Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.

BACKGROUND: Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

[FEES in the stroke unit: recommendations for implementation in the clinical routine]. / FEES auf der Stroke-Unit : Empfehlungen zur Umsetzung im klinischen Alltag.

Dysphagia occurs in about 50 % of patients with acute stroke, is strongly related to early complications, such as aspiration pneumonia and is a major cause of increased morbidity and mortality in acute stroke. Flexible endoscopic evaluation of swallowing (FEES) has proven to be an easy to use, non-invasive tool for assessment of dysphagia in acute stroke, significantly adding accuracy to the clinical evaluation of dysphagia. With respect to the growing use of FEES in German stroke units this article summarizes recommendations for implementation and execution.A 3-step process is recommended to acquire the relevant knowledge and skills for carrying out FEES. After a systematic training (first step), swallowing endoscopy should be done under close supervision (second step) which is then followed by independent practice coupled with indirect supervision (third step). In principle, FEES should adopt a team approach involving both neurologists and speech language pathologists (SLP) or alternatively speech therapists. The allocation of responsibilities between these two professions should be kept flexible and should be adjusted to the individual level of education. Reducing the role of the SLP to mere assistance work in particular should be avoided. To enhance interprofessional communication and to allow for a smooth and efficient workflow, endoscopic grading of stroke-related dysphagia should adopt a standardized score that also includes protective and rehabilitative measures as well as nutritional recommendations. A major task for the future is to develop an educational curriculum for FEES that takes the specific needs of stroke unit care into account and is applicable to both physicians and SLPs.

[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.

Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice.

Monocyte chemoattractant protein 1 (MCP-1) plays an important role in inflammatory reactions following cerebral ischemia. It is known that MCP-1 overexpression leads to increased infarct volume and elevated hematogenous cell recruitment, while MCP-1-deficient mice develop smaller infarcts. It was supposed that MCP-1 dependent macrophage recruitment might be the underlying mechanism of ischemic brain damage but a precise distinction of local microglia and invading macrophages was not performed. In this study we investigated the differential role of MCP-1 on inflammatory cells in MCP-1-deficient mice, using green fluorescent protein (GFP) transgenic bone marrow chimeras. After 30-min of focal cerebral ischemia microglia was rapidly activated and was not different between MCP-1-deficient mice and wild type controls. Activated microglia outnumbered GFP-positive macrophages over the study period. Furthermore, macrophage infiltration was significantly reduced at day 7 in MCP-1-deficient animals (31.2+/-20.1 cells/mm(2)) compared to MCP-1 wild type mice (131.5+/-66.7 cells/mm(2), P<0.001). Neutrophils were also significantly reduced in MCP-1-deficient mice (62% on day 4% and 87% on day 7; P<0.001). This is the first investigation in cerebral ischemia showing that MCP-1 is necessary for recruiting blood-borne cells to the injury site whereas it does not affect the microglia activation and migration. However, the remarkable predominance of activated microglia and the additional attenuation of invading macrophages suggest that different mechanisms than macrophage recruitment are responsible for the MCP-1-mediated neuroprotective effects after experimental stroke.

[Acute polyneuritis and polyradiculoneuritis: uncommon causes and their pathomechanisms]. / Akute Polyneuritiden und Polyradikuloneuritiden: Ungewöhnliche Ursachen und deren Pathomechanismen.

Although the total incidence rate of acute inflammatory polyneuropathies is low, it is the most frequent cause of acute progressive, generalized paresis in developed countries (> 50 %). The most common form of the disease is the Guillain-Barré syndrome (GBS). Even though the clinical and pathologic spectrum of GBS has substantially grown over the last decade, about 15 % of cases of acute polyneuritis or polyradiculoneuritis do not fulfil the revised and extended diagnostic criteria and classification for GBS and its variants. The underlying pathogenesis still remains unclear. It is assumed that these "untypical" acute inflammatory polyneuropathies and cases fulfilling the GBS criteria are variants of the same underlying immune disorder, but that pathogenetic mechanisms produce different acute neurological syndromes. Thus, immunotherapy (which is not GBS-specific) is also effective for treating acute inflammatory polyneuropathies that do not fulfil the diagnostic criteria for GBS, and early diagnosis and treatment of these cases is essential. Since no reliable serological and electrodiagnostic markers of autoimmune neuropathies are currently available, the diagnosis is based on its clinical presentation. However, clinical symptoms are variable, and a rational diagnostic decision can be challenging. Thus, it is important to know that acute inflammatory polyneuropathies not fulfilling the diagnostic criteria of GBS are less often preceded by an infective condition but frequently associated with uncommon causes and triggers. This report presents our experiences with uncommon variants of inflammatory polyneuropathies and polyradiculoneuritides that do not fulfil the international diagnostic criteria for GBS. We provide a detailed review of the pertinent literature discussing possible pathomechanisms, its clinical associations and possible dispositions.

Old friends in new constellations--the hematopoetic growth factors G-CSF, GM-CSF, and EPO for the treatment of neurological diseases.

Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.

Assessment of aspiration risk in acute ischaemic stroke--evaluation of the simple swallowing provocation test.

BACKGROUND: Aspiration is a common complication in acute stroke patients and is strongly associated with a poor outcome. Due to an insufficient sensitivity and specificity of clinical bedside tests, further refinements are needed to improve the accuracy of clinical aspiration screening in acute stroke. OBJECTIVE: To assess the ability of the simple 2-step swallowing provocation test (SPT) to detect aspiration risk in acute stroke patients. METHODS: 100 consecutive patients with first-ever stroke were examined by SPT and fiberoptic endoscopic evaluation of swallowing (FEES) within 72 hours of stroke onset. Using FEES as an objective instrumental technique to evaluate dysphagia, statistical measures representing the ability of SPT to detect aspiration risk were calculated. RESULTS: The incidence of endoscopically proven aspiration risk was 81%. The 1st-step SPT had a sensitivity of 74.1% and a specificity of 100%. Although the 2nd-step SPT showed the same 100% specificity, sensitivity was significantly lower. False-negative results of SPT appeared predominantly in subjects exhibiting leakage of liquids to pyriform sinus without a pronounced delay in swallow onset. CONCLUSIONS: In acute stroke patients with an impairment of the pharyngeal phase of swallowing, 1st-step SPT reliably detects aspiration risk. In patients with a sole or predominant impairment of the oral phase of swallowing and a relatively intact pharyngeal phase, SPT fails to detect aspiration risk sufficiently. In the latter group, FEES or additional clinical features more specifically indicating oral-phase pathology should be considered to accurately judge the patient's aspiration risk.

[Cerebrotendinous xanthomatosis, a treatable metabolic disorder]. / Zerebrotendinöse Xanthomatose. Eine behandelbare Stoffwechselerkrankung.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis which can be clinically diagnosed and specifically treated. It is an underdiagnosed disorder worldwide.Here,we describe two women who were diagnosed with CTX during their forties after symptoms had already developed 15 years earlier. Both patients showed gait ataxia, spastic paraparesis, polyneuropathy, bilateral premature cataracts, tendon xanthomas, and cognitive deficits. One of the patients had also chronic diarrhea. The deficiency of the mitochondrial enzyme sterol 27-hydroxylase results in a virtual absence of chenodeoxycholic acid. This leads to excessive production of cholestanol and cholesterol and accumulation of these sterols in many tissues, especially the eye lens, central nervous system,and tendons. The determination of a high cholestanol serum level allows the diagnosis,which can be confirmed through genetic analysis. Early diagnosis of CTX is important, since an effective therapy is available. Long-term therapy with chenodeoxycholic acid is effective for CTX, mainly in prevention of further deterioration.

Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia.

BACKGROUND AND PURPOSE: Pretreatment with intraventricular brain-derived neurotrophic factor (BDNF) reduces ischemic damage after focal cerebral ischemia. In this experiment we studied the effect of intravenous BDNF delivered after focal cerebral ischemia on neurological outcome, infarct size, and expression of proapoptotic and antiapoptotic proteins Bax and Bcl-2, respectively. METHODS: With the use of the suture occlusion technique, the right middle cerebral artery in rats was temporarily occluded for 2 hours. Thirty minutes after vessel occlusion, BDNF (300 microg/kg per hour in vehicle; n=12) or vehicle alone (n=13) was continuously infused intravenously for 3 hours. After 24 hours the animals were weighed and neurologically assessed on a 5-point scale. The animals were then killed, and brains underwent either 2,3,5-triphenyltetrazolium chloride staining for assessment of infarct volume or paraffin embedding for morphology and immunohistochemistry (Bax, Bcl-2). RESULTS: Physiological parameters (mean arterial blood pressure, PO(2), PCO(2), pH, body temperature, glucose) and weight revealed no difference between groups. Neurological deficit was improved in BDNF-treated animals versus controls (P:<0.05, unpaired, 2-tailed t test). Mean+/-SD infarct volume was 229.7+/-97.7 mm(3) in controls and 121.3+/-80.2 mm(3) in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test). Cortical infarct volume was 155.5+/-78.5 mm(3) in the placebo group and 69.9+/-50.2 mm(3) in the BDNF-treated group (P:<0.05, unpaired, 2-tailed t test). Subcortical infarct volume was 74.1+/-30.6 mm(3) in the placebo group and 51.1+/-26.8 mm(3) in the BDNF-treated group (P:=NS). Bax-positive neurons were significantly reduced in the ischemic penumbra in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test), whereas Bcl-2-positive neurons were significantly increased in this area (P:<0.001, unpaired, 2-tailed t test). CONCLUSIONS: This study demonstrates a neuroprotective effect of BDNF when delivered intravenously after onset of focal cerebral ischemia. As shown here, one possible mechanism of action of neuroprotection of BDNF after focal ischemia appears to be counterregulation of Bax/Bcl-2 proteins within the ischemic penumbra.

Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats.

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 micrograms/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls (P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 +/- 27.1 mm3 in BDNF-treated animals and 139.2 +/- 56.4 mm3 in controls (mean +/- SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 +/- 7.1 mm3 in BDNF-treated animals and 37.9 +/- 19.8 mm3 in controls (mean +/- SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

Decompressive craniectomy in a rat model of "malignant" cerebral hemispheric stroke: experimental support for an aggressive therapeutic approach.

Acute ischemia in the complete territory of the carotid artery may lead to massive cerebral edema with raised intracranial pressure and progression to coma and death due to uncal, cingulate, or tonsillar herniation. Although clinical data suggest that patients benefit from undergoing decompressive surgery for acute ischemia, little data about the effect of this procedure on experimental ischemia are available. In this article the authors present results of an experimental study on the effects of decompressive craniectomy performed at various time points after endovascular middle cerebral artery (MCA) occlusion in rats. Focal cerebral ischemia was induced in 68 rats using an endovascular occlusion technique focused on the MCA. Decompressive craniectomy was performed in 48 animals (in groups of 12 rats each) 4, 12, 24, or 36 hours after vessel occlusion. Twenty animals (control group) were not treated by decompressive craniectomy. The authors used the infarct volume and neurological performance at Day 7 as study endpoints. Although the mortality rate in the untreated group was 35%, none of the animals treated by decompressive craniectomy died (mortality 0%). Neurological behavior was significantly better in all animals treated by decompressive craniectomy, regardless of whether they were treated early or late. Neurological behavior and infarction size were significantly better in animals treated very early by decompressive craniectomy (4 hours) after endovascular MCA occlusion (p < 0.01); surgery performed at later time points did not significantly reduce infarction size. The results suggest that use of decompressive craniectomy in treating cerebral ischemia reduces mortality and significantly improves outcome. If performed early after vessel occlusion, it also significantly reduces infarction size. By performing decompressive craniectomy neurosurgeons will play a major role in the management of stroke patients.