[Zika virus infection and the nervous system]. / Zika-Virus-Infektion und das Nervensystem.

Zika virus is an arbovirus from the family of flaviviruses, which is transmitted by the mosquito Aedes aegyptii and also by the Asian mosquito Aedes albopticus. The largest observed Zika virus epidemic is currently taking place in North and South America, in the Caribbean, southern USA and Southeast Asia. In most cases the infection is an unspecific, acute, febrile disease. Neurological manifestations consist mainly of microcephaly in newborns and Guillain-Barré syndrome but other rare manifestations have also become known in the meantime, such as meningoencephalitis and myelitis. Therefore, the Zika virus, similar to other flaviviruses, has neuropathogenic properties. In particular, the drastic increase in microcephaly cases in Brazil has induced great research activities. The virus is transmitted perinatally and can be detected in the amniotic fluid, placenta and brain tissue of the newborn. Vaccination or a causal therapy does not yet exist. The significant increase in Guillain-Barré syndrome induced by the Zika virus was observed during earlier outbreaks. In the meantime, scientifically clear connections between a Zika virus infection and these neurological manifestations have been shown. Long-term studies and animal models should be used for a better understanding of the pathomechanisms of this disease.

The dopamine-related polymorphisms BDNF, COMT, DRD2, DRD3, and DRD4 are not linked with changes in CSF dopamine levels and frequency of HIV infection.

We showed previously that higher levels in CSF dopamine in HIV patients are associated with the presence of the dopamine transporter (DAT) 10/10-repeat allele which was also detected more frequently in HIV-infected individuals compared to uninfected subjects. In the current study, we investigated further whether other genetic dopamine (DA)-related polymorphisms may be related with changes in CSF DA levels and frequency of HIV infection in HIV-infected subjects. Specifically, we studied genetic polymorphisms of brain-derived neurotrophic factor, catechol-O-methyltransferase, and dopamine receptors DRD2, DRD3, and DRD4 genetic polymorphisms in uninfected and HIV-infected people in two different ethnical groups, a German cohort (Caucasian, 72 individuals with HIV infection and 22 individuals without HIV infection) and a South African cohort (Xhosan, 54 individuals with HIV infection and 19 individuals without HIV infection). We correlated the polymorphisms with CSF DA levels, HIV dementia score, CD4+ T cell counts, and HIV viral load. None of the investigated DA-related polymorphisms was associated with altered CSF DA levels, CD4+ T cell count, viral load, and HIV dementia score. The respective allele frequencies were equally distributed between HIV-infected patients and controls. Our findings do not show any influence of the studied genetic polymorphisms on CSF DA levels and HIV infection. This is in contrast to what we found previously for the DAT 3'UTR VNTR and highlights the specific role of the DAT VNTR in HIV infection and disease.

[Acute psychosis as a side effect of efavirenz therapy with metabolic anomalies: an important differential diagnosis of HIV-associated psychoses]. / Akute Psychose als Nebenwirkung der Therapie mit Efavirenz bei metabolischer Anomalie : Eine wichtige Differenzialdiagnose HIV-assoziierter Psychosen.

Among patients with human immunodeficiency virus (HIV) infections psychiatric disease poses a particular challenge for caregivers. Neuropsychiatric side effects of efavirenz have been described in up to 40% of patients showing dizziness, insomnia, unusual dreams, mood instability, personality alterations and thought disorders. In immigrants from Africa and South America these side effects may be related to elevated plasma concentrations of efavirenz due to polymorphisms of cytochrome P450 isozymes (especially G516T). Alleles for these polymorphisms are more frequent in African and South American patients. We report a case of a 52-year-old patient from Guinea who was referred to the department of neurology under the diagnosis of HIV-associated neurocognitive disorder (HAND). Since the start of combined antiretroviral therapy (cART) including efavirenz the patient had suffered severe personality alterations, acoustic and visual hallucinations and delusions which led to discrimination and reduced quality of life. Diagnostic procedures including magnetic resonance imaging (MRT) and spinal fluid analysis resulted in normal values and did not explain the disease. After switching to nevirapin instead of efavirenz the psychotic symptoms disappeared within 5 days.

Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration.

BACKGROUND AND PURPOSE: Biomarkers as indicators for the progression of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain still elusive. We performed a cross-sectional study to analyze the correlation between cognitive impairment, abnormalities in magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) markers of neurodegeneration in HIV-infected patients. METHODS: We enrolled 94 patients (82 men and 12 women; mean age 45 ± 10 years) with HIV infection, but without opportunistic infections of the CNS. All patients underwent MRI and CSF analysis. The global pattern of white matter signal intensity abnormalities, the index of atrophy, the severity of periventricular white matter abnormalities, and the severity of basal ganglia signal changes were analyzed. We measured CSF markers of neurodegeneration (total tau, phospho-tau, beta-amyloid). The findings of this evaluation were correlated with demographic and infection parameters of the patients in blood and CSF. RESULTS: We found a highly significant correlation between the severity of global brain atrophy, basal ganglia signal changes, and cognitive impairment in HIV-infected patients. Furthermore, cognitive impairment was significantly correlated with total tau, but not with phospho-tau or A-beta-amyloid in CSF analysis. CONCLUSIONS: Our results confirm the significant correlation between MRI changes and cognitive impairment in HIV infection. Furthermore, we could show that global brain atrophy and signal changes in basal ganglia are the typical MRI pattern in HAND. The correlation between cognitive impairment and total tau, but not phospho-tau, supports the hypothesis that HAND are not a subtype of Alzheimer's dementia.

[Treatment of neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome]. / Behandlung von Neuro-Aids auf der neurologischen Intensivstation : Epidemiologie, Outcome und Prädiktoren des Verlaufs.

BACKGROUND: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed. MATERIAL AND METHODS: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS. RESULTS: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit. DISCUSSION: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

Cluster headache and Alpha 1-antitrypsin deficiency.

Little is known about the pathophysiology of cluster headache (CH), one of the most debilitating primary headaches. Interestingly, associations of lung affecting diseases or lifestyle habits such as smoking and sleep apnoea syndrome and CH have been described. Certain genotypes for alpha 1-antitrypsin (alpha(1)-AT) are considered risk factors for emphysema. Our aim was to investigate possible associations between common genotypes of the SERPINA1 gene and CH. Our study included 55 CH patients and 55 controls. alpha(1)-AT levels in serum and the genotype were analysed. Patients CH characteristics were documented. We could not detect any association between CH and a genotype that does not match the homozygous wild type for alpha(1)-AT. Interestingly, there is a significant difference of CH attack frequency in patients who are heterozygous or homozygous M allele carriers. We conclude that the presence of an S or Z allele is associated with higher attack frequency in CH.

Efficacy of fixed combinations of acetylsalicyclic acid, acetaminophen and caffeine in the treatment of idiopathic headache: a review.

Headache is one of the most common reasons for patients to visit their general practitioner. Most of these patients suffer from migraine, tension-type headache, or a combination of the two; they tend to self-medicate using over the counter combination headache preparations, particularly acetylsalicyclic acid (ASA) and acetaminophen coformulated with caffeine, which is one of the most commonly used combination analgesics in these patients worldwide. We reviewed studies on the efficacy and safety of this combination. In the treatment of migraine and tension-type headache, the combination of ASA, acetaminophen, and caffeine has been shown to be more efficacious and superior to monotherapy with the single substances of the combination. According to literature, there is no evidence for higher prevalence of undesirable side-effects of combination analgesics in comparison to monotherapy.

[HIV-associated neuropathies]. / HIV-assoziierte Neuropathien.

Human immunodeficiency virus (HIV)-associated polyneuropathy has become the most common neurological complication of HIV infection and is one of the main risk factors for development of a neuropathy worldwide. Therefore HIV should always be considered as an underlying cause in patients with neuropathy. Many types of peripheral neuropathies are seen in HIV infection depending on the stage of infection. The inflammatory demyelinating neuropathies both acute (Guillain-Barré syndrome, GBS) and chronic (chronic inflammatory demyelinating neuropathy, CIDP) occur mainly at the time of seroconversion or early in the course of the disease while syndromes associated with opportunistic infections like CMV (i.e. polyradiculoneuropathy) occur in the late phase of HIV infection and are related to the loss of immune function. Distal symmetrical polyneuropathy (DSP) is the most common neuropathy in HIV-infected patients. We review the clinical manifestations, epidemiology, clinical diagnostics, pathophysiology and management strategies for HIV-associated polyneuropathies.

[Epidemiology and therapy of pain and depression during HIV and AIDS]. / Epidemiologie und Therapie von Schmerzen und Depression bei HIV und Aids.

Pain is one of the most common reasons for admission to hospital for patients suffering from AIDS. Pain and other symptoms very often cover depressive episodes. Pain induced by AIDS therapy represents a progressive problem and induces the necessity to alter the highly active antiretroviral therapy (HAART). Of HIV-infected people 90% complain of headaches. Headache may result from opportunistic infections, from side-effects of HAART or from the HIV in the CNS itself but also the high burden of idiopathic headaches must be considered. Up to 20% of all neuropathies in HIV-infected people are caused by HAART. In most cases changing of HAART is necessary. Problems of interactions between HAART and the substances used for pain therapy via the cytochrome P450 system represents a special therapeutic problem during HAART in order to avoid development of resistance by the HIV.

[Highly active antiretroviral therapy of neuro-AIDS. Side effects on the nervous system and interactions]. / Hochaktive antiretrovirale Therapie bei Neuro-AIDS. Nebenwirkungen auf das Nervensystem und Interaktionen.

Highly active antiretroviral therapy (HAART) has increased the mean survival time in the AIDS stage to sometimes more than 10 years. Five different groups of antiretroviral medications are known, of which integrase inhibitors and CCR5 antagonists represent the newest and most modern substances. The long AIDS survival time implies that side effects and interactions become relatively more important and must be differentiated from the symptoms of HIV itself. Side effects of HAART concern the central and peripheral nervous system and the muscles. The neurotoxicity of the components in HAART varies considerably and depends on the substance itself. Knowledge of side effects and interactions of HAART with antiepileptics, antidepressants, and analgetics are essential for the treatment of patients with neuro-AIDS.

[Severe aseptic leucoencephalopathy. Manifested as immune reconstitution inflammatory syndrome in Caucasian and African patients]. / Schwere Leukenzephalopathie. Manifestationsform des aseptischen Immune-reconstitution-inflammatory-Syndroms bei Kaukasiern und Afrikanern.

BACKGROUND: We hypothesize that CNS immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy (HAART) in HIV-1-positive patients may become manifest without any opportunistic infection as an aseptic leucoencephalopathy. This opens a window of opportunity for successful treatment with corticosteroids. DESIGN: We describe a case series of immunocompromised HIV-1-positive patients who were started on HAART. All of them had clinical laboratory follow-up tests and cerebral MRI in order to investigate the course and the underlying pathophysiology of this aseptic form of IRIS. One African patient died and we performed a neuropathological examination. RESULTS: No infectious agent was detected before and during HAART. Three of four immunocompromised patients were successfully treated with corticosteroids while HAART was never interrupted and have survived up to now. One African patient died within 2 days despite intensive care due to cerebral oedema. CONCLUSIONS: Starting HAART, HIV-1-positive patients may develop an aseptic type of IRIS of the CNS without any detectable opportunistic infection, a finding that has not yet been published. This makes them susceptible for successful treatment with corticosteroids. Perhaps IRIS has a higher incidence in African patients and the patients have a poorer outcome than Caucasians.

Migraine and left-handedness are not associated. A new case-control study and meta-analysis.

To investigate the possible association between migraine and left-handedness, we enrolled 100 patients with a diagnosis of migraine according to the International Headache Society diagnostic criteria and 100 age- and sex-matched control subjects into a case-control study. Handedness was determined by the Edinburgh Handedness Inventory. There was no significant difference in the frequency or grade of left-handedness between the two groups. Additionally, we pooled our data with those from five similar studies, which did not alter the result. Thus, neither our study nor the meta-analysis support Geschwind and Behan's hypothesis of an association between migraine and left-handedness.

[Magnetic resonance imaging findings of the brain in adult HIV and AIDS patients]. / Magnetresonanztomografische Befunde des Gehirns bei adulten Patienten mit HIV und AIDS.

The spectrum of pathology affecting the central nervous system (CNS) in patients suffering from acquired immunodeficiency syndrome (AIDS) includes not only the human immunodeficiency virus (HIV) infection itself but also opportunistic infections and tumors secondary to AIDS. Despite progress in antiretroviral therapy and the subsequent decrease in the incidence of associated diseases, opportunistic infections and tumors secondary to the HIV infection continue to be the limiting factor in terms of survival with AIDS. Therefore, the therapeutic aim is permanent antiretroviral therapy as well as early diagnosis and treatment of opportunistic infections. Magnetic resonance imaging is often the diagnostic method of choice in suspected CNS pathology of HIV patients. In the following, the typical clinical and radiological features of several AIDS-related pathologies are presented and discussed.

Frequency of seizures and epilepsy in neurological HIV-infected patients.

BACKGROUND: Infection with the human immunodeficiency virus (HIV) is associated both with infections of the central nervous system and with neurological deficits due to direct effects of the neurotropic virus. Seizures and epilepsy are not rare among HIV-infected patients. We investigated the frequency of acute seizures and epilepsy of patients in different stages of HIV infection. In addition, we compared the characteristics of patients who experienced provoked seizures only with those of patients who developed epilepsy. METHODS: The database of the Department of Neurology, University of Münster, was searched for patients with HIV infection admitted between 1992 and 2004. Their charts were reviewed regarding all available sociodemographic, clinical, neurophysiological, imaging and laboratory data, therapy and outcome. Stage of infection according to the CDC classification and the epileptogenic zone were determined. RESULTS: Of 831 HIV-infected patients treated in our department, 51 (6.1%) had seizures or epilepsy. Three of the 51 patients (6%) were diagnosed with epilepsy before the onset of the HIV infection. Fourteen patients (27%) only had single or few provoked seizures in the setting of acute cerebral disorders (eight patients), drug withdrawal or sleep withdrawal (two patients), or of unknown cause (four patients). Thirty-four patients (67%) developed epilepsy in the course of their HIV infection. Toxoplasmosis (seven patients), progressive multifocal leukencephalopathy (seven patients) and other acute or subacute cerebral infections (five patients) were the most frequent causes of seizures. EEG data of 38 patients were available. EEG showed generalized and diffuse slowing only in 9 patients, regional slowing in 14 patients and regional slowing and epileptiform discharges in 1 patient. Only 14 of the patients had normal EEG. At the last contact, the majority of the patients (46 patients=90%) were on highly active antiretroviral therapy (HAART). Twenty-seven patients (53%) were on anticonvulsant therapy (gabapentin: 14 patients, carbamazepine: 9 patients, valproate: 2 patients, phenytoin: 1 patient, lamotrigine: 1 patient). Patients with only provoked seizures had no epilepsy risk factors except HIV infection, and were less likely to be infected via intravenous drug abuse. CONCLUSIONS: Seizures are a relevant neurological symptom during the course of HIV infection. Although in some patients seizures only occur provoked by acute disease processes, the majority of patients with new onset seizures eventually develops epilepsy and require anticonvulsant therapy. Intravenous drug abuse and the presence of non-HIV-associated risk factors for epilepsy seem to be associated with the development of chronic seizures in this patient group.

Comorbidity of restless legs syndrome and HIV infection.

BACKGROUND: The lifetime prevalence of restless legs syndrome (RLS) is about 10 % in the general population. The association of RLS with HIV infection is unknown. We aimed to investigate the prevalence of RLS in HIV positive patients and to define predictors. METHODS: A standardized questionnaire was presented to 228 HIV infected patients of the HIV outpatient clinic at the Department of Neurology,University of Münster, Germany. 129 patients (57% recall; 15% female, 44 +/- 9 years; mean CD4(+) cell count 333 +/- 274/microl, 82% under highly active antiretroviral treatment) were included in the statistical analysis. 100 age- and sex-matched controls (20 % female, 42 +/- 13 years) were recruited from waiting relatives of surgical patients. Beside demographic and disease-specific data, the questionnaire included the diagnostic questions for RLS and the RLS severity scale by the International RLS Study Group. Diagnosis of RLS was confirmed by experienced neurologists. RESULTS: 33.3% of the HIV infected patients and 7% of the controls (p <0.001) fulfilled the diagnostic criteria for RLS. The mean RLS severity score was higher in HIV infected patients (19.5 +/- 7.2) than in controls (7.3 +/- 1.5; p <0.001) and correlated inversely with the CD4(+) cell count (r = -0.381; p = 0.024) and the BMI (r = -0.548; p <0.001) but not with other disease-specific factors. CONCLUSIONS: HIV infected patients show a significantly higher prevalence rate for RLS than the general population. The HIV infection itself with its immunological changes and involvement of the central nervous system may predispose for a risk of RLS in HIV infected patients.

Evidence of familial syringomyelia in discordant association with Chiari type I malformation.

We report a sister and two half brothers who presented with magnetic resonance imaging (MRI)-proven syringomyelia and associated Chiari type I malformation in two cases. The individuals have the same mother but two different fathers. The mother shows no clinical signs of syringomyelia. The two fathers died through unknown causes. In a third healthy son of the mother by a relationship with a third father syringomyelia was excluded by MRI. We believe that an autosomal-dominant predisposition is the primary factor in the appearance of syringomyelia in these cases.

Pharmacologic treatment of central post-stroke pain.

OBJECTIVES: Almost 100 years after the first report of the thalamic syndrome, the scientific basis for the treatment of central post-stroke pain (CPSP) is remarkably small. Therefore, the authors aimed to provide evidence-based recommendations for the treatment of CPSP. METHODS: The authors performed a systematic review of the literature on the pharmacologic treatment of CPSP. All studies and case series were included and evaluated according to their level of evidence. Only CPSP was considered, not other types of central pain. RESULTS: Amitriptyline and lamotrigine are the only oral drugs proven to be effective in the treatment of CPSP in a placebo-controlled study. IV drugs such as lidocaine, propofol, and ketamine have shown efficacy for short-term control of CPSP, but their application and potential side effects make them unsuitable for long-term treatment. The novel antiepileptic drug gabapentin has been reported to control CPSP in a few patients. CONCLUSIONS: Amitriptyline, lamotrigine, and gabapentin provide a more favorable efficacy and safety profile than the classic antiepileptic drugs carbamazepine and phenytoin, for which no placebo-controlled evidence of efficacy was found. Clinical trials are urgently needed to optimize pharmacologic treatment of CPSP.