Rapid changes in cerebrovascular compliance during vasovagal syncope.

PURPOSE: The compensatory mechanisms supporting cerebral perfusion throughout head-up tilt (HUT) in patients with vasovagal syncope (VVS) remain unclear. We tested the hypothesis that increased cerebrovascular compliance (Ci) and decreased cerebrovascular resistance (CVR) support cerebral blood velocity (CBV) during pre-syncope in VVS. METHODS: Finger arterial blood pressure (ABP) and right middle cerebral artery blood velocity (CBV) were recorded in 15 individuals diagnosed with VVS (n = 11 female, mean age: 40 ± 16 years, mean body mass index: 24.9 ± 4.0 kg/m2) at supine rest and during HUT (80 degree angle). Individual ABP and CBV waveforms during VVS were input into a modified Windkessel model to calculate Ci and ohmic CVR. Gosling's pulsatility index (Pi; pulse amplitude/mean CBV) was calculated. RESULTS: Diastolic ABP, systolic ABP, mean ABP (72 ± 11 to 51 ± 12 mmHg), and CVR decreased progressively during presyncope (all P ≤ 0.04). As expected, systolic CBV was sustained (all P ≥ 0.29) while diastolic and mean CBV (51 ± 13 to 38 ± 13 mmHg) fell during presyncope (all P ≤ 0.04). Both Ci and Pi increased during presyncope (128 ± 97 and 60 ± 41%, respectively; all P ≤ 0.049) and were positively correlated (R2 = 0.79, P < 0.01). Increased Ci contributed to changes in mean CBV (P < 0.01) but decreased CVR did not (P = 0.28). CONCLUSIONS: These data provide evidence that Ci increases during presyncope in patients with VVS and is likely involved in the maintenance of systolic CBV during a fall in diastolic CBV. However, this regulation is not sufficient to preserve CBV in the presence of such extreme and progressive reductions in ABP.

Prediction of the Time to Syncope Occurrence in Patients Diagnosed with Vasovagal Syncope.

OBJECTIVE: In this study we aimed to predict the time to syncope occurrence (TSO) in patients with vasovagal syncope (VVS), solely based on measurements recorded during the supine position of the head-up tilt (HUT) testing protocol. METHODS: We extracted various time and frequency domain features related to morphological aspects of arterial blood pressure (ABP) and the electrocardiogram (ECG) raw signals as well as to dynamic interactions between beat-to-beat ABP, heart rate, and cerebral blood flow velocity. From these we identified the most predictive features related to TSO. RESULTS: Specifically, when no orthostatic stress is involved, TSO in VVS patients can be predicted with high accuracy from a set of only five ECG features.

Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation.

Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes.

Impact of cancer and chemotherapy on autonomic nervous system function and cardiovascular reactivity in young adults with cancer: a case-controlled feasibility study.

BACKGROUND: Preliminary evidence suggests cancer- and chemotherapy-related autonomic nervous system (ANS) dysfunction may contribute to the increased cardiovascular (CV) morbidity- and mortality-risks in cancer survivors. However, the reliability of these findings may have been jeopardized by inconsistent participant screening and assessment methods. Therefore, good laboratory practices must be established before the presence and nature of cancer-related autonomic dysfunction can be characterized. The purpose of this study was to assess the feasibility of conducting concurrent ANS and cardiovascular evaluations in young adult cancer patients, according to the following criteria: i) identifying methodological pitfalls and proposing good laboratory practice criteria for ANS testing in cancer, and ii) providing initial physiologic evidence of autonomic perturbations in cancer patients using the composite autonomic scoring scale (CASS). METHODS: Thirteen patients (mixed diagnoses) were assessed immediately before and after 4 cycles of chemotherapy. Their results were compared to 12 sex- and age-matched controls. ANS function was assessed using standardized tests of resting CV (tilt-table, respiratory sinus arrhythmia and Valsalva maneuver) and sudomotor (quantitative sudomotor axon reflex test) reactivity. Cardiovascular reactivity during exercise was assessed using a modified Astrand-Ryhming cycle ergometer protocol. Our feasibility criteria addressed: i) recruitment potential, ii) retention rates, iii) pre-chemotherapy assessment potential, iv) test performance/tolerability, and v) identification and minimizing the influence of potentially confounding medication. T-tests and repeated measures ANOVAs were used to assess between- and within-group differences at baseline and follow-up. RESULTS: The overall success rate in achieving our feasibility criteria was 98.4 %. According to the CASS, there was evidence of ANS impairment at baseline in 30.8 % of patients, which persisted in 18.2 % of patients at follow-up, compared to 0 % of controls at baseline or follow-up. CONCLUSIONS: Results from our feasibility assessment suggest that the investigation of ANS function in young adult cancer patients undergoing chemotherapy is possible. To the best of our knowledge, this is the first study to report CASS-based evidence of ANS impairment and sudomotor dysfunction in any cancer population. Moreover, we provide evidence of cancer- and chemotherapy-related parasympathetic dysfunction - as a possible contributor to the pathogenesis of CV disease in cancer survivors.

Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance.

The current definition of postural orthostatic tachycardia syndrome (POTS) dates back to a small case series of patients with a subacute illness who presented with excessive orthostatic tachycardia and orthostatic intolerance, in the absence of another recognized disease. Conventional POTS criteria require an excessive orthostatic tachycardia in the absence of substantial orthostatic hypotension, and predominant symptoms of orthostatic intolerance, worse with upright posture and better with recumbence. POTS is a heterogeneous syndrome with likely several underlying pathophysiological processes, and not a specific disease. The primary panel for this Canadian Cardiovascular Society position statement sought to provide a contemporary update of the best evidence for the evaluation and treatment of POTS. We performed a systemic review of evidence for the evaluation of treatment of POTS using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, and developed recommendations on the basis of the Canadian Cardiovascular Society approach to position statements. One identified problem was that numerous patients who did not meet criteria for POTS would still be given that diagnoses by providers to validate the illness even though this diagnosis is incorrect. This includes patients with postural symptoms without tachycardia, orthostatic tachycardia without symptoms, and those with orthostatic tachycardia but another overt cause for excessive tachycardia. We developed a novel nomenclature ecosystem for orthostatic intolerance syndromes to increase clarity. We also provide more clarity on how to interpret the orthostatic vital signs. These concepts will need to be prospectively assessed.

Syncope: case studies.

In this series of clinical vignettes, the authors have attempted to provide a "feel" for the varied causes of syncope. The neurologist should be able to diagnose most causes of syncope using a simple algorithmic approach. Initial evaluation includes detailed clinical history, physical examination, and 12-lead ECG. Following initial evaluation, the cause of syncope is usually immediately apparent (typical story for vasovagal syncope, clinically demonstrable autonomic failure, long QT), strongly suspected (syncope preceded by chest pain or palpitations), or uncertain. In the latter group of patients, further workup will depend on the suspicion or documented presence of heart disease. In those with a single episode of syncope and no evidence of heart disease, further workup may not be necessary. In patients over 60 years of age with recurrent episodes and no cardiac history or abnormal ECG, tilt-table testing and carotid sinus massage may be diagnostic. If no diagnosis is found, an implantable loop monitor may be needed. Patients with heart disease will need the most comprehensive evaluations, possibly including exercise testing, cardiac electrophysiology, and tilt-table testing. As better understanding of pathophysiology and epidemiology emerge, under-standing of the diagnosis and treatment of syncope will improve. In the meantime, there is no substitute for astute clinical acumen.

Cerebral autoregulation is preserved in postural tachycardia syndrome.

To test whether cerebral autoregulation is impaired in patients with postural tachycardia syndrome (POTS), we evaluated 17 healthy control subjects and 27 patients with POTS. Blood pressure, heart rate, and cerebral blood velocity (transcranial Doppler) were recorded at rest and during 80 degree head-up tilt (HUT). Static cerebral autoregulation, as assessed from the change in cerebrovascular resistance during HUT, was the same in POTS and in controls. The properties of dynamic cerebral autoregulation were inferred from transfer gain, coherence, and phase of the relationship between blood pressure and cerebral blood velocity estimated from filtered data segments (0.02-0.8 Hz). Dynamic cerebral autoregulation of patients with POTS did not differ from that of controls. The patients' dynamic cerebral autoregulation did not change over the course of HUT, despite increased tachycardia suggestive of worsening orthostatic stress. Inflation of military anti-shock trouser pants substantially reduced the tachycardia of patients with POTS without affecting cerebral autoregulation. Symptoms of orthostatic intolerance were reduced in one-half of the patients following military anti-shock trouser pants inflation. We conclude that cerebral perfusion and autoregulation in many patients with POTS do not differ from that of normal control subjects.

Rhabdomyolysis and peroneal nerve compression associated with thyroid hormone withdrawal in the setting of remnant ablation: review of the literature.

OBJECTIVE: To review the putative mechanisms whereby hypothyroidism is associated with severe myopathy, neural injury, and acute compartment syndrome and report a case of nontraumatic common peroneal nerve compression associated with hypothyroidism-induced rhabdomyolysis in a patient with diabetes prepared for remnant ablation after thyroidectomy for differentiated thyroid carcinoma. METHODS: We performed a review of the English-language literature on the PubMed database using the terms hypothyroidism, muscle disease, hypothyroid myopathy, rhabdomyolysis, compression neuropathy, and acute compartment syndrome. RESULTS: Myopathy occurs frequently among patients with overt hypothyroidism; however, severe myoneural injury seems to be precipitated or accompanied by comorbid conditions. Focal peroneal neuropathy may be related to hypothyroidism-induced extrinsic compression from severe myopathy and soft tissue swelling in a narrowed fascial compartment. CONCLUSION: Severe short-term iatrogenic hypothyroidism may lead to severe myopathy and compression nerve injury in patients with underlying diabetic neuropathy. We recommend avoidance of withdrawal of thyroid hormone for purposes of remnant ablation among patients with preexisting diabetic neuropathy.

Unconscious confusion--a literature search for definitions of syncope and related disorders.

BACKGROUND: Imprecise definitions of syncope and related conditions appear common in the medical literature. To investigate the scope of the problem we systematically searched for definitions in high-ranking medical journals. METHODS: Literature review of articles on 'syncope', 'neurocardiogenic syncope', 'neurally mediated syncope', 'orthostatic intolerance', and 'orthostatic hypotension' with these keywords in the title, mainly published in the ten journals with the highest impact in the fields of cardiology, internal medicine, and neurology. RESULTS: Syncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension were defined in only 41%, 34%, 26%, 38%, and 48% of papers respectively. Definitions, when given, differed considerably among papers. Orthostatic hypotension was most frequently defined, with an increase in number and consistency of definitions after publication of a consensus in 1996. CONCLUSIONS: Syncope and related conditions proved to be infrequently and inconsistently defined in current medical literature. The lack of consistent terminology is likely to harm medical education, research, and patient care. There is a strong need for a systematic terminology for syncope and related conditions.

Electrodermal activity in patients with neurally mediated syncope.

Electrodermal activity (EDA) increases during arousal, emotional stimuli or thermoregulatory sweating and is sometimes apparent in unfiltered ECG recordings. We hypothesized that changes in EDA precede any change in blood pressure (BP) or cerebral blood velocity (CBV) observed at syncope. Data from 70 patients referred for recurrent syncope were retrospectively analyzed. 400Hz continuous waveforms were recorded of BP (Finapres), CBV (transcranial Doppler), expired CO(2) (PCO(2)) and ECG at rest and during 80 degrees head-up tilt (HUT). Two independent investigators determined the onset and termination of EDA in relation to syncope using the raw and a low pass filtered ECG trace. Of the 53 patients who experienced syncope during HUT, 33 (62 %) increased EDA 257 +/- 357s prior to syncope that continued for 75 +/- 73s following syncope. Seven patients (13%) had EDA only after syncope for 208 +/- 213s. In 13 patients (25 %), EDA was not detectable. In most cases, EDA preceded any change in BP, PCO(2) or CBV and persisted past the hemodynamic recovery following syncope. Although variable, EDA may be an objective correlate to the clinical observation that patients' symptoms precede any measurable change in cerebral perfusion. The actual relationship between EDA and symptoms of presyncope requires further investigation.

Sleep quality and psychological adjustment in chronic fatigue syndrome.

Without specific etiology or effective treatment, chronic fatigue syndrome (CFS) remains a contentious diagnosis. Individuals with CFS complain of fatigue and poor sleep--symptoms that are often attributed to psychological disturbance. To assess the nature and prevalence of sleep disturbance in CFS and to investigate the widely presumed presence of psychological maladjustment we examined sleep quality, sleep disorders, physical health, daytime sleepiness, fatigue, and psychological adjustment in three samples. individuals with CFS; a healthy control group; and individuals with a definite medical diagnosis: narcolepsy. Outcome measures included physiological evaluation (polysomnography), medical diagnosis, structured interview, and self-report measures. Results indicate that the CFS sample had a very high incidence (58%) of previously undiagnosed primary sleep disorder such as sleep apnea/hypopnea syndrome and restless legs/periodic limb movement disorder. They also had very high rates of self-reported insomnia and nonrestorative sleep. Narcolepsy and CFS participants were very similar on psychological adjustment: both these groups had more psychological maladjustment than did control group participants. Our data suggest that primary sleep disorders in individuals with CFS are underdiagnosed in primary care settings and that the psychological disturbances seen in CFS may well be the result of living with a chronic illness that is poorly recognized or understood.

Chronic fatigue syndrome: what role does the autonomic nervous system play in the pathophysiology of this complex illness?

Chronic fatigue syndrome (CFS) is a serious health concern affecting over 800000 Americans of all ages, races and socioeconomic groups and both genders. The etiology and pathophysiology of CFS are unknown, yet studies have suggested an involvement of the autonomic nervous system (ANS). A symposium was organized in December 2000 to explore the possibility of an association between ANS dysfunction and CFS, with special emphasis on the interactions between ANS dysfunction and other abnormalities noted in the immune and endocrine systems of individuals with CFS. This paper represents the consensus of the panel of experts who participated in this meeting.