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

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Abstract

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). To determine whether OH recovers faster with combined supine repositioning and abdominal compression than with supine repositioning alone. 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). 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). Combining supine repositioning with abdominal compression significantly accelerates recovery from OH and thus lowers the risk of hypotension-induced cerebral hypoperfusion.

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Orthostatic hypotension (OH) is the most disabling and serious manifestation of adrenergic failure, occurring in the autonomic neuropathies, pure autonomic failure (PAF) and multiple system atrophy (MSA). No specific treatment is currently available for most etiologies of OH. A reduction in venous capacity, secondary to some physical counter maneuvers (e.g., squatting or leg crossing), or the use of compressive garments, can ameliorate OH. However, there is little information on the differential efficacy, or the mechanisms of improvement, engendered by compression of specific capacitance beds. We therefore evaluated the efficacy of compression of specific compartments (calves, thighs, low abdomen, calves and thighs, and all compartments combined), using a modified antigravity suit, on the end-points of orthostatic blood pressure, and symptoms of orthostatic intolerance. Fourteen patients (PAF, n = 9; MSA, n = 3; diabetic autonomic neuropathy, n = 2; five males and nine females) with clinical OH were studied. The mean age was 62 years (range 31-78). The mean +/- SEM orthostatic systolic blood pressure when all compartments were compressed was 115.9 +/- 7.4 mmHg, significantly improved (p < 0.001) over the head-up tilt value without compression of 89.6 +/- 7.0 mmHg. The abdomen was the only single compartment whose compression significantly reduced OH (p < 0.005). There was a significant increase of peripheral resistance index (PRI) with compression of abdomen (p < 0.001) or all compartments (p < 0.001); end-diastolic index and cardiac index did not change. We conclude that denervation increases vascular capacity, and that venous compression improves OH by reducing this capacity and increasing PRI. Compression of all compartments is the most efficacious, followed by abdominal compression, whereas leg compression alone was less effective, presumably reflecting the large capacity of the abdomen relative to the legs.
Article
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.
Article
Although cardiorespiratory complications contribute to the high morbidity/mortality of familial dysautonomia (FD), the mechanisms remain unclear. We evaluated respiratory, cardiovascular, and cerebrovascular control by monitoring ventilation, end-tidal carbon dioxide (CO2-et), oxygen saturation, RR interval, blood pressure (BP), and midcerebral artery flow velocity (MCFV) during progressive isocapnic hypoxia, progressive hyperoxic hypercapnia, and during recovery from moderate hyperventilation (to simulate changes leading to respiratory arrest) in 22 subjects with FD and 23 matched control subjects. Subjects with FD had normal ventilation, higher CO2-et, lower oxygen saturation, lower RR interval, and higher BP. MCFV was also higher but depended on the higher baseline CO2-et. In the FD group, whereas hyperoxic hypercapnia induced normal cardiovascular and ventilatory responses, progressive hypoxia resulted in blunted increases in ventilation, paradoxical decreases in RR interval and BP, and lack of MCFV increase. Hyperventilation induced a longer hypocapnia-induced apneic period (51.5 +/- 9.9 versus 11.2 +/- 5.5 seconds, p < 0.008) with profound desaturation (to 75.8 +/- 3.5%), marked BP decrease, and RR interval increase. Subjects with FD develop central depression in response to even moderate hypoxia with lack of expected change in cerebral circulation, leading to hypotension, bradycardia, hypoventilation, and potentially respiratory arrest. Higher resting BP delays occurrence of syncope during hypoxia. Therapeutic measures preventing hypoxia/hypocapnia may correct cardiovascular accidents in patients with FD.
Article
Patients with familial dysautonomia (FD) exhibit orthostatic hypotension as well as recumbent hypertension. In addition, during dysautonomic crises, patients have hypertensive blood pressure that is presumed to be secondary to episodic vasoconstriction, as well as swollen hands that are presumed to be secondary to vasodilatation. This discrepancy in vascular control is poorly understood, yet may provide insight into the pathophysiology of autonomic crises. To evaluate the pathological mechanisms of overall blood flow and end-organ perfusion, we assessed resting and post-ischaemic limb and skin blood flow in FD patients. In groups of 15 FD patients and 15 controls, we measured resting and post-ischaemic forearm blood flow using venous occlusion plethysmography, and superficial skin blood flow using laser Doppler flowmetry. At rest, arterial inflow was averaged from eight venous occlusion measurements and expressed as percentage volume change/min. Post-ischaemic plethysmographic inflow was determined from the peak influx during the first venous occlusion following 3 min of ischaemia. Transcutaneous forearm partial pressures of oxygen and carbon dioxide were monitored continuously. At rest, plethysmographic limb perfusion was lower in FD patients than in controls, while skin blood flow did not differ between the two groups. After ischaemia, hyperperfusion of the forearm and hand was less pronounced in FD patients than in controls, while skin blood flow was significantly higher in patients than in controls. Partial pressures of O(2) and CO(2) did not differ between the two groups. We conclude that the reduced overall limb perfusion in patients with FD is due to hypertension-induced structural changes to vessel walls, with an increase in resistance vessel rigidity. The exaggerated post-ischaemic skin perfusion in FD patients seems to be due to deficient sympathetic innervation of precapillary vessels and arteriovenous shunts and to denervation hypersensitivity of intradermal small nerve fibres. Both the reduced limb perfusion and the dysfunctional end-organ blood supply in FD patients are likely to be major contributors to the vasomotor instability observed in these subjects, particularly during periods of stress.
Article
This study was performed to assess cutaneous nerve fibre loss in conjunction with temperature and sweating dysfunction in familial dysautonomia (FD). In ten FD patients, we determined warm and cold thresholds at the calf and shoulder, and sweating in response to acetylcholine iontophoresis over the calf and forearm. Punch skin biopsies from calf and back were immunostained and imaged to assess nerve fibre density and neuropeptide content. Mean temperature thresholds and baseline sweat rate were elevated in the patients, while total sweat volume and response time did not differ from controls. The average density of epidermal nerve fibres was greatly diminished in the calf and back. There was also severe nerve loss from the subepidermal neural plexus (SNP) and deep dermis. The few sweat glands present within the biopsies had had reduced innervation density. Substance P immunoreactive (-ir) and calcitonin gene related peptide-ir (CGRP-ir) were virtually absent, but vasoactive intestinal peptide-ir (VIP-ir) nerves were present in the SNP. Empty Schwann cell sheaths were observed. Temperature perception was more impaired than sweating. Epidermal nerve fibre density was found to be profoundly reduced in FD. Decreased SP and CGRP-ir nerves suggest that the FD gene mutation causes secondary neurotransmitter depletions. Empty Schwann cell sheaths and VIP-ir nerves suggest active denervation and regeneration.
Article
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. 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. 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. 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.
Article
Executive Summary ESC Committee for Practice Guidelines (CPG): Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindhal (Sweden), Gianfranco Mazzotta (Italy), JoA£o Morais (Portugal), Ali Oto (Turkey), Otto Smiseth (Norway) Document reviewers: Silvia G. Priori (CPG Review Coordinator) (Italy), Martin Cowie (UK), Carlo Menozzi (Italy), Hugo Ector (Belgium), Ali Oto (Turkey), Panos Vardas (Greece) Guidelines and Expert Consensus documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and by different organisations and other related societies. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents. In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources. The ESC Committee for …
Article
Treatment of familial dysautonomia, a genetic disorder affecting neuronal development and survival, has improved morbidity and survival for this disorder. Although this is primarily a neurological disorder causing sensory and autonomic dysfunction, there are secondary systemic perturbations affecting ophthalmological, gastrointestinal, respiratory, cardiovascular, orthopaedic and renal function. Penetrance is complete, but there is marked variability in expression. Preventative and supportive treatments have included measures to maintain eye moisture, fundoplication with gastrostomy, the use of central agents such as benzodiazepines and clonidine to control vomiting and the dysautonomic crisis, and fludrocortisone and midodrine to combat cardiovascular lability. With the identification of the familial dysautonomia gene, it has been suggested that it may be possible to treat patients by modifying production and expression of the genetic product.
Human baroreflexes in health and disease
  • Eckberg Dl
  • Sleight P
ECKBERG DL, SLEIGHT P. Human baroreflexes in health and disease. Oxford, NY: Oxford University Press, 1992.
Physiology of exercise and sports
  • Khurana I
KHURANA I. Physiology of exercise and sports. In: Khurana I.ed. Textbook of medical physiology. Noida, India: Elsevier, 2009; 1221-9.
Handbook of clinical neurology. The Autonomic nervous system part II -dysfunctions
  • Axelrod Fb
  • Hilz Mj
AXELROD FB, HILZ MJ. Familial dysautonomia. In: Appenzeller O, ed. Handbook of clinical neurology. The Autonomic nervous system part II -dysfunctions. Amsterdam: Elsevier, 2000; 143-60.
Orthostatic challenge reveals impaired vascular resistance control, but normal venous pooling and capillary filtration in familial dysautonomia
  • Brown Cm
  • Stemper B
  • Welsch G
  • Axelrod Brys M
  • Hilz Fb
  • Mj
BROWN CM, STEMPER B, WELSCH G, BRYS M, AXELROD FB, HILZ MJ. Orthostatic challenge reveals impaired vascular resistance control, but normal venous pooling and capillary filtration in familial dysautonomia. Clin Sci (Lond) 2003;104:163-9.
Familial dysautonomia: a review of the current pharmacological treatments
  • Axelrod Fb
AXELROD FB. Familial dysautonomia: a review of the current pharmacological treatments. Expert Opin Pharmacother 2005;6:561-7.
Transcranial Doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia
  • Axelrod Hilz Mj
  • Fb
  • Haertl U
  • Brown Cm
  • Stemper B
HILZ MJ, AXELROD FB, HAERTL U, BROWN CM, STEMPER B. Transcranial Doppler sonography during head up tilt suggests preserved central sympathetic activation in familial dysautonomia. J Neurol Neurosurg Psychiatry 2002;72:657-60.
Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia
  • Bernardi L
  • Hilz M
  • Stemper B
  • C Passino
  • Axelrod Welsch G
  • Fb
BERNARDI L, HILZ M, STEMPER B, PASSINO C, WELSCH G, AXELROD FB. Respiratory and cerebrovascular responses to hypoxia and hypercapnia in familial dysautonomia. Am J Respir Crit Care Med 2003;167:141-9.
Physical manoeuvres that reduce postural hypotension in autonomic failure
  • Lieshout Wieling W
  • Leeuwen Jjv
  • Amv
WIELING W, LIESHOUT JJV, LEEUWEN AMV. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clin Auton Res 1993;3:57-65.
Guidelines on management (diagnosis and treatment) of syncopeupdate 2004. Executive Summary
  • Brignole M
  • Benditt Alboni P
  • Dg
BRIGNOLE M, ALBONI P, BENDITT DG et al. Guidelines on management (diagnosis and treatment) of syncopeupdate 2004. Executive Summary. Eur Heart J 2004;25:2054-72.
Deficient sympathetic nervous response in familial dysautonomia
  • Ziegler Mg
  • Kopin Lake Cr
  • Ij
ZIEGLER MG, LAKE CR, KOPIN IJ. Deficient sympathetic nervous response in familial dysautonomia. N Engl J Med 1976;294:630-3.
Heart rate control and mechanical cardiopulmonary coupling to assess central volume: a systems analysis
  • Triedman Barbieri R
  • Saul Jk
  • Jp
BARBIERI R, TRIEDMAN JK, SAUL JP. Heart rate control and mechanical cardiopulmonary coupling to assess central volume: a systems analysis. Am J Physiol Regul Integr Comp Physiol 2002;283:R1210-20.