[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.

Structural gray and white matter changes in patients with HIV.

In this cross-sectional study we used magnetic resonance imaging (MRI)-based voxel based morphometry (VBM) in a sample of HIV positive patients to detect structural gray and white matter changes. Forty-eight HIV positive subjects with (n = 28) or without (n = 20) cognitive deficits (mean age 48.5 ± 9.6 years) and 48 age- and sex-matched HIV negative controls underwent MRI for VBM analyses. Clinical testing in HIV patients included the HIV dementia scale (HDS), Unified Parkinson's Disease Rating Scale (UPDRS) and the grooved pegboard test. Comparing controls with HIV positive patients with cognitive dysfunction (n = 28) VBM showed gray matter decrease in the anterior cingulate and temporal cortices along with white matter reduction in the midbrain region. These changes were more prominent with increasing cognitive decline, when assigning HIV patients to three cognitive groups (not impaired, mildly impaired, overtly impaired) based on performance in the HIV dementia scale. Regression analysis including all HIV positive patients with available data revealed that prefrontal gray matter atrophy in HIV was associated with longer disease duration (n = 48), while motor dysfunction (n = 48) was associated with basal ganglia gray matter atrophy. Lower CD4 cell count (n = 47) correlated with decrease of occipital gray matter. Our results provide evidence for atrophy of nigro-striatal and fronto-striatal circuits in HIV. This pattern of atrophy is consistent with motor dysfunction and dysexecutive syndrome found in HIV patients with HIV-associated neurocognitive disorder.

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.

The human cerebellum contributes to motor, emotional and cognitive associative learning. A review.

In this review results of human lesion studies are compared examining associative learning in the motor, emotional and cognitive domain. Motor and emotional learning were assessed using classical eyeblink and fear conditioning. Cerebellar patients were significantly impaired in acquisition of conditioned eyeblink and fear-related autonomic and skeletal responses. An additional finding was disordered timing of conditioned eyeblink responses. Cognitive learning was examined using stimulus-stimulus-response paradigms, with an experimental set-up closely related to classical conditioning paradigms. Cerebellar patients were impaired in the association of two visual stimuli, which could not be related to motor performance deficits. Human lesion and functional brain imaging studies in healthy subjects are in accordance with a functional compartmentalization of the cerebellum for different forms of associative learning. The medial zone appears to contribute to fear conditioning and the intermediate zone to eyeblink conditioning. The posterolateral hemispheres (that is lateral cerebellum) appear to be of additional importance in fear conditioning in humans. Future studies need to examine the reasonable assumption that the posterolateral cerebellum contributes also to higher cognitive forms of associative learning. Human cerebellar lesion studies provide evidence that the cerebellum is involved in motor, emotional and cognitive associative learning. Because of its simple and homogeneous micro-circuitry a common computation may underly cerebellar involvement in these different forms of associative learning. The overall task of the cerebellum may be the ability to provide correct predictions about the relationship between sensory stimuli.

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.

Gray matter changes related to chronic posttraumatic headache.

BACKGROUND: Although up to 15% of patients with whiplash injury develop chronic headache, the basis and mechanisms of this posttraumatic headache are not well understood. METHODS: Thirty-two patients with posttraumatic headache following whiplash injury were investigated within 14 days after the accident and again after 3 months using magnetic resonance-based voxel-based morphometry. Twelve patients developed chronic headache lasting longer than 3 months and were studied a third time after 1 year. RESULTS: Patients who developed chronic headache revealed decreases in gray matter in the anterior cingulate and dorsolateral prefrontal cortex after 3 months. These changes resolved after 1 year, in parallel to the cessation of headache. The same patients who developed chronic headache showed an increase of gray matter in antinociceptive brainstem centers, thalamus, and cerebellum 1 year after the accident. CONCLUSION: We demonstrate adaptive gray matter changes of pain processing structures in patients with chronic posttraumatic headache in regard to neuronal plasticity, thus providing a biologically plausible basis for this common, disabling problem.

Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound.

BACKGROUND: Flupirtine is a nonopioid drug without antipyretic or antiphlogistic properties and with a favorable tolerability. It constitutes a unique class within the group of nonsteroidal analgesics and displays a peculiar pharmacodynamic profile that invites the investigation of applications beyond the pain-relieving effect. OBJECTIVE: This review describes and evaluates the pharmacologic and clinical literature regarding flupirtine and discusses its future potential. METHODS: A search of the primary literature and conference abstracts was conducted using the keyword 'flupirtine'. Resulting articles were compiled and analyzed for this review. RESULTS/CONCLUSIONS: Although flupirtine has gained a firm place in the treatment of acute and chronic pain in various clinical settings since its introduction, a broader range of applications remains to be explored in clinical trials. Possible neuroprotective effects due to N-methyl-d-aspartate antagonistic properties of flupirtine might be promising in the treatment of Creutzfeld-Jakob disease, Alzheimer's disease, and multiple sclerosis. Trials in these fields are forthcoming.

Substantia nigra hyperechogenicity and CSF dopamine depletion in HIV.

Dopaminergic dysfunction is thought to play a pivotal role in human immunodeficiency virus (HIV)-related dementia. Decreased dopamine (DA) levels in the cerebrospinal fluid (CSF) and neuronal loss in the substantia nigra (SN) have been reported in HIV-infected patients, suggesting nigrostriatal damage. Structural changes detectable as hyperechogenicity in transcranial ultrasound (TCS) scans of the SN have been reported in patients with Parkinson's disease (PD) and other neurological conditions. In this study, we assessed the echomorphology of the SN in 40 HIV-positive patients compared to 40 age- and sex-matched healthy controls and correlated these findings with CSF levels of DA and the metabolites homovanillic acid (HVA) and 3,4-dihydroxy phenylacetic acid (DOPAC) and with neuropsychologic performance. We observed that the SN of HIV-infected patients was hyperechogenic relative to that of controls (0.07 +/- 0.05 vs. 0.04 +/- 0.07 cm(2); mean +/- SEM; P < 0.001) and that this SN hyperechogenicity was correlated with decreased DA levels in the CSF, decreased CD4 cell count, and an impaired performance in the psychopathology assessment scale (AMDP) subtest for drive and psychomobility. An association to CDC stage, duration of HIV infection, or presence of HIV dementia was not observed. Our results indicate changes in the nigrostriatal system in HIV-infected patients that are detectable as hyperechogenic SN precede prominent extrapyramidal symptoms and cognitive dysfunction.

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.

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.

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.

Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist in some cases. The mechanisms associated with the development of this chronic pain are not well understood. OBJECTIVE: To determine trigeminal nociceptive fiber impairment in patients with TN comparing symptomatic and nonsymptomatic sides using the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) and to identify possible central mechanisms of pain chronicity. METHODS: We investigated 24 patients with TN without and 18 patients with TN with concomitant chronic facial pain. PREP and nBR were investigated following nociception specific electrical stimulation on both sides of the face and in each division of the trigeminal nerve (V1, V2, and V3). RESULTS: We found prolonged PREP and nBR latencies and reduced amplitudes comparing symptomatic and nonsymptomatic sides in all patients with TN. In patients with chronic facial pain, however, PREP amplitudes were larger and latencies shorter compared to patients with TN without facial pain, while nBR results were similar across groups. CONCLUSION: The data suggest an impairment of the trigeminal nociceptive system due to demyelination and/or axonal dysfunction on the symptomatic side and locate this defect close to the root entry zone in the brainstem. Moreover, central facilitation of trigeminal nociceptive processing was observed in patients with trigeminal neuralgia with concomitant chronic facial pain indicating overactivation of central sensory transmission. This may represent a possible adaptive mechanism for the development of chronic pain.

Prevalence of trigeminal autonomic symptoms in migraine: a population-based study.

Epidemiological data on trigeminal unilateral autonomic symptoms in patients with migraine are scarce. The authors wanted to provide a population-based evaluation of the prevalence of unilateral autonomic features in migraine patients and an assessment of the expression of unilaterality of autonomic symptoms and head pain in patients with UAs compared to other migraine patients. A population based sample of 6000 inhabitants of the city of Essen in Germany was screened using a previously validated standard questionnaire. Three thousand three hundred and sixty subjects (56% of a total 6000) responded. 841 subjects had migraine, out of which 226 reported accompanying unilatral auetonomic symptoms (26.9%, CI 95% [23.9-30%]). Unilateral autonomic symptoms in patients with migraine are common and have been widely underestimated in the past. One out of four migraine patients regularly experiences one or more unilateral autonomic symptoms during their attack. Migraine patients with accompanying autonomic symptoms seem to experience their pain more unilateral and more severe than non-UA patients.

Intravenous thrombolysis in German stroke units before and after regulatory approval of recombinant tissue plasminogen activator.

BACKGROUND: Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) within 3 h after onset of focal cerebral ischemia was approved in Germany in August 2000. METHODS: 11 neurology departments with acute stroke units participated in the German Stroke Study Collaboration before (n = 2,925) and after (n = 3,204) approval of rt-PA in Germany and consecutively registered all patients admitted within 24 h following acute ischemic stroke. RESULTS: Frequency of intravenous thrombolysis in patients admitted within 24 h after symptom onset increased from 4.8% before approval to 7.9% after approval of rt-PA. Among patients treated with rtPA, age increased significantly and the delay between symptom onset and imaging was significantly shorter in the second study period. CONCLUSIONS: The observed improvement in management and quantity of intravenous thrombolysis may be explained by greater experience and greater legal security following regulatory approval of rtPA.

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.