Sebastian Rauer

Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures.

BACKGROUND Neuromyelitis optica (NMO, Devic disease) is a severely disabling autoimmune disorder of the CNS, which was considered a subtype of multiple sclerosis (MS) for many decades. Recently, however, highly specific serum autoantibodies (termed NMO-IgG or AQP4-Ab) have been discovered in a subset (60-80%) of patients with NMO. These antibodies were subsequently shown to be directly involved in the pathogenesis of the condition. AQP4-Ab positive NMO is now considered an immunopathogenetically distinct disease in its own right. However, to date little is known about the cerebrospinal fluid (CSF) in AQP4-Ab positive NMO. OBJECTIVE To describe systematically the CSF profile of AQP4-Ab positive patients with NMO or its formes frustes, longitudinally extensive myelitis and optic neuritis. MATERIAL AND METHODS Cytological and protein biochemical results from 211 lumbar punctures in 89 AQP4-Ab positive patients of mostly Caucasian origin with neuromyelitis optica spectrum disorders (NMOSD) were analysed retrospectively. RESULTS CSF-restricted oligoclonal IgG bands, a hallmark of MS, were absent in most patients. If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, transient, and, importantly, restricted to acute relapses. CSF pleocytosis was present in around 50% of samples, was mainly mild (median, 19 cells/μl; range 6-380), and frequently included neutrophils, eosinophils, activated lymphocytes, and/or plasma cells. Albumin CSF/serum ratios, total protein and CSF L-lactate levels correlated significantly with disease activity as well as with the length of the spinal cord lesions in patients with acute myelitis. CSF findings differed significantly between patients with acute myelitis and patients with acute optic neuritis at the time of LP. Pleocytosis and blood CSF barrier dysfunction were also present during remission in some patients, possibly indicating sustained subclinical disease activity. CONCLUSION AQP4-Ab positive NMOSD is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and NMOSD and add to our understanding of the immunopathogenesis of this devastating condition.

Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force

A great variety of neurological diseases require investigation of cerebrospinal fluid (CSF) to prove the diagnosis or to rule out relevant differential diagnoses. The objectives were to evaluate the theoretical background and provide guidelines for clinical use in routine CSF analysis including total protein, albumin, immunoglobulins, glucose, lactate, cell count, cytological staining, and investigation of infectious CSF. The methods included a Systematic Medline search for the above‐mentioned variables and review of appropriate publications by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. It is recommended that CSF should be analysed immediately after collection. If storage is needed 12 ml of CSF should be partitioned into three to four sterile tubes. Albumin CSF/serum ratio (Qalb) should be preferred to total protein measurement and normal upper limits should be related to patients’ age. Elevated Qalb is a non‐specific finding but occurs mainly in bacterial, cryptococcal, and tuberculous meningitis, leptomingeal metastases as well as acute and chronic demyelinating polyneuropathies. Pathological decrease of the CSF/serum glucose ratio or increased lactate concentration indicates bacterial or fungal meningitis or leptomeningeal metastases. Intrathecal immunoglobulin G synthesis is best demonstrated by isoelectric focusing followed by specific staining. Cellular morphology (cytological staining) should be evaluated whenever pleocytosis is found or leptomeningeal metastases or pathological bleeding is suspected. Computed tomography‐negative intrathecal bleeding should be investigated by bilirubin detection.

Polyspecific, antiviral immune response distinguishes multiple sclerosis and neuromyelitis optica

Background: A polyspecific, intrathecal humoral immune response against neurotropic viruses such as measles, rubella and varicella zoster virus (MRZ reaction, MRZR) is present in 80–100% of patients with multiple sclerosis (MS), but has not to date been evaluated in patients with neuromyelitis optica (NMO). Aims: To evaluate whether MRZR distinguishes NMO and MS. Methods: 20 patients with NMO and 42 with MS were included. The intrathecal synthesis of antibodies against measles, rubella and varicella zoster virus was detected by calculation of the respective antibody indices (AI). Results: A positive MRZ reaction, as defined by a combination of at least two positive AIs, was found in 37/42 MS, but in only 1/20 NMO patients (p<0.0001). Median AI values differed significantly between the groups (p<0.0005). Conclusions: The polyspecific antiviral humoral immune response characteristic for MS is widely missing in NMO, irrespective of the NMO-IgG status of the patients. Our findings further strengthen the case for NMO being pathologically distinct from MS.

1H MR spectroscopy of inflammation, infection and ischemia of the brain

Different pathologic patterns in multiple sclerosis (MS) are reflected by alterations of metabolites in (1)H MR spectroscopy of the brain. Elevated choline (Cho), lactate (Lac), lipids and macromolecules are reliable markers for acute demyelination regardless of the clinical entity (also in acute disseminated encephalomyelitis). N-acetyl-aspartate (NAA) is a suitable marker for neuronal integrity. It is reduced in acute MS lesions and in normal appearing white matter, even distant to acute and chronic-lesions. Recovery from reduced NAA levels to subnormal values during remyelination, and varying time courses of NAA in normal appearing white matter during relapsing remitting disease indicate the value of this spectroscopic marker for monitoring activity and recovery. Inositol (Ins) is increased in chronic MS lesions being a marker for astrocytic gliosis. In viral disease, Cho and Ins are always increased, whereas a reduction of NAA mostly reflects an advanced or a detoriated clinical state. In bacterial brain abscesses, numerous amino acids, lipids and Lac can be elevated. In ischemia, especially the Lac/NAA in comparison with perfusion and diffusion weighted imaging seems to be a new measure for areas of metabolic need, and may help to better characterise the penumbra of the stroke and the final infarct size.

Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types

In parallel to the detection of new neuronal autoantibodies, the diagnosis of non-infectious limbic encephalitis has risen. Given that cerebral imaging studies show highly variable results, the present retrospective study investigates imaging findings in association with autoantibody type. An institutional database search identified 18 patients with non-infectious limbic encephalitis who had undergone [18F] fluorodeoxyglucose positron emission tomography (FDG-PET). Sixteen of these patients also underwent magnetic resonance imaging (MRI). MRI and FDG-PET images were categorized as follows: normal (0); mesiotemporal abnormality (1); normal mesiotemporal finding but otherwise abnormal (2). Neuronal autoantibodies were determined in serum and/or CSF. Autoantibodies were grouped according to the cellular localization of their target antigen: antibodies against surface antibodies (i.e., VGKC, NMDAR): 9; antibodies against intracellular antigens (i.e., Hu, Ri, GAD): 4; no autoantibodies: 5. The fraction of abnormal scans was lower for MRI (10/16) than for FDG-PET (14/18). There was a significant association between PET findings and autoantibody type: All patients with autoantibodies against intracellular antigens showed mesiotemporal findings on FDG-PET. In turn, only 2/9 patients with autoantibodies against surface antigens displayed mesiotemporal hypermetabolism. In the remaining seven patients, four scans were rated as normal and three only showed findings outside the mesiotemporal region. A similar association was found using MRI, although this did not reach statistical significance. Autoantibody type was found to be associated with FDG-PET and, to a lesser extent, with MRI imaging results. Our observations may explain the heterogeneity of imaging data in LE and based on in vivo findings support the assumption of different patho mechanisms underlying LE due to antibodies against surface and intracellular antigens, respectively.

Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod

Fingolimod, a sphingosine 1-phosphate receptor modulator, is highly effective in the treatment of multiple sclerosis (MS).[1][1],[2][2] However, fatal cases of herpes infection have occurred in 2 patients on fingolimod therapy, 1 of whom presented with a primary disseminated varicella-zoster virus (

Verlauf und Prognose der FSME

ZusammenfassungMit der Frage möglicher Folgeschäden wurden 63 Patienten, die zwischen 1990 und 1995 an einer FSME erkrankt waren, klinisch, neuropsychologisch und elektroenzephalographisch nachuntersucht (Intervall zur akuten Erkrankung: Median: 12 Monate, Spanne: 1–44 Monate). Während der akuten Erkrankungsphase lagen folgende klinische Syndrome vor: Meningitis (M, n=12), Meningoenzephalitis (Me, n=27), Meningoenzephalomyelitis (My, n=15) und Meningoenzephaloradikulitis (R, n=9). Anamnestisch bestand bei 59 Patienten nach der Entfieberung ein neurasthenisches Syndrom, welches in Ausprägung und Dauer eine Korrelation zur Schwere der akuten Erkrankung zeigte. 20 Patienten waren nach der Entlassung aus der Klinik allein aufgrund einer erheblichen subjektiven Leistungsminderung, einer vermehrten Erschöpfbarkeit und einer erhöhten emotionalen Labilität bis zu 3 Monate arbeitsunfähig. Bei der Nachuntersuchung fanden sich bei 34 Patienten (M: 1, Me: 9, My: 15, R: 9) pathologische Befunde im neurologischen Status. Persistierende Störungen der Hirnnerven äußerten sich als Hypakusis (n=7), Dysphagie und Dysarthrie (n=4). Während die Extremitätenparesen bei 8/9 Patienten mit einer Radikulitis innerhalb von wenigen Monaten bis Jahren eine fast vollständige Rückbildung zeigten, war die Besserungstendenz der Para- und Tetraparesen bei der Myelitis auch nach bis zu 3 Jahren deutlich geringer. Elektroenzephalographisch war bei 41/55 nachuntersuchten Patienten bereits nach wenigen Monaten ein Normalbefund zu erheben. Überdauernde, objektivierbare kognitive Defizite bestanden nur bei 7/11 Patienten mit schwerer Verlaufsform einer FSME.SummarySixty-three patients with tick-borne encephalitis were studied for sequelae up to 5 years after the acute illness (median: 12 months, range: 1–44 months). Patients were examined clinically, by neuropsychological testing and by electroencephalography. The clinical presentation during the acute stage was as follows: Meningitis (M, n=12), Meningoencephalitis (Me, n=27), Meningoencephalomyelitis (My, n=15), and Meningoencephaloradiculitis (R, n=9). A total of 59 patients reported a neurasthenic syndrome after discharge, which correlated with the severity of the acute illness. Twenty patients were not able to work because of reduced stress tolerance, fatigue or an elevated emotional sensitivity, which lasted for 3 months at most. In some patients hypacusis (n=7), severe dysarthria and dysphagia (n=4) remained essentially unimproved for years following the acute illness. While in 8/9 patients with radiculitis paresis of the extremities improved well over months to years, improvement was quite limited in all patients with myelitis. In 41/55 patients, investigations by electroencephalography revealed normal findings even within months after acute illness. Persistent cognitive deficits were present only in 7/11 patients with a severe course of disease.

Qualitative evidence of anti-Yo-specific intrathecal antibody synthesis in patients with paraneoplastic cerebellar degeneration

We investigated the presence of anti-Yo-specific oligoclonal antibody bands in cerebrospinal fluid (CSF) and serum samples of 9 patients with anti-Yo syndrome and 11 controls. Isoelectric focusing combined with affinity blotting, revealed anti-Yo-specific intrathecal antibody synthesis in all patients with anti-Yo syndrome: Four patients had positive anti-Yo-specific oligoclonal IgG bands in CSF which were not demonstrable in their sera; five CSF/serum pairs showed additional, more intensive, oligoclonal bands in CSF compared to the corresponding serum. Interestingly, four patients with absence of oligoclonal bands of total IgG in CSF revealed positive anti-Yo-specific oligoclonal bands in the same sample. This speaks for a higher sensitivity of detection of oligoclonal bands using an affinity blot loaded with Yo-specific antigen compared to an affinity blot coated with anti-human IgG used for the detection of oligoclonal bands of total IgG. In conclusion, the presence of anti-Yo-specific oligoclonal IgG bands in CSF which were absent, or less strong, in patients sera provides qualitative evidence of anti-Yo-specific IgG synthesis by intrathecal B-cell clones. These results could be of interest in detection of intrathecal-specific IgG synthesis in nervous system infectious diseases provided that the target antigen is known.

Demonstration of anti-HuD specific oligoclonal bands in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes Qualitative evidence of anti-HuD specific IgG-synthesis in the central nervous system

The presence of HuD-specific oligoclonal IgG bands in the CSF was investigated in five patients with paraneoplastic neurological syndromes. All patients revealed intrathecal synthesis of HuD specific antibodies in the CSF, as estimated from elevated antibody indices (>1.5) in an IgG-ELISA using recombinant HuD-protein as antigen. Isoelectrofocussing combined with affinity blotting showed reactivity of IgG bands with recombinant HuD antigen in all CSF samples. These data support the idea that HuD specific antibodies in the CSF are produced mainly by B-cell clones in the central nervous system. These findings support the hypothesis of autoimmunity in the pathogenesis of anti-Hu associated paraneoplastic neurological syndromes.

Specific antibody index in cerebrospinal fluid from patients with central and peripheral paraneoplastic neurological syndromes

We evaluated the concentration of antineuronal antibodies in paired cerebrospinal fluid (CSF) and serum samples from 19 patients with central and peripheral paraneoplastic neurological syndromes (PNS), using an enzyme linked immunosorbent assay (ELISA) employing recombinant antineuronal antigens (HuD, Yo, Ri, CV2/CRMP5, amphiphysin, PNMA2/Ma2). The specific antibody index (AI) [Qspec/QIgG] was calculated to estimate specific intrathecal antibody synthesis. An AI>1.3 was considered as evidence of intrathecal specific antibody synthesis. 14 (88%) of 16 patients with exclusive or predominant paraneoplastic involvement of the central nervous system (CNS) showed an AI>1.3, indicating a specific intrathecal antibody synthesis, while all three patients with isolated involvement of the peripheral nervous system showed an AI<0.8. All together, in 17 of 19 patients (89%) we found a significant association (p<0.05) between central or peripheral neurological manifestations on the one hand and presence or absence of specific intrathecal synthesis respectively on the other hand. These data support the hypothesis that autoimmunity is involved in the pathogenesis of PNS.