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[Autopsy findings in a case of dementia with Lewy bodies with marked autonomic failure and repetitive cardiopulmonary arrest].

We report herein a patient with dementia with Lewy bodies (DLB) who presented with severe autonomic failure, dementia and parkinsonism. At onset, the 70-year-old man exhibited dementia and gait disturbance. Over the next 3 years, he developed symptoms of autonomic dysfunction, such as sleep apnea, orthostatic hypotension and bladder and bowel dysfunction. Cranial magnetic resonance imaging revealed moderate frontotemporal atrophy. Single photon emission computed tomography images depicted bilateral hypoperfusion in the parietal lobes. Interestingly, recurrent episodes of cardiopulmonary arrest together with unconsciousness occurred during the 2-year period before the patient died at the age of 74. At autopsy, axial slices of the brainstem showed depigmentation of the substantia nigra and locus ceruleus. Lewy bodies were present in areas of the brainstem such as the substantia nigra, locus ceruleus, solitary nucleus, raphe nucleus and dorsal vagal nucleus and in the intermediolateral column of the spinal cord, sympathetic ganglia, parahippocampal gyrus and cerebral cortex. Neuronal loss was observed in the intermediolateral column, but neurons in the sympathetic ganglia were well preserved. On the basis of the clinical history and pathological findings, we diagnosed this as a case of DLB. There are a few reported cases of DLB associated with various manifestations of autonomic failure. In our patient, autonomic failure including cardiopulmonary arrest may have resulted from widespread impairment of the autonomic nervous system.

Aged↗

[A Japanese family with probably autosomal dominant adult-onset leukodystrophy].

We report here a family with leukodystrophy clinical features of which are characterized as adult onset, probably autosomal dominant inheritance, hyperreflexia, cerebellar ataxia, autonomic dysfunction and no peripheral nerve involvement. T2-weighted brain MRI revealed diffuse high signal areas in the cerebral white matter. The disorder in our subjects can be distinguished from most leukodystrophies in terms of genetic inheritance, clinical manifestations and laboratory data. Our family is quite similar to the kindred which Eldridge et al. described in 1984 as "hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis". Our family is the third report of this type of leukodystrophy and the first among non-Irish/Scottish family.

Age of Onset↗

Ventilatory response to exercise correlates with impaired heart rate variability in patients with chronic congestive heart failure.

In chronic congestive heart failure (CHF) an overactivity of muscle ergoreceptors and peripheral chemoreceptors may lead to an increased ventilatory response to exercise and contribute to the autonomic imbalance. The analysis of heart rate variability (HRV), which is a reliable method of studying autonomic regulations within the cardiovascular system, showed depressed HRV indexes in CHF, but predictors of abnormal HRV pattern in CHF remain controversial. Considering a common mechanism involved in generation of both abnormal ventilation and autonomic dysfunction in CHF, we hypothesized that impaired ventilation may be better than other variables of CHF severity in determining HRV parameters. Seventy-two patients with CHF (57+/-9 years, ejection fraction: 28+/-11%) underwent cardiopulmonary exercise testing; the relation between ventilation and carbon dioxide production (VE/VCO2) was used as an index of the ventilatory response to exercise. Time and frequency-domain measurements of HRV were derived from 24-hour electrocardiographic monitoring. Patients had reduced exercise tolerance with abnormal ventilatory response (peak oxygen consumption [VO2max]: 17.8+/-5.5 ml/kg/min, VE/VCO2: 36.0+/-9.8). Correlations were found between HRV measures and etiology, New York Heart Association (NYHA) functional class, and VO2max, but the strongest relation was observed for VE/VCO2 slope (r values from -0.33 to -0.65, p <0.01). In the multiple regression analysis only VE/VCO2 was found to correlate independently with all HRV measurements. To investigate the role of peripheral chemoreceptor overactivity as the mechanism of autonomic imbalance and the increased ventilatory response to exercise, we assessed peripheral chemosensitivity in 22 patients (mean value of peripheral chemosensitivity: 0.62+/-0.34 L/min/%SaO2, significantly higher than in normal controls, mean value: 0.29+/-0.20 L/min/%SaO2 in our laboratory). The activity of the peripheral chemoreflex inversely correlated with all parameters of HRV. Increased ventilatory response to exercise correlated with depressed HRV measures in patients with CHF better than other clinical variables. An important role of the increased peripheral chemosensitivity in this relation may be relevant, being also a potential link between functional severity and sympathovagal imbalance in CHF.

Administration, Inhalation↗

Biologic rhythms and Parkinson's disease: a chronopharmacologic approach to considering fluctuations in function.

The existence of circadian rhythms and their implication in many pathologic processes have been underlined in several diseases but have not been evaluated in Parkinson's disease. The aim of this paper is to review diurnal variations of clinical, biologic, or experimental factors described with Parkinson's disease. Clinical data often report daily fluctuations of motor activity pattern, but the effect of the stage of the disease and the respective roles of drugs are difficult to evaluate. Sleep disturbances in Parkinson's disease patients also reveal alterations of circadian rhythms. Autonomic dysfunction, described in Parkinson's disease, reveals numerous alterations in circadian regulations including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability, and postprandial hypotension. Many biologic indices such as cortisol, catecholamines, and melatonin are also altered. Circadian rhythms in dopaminergic systems as well as possible daily fluctuations in kinetics of drug treatments are likely involved in such variations. Few clinical studies have been devoted to circadian patterns of drug response. As for other diseases where biologic rhythms are concerned Parkinson's disease therapy may be influenced by further understanding of circadian influence.

Animals↗

Nicotinic receptor mutant mice in the study of autonomic function.

Nicotinic acetylcholine receptors (nAChRs) have been implicated in Alzheimer's disease, Parkinson's disease, epilepsy, nicotine addiction, schizophrenia, and autonomic dysfunctions. Although nicotine may be used therapeutically either alone or in association with other drugs, its beneficial effects are limited by its addictive properties and a number of other side effects. A deeper understanding of nicotinic cholinergic mechanisms is necessary to develop nAChR ligands that are more selective, less toxic, and more therapeutically effective than nicotine. Although there has been significant progress identifying the nAChR subunits that form functional nAChRs, there is limited information associating the location and function of nAChR subtypes in the nervous system. Several groups have genetically engineered mice in which one or more genes encoding nAChR subunits has been deleted or altered. Mice with nAChR mutations targeted to subunits that are highly expressed in the CNS have brought insight into the nAChR mechanisms involved in nicotine addiction, analgesia, aging, and nicotine-induced behaviors. Mutations targeted to nAChR subunits that are highly expressed in the peripheral nervous system have opened a window on the complex mechanisms governing autonomic control of peripheral organs. This review examines nAChRs in the autonomic control of peripheral organ systems as gleaned from studies of nAChR mutant mice.

Animals↗

Alternating hemiplegia of childhood: a study of 10 patients and results of flunarizine treatment.

Alternating hemiplegia of childhood is a rare syndrome characterized by onset before 18 months of age of frequent attacks of alternating paralysis, transient ocular palsies, nystagmus, choreoathetosis, and autonomic dysfunction. We describe features of 10 patients followed for up to 27 years. The mechanism of alternating hemiplegia remains unknown but an association to migraine is suspected because of the strong family history of migraine and aura symptoms in some patients. We treated nine patients with flunarizine, a calcium channel blocker, for up to 5 years; they showed a reduction in duration of the hemiplegic attacks, but the episodes ceased completely in only one patient. With long-term follow-up, the persistent motor, movement, and cognitive deficits are more apparent. It is not certain if the flunarizine alters this course.

Adolescent↗

Autonomic and endothelial dysfunction in experimental diabetes.

The effect of streptozotocin induced diabetes on autonomic regulation of heart rate and endothelial function was examined in Sprague-Dawley rats. Weanling rats (3-4 weeks of age) of either sex were randomly assigned to a non-diabetic (male 5, female 6) or diabetic (male 4, female 5). Diabetes was induced with a single intraperitoneal (IP) injection of streptozotocin (STZ, 100 mg/kg). Nondiabetic rats received an IP injection of saline. Eight weeks after injection, rats were chronically instrumented with a left jugular venous catheter and a left carotid arterial catheter. After recovery (5 days) cardiac sympathetic tonus, parasympathetic tonus and intrinsic heart rate were determined. On an alternative day, the pressor response to nitric oxide synthase inhibition (NOS-X) was determined in areflexic rats. Cardiac sympathetic tonus (72 +/- 13 vs. 41 +/- 7), parasympathetic tonus (-51 +/- 10 vs. -22 +/- 7), and intrinsic heart rate (368 +/- 6 vs. 292 +/- 9), were reduced in diabetic rats. Furthermore, diabetic rats had a smaller pressor response (A33 +/- 7 vs. A66 +/- 5) to NOS-X. These results document impaired autonomic control of heart rate and endothelial dysfunction in 8-week streptozotocin induced diabetic rats.

Adrenergic beta-Antagonists↗

Investigation on diabetic autonomic neuropathy assessed by power spectral analysis of heart rate variability in WBN/Kob rats.

This article investigates the development of cardiovascular autonomic dysfunction caused by diabetes mellitus. We performed power spectral analysis of heart rate variability in WBN/Kob rats as a model of spontaneous diabetes. The heart rate of the rats was measured continuously for 24 hours with an implanted telemetric transmitter, and power spectral analysis of heart rate variability was performed on continuous electrocardiograms. At 4 to 5 months of age, the rats indicated a tendency toward a decrease in plasma insulin concentration without hyperglycemia. At 8 to 9 months of age, they showed remarkable hyperglycemia, loss of the circadian rhythm of the heart rate, and reversion or loss of the circadian rhythm of the blood pressure. By the power spectral analysis of heart rate variability, it became apparent that the circadian rhythm of the low frequency/high frequency ratio was absent even in prediabetic WBN/Kob rats. In addition, the circadian rhythms of the high-frequency power level and low frequency/high frequency ratio were absent in diabetic WBN/Kob rats. These findings indicate that the autonomic nervous system in WBN/Kob rats is progressively damaged from the prediabetic to diabetic state. In conclusion, diabetic autonomic neuropathy may be characterized by the appearance of sympathetic overactivity that precedes the impairment of parasympathetic activity.

Animals↗

[Pathophysiology and diagnosis in patients with sympathetically dependent pain].

Chronic pain in a distal extremity that is accompanied by autonomic dysfunction in the same region is taken to indicate reflex sympathetic dystrophy. Typically, hyperalgesia to light touch is present in addition to the spontaneous pain. The absence of heat hyperalgesia indicates that the underlying mechanism is central rather than peripheral sensitization. This mechanism is similar to that of secondary hyperalgesia in the intact skin surrounding an injury site. Sympathetically maintained pain (SMP) is diagnosed, when these sensory symptoms are reversible under sympathetic blockade. SMP is not due to hyperactivity of sympathetic efferents but to receptor supersensitivity, probably by overexpression of alpha(1)-adrenergic receptors on nociceptive primary afferents. This way normal levels of norepinephrine can cause pathological spontaneous activity of nociceptors which maintains the central sensitization. Chronic burning pain and cutaneous hyperalgesia may also be independent of the sympathetic innervation of the skin. In this case, central sensitization is maintained by other mechanisms. A role of the sympathetic nervous system in the pathogenesis of pain cannot be deduced simply from the simultaneous presence of sensory and autonomic clinical signs and symptoms. Therefore, sympathetic blockade in a patient initially is a diagnostic procedure, aiming to demonstrate the presence of the symptom SMP. Therapeutic blockade is only indicated after this demonstration. For the substantial number of patients with sympathetically independent pain, other treatment modalities are needed which may for example attack central sensitization.

English Abstract↗

The use of spectral measures of heart rate variability to differentiate between male snorers and patients with sleep apnoea syndrome.

Snoring is a characteristic feature of habitual snorers and patients with sleep apnoea syndrome. However, unlike snorers, sleep apnoea patients have an increased peri-operative morbidity. Presently available methods to differentiate between these two groups are either expensive, invasive or time consuming. As cardiac reflexes are impaired in sleep apnoea syndrome, we tested whether heart rate variability could discriminate between snorers and patients with sleep apnoea syndrome. Heart rate variability measurement detects cardiac autonomic dysfunction non-invasively in an ambulatory setting. We studied 32 male patients undergoing polysomnography for suspected sleep apnoea. Total, low- and high-frequency power were measured using a Holter electrocardiogram. Differences in night- and daytime variability were then calculated. Differences between day and night values were more pronounced in the sleep apnoea group and related to the apnoea-hypopnoea-index and low oxygen saturation. Higher values in sleep apnoea patients resulted from increasing variability at night. Heart rate variability might thus help to differentiate between snorers and patients with severe sleep apnoea syndrome.

Adult↗

A case of congenital non-progressive sensory neuropathy with tonic pupils.

One case of a non-progressive congenital neuropathy is reported. Clinical findings included subtotal analgesia, and diminished temperature, vibration and proprioceptive sense in arms and legs. The sensory nerve action potentials were absent. Autonomic dysfunctions were restricted to tonic pupils. Sural nerve biopsy taken at the age of 8 1/2 showed fascicular hypoplasia, subtotal loss of myelinated nerve fibers and severe loss of unmyelinated nerve fibers with a pathological size distribution. In the skin biopsy, including several cutaneous nerves, no myelinated nerve fibers were present, the unmyelinated nerve fibers were severely reduced and the collagen density was increased. Perivascular and periglandular innervation was significantly reduced. The findings in this case are suggestive of a malformative or fetally acquired lesion and further illustrate the difficulties in classification of the hereditary sensory neuropathies.

Child↗

Mitral valve prolapse syndrome. Evidence of hyperadrenergic state.

Although mitral valve prolapse (MVP) is a common valvular abnormality, its diagnostic classification has not been well defined. MVP is considered to be an anatomic entity with specific pathologic tissue characteristics and pathophysiologic consequences. The term "MVP syndrome" (MVPS) is used to refer to symptoms due to neuroendocrine or autonomic dysfunction that occur in patients with MVP and that cannot be explained on the basis of valvular abnormality alone. Several studies have shown that patients with MVPS have high urinary epinephrine and norepinephrine excretion, high plasma catecholamine concentrations, abnormal catecholamine response to volume expansion, and hyperresponse to adrenergic stimulation. In patients with MVPS and ventricular arrhythmias, the frequency of premature ventricular contractions parallels the urinary and plasma catecholamine values. The clinical presentation of MVPS may be related in part to high adrenergic tone and/or hyperresponse to adrenergic stimulation. Therefore, certain patients with MVPS and high adrenergic tone may benefit from beta blockade.

Adrenergic beta-Antagonists↗

Predictors of abnormal cardiovascular autonomic function measured by frequence domain analysis of heart rate variability and conventional tests in patients with type 1 diabetes.

OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.

Adult↗

Stress and chronic headache: a psychophysiological analysis of mechanisms.

This study investigated the effects of three types of laboratory stressors (stressful imagery, mental arithmetic, pain) on temporal artery, skeletal muscle, general autonomic [digital blood volume pulse (DBVP), spontaneous resistance responses (SRR's)] and self-report measures of distress in chronic migraine, mixed, muscle contraction and non-headache controls. All subjects were female, free of medication at time of testing and equated for age. Headache subjects reported a 19 year history of headache. Results revealed a pattern of digital BVP (constriction), SSR's (increase) and frontal EMG (increase) indicative of a general autonomic-skeletal muscle arousal response to all three stressors in all groups, while the temporal artery response to the pain stimulus was vasodilation. Distress ratings were elevated during the stress periods for all four group. Pain threshold and tolerance and the tendency to utilize cognitive coping strategies during exposure to pain did not differ across the four groups. The results do not support the general autonomic dysfunction theory of migraine or the specificity hypothesis implicating an overreactive temporal artery or skeletal muscle response to stress in migraine and muscle contraction headache, respectively. Despite epidemiological research supporting the stress-headache relationship, the present results indicate that the psychophysiological mechanism underlying this relationship does not appear to involve abnormal tonic levels or phasic response to stress. It is argued that the temporal artery dilation response to pain questions the role of stress in triggering the two stage vasoconstriction-dilation mechanism of migraine and suggests the need to evaluate a four stage model as a potential psychophysiological mechanism underlying the stress-headache relationship.

Adult↗

Automatic analysis of heart rate variation: I. Method and reference values in healthy controls.

Many patients referred to an electrophysiological laboratory may have autonomic dysfunction. Some parasympathetic tests are based on the assessment of heart rate variation induced by breathing, Valsalva maneuver, and standing. We have developed fast and practical computer-based methods to analyze heart rate variation using standard EMG equipment and a personal computer. For quantitative description we have evaluated different algorithms, both earlier described and new ones. Findings in patients with diabetes have been compared with those obtained from healthy subjects in order to determine the diagnostic utility of the various algorithms. The optimal algorithm has been chosen by this and other criteria, and a reference database from healthy subjects has been developed.

Adolescent↗

Evidence of alpha-adrenoceptor-mediated chronotropic action in children.

We investigated alpha-adrenoceptor-mediated positive chronotropic action in children using a pharmacological autonomic function test. Under cardiac vagal and sympathetic blockade, chronotropic responses to intravenous infusion of an alpha-agonist, phenylephrine, were determined in 129 patients with suspected autonomic dysfunction. Heart rate changes to phenylephrine infusion (0.4 microg/kg/min) for 5 minutes ranged from -2 to 50 beats/min (mean +/- SD, 13.8 +/- 9.7 beats/min). alpha-Adrenoceptor-mediated chronotropic (APC) action more than 5 beats/min was observed in 88 (68%) subjects. APC was negatively correlated with age. Multivariate analysis showed that APC was correlated negatively with beta-sympathetic tone and positively correlated with intrinsic heart rate. These results suggest that the alpha-adrenoceptor-mediated chronotropic action is a developmental phenomenon and may play an important role in controlling heart rate in response to cardiac sympathetic activation.

Adolescent↗

Spinal traumas: some postoperative complications in experimental animals.

Animals with severe spinal traumas show paraplegic syndrome and various somatic and autonomic dysfunctions. Of the various dysfunctions those related to hypothermia, bladder problems, and autophagia are of serious nature. The condition of animals with these complications deteriorates rapidly, and the animals are sacrificed for histological and pathological analyses. The findings show that the postoperative complications are related to the degree of severity of the trauma, and that 50-80% animals are lost due to these complications. Most of these animals are lost during the first two weeks after surgery, and the remaining at later stages. Transplantation of neural tissue at the site of lesion does not ameliorate these postoperative complications and improve the survival rate of the animals.

Animals↗

Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes.

In this paper, we provide a brief update of diagnostic considerations and biochemical phenotype in L-amino acid decarboxylase deficiency. We review clinical features and outcome data in 11 affected patients, including 7 previously unreported cases. All had onset of the characteristic movement disorder by 6 months of age. The phenomenology of the movement disorder is identical to that previously reported, and includes intermittent oculogyric crises and limb dystonia, generalized athetosis, and impaired voluntary movement in all patients. Autonomic dysfunction is characterized by a significant impairment of sympathetic regulation of heart rate and blood pressure, as documented via detailed studies with spectral analysis techniques in two patients. Functional clinical outcomes as a group remain poor, in spite of a variety of attempted treatment interventions, with marked impairment in motor abilities as well as in speech and communication; however, outcome was quite variable from patient to patient and covered a broad spectrum of neurological disability. Much further work remains to identify and refine the best treatment options for patients with L-amino acid decarboxylase deficiency.

Age of Onset↗