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Neurocardiological interactions can cause severe cardiac arrhythmias in patients with acute ischemic stroke. The relationship between the lesion location in the brain and the occurrence of cardiac arrhythmias is still discussed controversially. The aim of the present study was to correlate the lesion location with the occurrence of cardiac arrhythmias in patients with acute ischemic stroke. Cardiac arrhythmias were systematically assessed in patients with acute ischemic stroke during the first 72 h after admission to a monitored stroke unit. Voxel-based lesion-symptom mapping (VLSM) was used to correlate the lesion location with the occurrence of clinically relevant severe arrhythmias. Overall 150 patients, 56 with right-hemispheric and 94 patients with a left-hemispheric lesion, were eligible to be included in the VLSM study. Severe cardiac arrhythmias were present in 49 of these 150 patients (32.7%). We found a significant association (FDR correction, q < 0.05) between lesions in the right insular, right frontal and right parietal cortex as well as the right amygdala, basal ganglia and thalamus and the occurrence of cardiac arrhythmias. Because left- and right-hemispheric lesions were analyzed separately, the significant findings rely on the 56 patients with right-hemispheric lesions. The data indicate that these areas are involved in central autonomic processing and that right-hemispheric lesions located to these areas are associated with an elevated risk for severe cardiac arrhythmias.

Background: Growing evidence suggests that the heart rate (HR) at rest is an independent predictor of cardiovascular mortality. In ischemic stroke, continuous monitoring of HR is the standard of care, but systematic data on its dynamics and prognostic value during the acute phase are limited., Methods: In this prospective observational study, HR was measured by continuous electrocardiographic monitoring on admission and during the first 72 hours of care among patients who were awake with ischemic stroke and survived until discharge. Functional outcome was assessed after 90 days., Results: Data from 702 consecutive patients were analyzed (median age, 73 years, 54% men). The time course of HR was initially characterized by a rapid decline during the first 12 hours after admission. Among patients who survived until day 90, this was followed by a continuous downward trend in HR, whereas death after discharge was associated with a secondary increase and a reversal point 12 hours after admission. After adjustment for established risk factors, this secondary increase during the acute period was an independent predictor of death (hazard ratio, 3.73; 95% confidence interval, 1.47-9.43; P = .005)., Conclusions: A secondary rise of HR during care for acute ischemic stroke is an early sign of fatality and may represent a surrogate for an unfavorable sympathetic disinhibition. Further research is warranted to clarify the role of targeted HR reduction after ischemic stroke (http://clinicaltrials.gov/, unique identifier NCT01858779)., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: A study was undertaken to determine associations between ischemic stroke sites and poststroke hyperglycemia (PSH)., Methods: Nondiabetic patients with first ever ischemic stroke confirmed by imaging were prospectively included. Blood glucose level (BGL), National Institute of Health Stroke Scale (NIHSS) score, and clinical parameters were assessed on admission. BGL was dichotomized for elevated versus normal levels using a cutoff value of >7.0 mmol/l. Clinical parameters were correlated with BGL and were compared between patient groups with elevated versus normal glucose values. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating sites of ischemic lesions with PSH., Results: Of 1,281 stroke patients screened, 229 (mean age = 66.3 ± 15.9 years) met the inclusion criteria. Patients with elevated BGL were older, had higher NIHSS scores, and had larger infarcts compared to those without elevated glucose levels. Spearman rank analysis showed correlations between BGL and age, infarct size, heart rate (HR), and NIHSS scores (p ≤ 0.05). The VLSM analysis adjusted for these confounding factors demonstrated associations between PSH and damaged voxels in right hemispheric insular and opercular areas., Interpretation: The data indicate that damage in the right insulo-opercular areas contributes to PSH. The association between sympathetically mediated increase of HR and BGL suggests disinhibition of sympathetic outflow as a possible mechanism for PSH., (© 2014 American Neurological Association.)

Objective: To investigate feasibility and diagnostic accuracy of measurement of the peripheral pulse (MPP) at the radial artery as a simple, noninvasive screening tool for paroxysmal atrial fibrillation (pAF) in patients after acute ischemic stroke., Methods: Two hundred fifty-six patients with acute ischemic stroke and the patients' relatives at a tertiary stroke center were prospectively included. Participants were instructed for characteristics of atrial fibrillation (AF) in MPP using standardized educational material. Measurements of participants as well as a health care professional were then compared with simultaneous blinded ECG to evaluate diagnostic accuracy parameters., Results: MPP by the health care professional or patients' relatives had a diagnostic sensitivity of 96.5% and 76.5%, respectively, with 94.0% and 92.9% specificity for the detection of AF. Self-measurements were reliably performed by 89.1% of competent patients with a diagnostic sensitivity of 54.1% and 96.2% specificity. False-positive results were limited to 6 cases (2.7%) with a positive predictive value of 76.9% and a negative predictive value of 90.0%., Conclusion: With a low rate of false-positive results, MPP offers an easy, ubiquitously available, noninvasive, first-step screening tool to guide ECG diagnostics for pAF after ischemic stroke. The data warrant a prospective trial evaluating the efficacy of MPP-guided ECG diagnostics in secondary prevention after stroke, which is now underway., Classification of Evidence: This study provides Class I evidence that MPP by patients or relatives accurately distinguishes AF from normal heart rhythm as compared with continuous ECG., (© 2014 American Academy of Neurology.)

Background: Autonomic arousal-responses to emotional stimuli change with age. Age-dependent autonomic responses to music-onset are undetermined., Objective: To determine whether cardiovascular-autonomic responses to "relaxing" or "aggressive" music differ between young and older healthy listeners., Methods: In ten young (22.8±1.7 years) and 10 older volunteers (61.7±7.7 years), we monitored respiration (RESP), RR-intervals (RRI), and systolic and diastolic blood pressure (BPsys, BPdia) during silence and 180second presentations of two "relaxing" and two "aggressive" classical-music excerpts. Between both groups, we compared RESP, RRI, BPs, spectral-powers of mainly sympathetic low-frequency (LF: 0.04-0.15Hz) and parasympathetic high-frequency (HF: 0.15-0.5Hz) RRI-oscillations, RRI-LF/HF-ratios, RRI-total-powers (TP-RRI), and BP-LF-powers during 30s of silence, 30s of music-onset, and the remaining 150s of music presentation (analysis-of-variance and post-hoc analysis; significance: p<0.05)., Results: During silence, both groups had similar RRI, LF/HF-ratios and LF-BPs; RESP, LF-RRI, HF-RRI, and TP-RRI were lower, but BPs were higher in older than younger participants. During music-onset, "relaxing" music decreased RRI in older and increased BPsys in younger participants, while "aggressive" music decreased RRI and increased BPsys, LF-RRI, LF/HF-ratios, and TP-RRI in older, but increased BPsys and RESP and decreased HF-RRI and TP-RRI in younger participants. Signals did not differ between groups during the last 150s of music presentation., Conclusions: During silence, autonomic modulation was lower - but showed sympathetic predominance - in older than younger persons. Responses to music-onset, particularly "aggressive" music, reflect more of an arousal- than an emotional-response to music valence, with age-specific shifts of sympathetic-parasympathetic balance mediated by parasympathetic withdrawal in younger and by sympathetic activation in older participants., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Purpose: Pharmacological blockade showed sympathetic origin of 0.03 to 0.15 Hz blood pressure (BP) oscillations and parasympathetic origin of 0.15 to 0.5 Hz RR-interval (RRI) oscillations, but has not been used to determine origin of cerebral blood flow velocity (CBFV) oscillations at these frequencies. This study evaluated by pharmacological blockade whether 0.1 Hz CBFV oscillations are related to sympathetic and 0.2 Hz CBFV oscillations to parasympathetic modulation., Methods: In 11 volunteers (24.6 ± 2.3 years), we monitored RRIs, BP, and proximal middle cerebral artery CBFV, at rest, during 180 s sympathetic BP activation by 0.1 Hz sinusoidal neck suction (NS), and during 180 s parasympathetic RRI activation by 0.2 Hz NS. We repeated recordings after 25 mg carvedilol, and after 0.04 mg/kg atropine. Autoregressive analysis quantified RRI-, BP-, and CBFV-spectral powers at 0.1 Hz and 0.2 Hz. We compared parameters at rest, during 0.1 Hz, or 0.2 Hz NS, with and without carvedilol or atropine (analysis of variance, post hoc testing; significance, P<0.05)., Results: Carvedilol significantly increased RRIs and lowered BP, CBFV, and 0.1 Hz RRI-, BP-, and CBFV-powers at baseline (P=0.041 for CBFV-powers), and during 0.1 Hz NS-induced sympathetic activation (P<0.05). At baseline and during 0.2 Hz NS-induced parasympathetic activation, atropine lowered RRIs and 0.2 Hz RRI-powers, but did not change BP, CBFV, and 0.2 Hz BP- and CBFV-powers., Conclusions: Attenuation of both 0.1 Hz CBFV and BP oscillations after carvedilol indicates a direct relation between 0.1 Hz CBFV oscillations and sympathetic modulation. Absent effects of atropine on BP, CBFV, and 0.2 Hz BP and CBFV oscillations suggest that there is no direct parasympathetic influence on 0.2 Hz BP and CBFV modulation.

Background: Platelet counts (PCs) <100,000/µl are considered as a contraindication for intravenous thrombolysis (IVT). While US guidelines recommend IVT initiation before the availability of clotting tests, the guidelines of the European Stroke Organization give no such practical advice. We aimed to assess the incidence of thrombocytopenia in IVT patients, outcome after thrombolysis in affected patients and the time gained by initiating treatment prior to availability of PC results., Methods: All patients with thrombocytopenia were identified in our prospectively acquired thrombolysis database. Baseline demographic data, intracerebral hemorrhage rates as well as functional outcome were assessed. The median time between initiation of thrombolysis and availability of PCs was calculated., Results: Of 625 IVT patients, 3 (0.5%) had thrombocytopenia at stroke onset. None of them developed intracerebral hemorrhage (ICH) or died during the follow-up. Waiting for PCs would have delayed treatment in 72.4% of the patients, with a median hypothetical delay of 22 min (interquartile range: 11-41 min)., Conclusions: To date, there are no sufficient data to evaluate the ICH risk in thrombocytopenic patients. However, thrombocytopenia is rare in IVT patients. Thus, generally waiting for PC results prior to initiation of IVT is not warranted. Avoiding this significant delay yields shorter door-to-needle times and potentially more effective treatment., (Copyright © 2013 S. Karger AG, Basel.)

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., (© 2012 John Wiley & Sons A/S.)

Background and Purpose: Localized head and neck cooling might be suited to induce therapeutic hypothermia in acute brain injury such as stroke. Safety issues of head and neck cooling are undetermined and may include cardiovascular autonomic side effects that were identified in this study., Methods: Ten healthy men (age 35±13 years) underwent 120 minutes of combined head and neck cooling (Sovika, HVM Medical). Before and after onset of cooling, after 60 and 120 minutes, we determined rectal, tympanic, and forehead skin temperatures, RR intervals, systolic and diastolic blood pressures (BP), laser-Doppler skin blood flow at the index finger and cheek, and spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) and parasympathetic high-frequency (0.15-0.5 Hz) RR interval oscillations and sympathetic low-frequency oscillations of BP. We compared values before and during cooling using analysis of variance with post hoc analysis; (significance, P<0.05)., Results: Forehead skin temperature dropped by 5.5±2.2°C with cooling onset and by 12.4±3.2°C after 20 minutes. Tympanic temperature decreased by 4.7±0.7°C within 40 minutes, and rectal temperature by only 0.3±0.3°C after 120 minutes. Systolic and diastolic BP increased immediately on cooling onset and rose by 15.3±20.8 mm Hg and 16.5±13.4 mm Hg (P=0.004) after 120 minutes, whereas skin blood flow fell significantly during cooling. RR intervals and parasympathetic RR interval high-frequency powers increased with cooling onset and were significantly higher after 60 and 120 minutes than they were before cooling., Conclusions: Head and neck cooling prominently reduced tympanic temperature and thus might also induce intracerebral hypothermia; however, it did not significantly lower body core temperature. Profound skin temperature decrease induced sympathetically mediated peripheral vasoconstriction and prominent BP increases that are not offset by simultaneous parasympathetic heart rate slowing. Prominent peripheral vasoconstriction and BP increase must be considered as possibly harmful during head and neck cooling.

Background: Experimental evidence indicates that iron plays a key role in edema formation after intracerebral hemorrhage (ICH). We investigated the relationship between ICH radiopacity on CT as a marker of hematoma iron content and perihemorrhagic edema (PHE) after ICH., Methods: We retrospectively investigated patients with spontaneous lobar and ganglionic supratentorial ICH who received follow-up CT scans during the first 7days after symptom onset (d1, d2-4, d5-7). Measurements of ICH and edema volumes were taken using a semiautomatic threshold-based volumetric algorithm. Radiopacity of the blood clot was determined using the mean Hounsfield unit (HU) count of the ICH., Results: A total of 117 patients aged 71.92±11.55years with spontaneous ICH (34.63±32.44ml) were included in the analysis. Mean ICH radiopacity was 59.7±3.4HU. We found significantly larger relative PHE at d2-4 (1.7±0.9 vs. 1.3±0.8; P=0.032) and d5-7 (2.0±1.3 vs. 1.3±0.9; P=0.007) and larger peak relative PHE (2.3±1.6 vs. 1.6±1.1; P=0.006) in patients with ICH radiopacity >60HU (n=59), as compared to patients with ICH radiopacity <60HU (n=58)., Conclusions: Higher ICH radiopacity, reflecting higher in vivo hematoma iron content, is associated with more PHE after ICH., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Fabry disease (FD) is an X-linked lysosomal storage disorder which may lead to impaired peripheral nerve function, mostly affecting small nerve fibers, and to neuropathic pain. Characteristics of the neuropathy associated with FD and the covariates for its development and temporal course have not been described in a large cohort. We studied small fiber function and morphology in 120 Fabry patients at baseline and in subgroups of these until 4-year follow-up. Baseline neurological (89/120) and electrophysiological (106/120) examination was mostly normal. Quantitative sensory testing revealed impaired cold detection thresholds in 84% of men and 39% of women. Lower leg intraepidermal nerve fiber density (IENFD) was reduced to 46% in Fabry patients compared to controls and to 12.5% in men with impaired renal function. Patients with abnormal IENFD more often had pain. Group means for IENFD did not improve under enzyme replacement therapy (ERT), but IENFD in the back increased under ERT in 4/15 patients with good renal function and clinical improvement. Cutaneous cytokine gene expression did not differ from controls. We conclude that ERT may improve proximal skin innervation in patients with good renal function, but does not protect small fiber function in men with impaired renal function., (© 2011 Peripheral Nerve Society.)

Long-term mortality is increased after mild traumatic brain injury (mTBI). Central cardiovascular-autonomic dysregulation resulting from subtle, trauma-induced brain lesions might contribute to cardiovascular events and fatalities. We investigated whether there is cardiovascular-autonomic dysregulation after mTBI. In 20 mTBI patients (37±13 years, 5-43 months post-injury) and 20 healthy persons (26±9 years), we monitored respiration, RR intervals (RRI), blood pressures (BP), while supine and upon standing. We calculated the root mean square successive RRI differences (RMSSD) reflecting cardiovagal modulation, the ratio of maximal and minimal RRIs around the 30th and 15th RRI upon standing (30:15 ratio) reflecting baroreflex sensitivity (BRS), spectral powers of parasympathetic high-frequency (HF: 0.15-0.5 Hz) RRI oscillations, of mainly sympathetic low-frequency (LF: 0.04-0.15 Hz) RRI oscillations, of sympathetic LF-BP oscillations, RRI-LF/HF-ratios reflecting sympathovagal balance, and the gain between BP and RRI oscillations as additional BRS index (BRS(gain)). We compared supine and standing parameters of patients and controls (repeated measures analysis of variance; significance: p<0.05). While supine, patients had lower RRIs (874.2±157.8 vs. 1024.3±165.4 ms), RMSSDs (30.1±23.6 vs. 56.3±31.4 ms), RRI-HF powers (298.1±309.8 vs. 1507.2±1591.4 ms(2)), and BRS(gain) (8.1±4.4 vs. 12.5±8.1 ms·mmHg(-1)), but higher RRI-LF/HF-ratios (3.0±1.9 vs. 1.2±0.7) than controls. Upon standing, RMSSDs and RRI-HF-powers decreased significantly in controls, but not in patients; patients had lower RRI-30:15-ratios (1.3±0.3 vs. 1.6±0.3) and RRI-LF-powers (2450.0±2110.3 vs. 4805.9±3453.5 ms(2)) than controls. While supine, mTBI patients had reduced cardiovagal modulation and BRS. Upon standing, their BRS was still reduced, and patients did not withdraw parasympathetic or augment sympathetic modulation adequately. Impaired autonomic modulation probably contributes to cardiovascular irregularities post-mTBI.

Background and Purpose: Stroke is frequently associated with autonomic dysfunction, which causes secondary cardiovascular complications. Early diagnosis of autonomic imbalance prevents complications, but it is only available at specialized centers. Widely available surrogate markers are needed. This study tested whether stroke severity, as assessed by National Institutes of Health Stroke Scale (NIHSS) scores, correlates with autonomic dysfunction and thus predicts risk of autonomic complications., Methods: In 50 ischemic stroke patients, we assessed NIHSS scores and parameters of autonomic cardiovascular modulation within 24 hours after stroke onset and compared data with that of 32 healthy controls. We correlated NIHSS scores with parameters of total autonomic modulation (total powers of R-R interval [RRI] modulation; RRI standard deviation [RRI-SD], RRI coefficient of variation), parasympathetic modulation (square root of the mean squared differences of successive RRIs, RRI-high-frequency-powers), sympathetic modulation (normalized RRI-low-frequency-powers, blood pressure-low-frequency-powers), the index of sympatho-vagal balance (RRI-LF/HF-ratios), and baroreflex sensitivity., Results: Patients had significantly higher blood pressure and respiration, but lower RRIs, RRI-SDs, RRI coefficient of variation, square root of the mean squared differences of successive RRIs, RRI-low-frequency-powers, RRI-high-frequency-powers, RRI-total powers, and baroreflex sensitivity than did controls. NIHSS scores correlated significantly with normalized RRI-low-frequency-powers and RRI-LF/HF-ratios, and indirectly with RRIs, RRI-SDs, square root of the mean squared differences of successive RRIs, RRI-high-frequency-powers, normalized RRI-high-frequency-powers, RRI-total-powers, and baroreflex sensitivity. Spearman-Rho values ranged from 0.29 to 0.47., Conclusions: Increasing stroke severity was associated with progressive loss of overall autonomic modulation, decline in parasympathetic tone, and baroreflex sensitivity, as well as progressive shift toward sympathetic dominance. All autonomic changes put patients with more severe stroke at increasing risk of cardiovascular complications and poor outcome. NIHSS scores are suited to predict risk of autonomic dysregulation and can be used as premonitory signs of autonomic failure.

Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen., Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain., Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients., Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

Fabry disease is an inherited disorder of lipid metabolism caused by deficient activity of the lysosomal enzyme α-galactosidase A. Burning peripheral pain with triggered crises of excruciating pain and gastrointestinal dysmotility point to Fabry small fiber neuropathy; angiokeratoma, corneal deposits, and hypohidrosis are other common early manifestations. Progressive dysfunction of the kidneys, heart, and/or brain develops in adulthood. Diagnosis is often delayed which is of great concern, as therapeutic outcomes with enzyme replacement therapy are generally more favorable in early stages of Fabry disease. Results of a survey among 360 rheumatologists and pediatricians clinically managing patients with rheumatologic conditions demonstrate that Fabry manifestations are generally poorly recognized and that awareness of appropriate diagnostic tests is low. To raise awareness about the musculoskeletal aspects of Fabry disease among rheumatologists, the International Musculoskeletal Working Group on Lysosomal Storage Disorders has reviewed the current knowledge. We propose a diagnostic algorithm with burning pain in hands and feet and triggered attacks of excruciating pain as keystones. Evidence of autonomic nerve dysfunction and simple temperature sensitivity testing can provide important diagnostic clues. Multi-systemic involvement should be explored by taking a detailed medical history, including family history, and performing a thorough physical examination and appropriate laboratory workup. Confirmatory tests include the α-Gal A enzyme activity assay (males) and genetic testing (females). We propose that medical specialists use our diagnostic algorithm when evaluating individuals with peripheral neuropathic pain.

Objective: The time preceding brain death is associated with complex dysregulation including autonomic dysfunction that may compromise organ perfusion, thus inducing final organ failure. In this study, we assessed autonomic function in patients prior to brain death., Methods: In 5 patients (2 women, median 60 years, age range 52-75 years) with fatal cerebral hemorrhage or stroke and negative prognosis, we monitored RR-intervals (RRI), systolic and diastolic blood pressure (BP), and oxygen saturation. Adjustment of mechanical ventilation remained constant. We assessed autonomic function from spectral powers of RRI and BP in the mainly sympathetic low- (LF, 0.04-0.15 Hz) and parasympathetic high-frequencies (HF, 0.15-0.5 Hz), and calculated the RRI-LF/HF-ratio as index of sympathovagal balance. Three patients required norepinephrine (0.5-1.6 mg/h) for up to 72 h to maintain organ perfusion. Norepinephrine was reduced to 0.2-0.5 mg/h within 2 h before brain death was diagnosed according to the criteria of the German Medical Association. Wilcoxon test compared average values of ten 2-min epochs determined 2-3 h (measurement 1) and 1 h (measurement 2) before brain death., Results: We found higher systolic (127.3 ± 15.9 vs. 159.4 ± 44.8 mmHg) and diastolic BP (60.1 ± 15.6 vs. 74.0 ± 15.2 mmHg), RRI-LF/HF-ratio (1.2 ± 1.6 vs. 3.9 ± 4.0), and BP-LF-powers (2.7 ± 4.8 vs. 23.1 ± 28.3 mmHg²) during measurement 2 than during measurement 1 (p < 0.05)., Conclusions: The increase in BPs, in sympathetically mediated BP-LF-powers, and in the RRI-LF/HF-ratio suggests prominent sympathetic activity shortly before brain death. Prefinal sympathetic hyperactivity might cause final organ failure with catecholamine-induced tissue damage which impedes post-mortem organ transplantation.

In Fabry disease, deficiency of α-galactosidase A results in the accumulation of glycosphingolipids in body fluids and tissues including corneas, blood vessels, kidneys and also structures of the central and peripheral nervous system. Many patients show cardiovascular and cerebrovascular dysfunction. Cerebrovascular dysfunction is particularly associated with a high risk of strokes and of mortality even at a young age. The prevalence and severity of cerebrovascular complications increase with patients'age. Clinical data as well as histologic and neurophysiologic studies showed predominantly small fiber dysfunction in patients with Fabry disease. We recently performed quantitative sensory testing in patients with Fabry disease and found reduced cold and heat-pain detection thresholds, while nerve conduction velocities were only mildly reduced. From our findings, we concluded that small fiber dysfunction is more prominent than large fiber dysfunction in Fabry patients. Clinically, small fiber dysfunction contributes to recurrent episodes of burning and lancinating pain and paresthesias in the distal extremities. Such episodes can be typically triggered by changes of the environmental temperature, particularly by warming. Moreover, dysfunction of small thinly-myelinated and unmyelianated nerve fibers accounts for altered sympathetic and parasympathetic modulation. Sympathetic dysfunction explains the hypohidrosis and a subsequent poor exercise and heat tolerance. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A is available. We could demonstrate improvement of small fiber neuropathy and neuropathic pain after 18-23 months of ERT, which probably resulted from glycosphingolipid clearing from perineurial cells, axons and Schwann cells or from blood vessels supplying the nerves., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument's total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument's domains was estimated and the DS3's quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R(2)=0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Familial dysautonomia (FD) is a hereditary peripheral and central nervous system disorder with poorly defined central neuropathology. This prospective pilot study aimed to determine if MRI would provide objective parameters of central neuropathology. There were 14 study subjects, seven FD individuals (18.6 +/- 4.2 years, 3 female) and seven controls (19.1 +/- 5.8 years, 3 female). All subjects had standardized brain MRI evaluation including quantitative regional volume measurements, diffusion tensor imaging (DTI) for assessment of white matter (WM) microstructural integrity by calculation of fractional anisotropy (FA), and proton MR spectroscopy ((1)H MRS) to assess neuronal health. The FD patients had significantly decreased FA in optic radiation (p = 0.009) and middle cerebellar peduncle (p = 0.004). Voxel-wise analysis identified both GM and WM microstructural damage among FD subjects as there were nine clusters of WM FA reductions and 16 clusters of GM apparent diffusion coefficient (ADC) elevations. Their WM proportion was significantly decreased (p = 0.003) as was the WM proportion in the frontal region (p = 0.007). (1)H MRS showed no significant abnormalities. The findings of WM abnormalities and decreased optic radiation and middle cerebellar peduncle FA in the FD study group, suggest compromised myelination and WM micro-structural integrity in FD brains. These neuroimaging results are consistent with clinical visual abnormalities and gait disturbance. Furthermore the frontal lobe atrophy is consistent with previously reported neuropsychological deficits.

The size of the neurogenic axon reflex flare (ARFS) has been proposed to serve as a non-invasive measure of C-fiber neuropathies. This idea is based on the observation that ARFS is often reduced in patients with small-fiber neuropathies. In this study, we compared ARFS and electrically evoked axon reflex sweating with intraepidermal nerve fiber density (IENF) in patients with peripheral neuropathy in order to validate these methods against an objective standard method of diagnosing small-fiber neuropathy. ARFS was significantly correlated with IENF, while axon reflex sweating was not correlated to IENF. We conclude that measurement of ARFS is a potential objective non-invasive diagnostic tool for analysis of C-fiber function in patients with small-fiber neuropathies.

Objective: Tachyarrhythmias are common during epileptic seizures while bradyarrhythmias or asystoles are less frequent. Ictal asystole might be related to epilepsy-induced cardiac sympathetic denervation., Methods: To evaluate cardiac post-ganglionic denervation in epilepsy patients with ictal asystoles we assessed I123-meta-iodobenzylguanidine (MIBG) as a marker of post-ganglionic cardiac norepinephrine-uptake, using single photon emission computed tomography (MIBG-SPECT)., Results: In five of 844 patients with presurgical video-electroencephalography-monitoring, we recorded ictal asystoles during nine of 37 seizures. Asystole patients underwent cardiologic examination (Holter-electrocardiogram, echocardiogram) and cardiac MIBG-SPECT. We compared cardiac MIBG uptake in the asystole patients to the uptake in 18 temporal lobe epilepsy (TLE) patients without bradyarrhythmias and in 14 controls without cardiac or neurological disease. As the cardiological examinations were unremarkable in all subjects, the heart/mediastinum-MIBG-uptake ratios (H/M-ratios) differed significantly between the three groups (P = 0.004). H/M-ratios were lower in asystole TLE patients (mean +/- SD: 1.58 +/- 0.3) than in patients without asystole (1.81 +/- 0.18; P = 0.037) or controls (1.96 +/- 0.16)., Conclusions: Pronounced reduction in cardiac MIBG uptake of asystole patients indicates post-ganglionic cardiac catecholamine disturbance. Impaired sympathetic cardiac innervation limits adjustment and heart rate modulation, and may increase the risk of asystole and ultimately sudden unexpected death in epilepsy (SUDEP).

Background: Sildenafil, frequently used as on demand medication for the treatment of erectile dysfunction (ED), has been suggested to improve endothelial function but also to alter blood pressure (BP) and induce sympathetic activation. In people with type 2 diabetes mellitus (T2DM), a high-risk population, the safety profile and the effects on endothelial function of a maximal sildenafil dose (100 mg) have not been investigated and therefore constituted the aim of our study., Methods: A double-blind, placebo-controlled, cross-over trial using a single dose of 100 mg sildenafil or placebo has been conducted in 40 subjects with T2DM without known CVD. Haemodynamic parameters, flow mediated dilatation (FMD) in brachial artery, cardiovascular autonomic function tests and spontaneous baroreflex sensitivity (BRS) were measured., Results: Sixty minutes after administration of sildenafil but not placebo, a fall of supine systolic blood pressure (SBP) (-5.41 +/- 1.87 vs. + 0.54 +/- 1.71 mmHg) and diastolic blood pressure (DBP) (-4.46 +/- 1.13 vs. + 0.89 +/- 0.94 mmHg), as well as orthostatic SBP (-7.41 +/- 2.35 vs. + 0.94 +/- 2.06 mmHg) and DBP (-5.65 +/- 1.45 vs. + 1.76 +/- 1.00 mmHg) during standing occurred, accompanied by an increase in heart rate (+1.98 +/- 0.69 vs. - 2.42 +/- 0.59 beats/min) (all p < 0.01 vs. placebo). Changes in BP to standing up, FMD, time domain and frequency domain indices of heart rate variability (HRV) and BRS were comparable between sildenafil and placebo., Conclusions: Sildenafil administered at a maximum single dose to T2DM men results in a mild increase in heart rate and decrease in BP, but it induces neither an acute improvement of FMD nor any adverse effects on orthostatic BP regulation, HRV and BRS., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Background: Venous thromboembolism (VTE) is a common complication after stroke. Application of low molecular weight heparins (LMWH) has been proven to be beneficial for the prevention of VTE in ischemic stroke patients. However, there is no consensus whether and how to administer LMWH for prevention of thrombotic complications after acute spontaneous intracerebral hemorrhage (sICH), the main concern being possible hematoma growth. The objective of this study was to assess the safety of early subcutaneous LMWH in patients with sICH with respect to hemorrhage enlargement., Methods: A total of 97 patients with sICH were analyzed. LMWH (either enoxaparin-natrium or dalteparin-natrium) were initiated within 36 h after admission in all patients without clinical evidence of hemorrhage enlargement or an absence of evidence of hematoma growth on CT. Hematoma growth (significant when >33%, moderate when >20%) was assessed on follow-up CT between days 5 and 11., Results: None of the patients showed a significant hemorrhage growth. Between days 2 and 10, 2 patients experienced a moderate hematoma enlargement of 22.4 and 20.9%. None of the included patients developed a fatal lung embolism., Conclusions: Early application of subcutaneous LMWH for prevention of venous thromboembolism seems to be safe, and probably does not increase the risk of hematoma growth in patients with sICH., (Copyright (c) 2008 S. Karger AG, Basel.)

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.

Aims/hypothesis: Patients with diabetes mellitus have an increased risk of stroke and other cerebrovascular complications. The purpose of this study was to evaluate the autoregulation of cerebral blood flow in diabetic patients using a simple method that could easily be applied to the clinical routine screening of diabetic patients., Methods: We studied ten patients with type 2 diabetes mellitus and 11 healthy volunteer control participants. Continuous and non-invasive measurements of blood pressure and cerebral blood flow velocity were performed during deep breathing at 0.1 Hz (six breaths per minute). Cerebral autoregulation was assessed from the phase shift angle between breathing-induced 0.1 Hz oscillations in mean blood pressure and cerebral blood flow velocity., Results: The controls and patients all showed positive phase shift angles between breathing-induced 0.1 Hz blood pressure and cerebral blood flow velocity oscillations. However, the phase shift angle was significantly reduced (p < 0.05) in the patients (48 +/- 9 degrees ) compared with the controls (80 +/- 12 degrees ). The gain between 0.1 Hz oscillations in blood pressure and cerebral blood flow velocity did not differ significantly between the patients and controls., Conclusions/interpretation: The reduced phase shift angle between oscillations in mean blood pressure and cerebral blood flow velocity during deep breathing suggests altered cerebral autoregulation in patients with diabetes and might contribute to an increased risk of cerebrovascular disorders.

Glutamic acid decarboxylase (GAD) is the enzyme which catalyzes the production of gamma aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system (CNS). There is increasing evidence that severe GAD autoimmunity may be associated with refractory epilepsy. Immunomodulation and GABAergic drugs have been suggested as treatment options. We report here for the first time on a patient with sudden onset of refractory status epilepticus in the presence of strong intrathecal anti-GAD antibody synthesis who was successfully treated with cyclophosphamide, and give an overview of available data on epilepsy associated with GAD autoimmunity.

Objective: To evaluate the impact of vagus nerve stimulation (VNS) on heart rate and blood pressure (BP) modulation in epilepsy patients., Material and Methods: Twenty-one epilepsy patients with VNS were tested during on (60 s) and off (5 min) phases. We monitored BP, RR intervals (RRI) and respiration. Spectral analysis was performed in low- (LF: 0.04-0.15 Hz) and high-frequency bands (HF: 0.15-0.5 Hz). For coherences above 0.5, we calculated the LF transfer function between systolic BP and RRI, and the HF transfer function gain and phase between RRI and respiration. Differences between the on and off phases were evaluated using Wilcoxon test., Results: VNS did not change RRI and BP values. The LF power of BP and the LF and HF power of RRI increased significantly. There was a slight change in the RRI/BP LF gain and the RRI/respiration HF gain (ns). The HF phase between RRI and respiration decreased significantly., Conclusions: Our findings show that VNS influences both sympathetic and parasympathetic cardiovascular modulation. However, our results also show that VNS does not negatively influence autonomic cardiovascular regulation.

We report here a 27-year-old woman who presented with encephalitis of unknown origin. Magnetic resonance imaging (MRI) of the brain revealed leukoencephalopathy, cerebrospinal fluid showed signs of inflammation. Serum and brain biopsy tissue was tested positive for hepatitis C virus (HCV). Neuropathological investigation supported the hypothesis of viral encephalitis. C3, C4 and cryoglobulins as well as cerebral MR-angiography were normal. Neurological complications of HCV infection other than hepatic encephalopathy are generally attributed to parainfectious phenomena. This is the first case of HCV-RNA detection in vivo in human brain in literature and it raises the possibility that HCV is able to induce encephalitis caused by neurotrophism. This is supported by the fact that there is a growing body of literature on HCV-induced cerebral dysfunction and laboratory findings indicating HCV neuroinvasion.

Background: Autonomic dysregulation is frequent in acute ischemic stroke. Several studies concluded that imbalance between sympathetic and parasympathetic cardiovascular function predisposes to malignant cardiac arrhythmia. However, there are few data on cardiovascular autonomic function in post-acute stroke patients., Objective: To study cardiovascular autonomic function 18 to 43 months after lacunar stroke., Patients and Methods: We continuously monitored R-R intervals (RR(int)), mean blood pressure (BP(mean)), and respiration in 15 patients (8 women, aged 43 to 73 years) after right-sided stroke, in 13 patients (7 women, aged 50 to 75 years) after left-sided stroke, and in 21 age- and sex-matched controls at rest. We used autoregressive spectral analysis to assess sympathetic and parasympathetic modulation as powers of RR(int) and BP(mean) oscillations in the low-frequency (LF: 0.04 to 0.15 Hz) and high-frequency bands (HF: 0.15 to 0.5 Hz)., Results: Mean values of RR(int), BP(mean), and respiratory frequency did not differ between patients after right- or left-sided stroke and controls (p > 0.05). Patients after right-sided stroke showed a trend toward elevated LF power of RR(int) as compared with patients after left-sided stroke and controls (p < 0.10). HF powers of RR(int) were reduced in patients after right- and left-sided stroke as compared with controls (p < 0.05). LF/HF ratio of RR(int) was elevated in patients after right-sided stroke as compared with patients after left-sided stroke and controls (p < 0.05)., Conclusion: Irrespective of the side of the ischemia, post-acute stroke patients showed a parasympathetic cardiac deficit. Additionally, sympathetic cardiovascular modulation was increased in patients after right-sided stroke. Post-acute stroke patients might be at an increased risk for cardiac arrhythmia after unopposed sympathetic stimulation.

Since genetic analysis of the GFAP gene for the diagnosis of adult Alexander disease (AD) has been established in 2001, several cases of both sporadic and familial cases of AD have been described. Except for one patient, all subjects revealed glial fibrillary acidic protein (GFAP) mutations, and clinical progression of symptoms, mainly bulbar and pseudobulbar, were moderate. Here we report on a patient with acute onset of vegetative symptoms, rapid progression, and death within 2 months. Although histology and final magnetic resonance imaging (MRI) were characteristic of AD, sequencing of the encoding GFAP gene revealed no mutation. We believe that this case report expands the so far known clinical spectrum and MRI dynamics of adult AD, and suggest that analysis of the coding part of GFAP may be inconclusive in rare cases. In such patients, only histology may lead to definitive diagnosis.

In diabetic patients, vascular disease and autonomic dysfunction might compromise cerebral autoregulation and contribute to orthostatic intolerance. The aim of our study was to determine whether impaired cerebral autoregulation contributes to orthostatic intolerance during lower body negative pressure in diabetic patients. Thirteen patients with early-stage type 2 diabetes were studied. We continuously recorded RR-interval, mean blood pressure and mean middle cerebral artery blood flow velocity at rest and during lower body negative pressure applied at -20 and -40 mm Hg. Spectral powers of RR-interval, blood pressure and cerebral blood flow velocity were analyzed in the sympathetically mediated low (LF: 0.04-0.15 Hz) and the high (HF: 0.15-0.5 Hz) frequency ranges. Cerebral autoregulation was assessed from the transfer function gain and phase shift between LF oscillations of blood pressure and cerebral blood flow velocity. In the diabetic patients, lower body negative pressure decreased the RR-interval, i.e. increased heart rate, while blood pressure and cerebral blood flow velocity decreased. Transfer function gain and phase shift remained stable. Lower body negative pressure did not induce the normal increase in sympathetically mediated LF-powers of blood pressure and cerebral blood flow velocity in our patients indicating sympathetic dysfunction. The stable phase shift, however, suggests intact cerebral autoregulation. The dying back pathology in diabetic neuropathy may explain an earlier and greater impairment of peripheral vasomotor than cerebrovascular control, thus maintaining cerebral blood flow constant and protecting patients from symptoms of presyncope.

Ventromedial prefrontal cortex (VMPFC) lesions can alter emotional and autonomic responses. In animals, VMPFC activation results in cardiovascular sympathetic inhibition. In humans, VMPFC modulates emotional processing and autonomic response to arousal (e.g. accompanying decision-making). The specific role of the left or right VMPFC in mediating somatic responses to non-arousing, daily-life pleasant or unpleasant stimuli is unclear. To further evaluate VMPFC interaction with autonomic processing of non-stressful emotional stimuli and assess the effects of stimulus valence, we studied patients with unilateral VMPFC lesions and assessed autonomic modulation at rest and during physical challenge, and heart rate (HR) and blood pressure (BP) responses to non-stressful neutral, pleasant and unpleasant visual stimulation (VES) via emotionally laden slides. In 6 patients (54.0 +/- 7.2 years) with left-sided VMPFC lesions (VMPFC-L), 7 patients (43.3 +/- 11.6 years) with right-sided VMPFC lesions (VMPFC-R) and 13 healthy volunteers (44.7 +/- 11.6 years), we monitored HR as R-R interval (RRI), BP, respiration, end-tidal carbon dioxide levels, and oxygen saturation at rest, during autonomic challenge by metronomic breathing, a Valsalva manoeuvre and active standing, and in response to non-stressful pleasant, unpleasant and neutral VES. Pleasantness versus unpleasantness of slides was rated on a 7-point Likert scale. At rest, during physical autonomic challenge, and during neutral VES, parameters did not differ between the patient groups and volunteers. During VES, Likert scores also were similar across the three groups. During pleasant and unpleasant VES, HR decreased (i.e. RRI increased) significantly whereas BP remained unchanged in volunteers. In VMPFC-L patients, HR decrease was insignificant with pleasant and unpleasant VES. BP slightly increased (P = 0.06) with pleasant VES but was stable with unpleasant VES. In contrast, VMPFC-R patients had significant increases in HR and BP during pleasant and not quite significant HR increases (P = 0.06) with only slight BP increase during unpleasant VES. Other biosignals remained unchanged during VES in all groups. Our results show that VMPFC has no major influence on autonomic modulation at rest and during non-emotional, physical stimulation. The paradoxical HR and BP responses in VMPFC-R patients suggest hemispheric specialization for VMPFC interaction with predominant parasympathetic activation by the left, but sympathetic inhibition by the right VMPFC. Valence of non-stressful stimuli has a limited effect with more prominent left VMPFC modulation of pleasant and more right VMPFC modulation of unpleasant stimuli. The paradoxical sympathetic disinhibition in VMPFC-R patients may increase their risk of sympathetic hyperexcitability with negative consequences such as anxiety, hypertension or cardiac arrhythmias.

Aims/hypothesis: Assessment of cerebral regulation in diabetic patients is often problematic because of the presence of cardiac autonomic neuropathy. We evaluated the technique of oscillatory neck suction at 0.1 Hz to quantify cerebral regulation in diabetic patients and healthy control subjects., Subjects and Methods: In nine type 2 diabetic patients with cardiac autonomic neuropathy and 11 age-matched controls, we measured blood pressure and cerebral blood flow velocity responses to application of 0.1 Hz neck suction. We determined spectral powers and calculated the transfer function gain and phase shift between 0.1 Hz blood pressure and cerebral blood flow velocity oscillations as parameters of cerebral regulation., Results: In the patients and control subjects, neck suction did not significantly influence mean values of the RR interval, blood pressure and cerebral blood flow velocity. The powers of 0.1 Hz blood pressure and cerebral blood flow velocity oscillations increased in the control subjects, but remained stable in the patients. Transfer function gain remained stable in both groups. Phase shift decreased in the patients, but remained stable in control subjects., Conclusions/interpretation: The absence of an increase in the power of 0.1 Hz blood pressure and cerebral blood flow velocity oscillations confirmed autonomic neuropathy in the diabetic patients. Gain analysis did not show altered cerebral regulation. The decrease in phase shift in the patients indicates a more passive transmission of neck suction-induced blood pressure fluctuations onto the cerebrovascular circulation, i.e. altered cerebral regulation, in the patients, and is therefore suited to identifying subtle impairment of cerebral regulation in these patients.

Changes of cardiovascular function are frequent in temporal lobe epilepsy (TLE). The baroreflex - the most important reflex for cardiovascular stability - has not been studied systematically in TLE. We evaluated cardiovascular variability and baroreflex function in TLE. In 22 TLE patients and 20 controls, we continuously monitored heart rate (HR) and blood pressure (BP). Time-domain parameters were derived from recordings at rest and from standard cardiovascular reflex tests. Spectral analysis determined sympathetic and parasympathetic modulation of HR and BP in the low (LF-power) and high frequency range (HF-power). We calculated the relative LF- and HF-powers of HR in relation to the sum of LF- and HF-powers. LF/HF-ratio of HR was assessed as a parameter of sympatheticovagal balance. LF-transfer function gain between BP and HR determined baroreflex function.Time-domain parameters did not differ between TLE patients and controls. Spectral analysis showed decreased absolute LF- and HF-powers but increased relative LF-power and LF/HF-ratio of HR in TLE. LF-transfer function gain between BP and HR was reduced in TLE (p<0.05). The reduction of absolute LF- and HF-powers indicates decreased total autonomic variability in TLE. However, increased relative LF-power and LF/HF-ratio of HR in TLE show a relative increase of sympathetic tone. Most importantly, we demonstrate an impaired baroreflex function in TLE. These cardiovascular autonomic abnormalities may contribute to cardiac arrhythmia in TLE.

Sleep bruxism, an oral parafunction including teeth clenching and grinding, might be related to increased stress. To evaluate sympathetic cardiac activity in bruxism patients, we monitored cardiac autonomic modulation using spectral analysis of heart rate variability and compared results to those of age-matched healthy volunteers. In bruxism patients, sympathetic cardiac activity was higher than in volunteers. The increased sympathetic tone suggests increased stress and might be related to occlusal disharmonies.

It is not known whether C-fiber functional subclasses are differentially affected by diabetes mellitus or whether the patterns of C-fiber dysfunction are different between type 1 and type 2 diabetes. We therefore examined efferent sympathetic sudomotor and primary afferent nociceptor C-fiber function in diabetic patients. Acetylcholine (10%) was used to evoke C-fiber (axon-reflex)-mediated responses. The nociceptor (flare) response was measured using a laser Doppler device. The sudomotor response was quantified with silastic imprints. The nociceptor C-fiber-mediated flare response was reduced in type 2 diabetic patients (P < 0.008) but was similar to controls in type 1 diabetic patients. The sympathetic C-fiber-mediated responses, including sweat volume (P < 0.05) and the number of activated sweat glands (P = 0.003), were increased in patients with type 1 diabetes. There also was a trend toward a larger axon-reflex sweat area in patients with type 1 diabetes (P = 0.09). No differences in these sweat responses were found in patients with type 2 diabetes compared to controls. These findings suggest that the functional abnormalities in diabetic peripheral neuropathy are not homogeneous and that C-fiber subclasses are differentially affected in type 1 and 2 diabetes mellitus.

Dysfunction of the peripheral and central autonomic nervous system is common in many neurological and general medical diseases. The quantitative assessment of sympathetic and parasympathetic function is essential to confirm the diagnosis of autonomic failure, to provide the basis for follow-up examinations, and potentially to monitor successful treatment. Various procedures have been described as useful tools to quantify autonomic dysfunction. The most important tests evaluate cardiovascular and sudomotor autonomic function. In this review, we therefore focus on standard tests of cardiovascular and sudomotor function such as heart-rate variability at rest and during deep breathing, active standing, and the Valsalva maneuver, and on the sympathetic skin response. These tests are widely used for routine clinical evaluation in patients with peripheral neuropathies. Refined methods of studying heart-rate variability, baroreflex testing, and detailed measures of sweat output are mostly used for research purposes. In this context, we describe the spectral analysis of slow modulation of heart rate or blood pressure, reflecting sympathetic and parasympathetic influences, and consider various approaches to baroreflex testing, the thermoregulatory sweat test, and the quantitative sudomotor axon reflex test. Finally, we discuss microneurography as a technique of direct recording of muscle sympathetic nerve activity.

Familial dysautonomia (FD) patients frequently experience debilitating orthostatic hypotension. Since physical countermaneuvers can increase blood pressure (BP) in other groups of patients with orthostatic hypotension, we evaluated the effectiveness of countermaneuvers in FD patients. In 17 FD patients (26.4 +/- 12.4 years, eight female), we monitored heart rate (HR), blood pressure (BP), cardiac output (CO), total peripheral resistance (TPR) and calf volume while supine, during standing and during application of four countermaneuvers: bending forward, squatting, leg crossing, and abdominal compression using an inflatable belt. Countermaneuvers were initiated after standing up,when systolic BP had fallen by 40mmHg or diastolic BP by 30mmHg or presyncope had occurred. During active standing, blood pressure and TPR decreased, calf volume increased but CO remained stable. Mean BP increased significantly during bending forward (by 20.0 (17 - 28.5) mmHg; P = 0.005) (median (25(th) - 75(th) quartile)), squatting (by 50.8 (33.5 - 56) mmHg; P = 0.002), and abdominal compression (by 5.8 (-1 - 34.7) mmHg; P = 0.04) - but not during leg-crossing. Squatting and abdominal compression also induced a significant increase in CO (by 18.1 (-1.3 - 47.9) % during squatting (P = 0.02) and by 7.6 (0.4 - 19.6) % during abdominal compression (P=0.014)). HR did not change significantly during the countermaneuvers. TPR increased significantly only during squatting (by 37.2 (11.8 - 48.2) %; P = 0.01). However, orthopedic problems or ataxia prevented several patients from performing some of the countermaneuvers. Additionally, many patients required assistance with the maneuvers. Squatting, bending forward and abdominal compression can improve orthostatic BP in FD patients, which is achieved mainly by an increased cardiac output. Squatting has the greatest effect on orthostatic blood pressure in FD patients. Suitability and effectiveness of a specific countermaneuver depends on the orthopedic or neurological complications of each FD patient and must be individually tested before a therapeutic recommendation can be given.

Dysfunction of the autonomic nervous system is a frequent finding in many neurological and internal diseases. The quantitative assessment of cardiovascular and sudomotor function is important for diagnosing the autonomic impairment. In this review article, we focus on standard tests that allow evaluation of cardiovascular and sudomotor autonomic functions and describe methods of quantitative assessment that are better suited for research.

Cardiovascular autonomic neuropathy has been previously reported in patients with multiple sclerosis (MS) using standard reflex tests. However, no study has separately evaluated both parasympathetic and sympathetic cardiovascular autonomic regulation. We therefore assessed the baroreflex-mediated vagal and sympathetic control of the heart rate and sympathetic control of the blood vessels in MS patients using sinusoidal neck stimulation. We studied 13 multiple sclerosis patients aged 28-58 years and 18 healthy controls aged 26-58 years. The carotid baroreflex was stimulated by sinusoidal neck suction (0 to -30 mmHg) at 0.1 Hz to assess the autonomic control of the heart and blood vessels, and at 0.2 Hz to assess the vagal control of the heart. Continuous recordings were made of blood pressure, electrocardiographic RR-interval and respiration, with breathing paced at 0.25 Hz. Spectral analysis was used to evaluate the magnitude of the low frequency (LF, 0.03-0.14 Hz) and high frequency (HF, 0.15-0.50 Hz) oscillations in RR-interval and blood pressure in response to the sinusoidal baroreceptor stimulation. Responses to the applied stimulus were assessed as the change in the spectral power of the RR-interval and blood pressure fluctuations at the stimulating frequency from the baseline values. The increase in the power of 0.1 Hz RR-interval oscillations during the 0.1 Hz neck suction was significantly smaller (p<0.01) in the MS patients (4.47+/-0.27 to 5.62+/-0.25 ln ms(2)) than in the controls (4.12+/-0.37 to 6.82+/-0.33 ln ms(2)). The increase in the power of 0.1 Hz systolic BP oscillations during 0.1 Hz neck suction was also significantly smaller (p<0.01) in the MS patients (0.99+/-0.19 to 1.96+/-0.39 mmHg(2)) than in the healthy controls (1.27+/-0.34 to 9.01+/-4.10 mmHg(2)). Neck suction at 0.2 Hz induced RR-interval oscillations at 0.2 Hz that were significantly smaller (p<0.05) in the patients (3.22+/-0.45 ln ms(2)) than in the controls (5.27+/-0.29 ln ms(2)). These results indicate that in MS patients, baroreflex dysfunction is not only restricted to the cardiovagal limb of the baroreflex, but that the sympathetic modulation of the blood vessels is also affected.

Objectives: The aim of this study was to assess baroreflex regulation of the heart rate and blood vessels in migraine patients in comparison with healthy controls., Methods: In 30 migraine patients who were in a headache-free phase, aged 34 +/- 2 years, and 30 healthy controls, aged 34 +/- 3 years, we applied oscillatory neck suction at 0.1 Hz to assess the sympathetic modulation of the heart and blood vessels and at 0.2 Hz to assess the effect of parasympathetic stimulation on the heart. Breathing was paced at 0.25 Hz. Electrocardiographic RR-intervals, blood pressure and respiration were continuously recorded. Responses to the baroreflex stimulations were assessed as the changes in power of the RR-interval and blood pressure fluctuations at the relevant stimulating frequency from the baseline values., Results: Systolic and diastolic blood pressure responses to the 0.1 Hz neck suction pressure were not significantly different between the patients and controls. The RR-interval oscillatory response to 0.2 Hz neck suction was significantly less (P < 0.05) in the migraine patients (4.45 +/- 0.27 ln ms2) compared with the controls (5.48 +/- 0.36 ln ms2)., Conclusion: These results suggest that baroreflex-mediated cardiovagal responses are reduced in migraine patients. However, the sympathetic-mediated baroreflex control of the blood vessels is intact in the migraine patients. The autonomic nervous system may have a role in the pathophysiology of migraine.

Objectives: Enhanced external counterpulsation (EECP) rhythmically augments blood pressure (BP) by diastolic lower-body compression. Recently, we showed decreased mean cerebral blood flow velocity (CBFVmean) in young healthy persons during EECP, but unchanged CBFVmean in atherosclerotic patients. In this study, we assessed EECP effects on dynamic cerebral autoregulation (CA)., Material & Methods: In 23 healthy persons and 15 atherosclerotic patients we monitored heart rate (HR), mean BP (BPmean) and CBFVmean before and during 5 min EECP. We analyzed spectral powers of HR, BPmean and CBFVmean in the low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency ranges to determine CA from the LF-transfer function gain and phase shift between BPmean and CBFVmean oscillations., Results: EECP increased HR and BPmean, while transfer function gain and phase shift remained stable., Conclusions: Stable gain and phase values suggest that EECP does not compromise CA and, therefore, does not seem to bear cerebrovascular risks., (Blackwell Munksgaard 2004)

Patients with temporal lobe epilepsy (TLE) often show increased cardiovascular sympathetic modulation during the interictal period, that decreases after epilepsy surgery. In this study, we evaluated whether temporal lobectomy changes autonomic modulation of cerebral blood flow velocity (CBFV) and cerebral autoregulation. We studied 16 TLE patients 3-4 months before and after surgery. We monitored heart rate (HR), blood pressure (BP), respiration, transcutaneous oxygen saturation (sat-O(2)), end-expiratory carbon dioxide partial pressure (pCO(2)) and middle cerebral artery CBFV. Spectral analysis was used to determine sympathetic and parasympathetic modulation of HR, BP and CBFV as powers of signal oscillations in the low frequency (LF) ranges from 0.04-0.15Hz (LF-power) and in the high frequency ranges from (HF) 0.15-0.5Hz (HF-power). LF-transfer function gain and phase shift between BP and CBFV were calculated as parameters of cerebral autoregulation. After surgery, HR, BP(mean), CBFV(mean), respiration, sat-O(2), pCO(2) and HF powers remained unchanged. LF-powers of HR, BP, CBFV and LF-transfer function gain had decreased while the phase angle had increased (p<0.05). The reduction of LF powers and LF-gain and the higher phase angle showed reduced sympathetic modulation and improved cerebral autoregulation. The enhanced cerebrovascular stability after surgery may improve autonomic balance in epilepsy patients.

Although diabetic autonomic neuropathy involves most organs, diagnosis is largely based on cardiovascular tests. Light reflex pupillography (LRP) non-invasively evaluates pupillary autonomic function. We tested whether LRP demonstrates autonomic pupillary dysfunction in diabetics independently from cardiac autonomic neuropathy (CAN) or peripheral neuropathy (PN). In 36 type-II diabetics (39-84 years) and 36 controls (35-78 years), we performed LRP. We determined diameter (PD), early and late re-dilation velocities (DV) as sympathetic parameters and reflex amplitude (RA) and constriction velocity (CV) as parasympathetic pupillary indices. We assessed the frequency of CAN using heart rate variability tests and evaluated the frequency of PN using neurological examination, nerve conduction studies, thermal and vibratory threshold determination. Twenty-eight (77.8%) patients had abnormal pupillography results, but only 20 patients (56%) had signs of PN or CAN. In nine patients with PN, only pupillography identified autonomic neuropathy. Four patients had pupillary dysfunction but no CAN or PN. In comparison to controls, patients had reduced PD, late DV, RA and CV indicating sympathetic and parasympathetic dysfunction. The incidence and severity of pupillary abnormalities did not differ between patients with and without CAN or PN. LRP demonstrates sympathetic and parasympathetic pupillary dysfunction independently from PN or CAN and thus refines the diagnosis of autonomic neuropathy in type-II diabetics.

Background: Enhanced external counterpulsation (EECP) augments diastolic and reduces systolic blood pressures. Enhanced external counterpulsation has been shown to improve blood flow in various organ systems. Beneficial effects on skin perfusion might allow EECP to be used in patients with skin malperfusion problems. This study was performed to assess acute effects of EECP on superficial skin blood flow, transdermal oxygen and carbon dioxide pressures., Materials and Methods: We monitored heart rate, blood pressure, transdermal blood flow as well as oxygen and carbon dioxide pressures in 23 young, healthy persons (28 +/- 4 years) and 15 older patients (64 +/- 7 years) with coronary artery disease before, during and 3 min after 5 min EECP. Friedman test was used to compare the results of 90-s epochs before, during and after EECP. Significance was set at P < 0.05., Results: Enhanced external counterpulsation increased heart rate and mean blood pressure. During EECP, transdermal oxygen pressure and concentration of moving blood cells increased while transdermal carbon dioxide pressure and velocity of moving blood cells decreased significantly in both groups. After EECP, transdermal carbon dioxide pressure was still reduced while the other parameters returned to baseline values., Conclusions: Improved skin oxygenation and carbon dioxide clearance during EECP seem to result from the increased concentration and reduced flow velocity, i.e. prolonged contact time, of erythrocytes. The increased concentration of moving blood cells and the decreased velocity of moving blood cells at both tested skin sites indicate peripheral vasodilatation.