[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.

[Causes of death in amyotrophic lateral sclerosis : Results from the Rhineland-Palatinate ALS registry]. / Todesursachen bei amyotropher Lateralsklerose : Ergebnisse aus dem ALS-Register Rheinland-Pfalz.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is associated with an increased mortality. Knowledge of possible causes of death could lead to an individualization of the palliative treatment concept and result in a differentiated palliative treatment pathway. Currently, only few systematic data are available on the heterogeneity of causes of death associated with ALS. OBJECTIVE: Analysis of the various causes of death in a prospective population-based German cohort of ALS patients. MATERIAL AND METHODS: Analysis of data of the Rhineland-Palatinate ALS registry in which newly diagnosed patients who had been identified between October 2009 and September 2012 were prospectively enrolled and followed up at regular intervals. From this prospective cohort study the causes of death were elicited based on information provided by the attending physicians, family members and by means of death certificates registered by the regional health authorities in Rhineland-Palatinate. RESULTS: Out of 200 ALS patients registered 148 died between register initiation on 1 October 2009 and the end of follow-up on 30 September 2015 (78 males and 70 females, death rate 74%). The most frequent cause of death was respiratory failure as a consequence of weakness of respiratory muscles (n = 91, 61%). Less frequent causes of death were pneumonia (n = 13, 9%), terminal cachexia (n = 9, 6%) and death from cardiovascular causes including sudden death (n = 9, 6%). Cases of suicide were rare (n = 3, 2%) as were deaths due to concurrent diseases (n = 2). In 21 cases (14%) the exact cause of death could not be clarified. Differences in the causes of death only showed a tendency towards the ALS phenotype. Respiratory failure was the cause of death in all patients with a respiratory phenotype and in 78% of patients with flail arm syndrome. Despite the low number of patients (8%) with additional frontotemporal dementia (FTD) a distinct difference in causes of death between those with and without FTD could be observed. Death due to respiratory failure was less frequent in ALS patients with FTD (33% vs. 65%) while pneumonia was more frequent (27% vs. 7%). CONCLUSION: Respiratory failure was the most frequent cause of death in our cohort of ALS patients. In contrast, pneumonia and nutritional disorders played a less important role as the cause of death. The phenotypic expression of ALS might in part allow the cause of the prospective death to be predicted. Differentiation of ALS phenotypes is an important foundation for patient counseling on the process of dying to be expected and for the determination of an individual palliative concept.

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.

Efficacy of natalizumab in second line therapy of relapsing-remitting multiple sclerosis: results from a multi-center study in German speaking countries.

BACKGROUND: Natalizumab has been recommended for the treatment of relapsing-remitting multiple sclerosis (RRMS) in patients with insufficient response to interferon-beta/glatiramer acetate (DMT) or aggressive MS. The pivotal trials were not conducted to investigate natalizumab monotherapy in this patient population. METHOD: Retrospective, multicenter study in Germany and Switzerland. Five major MS centers reported all RRMS patients who initiated natalizumab >or=12 months prior to study conduction. RESULTS: Ninety-seven RRMS patients were included [69% female, mean age 36.5 years, mean Expanded Disability Status Scale (EDSS) 3.4; 93.8% were pre-treated with DMT], mean treatment duration with natalizumab was 19.3 +/- 6.1 months. We found a reduction of the annualized relapse rate from 2.3 to 0.2, 80.4% were relapse free with natalizumab. EDSS improved in 12.4% and 89.7% were progression free (change of >or= 1 EDSS point). Eighty-six per cent of patients with highly active disease (>or= 2 relapses in the year and >or= 1 Gadolinium (Gd)+ lesion at study entry, n = 20) remained relapse free. The mean number of Gd enhancing lesions was reduced to 0.1 (0.8 at baseline). Discontinuation rate was 8.2% (4.1% for antibody-positivity). CONCLUSION: Natalizumab is effective after insufficient response to other DMT and also in patients with high disease activity.

Efficacy of pregabalin in the treatment of trigeminal neuralgia.

This prospective, open-label study aimed to evaluate the efficacy of pregabalin treatment in patients suffering from trigeminal neuralgia with and without concomitant facial pain. Fifty-three patients with trigeminal neuralgia (14 with concomitant chronic facial pain) received pregabalin (PGB) 150-600 mg daily and were prospectively followed for 1 year. The primary outcome was number of patients pain free or with reduction of pain intensity by > 50% and of attack frequency by > 50% after 8 weeks. Secondary outcome was sustained pain relief after 1 year. Thirty-nine patients (74%) improved after 8 weeks with a mean dose of 269.8 mg/day (range 150-600 mg/day) PGB: 13 (25%) experienced complete pain relief and 26 (49%) reported pain reduction > 50%, whereas 14 (26%) did not improve. Patients without concomitant facial pain showed better response rates (32 of 39, 82%) compared with patients with concomitant chronic facial pain (7 of 14, 50%, P = 0.020). Concomitant chronic facial pain appears to be a clinical predictor of poor treatment outcome. PGB appears to be effective in the treatment of trigeminal neuralgia.

Increased basal-ganglia activation performing a non-dystonia-related task in focal dystonia.

BACKGROUND AND PURPOSE: We tried to determine whether altered sensorimotor cortex and basal-ganglia activation in blepharospasm (BSP) and cervical dystonia (CD) are restricted to areas directly responsible for the innervation of dystonic muscles, or whether impairment in focal dystonia reaches beyond these direct associations supporting a more global disturbance of sensory and motor control in focal dystonia. METHODS: Twenty patients with focal dystonia (11 BSP, 9 CD) and 14 healthy controls were investigated with functional magnetic resonance imaging (fMRI) performing a simple grip force forearm contraction task. RESULTS: BSP and CD patients and healthy controls showed similar activation in the pre-motor, primary motor and primary sensory cortex, whilst basal-ganglia activation was increased in BSP and CD with related activation patterns compared with controls. BSP patients had increased activation in the thalamus, caudate nucleus, putamen and lateral globus pallidus, whilst CD patients showed increased activation in the caudate nucleus, putamen and thalamus. No differences in applied grip force were detected between groups. CONCLUSIONS: In both, BSP and CD, increased basal-ganglia activation could be demonstrated in a task not primarily involving the dystonic musculature affected by these disorders. Comparable activation changes may also indicate a common pathway in the pathophysiology in BSP and CD.

Cerebellum and cognition: viewed from philosophy of mind.

Traditionally, it is believed, that the primary function of the cerebellum is to coordinate movement. During the past three decades, it has been controversially discussed, whether the cerebellum may also contribute to cognition and mental states like emotions. In this paper, no position relating to this controversy will be taken. Instead, the hypothesis of non-motor functions of the cerebellum will be viewed from the position of the philosophy of mind. The remarkably uniform microscopic structure and neuronal networks of the cerebellum have led to computer analogies by several authors. The main idea of functionalism, i.e., a theory within the philosophy of mind, is that the mental relates to the physical as computer software does to hardware. This raises the question, whether a cerebellar contribution to cognition and mental states would support functionalism in the philosophy of mind. No support of functionalism could be found in this study, investigating the classical philosophical arguments pro and con functionalism such as those of multiple realizability, the Chinese room and the explanatory gap, while taking the results of cerebellar research into account. On the other hand, philosophical reflection suggests a careful use of the phrases "cognitive dysmetria" (Andreasen et al. Proc Natl Acad Sci USA. 1996;93:9985-90) in the context of mental illness and of "dysmetria of thought" (Schmahmann Arch Neurol. 1991;48:1178-87). According to the argument of the explanatory gap there is at present little support for the assumption that the phenomenal experiencing of an altered emotion can be reduced to the dysmetria of movement.

Cavernous malformation with hemorrhage of the conus medullaris and progressive sensory loss.

Numerous studies have shown that cavernous malformations may be localized in almost every region of the brain as well as in the spinal cord. Spinal cord cavernous malformations (SCCM) have been diagnosed more frequently since magnetic resonance imaging (MRI) has become more widely available. Most are asymptomatic but may present as a diagnostic challenge with diffuse symptoms ranging from mere sensory deficits to paraparesis possibly affecting both upper and lower motor neuron. A 29-year-old Arabian man was admitted to the hospital with a progressive sensory loss to light touch, pin prick and vibration of the right and in a lesser extent of the left leg without any association to a particular dermatome. He additionally presented with progressing paresthesias in both legs, unsteady gait and incipient bladder- and bowl incontinence starting approximately 1 week prior to admission. Spinal MRI showed a central, slightly lateralized intramedullary lesion 1 cm in diameter located within the conus medullaris that was suspicious for an intramedullary cavernous malformation. The lesion was accompanied by a perifocal edema and showed an inhomogeneous hypointense core on T2WI consistent with an acute cavernous hemorrhage. Treatment of symptomatic intramedullary cavernous angiomas should, if possible, consist of total surgical excision. It is essential to achieve complete removal during the first operation to avoid any residues that may lead to further bleeding.

Evolution of purely infratentorial PML under HAART--negative outcome under rapid immune reconstitution.

Progressive multifocal leukoencephalopathy (PML) caused by the polyomavirus JC is a well-recognised complication of AIDS. Purely infratentorial manifestations are rare. Introduction of highly active antiretroviral therapy (HAART) has been associated with a reduction in morbidity and an improvement in overall survival among HIV-infected individuals. Recently, several reports have described adverse events in patients with PML who begin HAART and show evidence for immune reconstitution. We describe the clinical course of two patients with PML with purely infratentorial manifestation, whose clinical course deteriorated despite the successful introduction of HAART. Possible underlying immunological mechanisms are discussed.

Basal ganglia infarction mimicking glioblastoma.

Modern brain imaging techniques usually allow a very good differential diagnosis of intracerebral lesions, but in some cases the differential diagnosis is difficult. We report the case of a 52 year old male with acute brachiofacial paresis and a hyperintense lesion with mass effect and ring-enhancement in basal ganglia suspiciously to a tumor. The neurosurgeons recommend stereotactical brain biopsy for diagnosis, but the patient recovered in following time gradually and in repeated computer tomographic images contrast enhancement disappeared and a hypodense zone in the basal ganglia remains. Our case demonstrates that brain infarctions can mimick glioblastoma in taking cystic appearance and contrast enhancement. Stereotactic biopsy would have been a precipitated invasive procedure in this case.

Motor deficits cannot explain impaired cognitive associative learning in cerebellar patients.

There is a strong evidence that the cerebellum is involved in associative motor learning. The exact role of the cerebellum in motor learning, and whether it is involved in cognitive learning processes too, are still controversially discussed topics. A common problem of assessing cognitive capabilities of cerebellar patients is the existence of additional motor demands in all cognitive tests. Even if the patients are able to cope well with the motor requirements of the task, their performance could still involve compensating strategies which cost them more attentional resources than the normal controls. To investigate such interaction effects of cognitive and motor demands in cerebellar patients, we conducted a cognitive associative learning paradigm and varied systematically the motor demands and the cognitive requirements of the task. Nine patients with isolated cerebellar disease and nine matched healthy controls had to learn the association between pairs of color squares, presented centrally on a computer monitor together with a left or right answer button. In the simple motor condition, the answer button had to be pressed once and in the difficult condition three times. We measured the decision times and evaluated the correctly named associations after the test was completed. The cerebellar subjects showed a learning deficit, compared to the normal controls. However, this deficit was independent of the motor difficulty of the task. The cerebellum seems to contribute to motor-independent processes, which are generally involved in associative learning.

Opportunistic CNS infection after bone marrow transplantation.

We retrospectively identified opportunistic CNS infections in 655 patients who had undergone allogeneic, syngeneic or autologous BMT or PBSCT between 1990 and 1997. Twenty-seven patients (4%) developed CNS infections. All CNS infections occurred in allogeneic BMT or PBSCT patients. The most common CNS infections were toxoplasma encephalitis (74%) and cerebral aspergillosis (18%). Furthermore, we identified one patient with candida encephalitis and one patient with viral encephalitis. Overall mortality of patients with opportunistic CNS infection was 67%. There were two different groups of toxoplasma encephalitis with a different appearance on MR imaging. The first group showed edema, but no gadolinium enhancement, whereas the second group exhibited typical MRI appearances with the exception of frequent hemorrhagic transformation. The first group had a significant shorter latency between BMT and onset of CNS infection (mean 45 days vs 180 days, P = 0.02), a significant higher daily dose of corticosteroids as treatment for graft-versus-host disease (GVHD) (P = 0.01), more severe GVHD and a higher mortality (71% vs 36%). This study shows that the most common CNS infections in our patient population are toxoplasma encephalitis and cerebral aspergillosis, that there are two distinct subgroups of toxoplasma encephalitis and that CNS infections occur after allogeneic BMT only.

Posterior reversible encephalopathy syndrome due to severe hypercalcemia.

Posterior reversible encephalopathy syndrome (PRES) is a leukoencephalopathy clinically characterized by headache, altered mental status, visual loss and seizures. Neuroimaging demonstrates symmetrical posterior cortical and subcortical lesions. The exact pathophysiology is unknown but there is a strong association with immunosuppressants and hypertension. We report two cases of PRES in normotensive patients with severe hypercalcemia as the only identifiable cause. Possible pathophysiological mechanisms are discussed.

A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies.

BACKGROUND: Painful HIV-associated sensory neuropathies (HIV-SN) are a common complication of HIV infection. The pathogenesis is unknown and the treatment very limited. Gabapentin (GBP) is effective in painful diabetic neuropathy and postherpetic neuralgia and its effectiveness on painful HIV-SN has been reported anecdotally. DESIGN: Multicenter, prospective, randomised, double-blind, placebo-controlled study. METHODS: Patients were followed for a 1-week screening, a 4-week double-blind and a 2-week open treatment phase. GBP was initiated at 400 mg/d, titrated over 2 weeks to 1200 mg/d, and then either maintained at this level or-if not beneficial-titrated to 2400 mg/d. After 4 weeks the medication was unblinded and the patient had the choice to begin, to maintain or to increase GBP to 3600 mg/d. The primary outcome measure was an improvement in median pain on the Visual Analogue Scale (VAS) from the screening week compared to the 4(th) treatment week. A secondary efficacy measure was the median sleep score (VAS). RESULTS: 15 patients received GBP and 11 placebo. In each group one patient dropped out during the doubleblind phase. Median pain (GBP 5.1; placebo 4.7) and sleep score (GBP 4.5; placebo 5.6) did not differ between both groups at baseline. In the GBP-group there was a significant decrease of the pain to 2.85 (-44.1 %) as well as of the sleep VAS to 2.3 (-48.9 %). No significant decrease in the pain (median VAS=3.3, -29.8 %) as well as in the sleep score (median VAS=4.95, -11.6 %) was observed in the placebo-group. GBP was generally well tolerated. The most frequent side effect was somnolence reported in 80% of GBP-treated patients. CONCLUSIONS: GBP was more effective than placebo in reducing pain and sleep interference in patients with HIV-SN.

A possible role of the human cerebellum in conditioning of the jaw-opening reflex.

The role of the human cerebellum in classical conditioning of the jaw-opening reflex was investigated using positron emission tomography (PET) in healthy subjects. The jaw-opening reflex was elicited by electrical stimulation of the right corner of the mouth (unconditioned stimulus, US). The conditioned stimulus was a tone preceding the US and coterminating with the US. Changes of regional cerebral blood flow (rCBF) were correlated with the rate of conditioning per PET scan. Conditioning effects were present in one third of all subjects. In these subjects, a significant increase of rCBF in the ipsilateral, intermediate cerebellum was shown during ongoing conditioning. Thus, the intermediate cerebellum appears to be involved in classical conditioning of the jaw-opening reflex in humans.

Are allergic reactions to skin clips associated with delayed wound healing?

BACKGROUND: Metal skin clips are used in surgery. They may contain metals that might cause allergic reactions and delayed wound healing. METHODS: The metal composition of 18 different surgical clamps was examined. The allergy status of 184 patients was determined by patch tests and was correlated with the clinical outcome of wound healing after application of skin clips. RESULTS: Skin clips contained chromium, nickel, molybdenum, cobalt, and titanium in concentrations high enough to cause allergic reactions. Eighteen percent of the men and 23% of the women were sensitive to nickel and 16% of the men to chromium. We found a positive correlation between the grade of nickel allergy and the reaction to the skin clips. CONCLUSIONS: Our study suggests that allergic reactions and delayed wound healing can be caused by the use of surgical skin clips. Therefore skin clips are not recommended for patients with a history of contact dermatitis to metals and/or atopy.

Multiple intracerebral metastases of a 17-year-old girl with previously diagnosed neurofibromatosis type I.

We report a case of a 17-year-old girl with multiple intracerebral tumors. Previously, a neurofibroma in the posterior mediastinum and neurofibromatosis had been diagnosed. She developed a spastic tetraparesis with a prominent hemiparesis of the right side within several weeks. On admission we found clinical signs of elevated intracranial pressure. Cranial CT and MRI scans showed multiple space-occupying intracerebral tumors, thought to be multiple meningeoma. The patient was referred to the neurosurgical department, where two of the intracerebral tumors were excised. The histological examination revealed metastases of a neurosarcoma.

Is stereotactic biopsy a reliable method to differentiate tumor from radiation necrosis?

We report a case of a 37-year-old female who suffered from seizures and underwent external beam radiotherapy due to a suspected low-grade astrocytoma in the left hemisphere. After 7 years free of seizures under antiepileptic treatment and no signs of change in the yearly performed control MRI, she developed a progressive right-sided hemiparesis. MRI now showed an enhancing lesion with space occupying perifocal edema in the entire left hemisphere. Stereotactic biopsy revealed only inflammation. Due to further progress of the neurological deficit an open biopsy was performed. Histological examination revealed a middle-graded astrocytoma and a radiation necrosis. This case demonstrates that radiation necrosis and tumor recurrence may develop concurrently and that it may be difficult to distinguish them by clinical or radiological methods.