Neurological complications in Fabry disease.

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.

In vivo detection of hepatitis C virus (HCV) RNA in the brain in a case of encephalitis: evidence for HCV neuroinvasion.

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.

Cardiovascular autonomic function in poststroke patients.

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.

Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy.

BACKGROUND: Peripheral neuropathy in Fabry disease predominantly involves small nerve fibers. Recently, enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase A has become available. OBJECTIVE: To evaluate whether ERT improves Fabry neuropathy. METHODS: In 22 Fabry patients (age 27.9 +/- 8.0 years) undergoing ERT with recombinant human alpha-galactosidase A (agalsidase beta) for 18 (n = 11) or 23 (n = 11) months and in 25 control subjects (age 29.0 +/- 10.4 years), the authors performed quantitative sensory testing using the 4, 2, and 1 stepping algorithm (CASE IV). Detection thresholds of vibration (VDT) on the first toe were assessed; cold detection thresholds (CDT), heat-pain onset (HP 0.5), and intermediate heat-pain (HP 5.0) assessments were made on the dorsum of the feet. Patient values above mean + 2.5 SD of control values were considered abnormal. RESULTS: Before ERT, VDT, CDT, HP 0.5, and HP 5.0 were higher in patients than control subjects (p < 0.05). Following ERT, patients developed lower thresholds than prior to ERT for VDT (15.5 +/- 3.5 vs 14.3 +/- 4.1; p < 0.05), HP 0.5 (22.3 +/- 6.7 vs 19.4 +/- 1.3; p < 0.01), and HP 5.0 (27.3 +/- 5.6 vs 22.5 +/- 2.3; p < 0.01). Moreover, fewer patients had abnormal results of VDT (2 vs 4), CDT (7 vs 12), HP 0.5 (0 vs 9), and HP 5.0 (4 vs 20) after than before ERT. CONCLUSIONS: ERT therapy with agalsidase beta significantly improves function of C-, Adelta-, and Abeta-nerve fibers and intradermal vibration receptors in Fabry neuropathy. Lack of recovery in some patients with abnormal cold or heat-pain perception suggests the need for early ERT, prior to irreversible nerve fiber loss.

[Female sexual dysfunction: a systematic overview of classification, pathophysiology, diagnosis and treatment]. / Weibliche sexuelle Funktionsstörungen: Klassifikation, Diagnostik und Therapie.

Sexual dysfunction is defined as "disturbances in sexual desire and in the psychophysiological changes that characterize the sexual response cycle and cause marked distress and interpersonal difficulty". The female sexual response cycle consists of three phases: desire, arousal, and orgasm. Various organs of the external and internal genitalia, e.g. vagina, clitoris, labia minora, vestibular bulbs, pelvic floor muscles and uterus, contribute to female sexual function. During sexual arousal, genital blood flow and sensation are increased. The vaginal canal is moistened (lubrication). During orgasm, there is rhythmical contraction of the uterus and pelvic floor muscles. Within the central nervous system, hypothalamic, limbic-hippocampal structures play a central role for sexual arousal. Sexual arousal largely depends on the sympathetic nervous system. Moreover, nonadrenergic/noncholinergic neurotransmitters (NANC), e.g. vasoactive intestinal polypeptide (VIP) and nitric oxide (NO), are involved in smooth muscle relaxation and enhancement of genital blood flow. Furthermore, various hormones may influence female sexual function. Estrogen has a significant role in maintaining vaginal mucosal epithelium as well as sensory thresholds and genital blood flow. Androgens primarily affect sexual desire, arousal, orgasm and the overall sense of well-being. The internationally accepted classification of female sexual dysfunction consists of hypoactive sexual desire disorders, sexual aversion disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders. Vascular insufficiency, e.g. due to atherosclerosis, and neurologic diseases, e.g. diabetic neuropathy, are major causes of sexual dysfunction. Additionally, sexual dysfunction may be due to changes in hormonal levels, medications with sexual side effects or of psychological origin. For the diagnosis of female sexual dysfunction, a detailed history should be taken initially, followed by a physical examination and laboratory studies. Physiologic monitoring of parameters of arousal potentially allows to diagnose organic diseases. Recordings at baseline and following sexual stimulation are recommended to determine pathologic changes that occur with arousal. Duplex Doppler sonography, photoplethysmography or the measurement of vaginal and minor labial oxygen tension may help to evaluate genital blood flow. Moreover, measurements of vaginal pH and compliance should be performed. Neurophysiological examination, e.g. measurement of the bulbocavernosus reflex and pudendal evoked potentials, genital sympathetic skin response (SSR), warm, cold and vibratory perception thresholds as well as testing of the pressure and touch sensitivity of the external genitalia, should be performed to evaluate neurogenic etiologies. Medical management of female sexual dysfunction so far is primarily based on hormone replacement therapy. Application of estrogen results in decreased pain and burning during intercourse. The efficacy of various other medications, e.g. sildenafil, L-arginine, yohimbine, phentolamine, apomorphine and prostaglandin E1, in the treatment of female sexual dysfunction is still under investigation.

[Diagnosis and treatment of polyneuropathy: what can the family doctor do?]. / Polyneuropathie erkennen und behandeln. Mit Fingerspitzengefühl zur richtigen Diagnose.

Polyneuropathies are common disorders of the peripheral nervous system. Early diagnosis and therapy enables to stop the progression of the polyneuropathy and to ameliorate polyneuropathic symptoms in most cases. Clinical examination is sufficient to diagnose polyneuropathy. However, to reveal the etiology of a polyneuropathy additional diagnostic procedures are necessary. The general practitioner should recognize the signs and symptoms of a polyneuropathy and start necessary investigations. If the etiology of the polyneuropathy is revealed specific therapy can be started. Furthermore, polyneuropathic symptoms can be ameliorated independently of the underlying cause.

Small fiber dysfunction predominates in Fabry neuropathy.

Fabry disease is an X-linked recessive disease with a reduction of lysosomal alpha galactosidase A and consecutive storage of glycolipids e.g., in the brain, kidney, skin, and nerve fibers. Cardinal neurologic findings are hypohidrosis, painful episodes, and peripheral neuropathy. So far, the neurophysiological findings regarding the extent of large and small fiber dysfunction are contradictory. This study evaluated large and small nerve fiber function in a homogeneous group of Fabry patients. In 24 of 30 Fabry patients with creatinine below 194.7 mmol/L the authors assessed median, ulnar, and peroneal motor conduction velocity (MCV) and median, ulnar, and sural sensory conduction velocity (SCV) nerve conduction to study the function of thickly myelinated nerve fibers. In addition, the authors studied sympathetic skin responses (SSR) at both hands and feet in 24 patients. To evaluate A beta nerve fiber function, the authors determined vibratory detection thresholds (VDT) at the first toe in 30 patients. Function of A delta and C fibers was assessed by quantitative sensory testing of cold detection threshold (CDT) and heat-pain detection thresholds (HPDT). Nerve conduction studies showed significantly decreased amplitudes of MCVs and SCVs in Fabry patients as compared to controls. However, individual results of MCV and SCV studies were only mildly impaired. SSRs were present in all tested patients but SSR amplitudes were significantly decreased in Fabry patients in comparison to controls. VDT, CDT, and HPDT were significantly elevated in Fabry patients as compared to controls. However, only six patients had pathologic VDT, 19 had increased CDT, and 25 had elevated HPDT at a high level of stimulation. In Fabry patients, small fiber dysfunction is more prominent than large fiber dysfunction, confirming previous findings of sural nerve biopsies. The results suggest a higher vulnerability of small-diameter nerve fibers than of the thickly myelinated fibers.

Decrease of sympathetic cardiovascular modulation after temporal lobe epilepsy surgery.

In temporal lobe epilepsy (TLE), there is evidence of ictal and interictal autonomic dysregulation, predominantly with sympathetic overactivity. The effects of TLE surgery on autonomic cardiovascular control and on baroreflex sensitivity (BRS) have not been studied. To evaluate such effects, we monitored heart rate (HR), systolic blood pressure (BP(sys)) and respiration in 18 TLE patients 3-4 months before and after TLE surgery. We used Blackman-Tukey spectral analysis to assess sympathetic and parasympathetic modulation as powers of HR and BP(sys) oscillations in the low frequency (LF, 0.04-0.15 Hz) and high frequency (HF, 0.15-0.5 Hz) bands. BRS was determined as the LF transfer function gain between BP and HR. After surgery, HR, BP(sys), respiration and HF powers remained unchanged, while LF powers of HR (1.57 +/- 1.54 bpm(2)) and BP(sys) (2.19 +/- 1.34 mmHg(2)) and BRS (0.68 +/- 0.31 bpm/mmHg) were smaller than pre-surgical LF powers of HR (3.87 +/- 3.26 bpm(2)) and BP(sys) (4.80 +/- 3.84 mmHg(2)) and BRS (1.12 +/- 0.39 bpm/mmHg; P < 0.05). After TLE surgery, there is a reduction of sympathetic cardiovascular modulation and BRS that might result from decreased influences of interictal epileptogenic discharges on brain areas involved in cardiovascular autonomic control. TLE surgery seems to stabilize the cardiovascular control in epilepsy patients by reducing the risk of sympathetically mediated tachyarrhythmias and excessive bradycardiac counter-regulation, both of which might be relevant for the pathophysiology of sudden unexpected death in epilepsy patients (SUDEP). Thus, TLE surgery might contribute to reducing the risk of SUDEP.

[Syncope - a systematic overview of classification, pathogenesis, diagnosis and management]. / Synkopen - eine systematische Ubersicht zur Klassifikation, Pathogenese, Diagnostik und Therapie.

Syncope is defined as a temporary interruption of cerebral perfusion with a sudden and transient loss of consciousness and spontaneous recovery. Approximately one third of the population experiences syncope at least once during a lifetime. Presyncopal signs and symptoms, including weakness, headache, blurred vision, diaphoresis, nausea, and vomiting are sometimes present for seconds or minutes prior to loss of consciousness. After syncope, the patients may present with persisting drowsiness, headache, dizziness, nausea, but not usually confusion. Causes of syncope have been categorized as cardiovascular, non-cardiovascular, and unexplained. Cardiovascular causes can be subdivided into structural heart disease, coronary heart disease, and arrhythmia. Non-cardiovascular causes include neurological, metabolic, psychiatric and other disorders.Orthostatic hypotension - one of the most frequent causes of syncope - has manifold etiologies comprising various neurological and internal diseases. Orthostatic hypotension usually can be attributed to an impairment of peripheral vasoconstriction or to a reduction of the intravascular volume. Signs and symptoms, including the above prodromi are often present just after rising from a supine or sitting position. Frequently, blood pressure decreases significantly without an increase in heart rate. Autonomic cardiovascular modulation is often reduced. Many of the patients with "unexplained" syncope experience neurally mediated (i. e. neurocardiogenic or vasovagal) syncope. In these patients, cardiovascular control may be stable for an extended period of time during orthostatic stress, then there is a sudden decrease in blood pressure and heart rate. Neurocardiogenic or neurally mediated syncope can be associated with painful or emotionally stressful situations such as anxiety or fear, with prolonged standing or specific trigger situations such as micturition, defecation, coughing or sneezing, visceral or carotid sinus stimulation, or with trigeminal or glossopharyngeal neuralgia. So far, the mechanisms of neurocardiogenic syncope are not completely understood. The passive 60 degrees to 70 degrees head-up tilt test is useful for the diagnosis of orthostatic and neurally mediated syncope. The sensitivity of the test can be improved by additional pharmacological provocation, e. g. by isoproterenol, or by increased orthostatic stress using lower body negative pressure stimulation. For the treatment of syncope one should first consider non-pharmacological options. Patients with orthostatic hypotension should avoid rapid changes of the body position from supine to standing, as well as high room temperature or other situations inducing peripheral vasodilatation. An increased intake of sodium and fluids, mild physical exercise or so-called postural counter-maneuvers can improve orthostatic tolerance. Among the drugs recommended for pharmacologic treatment are mineralocorticoids (e. g. fludrocortisone), vasoconstrictor agents (e. g. ephedrine, midodrine), adenosine receptor blockers (theophylline) and beta2-blockers (propanolol), anticholinergic agents, e. g. scopolamine or disopyramide, and negative cardiac inotropes, e. g. beta1-adrenergic blockers or disopyramide. Serotonin reuptake inhibitors (e. g. fluoxetine, sertraline), alpha2-adrenergic agonists (clonidine), central nervous system stimulants such as methylphenidate or phentermine are thought to be beneficial in specific cases. Cardiac pacemakers often seem to be recommended without adequate indication. The antidiuretic, V2-receptor specific, vasopressin analogue desmopressin increases the intravascular volume. Erythropoietin improves anemia and red blood cell decrease and augments blood pressure and cerebral oxygenation. In postprandial hypotension, octreotide, a somatostatin analogue, prostaglandin inhibitors such as indomethacin or ibuprofen, as well as metoclopramide or two cups of coffee per day might be beneficial.

Evaluation of peripheral and autonomic nerve function in Fabry disease.

UNLABELLED: The neurological manifestations of Fabry disease include severe episodes of lancinating pain and burning paraesthesias in the extremities, often triggered by changes in temperature. The preferential involvement of small nerve fibres and the accumulation of storage product in the central autonomic nervous system and autonomic ganglia means that standard neurophysiological procedures cannot adequately evaluate the peripheral and autonomic nervous systems of affected patients. This paper describes the various methods that have been developed to assess impairment of temperature perception, vibratory perception, sudomotor and sweat gland function, and limb and superficial skin blood flow and vasoreactivity. These methods, including thermal provocation tests, quantitative sudomotor axon reflex testing and venous occlussion plethsmography, have been used effectively in patients with Fabry disease to measure the extent of neurological dysfunction. CONCLUSIONS: Effective methods for measuring neurological involvement in patients with Fabry disease have been developed. These methods will be valuable in assessing the response of patients to enzyme replacement therapy.

[Erectile dysfunction. An important manifestation of autonomic diabetic neuropathy]. / Erektile Dysfunktion. Eine wichtige Manifestation der autonomen diabetischen Neuropathie.

In Germany, some 4-6 million men, including 1.2 million diabetics, suffer from erectile dysfunction (ED). Various other diseases including heart disease, hypertension, arteriosclerosis, hyperlipidemia, endocrine disorders, chronic renal insufficiency, prior radical prostatectomy, neurological diseases, trauma and the abuse of alcohol, tobacco, and side effects of medications, are frequently associated with ED. Medical history, clinical examination, routine blood chemistry and sexual hormone levels may help clarify the etiology of ED. Normally, relaxation of the smooth muscles of the corpus cavernosum--mediated by cGMP and cAMP--together with dilatation of penile arteries and occlusion of venous outflow, results in an erection. The oral type V phosphodiesterase inhibitor, Sildenafil, or prostaglandin E1 injection elevates the cGMP and cAMP levels, respectively. Other therapeutic options include mechanical aids, surgery, hormone replacement or sublingual apomorphine. Since 1998, Sildenafil, an effective, simple and safe oral treatment, has been available.

Ictal SPECT during autonomic crisis in familial dysautonomia.

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

Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients.

In Fabry disease, an X-linked alpha-galactosidase A deficiency, painful crises and limb paresthesias are possibly linked to thermal exposure. Small nerve fiber function has not yet been tested after cold challenge. In two Fabry patients (15 and 17 years old), their heterozygote mother, their healthy sister, and eight controls, we determined warm and cold perception thresholds at the dorsal foot and the lower medial calf (method of limits, Somedic-Thermotest), before and 1, 5, 10 and 15 min after 30 s immersion of one leg into 5 degrees C water. Discomfort was rated from 0 to 10. At baseline, thermal thresholds of all participants were normal. In contrast to controls, the patients tolerated 30 s cold stimulation only with interruptions. The mother aborted stimulation after 6 s because of pain. The patients and their mother reported intense burning pain and numbness during and after stimulation. After cold exposure, thermal sensation was highly abnormal for 20 min in one and 80 min in the other brother. In controls, thermal thresholds were somewhat elevated after stimulation but normalized within 10.0+/-4.6 min. Discomfort during cold exposure was rated 8-10 by the patients and their mother, but 3-5 by the healthy persons. We assume that glycolipid accumulation in cutaneous and vasa nervorum vessels as well as small nerve axons accounts for skin and small fiber malperfusion during cold induced vasoconstriction. Transitory ischemia initiated burning pain and prolonged small fiber dysfunction.

[Autonomic disorders in polyneuropathies]. / Autonome Störungen bei Polyneuropathien.

BACKGROUND: Many polyneuropathies manifest autonomic disturbances. Diabetic neuropathy, the most frequent neuropathy in the western world, serves as model of the symptomatology of autonomic disturbances. DIABETIC NEUROPATHY: Clinical symptoms comprise pupillary and cardiovascular dysfunction such as orthostatic hypotonia and syncopes, thermoregulatory, gastrointestinal symptoms, disturbances in urogenital and respiratory function and unawareness of hypoglycemia. OTHER NEUROPATHIES: This article also describes autonomic symptoms in alcoholic neuropathy, in Guillain-Barré syndrome, in paraneoplastic polyneuropathies, in toxic neuropathies, in acute and subacute autonomic neuropathy, in amyloidosis, in porphyria, in familiar dysautonomia, in HIV infection and in botulism.

[Follow-up and prognosis of patients of a neurologic intensive care unit with special reference to age]. / Zum Verlauf und zur Prognose von Patienten einer neurologischen Intensivstation unter besonderer Berücksichtigung des Alters.

To evaluate risk factors effecting course and prognosis of neurological intensive care (ICU) patients with special respect to age, 422 patients (235 male, 187 female, mean age 56.7 years, standard deviation +/- 18.8 years) admitted to the ICU of the Department of Neurology, University Erlangen-Nürnberg, were retrospectively studied. The status at the time of ICU discharge was compared to that assessed 18-30 months later using the Barthel-Index, a five grade scale of independence, and the Glasgow Outcome Scale. At the time of reexamination, 203 of the 422 patients (48.2%) were still alive. The fatality rate increased with age. However, approximately 70% of the patients above the age of 70 years were still alive two years after ICU treatment with the majority of patients describing their life as satisfying. Multivariate analysis demonstrated that age by itself does not determine the course of disease. Age affects the prognosis only in combination with other variables such as preexisting diseases (e.g. stroke, carotid surgery, occlusive arterial disease), secondary complications (e. g. pneumonia), and specific ICU treatment (e.g. mechanical ventilation, nasogastric tube), and the patient's state at the time of ICU discharge (bedriddenness, aphasia, dementia).

[Successful treatment of the neuroleptic malignant syndrome using i.v. dantrolene sodium in the neurologic intensive care station]. / Erfolgreiche Behandlung des malignen neuroleptischen Syndroms mit Dantrolen-Natrium i.v. auf der neurologischen Intensivstation.

The neuroleptic malignant syndrome (NMS) is one of the most dramatic psychiatric disorders every doctor in intensive care medicine can be confronted with. Two cases of successful treatment of NMS with intravenous application of dantrolene are presented. Although we used two very different doses, the treatment results were the same. Further studies will therefore be necessary to assess the optimal doses for this therapy.

[Fecal excretion of cadmium and copper after mushroom (Agaricus) diet (author's transl)]. / Cadmium- und Kupferausscheidung nach Aufnahme von Champignon-Mahlzeiten.

High contents of cadmium in some agaricus species led to the warning that the eating of wild-grown mushrooms may bear the possibility of cadmium-intoxication. The low digestion rate due to the chitin membrane of fungi was not discussed. Therefore, in this investigation the cadmium- and copper-concentrations in feces of five subjects were estimated before and after a three days mushrooms diet. The high amount of fecal cadmium and copper increasing after the diet confirm the suggestion, that eaten fungi mostly pass through the intestinal tract unscathed without resorption. By this even larger ingestions of agaricus fungi may not cause cadmium intoxication in humans.