Cardiac sympathetic hypo-innervation in familial dysautonomia

OBJECTIVE: Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD. METHODS: Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model. RESULTS: FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity. CONCLUSIONS: FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.     

Transcranial Doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia

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.     

Intracerebral vascular changes induced by cold pressor test: A model of sympathetic activation

Abstract

Cerebral vascular changes seem to play a fundamental role in the pathogenesis of various functional disturbances, (i.e. those suggested for migraine pathogenesis). However the exact role of single regulatory aspects (metabolic-neuronal-mechanic) are not completely understood and easily investigated in man. In particular; the role of autonomic nervous system is widely debated and recently the stimulation of tegmental noradrenergic nuclei (locus coeruleus in particular), has proved capable of inducing, in the animalboth the reduction and the increase of extracerebral blood flow. In order to evaluate the vascular effect of locus coeruleus stimulation in man, we investigated intracerebral vascular changes induced by the cold pressor test (CPT) (a well standardized method for activating both nociceptive and sympathetic pathways) by means of transcranial Doppler sonography. The examinations were performed in 14 healthy controls. CPT induced a constant and evident reduction in mean arterial velocity of the middle cerebral artery. The response was triggered during the first minute following hand immersion in ice water and reached its maximum level by the 3rd minute. Pretreatment with the alfa2-agonist clonidine caused a marked reduction of the cerebrovascular response. These data suggest that: a) intracerebral vascular response induced by CPT may be attributed to a central noradrenergic mechanism (possibly modulated at the locus coeruleus level) and b) transcranial Doppler monitoring of CPT effect is a potential tool for investigating peculiar patterns of functional disturbances of cerebral circulation. [Neurol Res 1994; 16: 163-167]     

Effect of generalized sympathetic activation by cold pressor test on cerebral hemodynamics in diabetics with autonomic dysfunction

BACKGROUND: We examined the effects of the cold pressor test on the cerebral circulation in diabetics with autonomic dysfunction without orthostatic hypotension using transcranial Doppler. METHODS: Twenty diabetics with autonomic dysfunction and 19 age-matched healthy controls participated in the study. The mean arterial blood velocity was measured in the middle cerebral artery during the cold pressor test together with the mean arterial blood pressure. RESULTS: The mean arterial blood velocity significantly (p < 0.01) increased during the 1st, 2nd, and 3rd min of the cold pressor test by 10.6, 14.1, and 13.4%, respectively, in the control subjects and by 5.8, 7.2, and 6.8%, respectively, in the diabetics. Simultaneously, the mean arterial blood pressure significantly (p < 0.01) increased by 12, 26, and 23%, respectively, in the controls and by 9.4, 12.4 and 12.9%, respectively, in the diabetics. The increases in the mean arterial velocity as well as in the mean arterial blood pressure were significantly higher in the controls than in the diabetics (p < 0.01). The change in the mean arterial blood pressure related significantly to the change in the mean arterial blood velocity both in the controls (p < 0.01, r = 0.76) and in the diabetics (p < 0.01; r = 0.59). The slope of the regression line was significantly steeper in the controls (b = 0.42, SE = 0.05) as compared with the diabetics with autonomic dysfunction (b = 0.27, SE = 0.05; p = 0.02). Moreover, also the relative increase in the cerebrovascular resistance index was higher in the controls than in the diabetics (p < 0.05). CONCLUSION: These findings in the diabetics with autonomic neuropathy, but without orthostatic hypotension, suggest a failure in the cerebral autoregulation due to impaired cerebrovascular neurogenic control.     

Heat stroke in familial dysautonomia

A 14-month-old female with familial dysautonomia was referred to the pediatric department with high fever (41.6 degrees C), watery diarrhea, and vomiting. A few hours later, signs of encephalopathy appeared. Laboratory tests revealed elevated levels of lactate dehydrogenase (3500 U/L), aspartate aminotransferase (640 U/L), alanine aminotransferase (320 U/L), and creatine kinase (28,420 U/L). The diagnosis was heat stroke. Impaired autonomic nervous system function may be another risk factor for the development of heat stroke in young children.     

Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia

In adult patients with familial dysautonomia the mean volume of superior cervical sympathetic ganglia is reduced to 34% of the normal of 222 mm³. Packing density of neurons is reduced to 37% of normal. The mean total number of ganglionic neurons is 120,000 as compared to 1,060,000 in controls. The mean totals of preganglionic neurons in the first three thoracic cord segments are 13,600 in patients and 25,150 in controls. Deficits in sympathetic neurons account for many of the clinical, pharmacological and biochemical manifestations of familial dysautonomia.     

Mother-induced hypertension in familial dysautonomia

Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother’s involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control.     

Sudomotor function in familial dysautonomia

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.     

Pacemakers in patients with familial dysautonomia

Familial dysautonomia (FD) is a genetic disease associated with a high incidence of sudden death. If fatal bradyarrhythmia is an etiological factor then the incidence of sudden death should decrease after pacemaker placement. Retrospective review of 596 registered FD patients revealed that 22 FD patients (3.7%) had pacemakers placed between December 1984 and June 2003. Clinical and electrocardiographic indications for placement and demographic data were assessed for 20 of the 22 patients (10 males, 10 females, ages 4 to 48 years). Two patients were excluded because of insufficient data. Prior to pacemaker placement, presenting symptoms were syncope and cardiac arrest, 16/20 (80%) and 6/20 (30 %), respectively. Asystole was the most frequent electrocardiographic finding and was documented in 17/20 patients (85 %). Other electrocardiographic abnormalities included bradycardia, AV block, prolonged QTc and prolonged JTc. The average duration of pacemaker utilization was 5.7 years (range 5 months to 14.5 years). Complications included infection (1 patient) and wire migration (2 patients). In the one patient with infection, the pacemaker was permanently removed. This patient then experienced multiple syncopal episodes and death. There were 7 other deaths. Three deaths occurred suddenly without preceding events, and 4 patients had non-cardiac causes of death. None of these 7 deceased patients had recurrence of syncope after pacemaker placement. In the 12 surviving patients, 6 had recurrence of syncope but none had cardiac arrest. Pacemaker placement may protect FD patients from fatal bradyarrhythmia and may decrease the incidence of syncope. However, data are limited and prospective analysis is needed.     

Cardiovascular dysautonomia in fatal familial insomnia

Autonomic control of the cardiovascular system was assessed in two patients with Fatal Familial Insomnia. The diagnosis was confirmed at autopsy in patient 1. In the resting state blood pressure and heart rate were higher than controls in patient 1; plasma noradrenaline levels were elevated in both patients. Evaluation of cardiovascular reflexes indicated intact baroreflex pathways but with exaggerated blood pressure and biochemical responses to certain stimuli (postural change, Valsalva manoeuvre, isometric handgrip). There was no pressor response to intravenously infused noradrenaline, an increased response to atropine and diminished depressor and sedative effects to clonidine. Overall these results are indicative of an unbalanced autonomic control with preserved parasympathetic and higher background and stimulated sympathetic activity. These physiological, biochemical and pharmacological data, together with known neuro-pathological findings in this disorder, emphasize the possible role played by the thalamus in regulating autonomic control of cardiovascular function in man.     

Taste and smell in familial dysautonomia

Familial dysautonomia (FD) is one of the classic diseases characterized by taste and smell abnormalities. However, these typical features are based on data obtained from two separate crude studies published in 1964. In the present study psychophysicatcoghitive and reflex-like facial-behavioral responses to taste and smell, in nine patients with FD and 15 healthy controls, were recorded. Five taste stimulants were presented to both study groups, while a selection of common household odors was used for FD patients only. The patients with FD showed a markedly higher incidence of recognition failures for salty, bitter, sweet, and water stimuli than the controls, but rate of recognition of sour stimuli was almost identical in the two groups. Estimates by the subjects on a hedonic scale of 0 to 10 and facial display in FD indicated a relatively normal sensitivity to sour stimuli and to a lesser extent to bitter stimuli. Water, sweet, and salty stimuli evoked non-discriminatory responses. These findings indicate specific dysgeusia rather than general ageusia. Smell was found to be normal. In children with taste and smell impairment, a systematic evaluative approach may help in planning palatable diets for adequate and comfortable nutrition.     

Fludrocortisone in patients with familial dysautonomia

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.     

Hypnosis prevents the cardiovascular response to cold pressor test

To highlight the effects of hypnotic focused analgesia (HFA), 20 healthy participants underwent a cold pressor test (CPT) in waking basal conditions (WBC) by keeping the right hand in icy water until tolerable (pain tolerance); subjective pain was quantified by visual scale immediately before extracting the hand from water. The test was then repeated while the participants were under hypnosis and underwent HFA suggestions. Cardiovascular parameters were continuously monitored. Pain tolerance was 121.5+/-96.1 sec in WBC and 411.0+/-186.7 sec during HFA (p < 0.0001), and visual rating score 7.75+/-2.29 and 2.45+/-2.98 (p < 0.0001), respectively. CPT-induced increase of total peripheral resistance was non significant during HFA and +21% (p < 0.01) in WBC. HFA therefore reduced both perception and the reflex cardiovascular consequences of pain as well. This indicates that hypnotic analgesia implies a decrease of sensitivity and/or a block of transmission of painful stimuli, with depression of the nervous reflex arc.     

Calcitonin gene related peptide in familial dysautonomia

Familial dysautonomia (FD) patients have diminished sensory C-fibers. Calcitonin gene related peptide (CGRP) is a widely distributed neuropeptide and prominent neurotransmitter in C-fibers. We show that plasma CGRP levels measured by radioimmunoassay is significantly lower in 51 FD patients compared to controls (P<0.001). In 11/51 FD patients with FD crisis and in 19/51 FD patients with pneumonia, the mean CGRP levels rose significantly as compared to their baseline (P<0.003, P<0.001, respectively).The deficiency of CGRP in FD patients is consistent with their depletion of C-fibers, and may explain some of their symptoms, either directly or via modulation of sympathetic activity.