Horacio Kaufmann, M.D.

Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia
Axelrod FB; Liebes L; Simson GG; Mendoza S; Mull J; Leyne M; Norcliffe-Kaufmann L; Kaufmann H; Slaugenhaupt SA
2011 Nov;70(5):480-483, Pediatric research
Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::
— id: 139909, year: 2011, vol: 70, page: 480, 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,

Cardiovascular and neuroendocrine features of Panayiotopoulos syndrome in three siblings
Gonzalez-Duarte, Alejandra; Norcliffe-Kaufmann, Lucy; Martinez, Jose; Rodriguez, Alcibiades J; Kuzniecky, Ruben; Axelrod, Felicia; Kaufmann, Horacio
2011 Jul;21(3):296-300, Epilepsy & behavior
OBJECTIVE: Panayiotopoulos syndrome is a benign idiopathic childhood epilepsy characterized by altered autonomic activity at seizure onset. METHODS: Three siblings with Panayiotopoulos syndrome underwent 24-hour EEG recording and head-up tilt testing with continuous blood pressure and RR interval monitoring. Plasma catecholamines and vasopressin were measured while supine, upright, and during a typical seizure. RESULTS: Patient 1, a 12-year-old girl, had a history of involuntary lacrimation, abdominal pain, and recurrent episodes of loss of muscle tone and unresponsiveness followed by somnolence. Her EEG revealed bilateral frontotemporal spikes. Patient 2, a 10-year-old boy, had episodic headaches with pinpoint pupils, skin flushing of the face, trunk, and extremities, purple discoloration of hands and feet, diaphoresis, nausea, and vomiting. Tilt testing triggered a typical seizure after 9minutes; there was a small increase in blood pressure (+5/4mm Hg, systolic/diastolic) and pronounced increases in heart rate (+59bpm) and norepinephrine (+242pg/mL), epinephrine (+175pg/mL), and vasopressin (+22.1pg/mL) plasma concentrations. Serum glucose was elevated (206mg/dL). His EEG revealed right temporal and parietal spikes. Patient 3, an 8-year-old boy, had a history of restless legs at night, enuresis, night terrors, visual hallucinations, cyclic abdominal pain, and nausea. His EEG showed bitemporal spikes. CONCLUSION: Hypertension, tachycardia, and the release of vasopressin suggest activation of the central autonomic network during seizures in familial Panayiotopoulos syndrome. These autonomic and neuroendocrine features may be useful in the diagnosis and may have therapeutic implications
— id: 136485, year: 2011, vol: 21, page: 296, stat: Journal Article,

Bursts of muscle sympathetic nerve activity are absent in familial dysautonomia
Macefield V.G.; Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):219-219, Clinical autonomic research
Familial dysautonomia is an hereditary sensory and autonomic neuropathy (HSAN type III), expressed at birth, that is associated with reduced or absent pain and temperature sensibilities, postural hypotension, absent baroreflex function and labile blood pressure that increases markedly during emotional excitement (Norcliffe-Kaufmann et al. 2010). Given the absent baroreflex function we tested the hypothesis that cardiac-locked bursts of muscle sympathetic nerve activity (MSNA) are absent in familial dysautonomia. Tungsten microelectrodes were inserted percutaneously into muscle or cutaneous fascicles of the common peroneal nerve in 10 patients with FD. Spontaneous bursts of MSNA were absent, but we found evidence of tonically firing sympathetic neurones that increased during emotional arousal. Conversely, skin sympathetic nerve activity (SSNA) appeared normal. We conclude that the loss of phasic bursts of MSNA and the loss of baroreflex modulation of muscle vasoconstrictor drive contributes to the poor control of blood pressure in familial dysautonomia
— id: 137865, year: 2011, vol: 21, page: 219, stat: Journal Article,

Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome?
Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Gutierrez, Joel; Axelrod, Felicia B; Kaufmann, Horacio
2011 Nov;134(Pt 11):3198-3208, Brain
The Riley-Day syndrome is the most common of the hereditary sensory and autonomic neuropathies (Type III). Among the well-recognized clinical features are reduced pain and temperature sensation, absent deep tendon reflexes and a progressively ataxic gait. To explain the latter we tested the hypothesis that muscle spindles, or their afferents, are absent in hereditary sensory and autonomic neuropathy III by attempting to record from muscle spindle afferents from a nerve supplying the leg in 10 patients. For comparison we also recorded muscle spindles from 15 healthy subjects and from two patients with hereditary sensory and autonomic neuropathy IV, who have profound sensory disturbances but no ataxia. Tungsten microelectrodes were inserted percutaneously into fascicles of the common peroneal nerve at the fibular head. Intraneural stimulation within muscle fascicles evoked twitches at normal stimulus currents (10-30 microA), and deep pain (which often referred) at high intensities (1 mA). Microneurographic recordings from muscle fascicles revealed a complete absence of spontaneously active muscle spindles in patients with hereditary sensory and autonomic neuropathy III; moreover, responses to passive muscle stretch could not be observed. Conversely, muscle spindles appeared normal in patients with hereditary sensory and autonomic neuropathy IV, with mean firing rates of spontaneously active endings being similar to those recorded from healthy controls. Intraneural stimulation within cutaneous fascicles evoked paraesthesiae in the fascicular innervation territory at normal stimulus intensities, but cutaneous pain was never reported during high-intensity stimulation in any of the patients. Microneurographic recordings from cutaneous fascicles revealed the presence of normal large-diameter cutaneous mechanoreceptors in hereditary sensory and autonomic neuropathy III. Our results suggest that the complete absence of functional muscle spindles in these patients explains their loss of deep tendon reflexes. Moreover, we suggest that their ataxic gait is sensory in origin, due to the loss of functional muscle spindles and hence a compromised sensorimotor control of locomotion
— id: 146233, year: 2011, vol: 134, page: 3198, stat: Journal Article,

Somatic vigilance: An unrecognized cause of orthostatic intolerance
Martinez J.M.; Norcliffe-Kaufmann L.J.; Acosta J.; Adhikari I.; Kaufmann H.
2011 ;21(4):277-278, Clinical autonomic research
Background: Visceral sensations are relayed to the brain through a network of afferent nerves. Awareness of these sensations differs among individuals, likely due to different thresholds and CNS processing characteristics. Differences in the conscious awareness of bodily sensations may explain specific cardiovascular phenotypes. Thus, our goal was to evaluate the role, if any, of conscious awareness of body sensations and their relationship with hemodynamic responses to tilt in patients with orthostatic intolerance. Methods: Thirty-two otherwise healthy patients who complained of orthostatic intolerance participated in the study. We assessed perception of body sensations on a self-reported body vigilance scale. We measured blood pressure, heart rate and plasma catecholamine responses to passive upright tilt. Thirteen patients experienced typical vasovagal syncope (i.e., a fall in blood pressure and heart rate) 4; patients had an increase in heart rate >30 beat/min without a fall in blood pressure and were diagnosed as postural tachycardia syndrome; and 15 patients had normal cardiovascular responses to tilt and were classified as having unexplained orthostatic intolerance. Results: Self-reported feelings of shortness of breath (p<0.05), tingling (p<0.01), numbness (p<0.003) and chest discomfort (p<0.01) were correlated positively with supine plasma epinephrine levels and the increase in plasma epinephrine levels with tilt (p<0.02). Higher body vigilance was significantly related with the increase in heart rate during tilt, both at 3 min (p<0.02) and the maximum heart rate recorded (p<0.002). Patients with unexplained orthostatic intolerance scored higher for the time spent 'scanning their body for sensations' compared with patients who had vasovagal syncope during tilt (52 +/- 9 vs. 23 +/- 6%, p<0.02). Conclusion: Increased somatic vigilance is associated with a greater release of epinephrine on standing and faster heart rates. Increased somatic vigilance is associated with the postural tachycardia syndrome and may be the cause of hitherto unexplained orthostatic intolerance
— id: 137863, year: 2011, vol: 21, page: 277, stat: Journal Article,

Clinical Neuro-ophthalmic Findings in Familial Dysautonomia
Mendoza-Santiesteban CE; Hedges TR 3rd; Norcliffe-Kaufmann L; Warren F; Reddy S; Axelrod FB; Kaufmann H
2011 Sep 13;:?-?, Journal of neuroophthalmology
BACKGROUND:: To define the clinical neuro-ophthalmic abnormalities of patients with familial dysautonomia (FD). METHODS:: Sixteen patients (32 eyes) with the clinical and molecular diagnoses of FD underwent thorough neuro-ophthalmic clinical evaluation. RESULTS:: Visual acuity ranged from 0.05 to 1.0 decimal units and was reduced in 15 of 16 patients. Mild to moderate corneal opacities were found in most patients but were visually significant in only 2 eyes. Red-green color vision was impaired in almost all cases. Depression of the central visual fields was present on automated visual fields in all patients, even in those with normal visual acuity. Temporal optic nerve pallor was present in all cases and was associated with retinal nerve fiber layer loss in the papillomacular region. Various ocular motility abnormalities also were observed. CONCLUSION:: Patients with FD have a specific type of optic neuropathy with predominant loss of papillomacular nerve fibers, a pattern similar to other hereditary optic neuropathies caused by mutations either in nuclear or in mitochondrial DNA, affecting mitochondrial protein function. Defects of eye movements, particularly saccades, also appear to be a feature of patients with FD
— id: 146235, year: 2011, vol: , page: ?, stat: Journal Article,

Seropositive myasthenia and autoimmune autonomic ganglionopathy: Cross reactivity or subclinical disease?
Miglis, Mitchell G; Racela, Rikki; Kaufmann, Horacio
2011 Oct 28;164(1-2):87-88, Autonomic neuroscience
Autoimmune autonomic ganglionopathy (AAG) and myasthenia gravis (MG) are both autoimmune channelopathies mediated by antibodies directed against nicotinic acetylcholine receptors. While both diseases target acetylcholine receptors, skeletal muscle and ganglionic receptor subtypes have key immunologic and genetic distinctions, and reports of patients with both AAG and MG are rare. We report a patient with antibody-confirmed AAG and elevated levels of ACh binding antibodies that did not meet clinical or electrodiagnostic criteria for MG. We presume that his skeletal muscle nAChR seropositivity was a false positive, perhaps due to the cross reactivity of the patient's ganglionic nAChR antibodies with skeletal nAChR subtypes
— id: 137964, year: 2011, vol: 164, page: 87, stat: Journal Article,

Hyper-dopaminergic vomiting crises in familial dysautonomia
Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):244-245, Clinical autonomic research
Background: Patients with familial dysautonomia have a selective defect in the afferent neurons of the baroreflex. Failure to sense blood pressure result in the unregulated release of plasma catecholamines and volatile blood pressure. One of the most disabling features of familial dysautonomia are the recurrent attacks of nausea, retching and vomiting triggered by emotional or physiological stressors and associated with hypertension, tachycardia and psychomotor agitation. A pronounced surge in circulating norepinephrine during these crises readily explains the hypertension, but the cause of the nausea and vomiting remains unknown. Methods: Seven patients with familial dysautonomia (mean age 17 +/- 3 years, 4 females) confirmed by genetic testing were studied. We monitored blood pressure and heart rate and measured plasma catecholamines when they were feeling well and during typical vomiting crises triggered by emotionally charged situations. Results: When the patients were feeling well, average supine blood pressure was 124 +/- 7/64 +/- 5 mmHg with a heart rate of 81 +/- 3 beats/min. All patients experienced typical crises when they complained of severe nausea and were retching loudly. Vomiting was prevented by the fundoplication surgery. During crises, all patients were hypertensive (180 +/- 9/116 +/- 4 mmHg) and tachycardic (124 +/- 4 beats/min) but denied feeling palpitations. While supine, plasma norepinephrine levels increased from 130 +/- 42 to 772 +/- 151 pg/ml (p<0.002), plasma epinephrine levels increased from 20 +/- 5 to 63 pg/ml, and plasma dopamine levels increased markedly from 22 +/- 2 to 96 +/- 20 pg/ml. Conclusions: Our finding of high levels of circulating dopamine during crises in patients with familial dysautonomia suggest that the severe nausea and vomiting is due to activation of dopamine receptors in the chemoreceptor trigger zone
— id: 137864, year: 2011, vol: 21, page: 244, stat: Journal Article,

The norepinephrine paradox in hereditary sensory and autonomic neuropathy type IV
Norcliffe-Kaufmann L.J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):286-286, Clinical autonomic research
Background: Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is a recessive disease caused by mutations affecting the tyrosine kinase receptor. The disorder affects the development of sensory and sudomotor sympathetic nerve fibers resulting in complete insensitivity to pain and anhidrosis. However, little is known about the cardiovascular autonomic phenotype of the disorder. Methods: We measured blood pressure, heart rate and catecholamines, vasopressin, endothelin and renin activity in plasma while supine and after 10 min of passive upright tilt in 10 patients with typical clinical features of HSAN-IV and diagnostic confirmation with genetic testing (mean age 9 +/- 2 years old, 4 females). Results: In the supine position, blood pressures (104 +/- 5/ 58 +/- 4 mmHg) and heart rates (87 +/- 9 beats/min) were normal. During upright tilt, mean arterial blood pressure changed little (-5 +/- 5 mmHg, p = 0.17) and heart rate increased appropriately (+23 +/- 5 beat/min, p<0.001). In all patients, plasma norepinephrine levels were low or undetectable while in the supine position (31 +/- 3 pg/ml) and failed to increase with upright tilt (4 +/- 5 pg/ml). Plasma renin activity levels increased slightly from 2.0 +/- 0.6 to 3.6 +/- 1.1 pg/ml with head-up tilt (+68 +/- 33 D%, p<0.03). Plasma vasopressin increased little and endothelin levels were essentially unchanged during upright tilt. Conclusions: Patients with HSAN-IV have very low levels of norepinephrine while supine and upright, but do not have orthostatic hypotension. Other vasoactive peptides involved in orthostatic blood pressure maintenance are not increased. These results challenge our current concepts of the role of norepinephrine in the regulation of blood pressure. The mechanism by which patients with HSAN-IV maintain their blood pressure is unknown
— id: 137861, year: 2011, vol: 21, page: 286, stat: Journal Article,

Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome
Norcliffe-Kaufmann L; Axelrod FB; Kaufmann H
2011 Dec 1;:?-?, Journal of human hypertension
Riley Day syndrome, commonly referred to as familial dysautonomia (FD), is a genetic disease with extremely labile blood pressure owing to baroreflex deafferenation. Chronic renal disease is very frequent in these patients and was attributed to recurrent arterial hypotension and renal hypoperfusion. Aggressive treatment of hypotension, however, has not reduced its prevalence. We evaluated the frequency of kidney malformations as well as the impact of hypertension, hypotension and blood pressure variability on the severity of renal impairment. We also investigated the effect of fludrocortisone treatment on the progression of renal disease. Patients with FD appeared to have an increased incidence of hydronephrosis/reflux and patterning defects. Patients <4 years old had hypertension and normal estimated glomerular filtration rates (eGFR). Patients with more severe hypertension and greater variability in their blood pressure had worse renal function (both, P<0.01). In contrast, there was no relationship between eGFR and the lowest blood pressure recorded during upright tilt. The progression of renal disease was faster in patients receiving fludrocortisone (P<0.02). Hypertension precedes kidney disease in these patients. Moreover, increased blood pressure variability as well as mineralocorticoid treatment accelerate the progression of renal disease. No association was found between hypotension and renal disease in patients with FD.Journal of Human Hypertension advance online publication, 1 December 2011; doi:10.1038/jhh.2011.107
— id: 146234, year: 2011, vol: , page: ?, stat: Journal Article,

The Movement Disorders Task Force Review of Dysautonomia Rating Scales in Parkinson's Disease with Regard to Symptoms of Orthostatic Hypotension
Pavy-Le Traon, Anne; Amarenco, Gerard; Duerr, Susanne; Kaufmann, Horacio; Lahrmann, Heinz; Shaftman, Stephanie R.; Tison, Francois; Wenning, Gregor K.; Goetz, Christopher G.; Poewe, Werner; Sampaio, Cristina; Schrag, Anette; Stebbins, Glenn T.; Rascol, Olivier
2011 SEP ;26(11):1985-1992, Movement disorders
Orthostatic hypotension is defined as a blood pressure fall of > 20 mm Hg systolic and/or 10 mm Hg diastolic within 3 minutes of an upright position. The Movement Disorders Society commissioned a task force to assess existing clinical rating scales addressing symptoms of orthostatic hypotension in Parkinson's disease. Seven neurologists and a clinimetrician assessed each scale's previous use and critiqued its clinimetric properties. A scale was 'recommended' if it had been applied to populations of patients with Parkinson's disease, with data on its use in studies beyond the group that developed the scale, and was found to be clinimetrically valid. A scale was considered 'suggested' if it had been applied to Parkinson's disease, but only 1 of the other criteria was applied. A scale was 'listed' if it met only 1 criterion. Symptoms of orthostatic hypotension are generally assessed in scales on wider autonomic or nonmotor symptoms. Some scales designed to detect orthostatic hypotension-related symptoms provide information on their severity: the AUTonomic SCale for Outcomes in PArkinson's Disease and the COMPosite Autonomic Symptom Scale met criteria for recommended with some limitations; the Novel Non-Motor Symptoms Scale and the Orthostatic Grading Scale were classified as suggested. The Self-completed Non-Motor Symptoms Questionnaire for Parkinson's Disease was classified as suggested as a tool for screening orthostatic symptoms. However, these and the listed scales need further validation and application before they can be recommended for clinical use in patients with Parkinson's disease. (C) 2011 Movement Disorder Society
— id: 140057, year: 2011, vol: 26, page: 1985, stat: Journal Article,

Is end-tidal CO2 a valid measurement to assess hypoventilation in patients with familial dysautonomia?
Perez M.A.; Norcliffe-Kaufmann L.J.; Reyes J.; Axelrod F.B.; Kaufmann H.
2011 ;21(4):286-286, Clinical autonomic research
Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep
— id: 137860, year: 2011, vol: 21, page: 286, stat: Journal Article,

Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the synuclein gene
Tijero Merino B.; Gomez-Esteban J.C.; Kaufmann H.; Llorens V.; Zarranz J.J.
2011 ;21(4):285-285, Clinical autonomic research
Background: Sympathetic denervation of the heart is frequent in patients with sporadic and genetic synucleinopathies. In 2004, we described a new mutation in the synuclein gene (E46K). The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of this mutation. Patients and methods: We studied 6 members of the original family, four symptomatic (i.e., with parkinsonism, ages 88, index case, deceased, 46, 59 and 52 years) and two asymptomatic carriers (i.e., without motor impairment, age 52 and 29 years). Patients filled the SCOPA autonomic questionnaire, and underwent blood pressure and heart rate monitoring during head up tilt with measurements of plasma norepinephrine, Valsalva maneuver and deep breathing, recording of sympathetic skin response (SSR), and cardiac MIBG scintigraphy. The myocardium of the index case was stained with tyrosine hydroxylase to identify sympathetic nerve terminals. Results: All symptomatic and the older asymptomatic carrier reported abnormalities in the SCOPA questionnaire. Plasma norepinephrine supine and tilted was normal in all subjects. One patient had significant orthostatic hypotension. Heart rate during deep breathing was reduced in one patient and during Valsalva in 2 patients. SSR was normal in all subjects. All the symptomatic and the older asymptomatic carrier of the mutation had markedly diminished cardiac MIBG uptake. There was complete absence of tyrosine hydroxylase immune staining of the myocardium. Conclusions: We found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K synuclein gene mutation. Cardiac innervation was preserved in a young asymptomatic carrier of the mutation. The sympathetic denervation appears to be organ specific selectively affecting the heart because plasma norepinephrine, blood pressure and SSR responses were normal. Follow up of asymptomatic carriers will help determine the precise sequence of synuclein-related neurodegeneration, an important step for neuroprotective strategies
— id: 137862, year: 2011, vol: 21, page: 285, stat: Journal Article,

Complicated peptic ulcer disease in three patients with familial dysautonomia
Wan, David W; Levy, Joseph; Ginsburg, Howard B; Kaufmann, Horacio; Axelrod, Felicia B
2011 Aug;45(7):611-613, Journal of clinical gastroenterology
Familial dysautonomia (FD) is an autosomal recessive disorder characterized by autonomic and sensory neuropathy. Owing to pervasive dysfunction, the disease has protean clinical manifestations, affecting the ocular, gastrointestinal, pulmonary, orthopedic, vasomotor, and neurologic systems. The gastrointestinal perturbations, including dysphagia, gastroesophageal dysmotility, gastroesophageal reflux, and vomiting crises, are among the earliest signs. Here, we present the first 3 instances of gastric ulcers in patients with FD and discuss their common presenting features and the special management that was required
— id: 138323, year: 2011, vol: 45, page: 611, stat: Journal Article,

Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels
Graber, J J; Sherman, F T; Kaufmann, H; Kolodny, E H; Sathe, S
2010 Dec;81(12):1369-1371, Journal of neurology neurosurgery & psychiatry
Leukoencephalopathy and autonomic dysfunction have been described in individuals with very low serum B(12) levels (<200 pg/ml), in addition to psychiatric changes, neuropathy, dementia and subacute combined degeneration. Elevated homocysteine and methylmalonic acid levels are considered more sensitive and specific for evaluating truly functional B(12) deficiency. A previously healthy 62-year-old woman developed depression and cognitive deficits with autonomic dysfunction that progressed over the course of 5 years. The patient had progressive, severe leukoencephalopathy on multiple MRI scans over 5 years. Serum B(12) levels ranged from 267 to 447 pg/ml. Homocysteine and methylmalonic acid levels were normal. Testing for antibody to intrinsic factor was positive, consistent with pernicious anaemia. After treatment with intramuscular B(12) injections (1000 mug daily for 1 week, weekly for 6 weeks, then monthly), she made a remarkable clinical recovery but remained amnesic for major events of the last 5 years. Repeat MRI showed partial resolution of white matter changes. Serum B(12), homocysteine and methylmalonic acid levels are unreliable predictors of B(12)-responsive neurologic disorders, and should be thoroughly investigated and presumptively treated in patients with unexplained leukoencephalopathy because even long-standing deficits may be reversible
— id: 141324, year: 2010, vol: 81, page: 1369, stat: Journal Article,

Experience with droxidopa (NortheraTM) in a phase III multinational, placebo-controlled, parallel group, induction-design study to assess clinical benefit and safety in subjects with neurogenic orthostatic hypotension
Kaufmann H.; Mathias C.; Low P.; Biaggioni I.; Freeman R.
2010 ;(20):5-5, Clinical autonomic research
Background: Neurogenic orthostatic hypotension (NOH) is a disabling feature of autonomic failure. NOH causes a variety of symptoms such as dizziness, vision disturbance, fatigue, generalized weakness and impairment or loss of consciousness. Symptomatic NOH results from impaired norepinephrine release from sympathetic nerve terminals leading to low blood pressure (BP) upon standing and tissue hypoperfusion. Droxidopa is a synthetic amino acid that can augment norepinephrine levels and improve standing BP thereby reducing the signs and symptoms of NOH. We are conducting a study to evaluate the clinical benefit, safety and tolerability of droxidopa to treat symptomatic NOH. Methods: This clinical trial is being conducted at 85 centers in Austria, Canada, Czech Republic, France, Germany, Italy, Romania, Ukraine, and USA. The study enrolled 142 patients between January 2008 and May 2010. It is projected that the complete sample size of 150 will be enrolled by the end of June 2010. Patients were confirmed to have symptomatic NOH of non-diabetic origin during a 2-week baseline evaluation period. At the time of writing, 39% of patients were diagnosed with Parkinson's disease, 15% with multiple system atrophy, 33% with pure autonomic failure and 13% with other autonomic neuropathies. The population is equally distributed between females (51%) and males (49%) and is predominantly Caucasian (98%) with a mean age of 54 years. Patients enter an open-label, forced titration to determine an optimal treatment dose of droxidopa ranging from 100 mg T.I.D. to 600 mg T.I.D in 100 mg T.I.D. increments. No apparent trend has emerged to date with respect to dose as an approximately equal number of patients have been determined to be optimally treated at all dose levels. Following titration, patients are washed out of drug for 1 week. Subsequently, patients are randomized in a blinded fashion to either resume droxidopa treatment at their previously determined optimal dose or receive placebo (1:1). Study outcome measures are assessed 1 week later. Results/Conclusion: The clinical effectiveness of droxidopa will be discussed in terms of its impact on each of the 10 components of the Orthostatic Hypotension Questionnaire (OHQ), clinical global impressions of disease severity and hemodynamics. The primary efficacy variable for the trial is the OHQ composite score, which measures the global impact of NOH in a patient's life. Data currently available from the open-label titration on the first 120 patients indicates a highly significant average improvement in standing systolic blood pressure of 23 mmHg measured during clinical testing. Finally, the safety of droxidopa based on the occurrence of treatment-emergent adverse events, ECG, and laboratory findings across the study will be presented
— id: 114621, year: 2010, vol: , page: 5, stat: Journal Article,

Pure autonomic failure: A restricted Lewy body synucleinopathy or early Parkinson disease?
Kaufmann, Horacio; Goldstein, David S
2010 Feb 16;74(7):536-537, Neurology
— id: 107285, year: 2010, vol: 74, page: 536, stat: Journal Article,

DIAGNOSIS OF FAMILIAL DYSAUTONOMIA IN THE UK: THE NEED FOR INCREASED AWARNESS
Maayan, C.; Gerson-Sofer, N.; Brogan, P.; Rosenfeld, N.; Norcliffe-Kaufmann, L.; Kaufmann, H.; Axelrod, F.
2010 DEC ;99(6):79-79, Acta paediatrica
— id: 121342, year: 2010, vol: 99, page: 79, stat: Journal Article,

Heart rate and blood pressure changes during autonomic nervous system challenge in panic disorder patients
Martinez, Jose M; Garakani, Amir; Kaufmann, Horacio; Aaronson, Cindy J; Gorman, Jack M
2010 Jun;72(5):442-449, Psychosomatic medicine
OBJECTIVE: To test the hypothesis that panic disorder (PD) patients have a heightened or deregulated autonomic nervous system at rest and during autonomic challenge compared with healthy controls (HC); and to test a second hypothesis that severity of illness differentiates patients'; sympathovagal balance both at rest and during orthostatic challenge. METHODS: Spectral analysis of heart rate (HR) and blood pressure was performed on 30 PD and 10 HC participants during an orthostatic challenge (head-up tilt). RESULTS: PD patients presented higher HR (p < .001), lower heart rate variability (HRV) (p < .015), higher mean diastolic blood pressure (p < .006), higher low-frequency component of HR (p < .001), and a higher ratio of low-frequency to high-frequency component of HR (LF/HF) (p < .022) than HC at baseline. During tilt, PD patients responded with higher HR (p < .039), lower HRV (p < .043), increased mean diastolic blood pressure (p < .028), and a mild increase in LF/HF, whereas controls responded with a five-fold increase in LF/HF (p < .022). Patients with higher illness severity ratings (Clinical Global Impression Scale) showed higher HR (p < .002), lower HRV (p < .026), and a lower total power of systolic blood pressure (p < .02) compared with less ill patients. CONCLUSION: These findings demonstrate a consistently higher or deregulated autonomic arousal in PD patients at rest and during orthostatic challenge compared with HC. These data also reveal a possible association between the level of anxiety illness severity and sympathovagal balance, which may imply greater cardiac risk
— id: 126646, year: 2010, vol: 72, page: 442, stat: Journal Article,

Volatile hypertension is a risk factor for renal failure in patients with familial dysautonomia
Norcliffe-Kaufmann L.; Voustianiouk A.; Axelrod F.; Kaufmann H.
2010 ;20(2):144-144, Clinical autonomic research
Renal failure is a common problem in patients with familial dysautonomia (FD). By age 25, 20% of patients with FD have end stage renal disease. To determine the role of arterial hypertension in the development and progression of kidney disease, we compared glomerular filtration rate (Cockcroft-Gault equation) over time in 50 patients with FD according to their level of arterial hypertension throughout childhood (until age 15). In addition, to assess the possible impact of increased blood pressure variability on renal function we examined the relationship between the standard deviation of ambulatory blood pressure over 24-h, an indicator of blood pressure volatility, and glomerular filtration rate. Patients with average systolic blood pressure[180 mmHg during childhood (stage III and IV hypertension American Heart Association) had a faster decline in glomerular filtration rate over time than patients with lower blood pressures (Kaplan-Meyer survival curve). There was an inverse relationship between the standard deviation of ambulatory blood pressure over 24-h and glomerular filtration rate, i.e., patients with higher standard deviation had lower glomerular filtration rates (y = - 3.3044x + 167.54, R² = 0.1949, p<0.01). Our results indicate that arterial hypertension during childhood and the magnitude of blood pressure volatility are risk factors for the development of renal failure in patients with familial dysautonomia. Prospective studies are warranted to determine whether controlling hypertension and blood pressure variability can delay the onset or slow the progression of renal failure in these patients
— id: 134744, year: 2010, vol: 20, page: 144, stat: Journal Article,

Afferent baroreflex failure in familial dysautonomia
Norcliffe-Kaufmann, Lucy; Axelrod, Felicia; Kaufmann, Horacio
2010 Nov 23;75(21):1904-1911, Neurology
BACKGROUND: Familial dysautonomia (FD) is due to a genetic deficiency of the protein IKAP, which affects development of peripheral neurons. Patients with FD display complex abnormalities of the baroreflex of unknown cause. METHODS: To test the hypothesis that the autonomic phenotype of FD is due to selective impairment of afferent baroreceptor input, we examined the autonomic and neuroendocrine responses triggered by stimuli that either engage (postural changes) or bypass (cognitive/emotional) afferent baroreflex pathways in 50 patients with FD and compared them to those of normal subjects and to those of patients with pure autonomic failure (PAF), a disorder with selective impairment of efferent autonomic neurons. RESULTS: During upright tilt, in patients with FD and in patients with PAF blood pressure fell markedly but the heart rate increased in PAF and decreased in FD. Plasma norepinephrine levels failed to increase in both groups. Vasopressin levels increased appropriately in patients with PAF but failed to increase in patients with FD. Head-down tilt increased blood pressure in both groups but increased heart rate only in patients with FD. Mental stress evoked a marked increase in blood pressure and heart rate in patients with FD but little change in those with PAF. CONCLUSION: The failure to modulate sympathetic activity and to release vasopressin by baroreflex-mediated stimuli together with marked sympathetic activation during cognitive tasks indicate selective failure of baroreceptor afference. These findings indicate that IKAP is critical for the development of afferent baroreflex pathways and has therapeutic implications in the management of these patients
— id: 114841, year: 2010, vol: 75, page: 1904, stat: Journal Article,

Tachyarrythmias with elevated cardiac enzymes in Munchausen syndrome
Norcliffe-Kaufmann, Lucy; Gonzalez-Duarte, Alejandra; Martinez, Jose; Kaufmann, Horacio
2010 Aug;20(4):259-261, Clinical autonomic research
We report the case of a woman with Munchausen syndrome who surreptitiously injected epinephrine causing recurrent ventricular tachyarrhythmias accompanied by dramatically high plasma levels of epinephrine and normal norepinephrine levels
— id: 111624, year: 2010, vol: 20, page: 259, stat: Journal Article,

Renal transplantation in familial dysautonomia: report of two cases and review of the literature
Rekhtman, Yelena; Bomback, Andrew S; Nash, Martin A; Cohen, Scott D; Matalon, Albert; Jan, Dominique M; Kaufmann, Horacio; Axelrod, Felicia B; Radhakrishnan, Jai; Appel, Gerald B
2010 Sep;5(9):1676-1680, Clinical journal of the American Society of Nephrology : CJASN.
BACKGROUND AND OBJECTIVES: Chronic kidney disease (CKD) is an increasingly recognized complication of familial dysautonomia (FD), a neurodevelopmental disorder with protean systemic manifestations that are the result of sensory and autonomic dysfunction. Progressive renal dysfunction occurs due to chronic volume depletion and cardiovascular lability with supine hypertension and orthostatic hypotension. By age 25, nearly one-half of all patients with FD will have reached stage 3 CKD. Furthermore, dialysis for ESRD in FD patients is associated with multiple complications and poor outcomes. Design, settings, participants, & measurements: We report two patients with FD who developed ESRD at ages 27 and 16, respectively, and underwent renal transplantation. Transplant was performed after 3 months on intermittent hemodialysis (HD) in the first case and after 1 month on twice-weekly continuous veno-venous hemodialysis (CVVHD) in the second case. RESULTS: Both patients tolerated surgery well and have maintained good graft function at 20 and 24 months posttransplantation, respectively. Symptomatic and functional improvements have included lower supine BP and increased sensitivity to antihypertensive agents. CONCLUSIONS: As general supportive care improves the lifespan of FD patients, issues related to the management of ESRD will become more important. Renal transplantation provides a viable alternative to dialysis for FD patients with ESRD
— id: 138213, year: 2010, vol: 5, page: 1676, stat: Journal Article,

Guidelines for the diagnosis and management of syncope (version 2009): The Task Force for the Diagnosis and Management of Syncope of the European Society of Cardiology (ESC)
Moya, Angel; Sutton, Richard; Ammirati, Fabrizio; Blanc, Jean-Jacques; Brignole, Michele; Dahm, Johannes B; Deharo, Jean-Claude; Gajek, Jacek; Gjesdal, Knut; Krahn, Andrew; Massin, Martial; Pepi, Mauro; Pezawas, Thomas; Granell, Ricardo Ruiz; Sarasin, Francois; Ungar, Andrea; van Dijk, J Gert; Walma, Edmond P; Wieling, Wouter; Abe, Haruhiko; Benditt, David G; Decker, Wyatt W; Grubb, Blair P; Kaufmann, Horacio; Morillo, Carlos; Olshansky, Brian; Parry, Steve W; Sheldon, Robert; Shen, Win K; Vahanian, Alec; Auricchio, Angelo; Bax, Jeroen; Ceconi, Claudio; Dean, Veronica; Filippatos, Gerasimos; Funck-Brentano, Christian; Hobbs, Richard; Kearney, Peter; McDonagh, Theresa; McGregor, Keith; Popescu, Bogdan A; Reiner, Zeljko; Sechtem, Udo; Sirnes, Per Anton; Tendera, Michal; Vardas, Panos; Widimsky, Petr; Auricchio, Angelo; Acarturk, Esmeray; Andreotti, Felicita; Asteggiano, Riccardo; Bauersfeld, Urs; Bellou, Abdelouahab; Benetos, Athanase; Brandt, Johan; Chung, Mina K; Cortelli, Pietro; Da Costa, Antoine; Extramiana, Fabrice; Ferro, Jose; Gorenek, Bulent; Hedman, Antti; Hirsch, Rafael; Kaliska, Gabriela; Kenny, Rose Anne; Kjeldsen, Keld Per; Lampert, Rachel; Molgard, Henning; Paju, Rain; Puodziukynas, Aras; Raviele, Antonio; Roman, Pilar; Scherer, Martin; Schondorf, Ronald; Sicari, Rosa; Vanbrabant, Peter; Wolpert, Christian; Zamorano, Jose Luis
2009 Nov;30(21):2631-2671, European heart journal
— id: 102281, year: 2009, vol: 30, page: 2631, stat: Journal Article,

The R3 component of the electrically elicited blink reflex is present in patients with congenital insensitivity to pain
Tellez, Maria J; Axelrod, Felicia; Kaufmann, Horacio
2009 Jan;141(1-2):178-180, Pain
To clarify whether the R3 component of the electrically elicited blink reflex is a nociceptive response we studied two patients with congenital insensitivity to pain due to the impaired development of Adelta and C nerve fibers (hereditary sensory and autonomic neuropathy types III and IV). We postulated that if the R3 component is a nociceptive reflex, it should be absent in these patients. The R3 responses were elicited in both sides in both the patients at all intensities, strongly suggesting that the R3 component of the blink reflex is not a nociceptive response
— id: 94974, year: 2009, vol: 141, page: 178, stat: Journal Article,

Usefulness of tilt-induced heart rate changes in the differential diagnosis of vasovagal syncope and chronic autonomic failure
Tellez, Maria J; Norcliffe-Kaufmann, Lucy J; Lenina, Svetlana; Voustianiouk, Andrei; Kaufmann, Horacio
2009 Dec;19(6):375-380, Clinical autonomic research
OBJECTIVE: To determine whether the heart rate changes during tilt table testing could be used in the differential diagnosis between vasovagal syncope and chronic autonomic failure. METHODS: We compared the relationship between electrocardiographic R-R intervals and beat-to-beat blood pressure in 43 patients with typical vasovagal responses and 30 patients with chronic autonomic failure (6 pure autonomic failure, 23 multiple system atrophy, and 1 Parkinson's disease). RESULTS: In every patient with vasovagal syncope, at the time when the blood pressure was falling, it was possible to identify at least 12 successive heart beats (mean 33 +/- 2 heart beat, range 12-57) when blood pressure and heart rate fell in parallel, i.e., there was a negative relationship between blood pressure and R-R intervals (P < 0.001). In contrast, the relationship between blood pressure and R-R intervals in patients with chronic autonomic failure was never negative, i.e., heart rate always increased, albeit less than expected for the given fall in blood pressure, or remained unchanged. INTERPRETATION: The heart rate changes during the fall in blood pressure can distinguish patients with vasovagal responses from those with chronic autonomic failure
— id: 104369, year: 2009, vol: 19, page: 375, stat: Journal Article,

Effect of medication and psychotherapy on heart rate variability in panic disorder
Garakani, Amir; Martinez, Jose M; Aaronson, Cindy J; Voustianiouk, Andrei; Kaufmann, Horacio; Gorman, Jack M
2008 Oct 6;26(3):251-258, Depression & anxiety
Background: Panic disorder (PD) patients have been shown to have reduced heart rate variability (HRV). Low HRV has been associated with elevated risk for cardiovascular disease. Our aim was to investigate the effects of treatment on heart rate (HR) in patients with PD through a hyperventilation challenge. Methods: We studied 54 participants, 43 with Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) PD and 11 controls. Subjects lay supine with their heads in a plastic canopy chamber, resting for 15 min and then breathing at a rate of 30 breaths per minute for 10 min. HRV was sampled for spectral analysis. Clinical and behavioral measures of anxiety were assessed. Treatment was chosen by patients: either 12 weeks of CBT alone or CBT with sertraline. Results: All patients showed significant decrease on clinical measures from baseline and 31 were treatment responders, 8 dropped out of the study before completion of the 12-week treatment phase and 4 were deemed nonresponders after 12 weeks of treatment. Although both treatments led to significant clinical improvement, only CBT alone demonstrated a significant reduction in HR and increase in HRV. Conclusions: Our study replicated the finding that increased HR and decreased HRV occur in PD patients. Given the evidence of cardiac risk related to HRV, CBT appears to have additional benefits beyond symptom reduction. The mechanisms of this difference between CBT and sertraline are unclear and require further study. Depression and Anxiety 0:1-8, 2008. (c) 2008 Wiley-Liss, Inc
— id: 92783, year: 2008, vol: 26, page: 251, stat: Journal Article,

Second consensus statement on the diagnosis of multiple system atrophy
Gilman, S; Wenning, GK; Low, PA; Brooks, DJ; Mathias, CJ; Trojanowski, JQ; Wood, NW; Colosimo, C; Duerr, A; Fowler, CJ; Kaufmann, H; Klockgether, T; Lees, A; Poewe, W; Quinn, N; Revesz, T; Robertson, D; Sandroni, P; Seppi, K; Vidailhet, M
2008 AUG 26 ;71(9):670-676, Neurology
Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here. Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology. Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality. Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease
— id: 86806, year: 2008, vol: 71, page: 670, stat: Journal Article,

L-dihydroxyphenylserine (Droxidopa): a new therapy for neurogenic orthostatic hypotension: the US experience
Kaufmann, Horacio
2008 Mar;18 Suppl 1:19-24, Clinical autonomic research
Neurogenic orthostatic hypotension results from failure to release norepinephrine, the neurotransmitter of sympathetic postganglionic neurons, appropriately upon standing. In double blind, cross over, placebo controlled trials, administration of droxidopa, a synthetic amino acid that is decarboxylated to norepinephrine by the enzyme L: -aromatic amino acid decarboxylase increases standing blood pressure, ameliorates symptoms of orthostatic hypotension and improves standing ability in patients with neurogenic orthostatic hypotension due to degenerative autonomic disorders. The pressor effect results from conversion of droxidopa to norepinephrine outside the central nervous system both in neural and non-neural tissue. This mechanism of action makes droxidopa effective in patients with central and peripheral autonomic disorders
— id: 79299, year: 2008, vol: 18 Suppl 1, page: 19, stat: Journal Article,

Neurogenic orthostatic hypotension: new prospects in treatment. Introduction
Kaufmann, Horacio
2008 Mar;18 Suppl 1:1-1, Clinical autonomic research
— id: 95674, year: 2008, vol: 18 Suppl 1, page: 1, stat: Journal Article,

Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Naumann, M; So, Y; Argoff, C E; Childers, M K; Dykstra, D D; Gronseth, G S; Jabbari, B; Kaufmann, H C; Schurch, B; Silberstein, S D; Simpson, D M
2008 May 6;70(19):1707-1714, Neurology
OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I-IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. RESULTS: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). RECOMMENDATIONS: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data
— id: 93610, year: 2008, vol: 70, page: 1707, stat: Journal Article,

Enhanced vascular responses to hypocapnia in neurally mediated syncope
Norcliffe-Kaufmann, Lucy Jane; Kaufmann, Horacio; Hainsworth, Roger
2008 Mar;63(3):288-294, Annals of neurology
OBJECTIVE: The susceptibility to suffer neurally mediated syncope and loss of consciousness varies markedly. In addition to vasodilatation and bradycardia, hyperventilation precedes loss of consciousness. The resultant hypocapnia causes cerebral vasoconstriction and peripheral vasodilatation. We postulate that more pronounced cerebral and peripheral vascular responses to reductions in arterial CO(2) levels underlie greater susceptibility to neurally mediated syncope. METHODS: We compared vascular responses to CO(2) among 31 patients with histories of recurrent neurally mediated syncope and low orthostatic tolerance and 14 age- and sex-matched control subjects with no history of syncope and normal orthostatic tolerance. Vascular responses to CO(2) were calculated after all subjects had fully recovered and their blood pressures and heart rates were stable. We measured blood flow velocity in the middle cerebral artery (transcranial Doppler) and in the left brachial artery (brachial Doppler), and end-tidal CO(2) during voluntary hyperventilation and hypoventilation (end-tidal CO(2) from 21-45mm Hg), and determined the slopes of the relations. RESULTS: Hypocapnia produced a significantly greater reduction in cerebral blood flow velocity and in forearm vascular resistance in patients with neurally mediated syncope than in control subjects. Opposite changes occurred in response to hypercapnia. In all subjects, the changes in cerebral blood flow velocity and forearm vasodilatation were inversely related with orthostatic tolerance. INTERPRETATION: Susceptibility to neurally mediated syncope can be explained, at least in part, by enhanced cerebral vasoconstriction and peripheral vasodilatation in response to hypocapnia. This may have therapeutic implications. Ann Neurol 2007
— id: 74776, year: 2008, vol: 63, page: 288, stat: Journal Article,

Patient management problem
Biaggioni I.; Kaufmann H.
2007 ;13(6):239-247, Continuum : lifelong learning in neurology
— id: 75466, year: 2007, vol: 13, page: 239, stat: Journal Article,

Disorders of orthostatic tolerance-orthostatic hypotension, postural tachycardia syndrome, and syncope
Freeman R.; Kaufmann H.
2007 ;13(6):50-88, Continuum : lifelong learning in neurology
Orthostatic intolerance with orthostatic hypotension and syncope are disabling features of patients with disorders of autonomic cardiovascular control. The hallmark of both central and peripheral autonomic disorders is the failure of the sympathetic postganglionic neurons to release norepinephrine appropriately upon standing. Impaired norepinephrine release is permanent in patients with autonomic failure, and upon standing, blood pressure always falls. On the other hand, in patients with neurally mediated syncopal syndromes (also known as vasovagal, vasodepressor, or reflex syncope) impaired norepinephrine release occurs episodically, typically in response to a trigger. Between syncopal episodes, patients with neurally mediated syncope usually have normal blood pressure and orthostatic tolerance. Orthostatic intolerance without a fall in blood pressure, but with a pronounced increase in heart rate, occurs in the postural tachycardia syndrome, a puzzling disorder with several possible causes characterized by excessive sympathetic activation in response to physiologic stimuli. The distinction between these disorders is important because their prognosis and management is different. Autonomic failure can be severely disabling, while neurally mediated syncopal syndromes and the postural tachycardia syndrome are always benign. Patient education is key to managing these disorders. Several simple measures should be implemented to improve orthostatic tolerance prior to pharmacologic intervention. copyright 2007 American Academy of Neurology
— id: 75468, year: 2007, vol: 13, page: 50, stat: Journal Article,

Autonomic failure in neurodegenerative disorders
Kaufmann H.; Goldstein D.S.
2007 ;13(6):111-142, Continuum : lifelong learning in neurology
Autonomic failure is a frequent feature of two types of neurodegenerative disorders-multiple system atrophy and the Lewy body syndromes, which include Parkinson's disease, pure autonomic failure, and dementia with Lewy bodies. These disorders are known collectively as synucleinopathies because accumulations of the protein alpha-synuclein are found intracellularly in the brains of affected patients. Other neurodegenerative disorders, including the amyloidopathies or tauopathies (eg, Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia, sporadic and inherited ataxias, and prion diseases), only rarely entail clinically significant autonomic failure. copyright 2007 American Academy of Neurology
— id: 75467, year: 2007, vol: 13, page: 111, stat: Journal Article,

Autonomic dysfunction in Parkinson's disease
Kaufmann, Horacio; Goldstein, David S
2007 ;83:343-363, Handbook of clinical neurology
— id: 95673, year: 2007, vol: 83, page: 343, stat: Journal Article,

Hoeldtke RD (2003) Nitrosative stress in early Type 1 diabetes. Clin Auton Res 13:406-421
Kaufmann, Horacio; Mathias, Christopher J
2007 Jun;17(3):197-197, Clinical autonomic research
— id: 95675, year: 2007, vol: 17, page: 197, stat: Journal Article,

Dopamine beta-hydroxylase deficiency involves the central autonomic network
Cheshire, William P Jr; Dickson, Dennis W; Nahm, Kirsty F; Kaufmann, Horacio C; Benarroch, Eduardo E
2006 Aug;112(2):227-229, Acta neuropathologica
— id: 74761, year: 2006, vol: 112, page: 227, stat: Journal Article,

Electrical activation of the human vestibulo-sympathetic reflex
Voustianiouk, Andrei; Kaufmann, Horacio; Diedrich, Andre; Raphan, Theodore; Biaggioni, Italo; Macdougall, Hamish; Ogorodnikov, Dmitri; Cohen, Bernard
2006 May;171(2):251-261, Experimental brain research
Muscle sympathetic nerve activity (MSNA) is modulated on a beat-to-beat basis by the baroreflex. Vestibular input from the otolith organs also modulates MSNA, but characteristics of the vestibulo-sympathetic reflex (VSR) are largely unknown. The purpose of this study was to elicit the VSR with electrical stimulation to estimate its latency in generating MSNA. The vestibular nerves of seven subjects were stimulated across the mastoids with short trains of high frequency, constant current pulses. Pulse trains were delivered every fourth heartbeat at delays of 300-700 ms after the R wave of the electrocardiogram. Vestibular nerve stimulation given 500 ms after the R wave significantly increased baroreflex-driven MSNA, as well as the diastolic blood pressure threshold at which bursts of MSNA occurred. These changes were specific to beats in which vestibular stimulation was applied. Electrical stimulation across the shoulders provided a control condition. When trans-shoulder trials were subtracted from trials with vestibular nerve stimulation, eliminating the background baroreflex-driven sympathetic activity, there was a sharp increase in MSNA beginning 660 ms after the vestibular nerve stimulus and lasting for about 60 ms. The increase in the MSNA produced by vestibular nerve stimulation, and the associated increase in the diastolic blood pressure threshold at which the baroreflex-driven bursts occurred, provide evidence for the presence of a short-latency VSR in humans that is likely to be important for the maintenance of blood pressure during rapid changes in head and body position with respect to gravity
— id: 74753, year: 2006, vol: 171, page: 251, stat: Journal Article,

L-DOPS therapy for refractory orthostatic hypotension in autoimmune autonomic neuropathy
Gibbons, Christopher H; Vernino, Steven A; Kaufmann, Horacio; Freeman, Roy
2005 Oct 11;65(7):1104-1106, Neurology
The authors report a 46-year-old woman with antibodies to the nicotinic acetylcholine receptor (NiAchR) of the autonomic ganglia. She presented with severe orthostatic intolerance refractory to treatment with midodrine, fludrocortisone, erythropoietin, vasopressin, salt, and fluid loading. Addition of L-threo-3,4-dihidroxyphenylserine (L-DOPS) substantially improved blood pressure and orthostatic tolerance. L-DOPS may benefit patients with severe orthostatic intolerance and be particularly effective in patients with ganglionic NiAchR antibodies
— id: 74751, year: 2005, vol: 65, page: 1104, stat: Journal Article,

[Pure autonomic failure. Bradbury Eggleston Syndrome. Case report]
Idiaquez, Juan; Kaufmann, Horacio; Soza, Marco; Necochea, Cecilia
2005 Feb;133(2):215-218, Revista medica de Chile
Pure Autonomic Failure is a progressive, adult onset, degenerative disorder of the autonomic nervous system characterized clinically by orthostatic hypotension, bladder, sexual and sudomotor dysfunction. Since there are no other associated somatic neurological deficits, this condition must be considered in the differential diagnosis of orthostatic hypotension. We report a 64 years old man with a history of seven years of autonomic dysfunction, with severe orthostatic hypotension, erectile and bladder dysfunction. Autonomic tests showed low circulating norepinephrine levels, sweating abnormalities with regional anhydrosis of the left side of the trunk and abnormal cardiovagal response, indicating generalized autonomic failure. Peripheral somatic neuropathies with autonomic involvement were excluded by normal electrophysiologic tests and the patient was diagnosed pure autonomic failure. Treatment with fludrocortisone and midodrine improved orthostatic tolerance
— id: 74745, year: 2005, vol: 133, page: 215, stat: Journal Article,

Artificial gravity: a possible countermeasure for post-flight orthostatic intolerance
Moore, Steven T; Diedrich, Andre; Biaggioni, Italo; Kaufmann, Horacio; Raphan, Theodore; Cohen, Bernard
2005 May-Jun;56(9-12):867-876, Acta Astronautica
Four payload crewmembers were exposed to sustained linear acceleration in a centrifuge during the Neurolab (STS-90) flight. In contrast to previous studies, otolith-ocular reflexes were preserved during and after flight. This raised the possibility that artificial gravity may have acted as a countermeasure to the deconditioning of otolith-ocular reflexes. None of the astronauts who were centrifuged had orthostatic intolerance when tested with head-up passive tilt after flight. Thus, centrifugation may also have helped maintain post-flight hemodynamic responses to orthostasis by preserving the gain of the otolith-sympathetic reflex. A comparison with two fellow Neurolab orbiter crewmembers not exposed to artificial gravity provided some support for this hypothesis. One of the two had hemodynamic changes in response to post-flight tilt similar to orthostatically intolerant subjects from previous missions. More data is necessary to evaluate this hypothesis, but if it were proven correct, in-flight short-radius centrifugation may help counteract orthostatic intolerance after space flight
— id: 74746, year: 2005, vol: 56, page: 867, stat: Journal Article,

Clinical pharmacokinetics of the norepinephrine precursor L-threo-DOPS in primary chronic autonomic failure
Goldstein, David S; Holmes, Courtney; Kaufmann, Horacio; Freeman, Roy
2004 Dec;14(6):363-368, Clinical autonomic research
BACKGROUND : Oral L-threo-3,4-dihydroxyphenylserine (L-DOPS), a synthetic catechol amino acid, increases standing blood pressure and improves standing ability in patients with neurogenic orthostatic hypotension, by conversion of L-DOPS to norepinephrine (NE) outside the brain. This study assessed the pharmacokinetics of L-DOPS, NE, and dihydroxyphenylglycol (DHPG), the main neuronal metabolite of NE, in patients with primary chronic autonomic failure from pure autonomic failure (PAF) or multiple system atrophy (MSA). METHODS : In 5 MSA and 4 PAF patients, antecubital venous blood was drawn during supine rest and plasma levels of catechols measured at various times for 48 hours after a single oral dose of 400 mg of L-DOPS. RESULTS : Plasma L-DOPS peaked at 1.9 microg/ml (9 micromol/L) about 3 hours after drug administration, followed by a monoexponential decline with a half-time of 2-3 hours in both patient groups. Plasma NE and DHPG also peaked at about 3 hours, but at much lower concentrations (4 and 42 nmol/L). Compared to the MSA group, the PAF group had a smaller calculated volume of distribution of L-DOPS and up to 10-fold lower plasma NE levels at all time points. Plasma NE was above baseline in MSA even at 48 hours after L-DOPS. CONCLUSIONS : The relatively long half-time for disappearance of L-DOPS compared to that of NE explains their very different attained plasma concentrations. The similar NE and DHPG responses in PAF and MSA suggests production of NE from LDOPS mainly in non-neuronal cells. Persistent elevation of plasma NE in MSA suggests residual release of NE from sympathetic nerves
— id: 74741, year: 2004, vol: 14, page: 363, stat: Journal Article,

Pharmacological treatment of reflex syncope
Kaufmann, Horacio; Freeman, Roy
2004 Oct;14 Suppl 1:71-75, Clinical autonomic research
Patient education, identification of possible triggers of syncope and reassurance are a central feature of the management of patients with reflex syncope. Patients should be advised as to the importance of adequate hydration and taught physical countermaneuvers to enhance cardiac venous return. These maneuvers are sufficient for most patients, however, for a small number of patients who continue to have recurrent syncopal events, pharmacological intervention may be considered. Volume expansion can be enhanced with salt and fludrocortisone. Agents from diverse pharmacological classes have been used to attenuate the reflex response, enhance vasoconstriction and attenuate vagal outflow. Alpha adrenoreceptor agonists, anticholinergic agents, theophylline, beta adrenoreceptor antagonists, serotonin reuptake inhibitors and disopyramide are the most widely studied. None of these agents has shown a consistent therapeutic benefit in clinical trials
— id: 74738, year: 2004, vol: 14 Suppl 1, page: 71, stat: Journal Article,

Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies
Kaufmann, Horacio; Nahm, Kirsty; Purohit, Dushyant; Wolfe, David
2004 Sep 28;63(6):1093-1095, Neurology
The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications
— id: 74736, year: 2004, vol: 63, page: 1093, stat: Journal Article,

Syncope: a clinically guided diagnostic algorithm
Kaufmann, Horacio; Wieling, Wouter
2004 Oct;14 Suppl 1:87-90, Clinical autonomic research
The initial evaluation of a patient with syncope should include a thorough clinical history, physical examination and 12 lead electrocardiogram (ECG). The history is the best diagnostic tool. Clinical findings guide further testing. Patients with syncope and heart disease require echocardiography, Holter monitoring or exercise testing. The tilt test and carotid sinus massage are useful to reproduce reflex syncope. An insertable subcutaneous loop recorder can provide prolonged ECG monitoring
— id: 74739, year: 2004, vol: 14 Suppl 1, page: 87, stat: Journal Article,

Defining and classifying syncope
Thijs, Roland D; Wieling, Wouter; Kaufmann, Horacio; van Dijk, Gert
2004 Oct;14 Suppl 1:4-8, Clinical autonomic research
There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences between syncope and other causes of TLOC such as epilepsy, and disorders mimicking TLOC are described. A pathophysiological classification of syncope is proposed
— id: 74737, year: 2004, vol: 14 Suppl 1, page: 4, stat: Journal Article,

Autonomic failure in neurodegenerative disorders
Kaufmann, Horacio; Biaggioni, Italo
2003 Dec;23(4):351-363, Seminars in neurology
Autonomic failure with orthostatic and postprandial hypotension, bowel and bladder disturbances, and sexual dysfunction are frequent, disabling features in patients with the three most prevalent neurodegenerative movement disorders: Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA), and the related neurodegenerative Lewy-body disorder characterized by isolated severe autonomic failure (pure autonomic failure, PAF). All of these disorders have in common the presence of alpha-synuclein in the cytoplasmic precipitates found in neurons in Lewy body disorders or glia in MSA. Autonomic failure with disabling orthostatic hypotension is the clinical hallmark of PAF. It may also be the initial presentation of MSA, making diagnosis difficult. Within a few years, however, MSA patients develop movement disorders, which are differentiated from PD by the paucity of unilateral resting tremor, the lack of response to levodopa, and their rapidly progressive nature, resulting in disability and death in 7 to 8 years. Moderately effective treatment is available for autonomic symptoms, but management of movement disorders remains unsuccessful. Discoveries relevant to physiology and common pathological conditions were initially made in patients with autonomic failure. Meals induce profound hypotension in these patients. Conversely, commonly used nasal decongestants can produce substantial pressor effects. Even 500 mL of water can increase blood pressure by a previously unrecognized sympathetic reflex. Residual sympathetic tone is able to induce sustained supine hypertension in MSA, because it is resolved after ganglionic blockade. These phenomena were not previously recognized because of the buffering capacity of the baroreflex, but were unmasked in autonomic failure patients
— id: 74724, year: 2003, vol: 23, page: 351, stat: Journal Article,

Primary hyperhidrosis--evidence for autosomal dominant inheritance
Kaufmann, Horacio; Saadia, Daniela; Polin, Charlene; Hague, Stephen; Singleton, Amanda; Singleton, Andrew
2003 Apr;13(2):96-98, Clinical autonomic research
Primary hyperhidrosis is a neurogenic disorder of unknown cause characterized by excessive sweating in the palmar surface of the hands, armpits, groin and feet. In the course of a therapeutic trial for primary hyperhidrosis, 62 % of patients reported a positive family history. Examination of these pedigrees demonstrated a sibling recurrence risk of lambdas = 29-48 and an offspring recurrence risk of lambdao = 41-68 indicating that hyperhidrosis can be an inherited condition. The pattern of inheritance suggests an autosomal dominant mode of transmission with incomplete disease penetrance
— id: 74712, year: 2003, vol: 13, page: 96, stat: Journal Article,

Norepinephrine precursor therapy in neurogenic orthostatic hypotension
Kaufmann, Horacio; Saadia, Daniela; Voustianiouk, Andrei; Goldstein, David S; Holmes, Courtney; Yahr, Melvin D; Nardin, Rachel; Freeman, Roy
2003 Aug 12;108(6):724-728, Circulation
BACKGROUND: In patients with neurogenic orthostatic hypotension (NOH), the availability of the sympathetic neurotransmitter norepinephrine (NE) in the synaptic cleft is insufficient to maintain blood pressure while in the standing posture. METHODS AND RESULTS: We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine (L-DOPS), which is decarboxylated to NE by the enzyme L-aromatic amino acid decarboxylase (L-AADC) in neural and nonneural tissue, on blood pressure and orthostatic tolerance in 19 patients with severe NOH (8 with pure autonomic failure and 11 with multiple-system atrophy). A single-blind dose-titration study determined the most appropriate dose for each patient. Patients were then enrolled in a double-blind, placebo-controlled, crossover trial. L-DOPS significantly raised mean blood pressure both supine (from 101+/-4 to 141+/-5 mm Hg) and standing (from 60+/-4 to 100+/-6 mm Hg) for several hours and improved orthostatic tolerance in all patients. After L-DOPS, blood pressure increases were closely associated with increases in plasma NE levels. Oral administration of carbidopa, which inhibits L-AADC outside the blood-brain barrier, blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients CONCLUSIONS: Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH. The pressor effect results from conversion of L-DOPS to NE outside the central nervous system
— id: 74716, year: 2003, vol: 108, page: 724, stat: Journal Article,

Brain magnetic resonance imaging in multiple-system atrophy and Parkinson disease: a diagnostic algorithm
Bhattacharya, Kirsty; Saadia, Daniela; Eisenkraft, Barbara; Yahr, Melvin; Olanow, Warren; Drayer, Burton; Kaufmann, Horacio
2002 May;59(5):835-842, Archives of neurology
BACKGROUND: Brain magnetic resonance (MR) imaging offers the potential for objective criteria in the differential diagnosis of multiple system atrophy with predominant parkinsonism (MSA-P) and Parkinson disease (PD), since it frequently shows characteristic abnormalities in patients with MSA-P and is believed to be normal in patients with PD. OBJECTIVE: To determine concordance between clinical and MR imaging-based diagnoses of MSA-P and PD. DESIGN: Two neuroradiologists identified and rated striatal and infratentorial abnormalities in 39 brain MR images and assigned a diagnosis of PD, MSA-P, or MSA with additional marked cerebellar ataxia (MSA-C). SETTING: Academic medical center. PATIENTS: Thirty-nine patients with parkinsonism, including 21 with a clinical diagnosis of PD, 14 with MSA-P, and 4 with MSA-C. RESULTS: All patients with MSA and 14 (67%) of 21 patients with PD had some abnormality on brain MR imaging. Brainstem atrophy was seen in patients with MSA-P and MSA-C. Putaminal atrophy was seen only in MSA-P. Putaminal hypointensity and lateral slitlike hyperintensity were seen in both PD and MSA-P but were always mild in PD. Cerebellar abnormalities, seen in all patients with MSA-C and 11 patients with MSA-P, were also identified in 6 patients with PD, albeit always rated as mild. Nonconcordance between clinical and radiological diagnosis occurred in 2 patients with PD, 5 with MSA-P, and 1 with MSA-C. CONCLUSION: Since several features on brain MR imaging are seen only in MSA-P, a simple diagnostic algorithm may improve the MR imaging diagnosis of MSA-P and PD
— id: 74697, year: 2002, vol: 59, page: 835, stat: Journal Article,

Autonomic cardiovascular reflexes in Wilson's disease
Bhattacharya, Kirsty; Velickovic, Miodrag; Schilsky, Michael; Kaufmann, Horacio
2002 Jun;12(3):190-192, Clinical autonomic research
We studied autonomic cardiovascular function in fourteen patients with Wilson's disease. Four had abnormalities on autonomic testing and, of these, three had evidence of severe central nervous system abnormalities. In contrast, of the remaining ten patients with normal cardiovascular reflexes, only two had severe deficits of the central nervous system. We suggest that autonomic impairment in Wilson's disease is due to involvement of central autonomic neurons
— id: 74701, year: 2002, vol: 12, page: 190, stat: Journal Article,

Treatment of patients with orthostatic hypotension and syncope
Kaufmann, Horacio
2002 May-Jun;25(3):133-141, Clinical neuropharmacology
— id: 74698, year: 2002, vol: 25, page: 133, stat: Journal Article,

Diagnosis and treatment of neurally mediated syncope
Kaufmann, Horacio; Bhattacharya, Kirsty
2002 May;8(3):175-185, Neurologist
BACKGROUND: Syncope is caused by a severe but reversible reduction in blood flow to the brain stem neurons responsible for supporting consciousness (reticular activating system). Neurally mediated syncope, also referred to as vasovagal or reflex syncope, is the most frequent cause of loss of consciousness in apparently normal subjects. REVIEW SUMMARY: Neurally mediated syncope is believed to be a reflex response with afferent, central, and efferent pathways. Characteristic autonomic changes in neurally mediated syncope are an increase in parasympathetic efferent activity causing bradycardia and a reduction in sympathetic vasoconstrictor outflow causing vasodilatation. Premonitory symptoms, such as nausea, diaphoresis, abdominal discomfort, and blurred vision, are caused by autonomic activation and are distinguishing features of neurally mediated syncope. Neurally mediated syncope frequently has a characteristic trigger, although this may not be apparent. Testing orthostatic tolerance during passive head-up tilt is the best available diagnostic procedure to evaluate patients with syncope in whom a cardiac cause has been excluded. In many cases, once the diagnosis of neurally mediated syncope is confirmed, it may suffice to reassure the patient and teach him to avoid known triggers and to recognize and act upon early warning symptoms. Because subjects with neurally mediated syncope may potentially be sodium depleted, increasing salt intake can be beneficial in improving their orthostatic intolerance. CONCLUSIONS: Neurally mediated syncope is the most common form of syncope in healthy adults. The best diagnostic tools are the clinical history and passive head-up tilt. The best treatment strategies are the avoidance of triggering factors as well as intravascular volume expansion
— id: 74715, year: 2002, vol: 8, page: 175, stat: Journal Article,

Midodrine in neurally mediated syncope: a double-blind, randomized, crossover study
Kaufmann, Horacio; Saadia, Daniela; Voustianiouk, Andrei
2002 Sep;52(3):342-345, Annals of neurology
Neurally mediated syncope is the most frequent cause of syncope in patients without structural heart disease. Its most common trigger is a reduction in venous return to the heart due to excessive venous pooling in the legs. We conducted a double-blind, randomized, crossover trial to investigate the efficacy of midodrine, a selective alpha-1 adrenergic agonist that decreases venous capacitance, in preventing neurally mediated syncope triggered by passive head-up tilt. Twelve patients with history of recurrent neurally mediated syncope, which was reproduced during head-up tilt, were randomized to receive a nonpressor dose of midodrine (5mg) or placebo on day 1 and the opposite on day 3. One hour after drug or placebo administration, patients underwent 60-degree head-up tilt lasting 40 minutes (unless hypotension or bradycardia developed first). In the supine position, midodrine produced no significant change in blood pressure or heart rate. The responses to head-up tilt were significantly different on the midodrine and the placebo day: on the placebo day, 67% (8/12) of the subjects suffered neurally mediated syncope, whereas only 17% (2/12) of the subjects developed neurally mediated syncope on the midodrine day (p < 0.02). These results indicate that midodrine significantly improves orthostatic tolerance during head-up tilt in patients with recurrent neurally mediated syncope
— id: 74700, year: 2002, vol: 52, page: 342, stat: Journal Article,