz MJ; Brinkmann HG; Druschky KF; Neundorfer B
1989 Jul;236(5):296-299, Journal of neurology
A 35-year-old female patient suffering from epilepsy was examined during status epilepticus with simple partial and complex partial seizures by means of EEG, CT, MRI and ictal SPECT. All these examinations showed focal abnormalities with identical location due to oedema and hypervascularisation; these were, however, absent during examinations carried out before and after status epilepticus
— id: 37069, year: 1989, vol: 236, page: 296, stat: Journal Article,

Fat deposition surrounding intracerebral hemorrhage in a patient suffering from Zieve syndrome
Hilz MJ; Huk W; Druschky KF; Erbguth F
1989 ;31(1):102-103, Neuroradiology
In a 42-year-old man, admitted a few hours after an acute cerebrovascular event, CT demonstrated a hyperdense hemorrhage surrounded by a hypodense rim similar to perifocal edema or liquefying blood, thus raising doubts about the acuteness of the event. Laboratory findings revealed Zieve-syndrome (alcoholic hyperlipemia, hemolytic anemia, and alcoholic fatty liver) and negative Hounsfield Unit measurement of the hypodense rim finally identified it as a layer of fat around the clot
— id: 37070, year: 1989, vol: 31, page: 102, stat: Journal Article,

DETECTION OF SMALL FIBER LESIONS IN UREMIC NEUROPATHY BY MARSTOCK THERMOTESTING
HILZ, MJ; CLAUS, D; NEUNDORFER, B; CARVALHO, VP; BRAUN, J
1989 ;36(2):323-323, Kidney international
— id: 104785, year: 1989, vol: 36, page: 323, stat: Journal Article,

ELECTROMAGNETIC MEASUREMENT OF VIBRATORY THRESHOLDS IN CHRONIC RENAL-FAILURE
HILZ, MJ; CLAUS, D; NEUNDORFER, B; SCHULIG, B; BRAUN, J
1989 ;36(2):320-320, Kidney international
— id: 104784, year: 1989, vol: 36, page: 320, stat: Journal Article,

ABOUT THE METHOD OF THERMAL TESTING IN NORMAL SUBJECTS AND PATIENTS WITH DIABETIC POLYNEUROPATHY
CLAUS, D; HILZ, MJ; BLAISE, JF; NEUNDORFER, B
1988 ;70(3):P49-P50, Electroencephalography & clinical neurophysiology
— id: 104786, year: 1988, vol: 70, page: P49, stat: Journal Article,

Early diagnosis of diabetic small fiber neuropathy by disturbed cold perception
Hilz MJ; Claus D; Neundorfer B
1988 Jan-Mar;2(1):38-43, The Journal of diabetic complications
In diabetes mellitus, polyneuropathy is an important complication and should be diagnosed as early as possible in order to prevent damage to the patient. Determination of warm, cold, and heat pain thresholds enables one to judge small nerve fiber sensitivity. This investigation was carried out to determine which parameters best predict such alterations. Using a 'Marstock' Thermostimulator, 26 diabetics and 32 healthy subjects were stimulated behind both medial malleoli. At three different rates of temperature rise, repeated warm, cold, and heat pain threshold determinations were performed. The variability of intraindividual threshold ranges was noted. While heat pain determinations were not useful, determination of cold perception, at a moderate rate of temperature change, proved to be the most reliable indicator of small fiber lesions. Cold thresholds as well as their intraindividual ranges were most often impaired. The importance of this clinical investigatory method is discussed with respect to the importance of early prophylaxis of complications such as trophic lesions
— id: 37071, year: 1988, vol: 2, page: 38, stat: Journal Article,

Methods of measurement of thermal thresholds
Claus D; Hilz MJ; Hummer I; Neundorfer B
1987 Oct;76(4):288-296, Acta neurologica Scandinavica
Thermal tests were performed in 117 healthy subjects on the face, wrist and leg; 32 were tested on the legs with different rates of cooling and warming. Additionally 2 groups of diabetics (37 patients) were tested. Thermotesting was most sensitive on the legs using a rate of temperature change of 2.5-2.8 oC/s. Warm and cold perception should be tested separately. Cold perception testing is most sensitive. Combined tests of warm and cold thresholds as well as the testing of cool pain and heat pain do not improve results. Abnormal cold perception may be an early indicator of diabetic small fibre polyneuropathy, leading to cold trauma and ulcers on the feet
— id: 37072, year: 1987, vol: 76, page: 288, stat: Journal Article,

SCHIZOAFFECTIVE PSYCHOSES AND THEIR POSITION IN THE CLASSIFICATION OF PSYCHIATRIC-DISORDERS
HILZ, MJ
1987 ;6(4):164-170, Nervenheilkunde
— id: 104787, year: 1987, vol: 6, page: 164, stat: Journal Article,

[Fecal excretion of cadmium and copper after mushroom (Agaricus) diet (author's transl)]
Schellmann B; Hilz MJ; Opitz O
1980 Sep;171(3):189-192, Zeitschrift fur Lebensmittel-Untersuchung und -Forschung
High contents of cadmium in some agaricus species led to the warning that the eating of wild-grown mushrooms may bear the possibility of cadmium-intoxication. The low digestion rate due to the chitin membrane of fungi was not discussed. Therefore, in this investigation the cadmium- and copper-concentrations in feces of five subjects were estimated before and after a three days mushrooms diet. The high amount of fecal cadmium and copper increasing after the diet confirm the suggestion, that eaten fungi mostly pass through the intestinal tract unscathed without resorption. By this even larger ingestions of agaricus fungi may not cause cadmium intoxication in humans
— id: 37073, year: 1980, vol: 171, page: 189, stat: Journal Article,