Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome.

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.

Combined counter-maneuvers accelerate recovery from orthostatic hypotension in familial dysautonomia.

BACKGROUND: In patients with familial dysautonomia (FD), prominent orthostatic hypotension (OH) endangers cerebral perfusion. Supine repositioning or abdominal compression improves systolic and diastolic blood pressure (BPsys and BPdia). OBJECTIVE: To determine whether OH recovers faster with combined supine repositioning and abdominal compression than with supine repositioning alone. METHODS: In 9 patients with FD (17.8 ± 3.9 years) and 10 healthy controls (18.8 ± 5 years), we assessed 2-min averages of BPsys, BPdia, and heart rate (HR) during supine rest, standing, supine repositioning, another supine rest, second standing, and supine repositioning with abdominal compression by leg elevation and flexion. We determined BPsys- and BPdia-recovery-times as intervals from return to supine until BP reached values equivalent to each participant's 2-min average at supine rest minus two standard deviations. Differences in signal values and BP-recovery-times between groups and positions were assessed by ANOVA and post hoc testing (significance: P < 0.05). RESULTS: Patients with FD had pronounced OH that improved with supine repositioning. However, BP only reached supine rest values with additional abdominal compression. In controls, BP was stable during positional changes. Without abdominal compression, BP-recovery-times were longer in patients with FD than those in controls, but similar to control values with compression (BPsys: 83.7 ± 64.1 vs 36.6 ± 49.5 s; P = 0.013; BPdia: 84.6 ± 65.2 vs 35.3 ± 48.9 s; P = 0.009). CONCLUSION: Combining supine repositioning with abdominal compression significantly accelerates recovery from OH and thus lowers the risk of hypotension-induced cerebral hypoperfusion.

Advanced electrocardiographic predictors of mortality in familial dysautonomia.

OBJECTIVE: To identify electrocardiographic predictors of mortality in patients with familial dysautonomia (FD). METHODS: Ten-minute resting high-fidelity 12-lead electrocardiograms (ECGs) were obtained from 14 FD patients and 14 age/gender-matched healthy subjects. Multiple conventional and advanced ECG parameters were studied for their ability to predict mortality over a subsequent 4.5-year period, including representative parameters of heart rate variability (HRV), QT variability (QTV), T-wave complexity, signal averaged ECG, and 3-dimensional ECG. RESULTS: Four of the 14 FD patients died during the follow-up period, three with concomitant pulmonary disorder. Of the ECG parameters studied, increased non-HRV-correlated QTV and decreased HRV were the most predictive of death. Compared to controls as a group, FD patients also had significantly increased ECG voltages, JTc intervals and waveform complexity, suggestive of structural heart disease. CONCLUSION: Increased QTV and decreased HRV are markers for increased risk of death in FD patients. When present, both markers may reflect concurrent pathological processes, especially hypoxia due to pulmonary disorders and sleep apnea.

Sympathetic and parasympathetic baroreflex dysfunction in familial dysautonomia.

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

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.

Clonidine improves postprandial baroreflex control in familial dysautonomia.

BACKGROUND: Patients with familial dysautonomia (FD) frequently experience hypertensive crises after gastrostomy feeding. The central alpha2-agonist clonidine attenuates feeding-induced crises. The aim of this study was to assess the effect of clonidine on cardiovascular autonomic modulation and particularly baroreflex sensitivity in familial dysautonomia after gastrostomy feeding. MATERIAL AND METHODS: In nine patients, we monitored the RR-interval and systolic blood pressure at supine rest before (baseline 1) and after gastrostomy feeding (GF1). One day later, recordings were repeated after clonidine intake (baseline 2, GF2). We determined spectral powers of RR-interval and systolic blood pressure in the low- (LF) and high-frequency range (HF). Sympathovagal balance was determined from the LF/HF ratio of RR-interval. Baroreflex sensitivity was assessed from the alpha-index of systolic blood pressure and RR-interval. RESULTS: Gastrostomy feeding decreased RR-interval, while systolic blood pressure remained stable. Clonidine induced higher RR-intervals before and after gastrostomy feeding but decreased systolic blood pressure at baseline only. Gastrostomy feeding decreased HF-power of RR-interval significantly without clonidine, but only slightly after premedication. Clonidine increased the HF-power of RR-interval slightly at baseline and significantly after gastrostomy feeding. Gastrostomy feeding increased the LF/HF ratio without clonidine only. Clonidine decreased the LF/HF ratio at baseline and after gastrostomy feeding. Gastrostomy feeding did not change baroreflex sensitivity, but baroreflex sensitivity was higher at visit 2 than visit 1. CONCLUSIONS: In familial dysautonomia, clonidine augments baroreflex sensitivity and parasympathetic modulation. The resulting cardiovascular stabilization might attenuate feeding-induced crises.

Urinary incontinence in familial dysautonomia.

The aim of this study was to determine the prevalence of urinary incontinence in women with familial dysautonomia (FD). A telephone survey was conducted on 68 known surviving female FD patients over 13 years of age registered with the Dysautonomia Centers in the USA and Israel. The mean age of the surveyed group was 27.1+/-9.8 years and 99% of the patients were nulliparous. The overall reported prevalence of urinary incontinence was 82% (n=56). Of the patients with incontinence, 59% (n=33) reported stress incontinence, 11% (n=6) reported urge incontinence, and 30% (n=17) reported symptoms of both, or mixed incontinence. In most women urinary loss was both small and infrequent, but 36% of women (n=20) with incontinence experienced a loss sufficient to necessitate the use of protection (panty liners, pads or diapers); in 7% (n=4) such loss occurred daily. Twelve per cent of all women with FD surveyed experienced primary nocturnal enuresis and 26% experienced nocturia. The prevalence of urinary incontinence is high in young female patients with familial dysautonomia. Neurophysiologic testing in this population may provide a better understanding of the role of the autonomic nervous system in urinary incontinence.

Valsalva maneuver suggests increased rigidity of cerebral resistance vessels in familial dysautonomia.

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

Dermal microdialysis provides evidence for hypersensitivity to noradrenaline in patients with familial dysautonomia.

OBJECTIVES: To use the technique of dermal microdialysis to examine sensitivity of skin vessels to noradrenaline (NA) in patients with familial dysautonomia (FD) and in healthy controls. METHODS: In 14 patients with FD and 12 healthy controls, plasma extravasation, local laser Doppler blood flow, and skin blanching were observed before, during, and after application of 10(-6) M NA through a microdialysis membrane, located intradermally in the skin of the lower leg. RESULTS: Maximum local vasoconstriction measured by laser Doppler blood flow did not differ between patients with FD and controls. In contrast, patients with FD had an earlier onset of vasoconstriction (p = 0.02). Moreover, reaction to NA was more prominent and prolonged in FD, shown by a larger zone of skin blanching around the microdialysis membrane (p < 0.001) and delayed reduction of the protein content in the dialysate after termination of NA application (p = 0.03). CONCLUSION: These data support the hypothesis that peripheral blood vessels of patients with FD show a denervation hypersensitivity to catecholamines. This may be one mechanism contributing to the major hypertension that frequently occurs during "dysautonomic crises" in FD.

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.

Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia.

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

Sympathetic and parasympathetic pupillary dysfunction in familial dysautonomia.

Objective assessment of autonomic dysfunction in familial dysautonomia (FD) is largely based on the analysis of cardiovascular responses to challenge maneuvers such as orthostatic stress. Infrared pupillometry (IPM) provides an additional reliable method for cranial autonomic evaluation and has the advantage of requiring minimal cooperation.This study was performed to determine whether IPM contributes to the assessment of autonomic function in FD patients. In 14 FD patients and 14 healthy controls, we studied absolute and relative light reflex amplitude, pupillary constriction velocity (v(constr)), pupillary diameter, early and late pupillary re-dilatation velocity (v(dil 1), v(dil 2)) after dark adaptation. Prior to IPM, all patients had an ophthamological examination to evaluate refraction and corneal integrity. In comparison to controls, patients had a significant reduction of the parameters reflecting parasympathetic pupillary function (absolute light reflex amplitude 1.34 +/- 0.21 vs. l.86 +/- 0.14 mm, relative light reflex amplitude 22.74 +/- 7.11% vs. 30.76 +/- 3.57%, v(constr) 3.75 +/- 1.09 vs. 5.80 +/- 0.59 mm/s) and of the parameters reflecting sympathetic pupillary function (diameter 5.69 +/- 0.66 vs. 6.35 +/- 0.60 mm, v(dil 1) 1.29 +/- 0.23 vs. 1.95 +/- 0.23 mm/s, v(dil 2) 0.64 +/- 0.13 vs. 0.72 +/- 0.l2 mm/s; Mann-Whitney U-test: p<0.05). The non-invasive technique of IPM demonstrates dysfunction not only of the cranial parasympathetic, but also of the cranial sympathetic nervous system and, thus, further characterizes autonomic dysfunction in FD.

Cytomegalovirus infectivity in whole blood following leukocyte reduction by filtration.

Cytomegalovirus (CMV) may be transmitted by transfusion of whole blood and cellular components processed according to standard processing procedures. A need exists to develop new procedures to remove CMV and other leukocyte-borne viruses from donor blood. Ten patients (AIDS/bone marrow transplants) who were CMV antigenemic (virus subsequently confirmed by isolation), donated 50 mL of venous blood within 24 to 72 hours of the initial antigen detection. Twenty-five-milliliter aliquots of each specimen were passed through Purecell Neo Neonatal Leukocyte Reduction Filters (Pall, East Hills, NY). The remaining 25-mL nonfiltered aliquots, as well as the blood filtrates, were subjected to infectivity endpoint determinations. The Purecell Neo filter effected a 3 to 4 log10 leukocyte reduction. CMV input titers ranged from less than 10 to 7.3 x 10(1) median tissue culture infectious dose (TCID50) per milliliter. CMV was not isolated from any postfiltration effluent (i.e., leukocytes, erythrocytes, or plasma). CMV DNA was not detected by nested polymerase chain reaction in 8 of 10 postfiltrate blood specimens. The Purecell Neo filter was efficacious in eliminating or significantly reducing viral (CMV) load in venous blood.

Nonspinal orthopaedic problems in familial dysautonomia (Riley-Day syndrome).

Familial dysautonomia (FD) is a rare autosomal recessive disease occurring in Ashkenazi Jews. It affects the autonomic, central, and peripheral nervous systems. The purpose of this study was to assess the prevalence and characteristics of orthopedic deformities, other than spinal deformities, in this population. A retrospective review of the medical records and radiographs of 182 patients was made. Three main groups of orthopaedic conditions were evaluated: (a) Fractures: 60% of the patients had one or more fractures; the average fracture rate was 1.4/patient. (b) Neuropathic joints: 11% of the cases had one or more neuropathic joints, the knee being the most common. (c) Other musculoskeletal deformities: 26% of the patients had one or more deformities. Lower extremity rotational problems and foot anomalies accounted for most of these deformities. Patients with FD have a higher prevalence of fractures and neuropathic joints than do their peers. The fracture pattern also is different, with a higher incidence of proximal femoral fractures.

Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia.

Familial dysautonomia (FD; also known as "Riley-Day syndrome"), an Ashkenazi Jewish disorder, is the best known and most frequent of a group of congenital sensory neuropathies and is characterized by widespread sensory and variable autonomic dysfunction. Previously, we had mapped the FD gene, DYS, to a 0.5-cM region on chromosome 9q31 and had shown that the ethnic bias is due to a founder effect, with >99.5% of disease alleles sharing a common ancestral haplotype. To investigate the molecular basis of FD, we sequenced the minimal candidate region and cloned and characterized its five genes. One of these, IKBKAP, harbors two mutations that can cause FD. The major haplotype mutation is located in the donor splice site of intron 20. This mutation can result in skipping of exon 20 in the mRNA of patients with FD, although they continue to express varying levels of wild-type message in a tissue-specific manner. RNA isolated from lymphoblasts of patients is primarily wild-type, whereas only the deleted message is seen in RNA isolated from brain. The mutation associated with the minor haplotype in four patients is a missense (R696P) mutation in exon 19, which is predicted to disrupt a potential phosphorylation site. Our findings indicate that almost all cases of FD are caused by an unusual splice defect that displays tissue-specific expression; and they also provide the basis for rapid carrier screening in the Ashkenazi Jewish population.

Spinal deformity in familial dysautonomia. Prevalence, and results of bracing.

BACKGROUND: Familial dysautonomia (Riley-Day syndrome) is an autosomal recessive disorder primarily affecting individuals of Ashkenazi Jewish extraction. It affects the autonomic, central, and peripheral nervous systems. Spinal deformity (mainly scoliosis) is the most common orthopaedic problem in patients with familial dysautonomia. The objectives of our study were to document the prevalence of spinal deformity in a referral center for familial dysautonomia and to determine the effectiveness of bracing. METHODS: We performed a retrospective radiographic and clinical study of 123 patients with familial dysautonomia who had survived to the age of twenty years or older. RESULTS: One hundred and two (83 percent) of the 123 patients had spinal deformity: sixty-nine (56 percent) had scoliosis only, thirty-one (25 percent) had scoliosis as well as kyphosis, and two (2 percent) had kyphosis only. Scoliosis was diagnosed by the age of ten years in sixty-four (52 percent) of the patients. Of the sixty-five patients who were treated with bracing, fifty-eight (89 percent) had progression and twenty-four (37 percent) underwent spinal arthrodesis. No risk factors for the presence or progression of the curves could be found. CONCLUSIONS: The prevalence of spinal deformity in patients with familial dysautonomia who had lived for at least twenty years was found to be 83 percent. By the age of ten years, 52 percent of the patients had scoliosis and 21 percent had kyphosis with or without scoliosis. Bracing was found to be of limited effectiveness as a definitive treatment for spinal deformity. The curve progressed despite bracing in fifty-eight (89 percent) of sixty-five patients.

Quantitative sensory testing of thermal and vibratory perception in familial dysautonomia.

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

Ictal SPECT during autonomic crisis in familial dysautonomia.

The authors report results of SPECT cerebral perfusion studies in two patients with familial dysautonomia (FD) during dysautonomic crises and when clinically stable. SPECT imaging studies used 99mTc ethylene cysteine dimer. During dysautonomic crises, regions in the temporoparietal and frontal lobes had increased uptake. Uptake in these areas was less during asymptomatic periods. Episodic asymmetric cerebral perfusion during crises especially affecting the frontal and temporal lobes is suggestive of ictal activity.