Autoantibody status, neuroradiological and clinical findings in children with acute cerebellitis.

BACKGROUND: Acute cerebellitis (AC) in children and adolescents is an inflammatory disease of the cerebellum due to viral or bacterial infections but also autoimmune-mediated processes. OBJECTIVE: To investigate the frequency of autoantibodies in serum and CSF as well as the neuroradiological features in children with AC. MATERIAL AND METHODS: Children presenting with symptoms suggestive of AC defined as acute/subacute onset of cerebellar symptoms and MRI evidence of cerebellar inflammation or additional CSF pleocytosis, positive oligoclonal bands (OCBs), and/or presence of autoantibodies in case of negative cerebellar MRI. Children fulfilling the above-mentioned criteria and a complete data set including clinical presentation, CSF studies, testing for neuronal/cerebellar and MOG antibodies as well as MRI scans performed at disease onset were eligible for this retrospective multicenter study. RESULTS: 36 patients fulfilled the inclusion criteria for AC (f:m = 14:22, median age 5.5 years). Ataxia was the most common cerebellar symptom present in 30/36 (83 %) in addition to dysmetria (15/36) or dysarthria (13/36). A substantial number of children (21/36) also had signs of encephalitis such as somnolence or seizures. In 10/36 (28 %) children the following autoantibodies (abs) were found: MOG-abs (n = 5) in serum, GFAPα-abs (n = 1) in CSF, GlyR-abs (n = 1) in CSF, mGluR1-abs (n = 1) in CSF and serum. In two further children, antibodies were detected only in serum (GlyR-abs, n = 1; GFAPα-abs, n = 1). MRI signal alterations in cerebellum were found in 30/36 children (83 %). Additional supra- and/or infratentorial lesions were present in 12/36 children, including all five children with MOG-abs. Outcome after a median follow-up of 3 months (range: 1 a 75) was favorable with an mRS ≤2 in 24/36 (67 %) after therapy. Antibody (ab)-positive children were significantly more likely to have a better outcome than ab-negative children (p = .022). CONCLUSION: In nearly 30 % of children in our study with AC, a range of abs was found, underscoring that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected AC. The detection of MOG-abs in AC does expand the MOGAD spectrum.

S1 guidelines "lumbar puncture and cerebrospinal fluid analysis" (abridged and translated version).

INTRODUCTION: Cerebrospinal fluid (CSF) analysis is important for detecting inflammation of the nervous system and the meninges, bleeding in the area of the subarachnoid space that may not be visualized by imaging, and the spread of malignant diseases to the CSF space. In the diagnosis and differential diagnosis of neurodegenerative diseases, the importance of CSF analysis is increasing. Measuring the opening pressure of CSF in idiopathic intracranial hypertension and at spinal tap in normal pressure hydrocephalus constitute diagnostic examination procedures with therapeutic benefits.Recommendations (most important 3-5 recommendations on a glimpse): The indications and contraindications must be checked before lumbar puncture (LP) is performed, and sampling CSF requires the consent of the patient.Puncture with an atraumatic needle is associated with a lower incidence of postpuncture discomfort. The frequency of postpuncture syndrome correlates inversely with age and body mass index, and it is more common in women and patients with a history of headache. The sharp needle is preferably used in older or obese patients, also in punctures expected to be difficult.In order to avoid repeating LP, a sufficient quantity of CSF (at least 10 ml) should be collected. The CSF sample and the serum sample taken at the same time should be sent to a specialized laboratory immediately so that the emergency and basic CSF analysis program can be carried out within 2 h.The indication for LP in anticoagulant therapy should always be decided on an individual basis. The risk of interrupting anticoagulant therapy must be weighed against the increased bleeding risk of LP with anticoagulant therapy.As a quality assurance measure in CSF analysis, it is recommended that all cytological, clinical-chemical, and microbiological findings are combined in an integrated summary report and evaluated by an expert in CSF analysis. CONCLUSIONS: In view of the importance and developments in CSF analysis, the S1 guideline "Lumbar puncture and cerebrospinal fluid analysis" was recently prepared by the German Society for CSF analysis and clinical neurochemistry (DGLN) and published in German in accordance with the guidelines of the AWMF (https://www.awmf.org). /uploads/tx_szleitlinien/030-141l_S1_Lumbalpunktion_und_Liquordiagnostik_2019-08.pdf). The present article is an abridged translation of the above cited guideline. The guideline has been jointly edited by the DGLN and DGN.

Identification of the flotillin-1/2 heterocomplex as a target of autoantibodies in bona fide multiple sclerosis.

BACKGROUND: Autoantibodies, in particular those against aquaporin-4 and myelin-oligodendrocyte glycoprotein (MOG), aid as biomarkers in the differential diagnosis of demyelination. Here, we report on discovery of autoantibodies against flotillin in patients with multiple sclerosis (MS). METHODS: The target antigen was identified by histo-immunoprecipitation using the patients' sera and cryosections of rat or pig cerebellum combined with mass spectrometrical analysis. Correct identification was ascertained by indirect immunofluorescence and neutralization tests using the target antigens recombinantly expressed in HEK293 cells. RESULTS: Serum and CSF of the index patient produced a fine-granular IgG indirect immunofluorescence staining of the hippocampal and cerebellar molecular layers. Flotillin-1 and flotillin-2 were identified as target autoantigens. They also reacted with recombinant human flotillin-1/2 co-expressed in HEK293 cells, but not with the individual flotillins in fixed- and live-cell assays. Moreover, neutralization using flotillin-1/2, but not the single flotillins, abolished the tissue reactivity of patient serum. Screening of 521 patients, for whom anti-aquaporin-4 testing was requested and negative, revealed 8 additional patients with anti-flotillin-1/2 autoantibodies. All eight were negative for anti-MOG. Six patients ex post fulfilled the revised McDonald criteria for MS. Vice versa, screening of 538 MS sera revealed anti-flotillin-1/2 autoantibodies in eight patients. The autoantibodies were not found in a cohort of 67 patients with other neural autoantibody-associated syndromes and in 444 healthy blood donors. CONCLUSIONS: Autoantibodies against the flotillin-1/2 heterocomplex, a peripheral membrane protein that is involved in axon outgrowth and regeneration of the optic nerve, are present in 1-2% of patients with bona fide MS.

[Autoantibody-associated autoimmune encephalitis and cerebellitis : Clinical presentation, diagnostic work-up and treatment]. / Autoantikörperassoziierte autoimmune Enzephalitiden und Zerebellitiden : Klinik, Diagnostik und Therapie.

There is no other field of neurology where clinically relevant serological biomarkers have witnessed a surge in importance over the past decade resembling that in autoimmune encephalitis and cerebellitis. A multitude of newly discovered neuronal autoantibodies facilitate early diagnosis, estimation of prognosis, and therapeutic decision-making. However, this has led to growing uncertainty with regard to meaningful patient selection, the appropriate extent of testing, and management of seronegative cases. This review summarizes the essential aspects of the clinical presentation, diagnostic work-up, pathophysiology, and treatment of autoimmune encephalitis and cerebellitis.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Psychotic syndrome associated with anti-Ca/ARHGAP26 and voltage-gated potassium channel antibodies.

BACKGROUND: Antibodies to the Rho GTPase-activating protein 26 (ARHGAP26, GRAF1) (also termed anti-Ca) were first described in patients with cerebellar ataxia. However, ARHGAP26 is also expressed in some hippocampal neurons. Moreover, some of the previously reported patients showed cognitive and affective symptoms. It is unknown whether those symptoms reflected involvement of the limbic system or were part of the so-called cerebellar cognitive/affective syndrome. CASE REPORT: Here, we report a newly diagnosed anti-Ca/ARHGAP26-IgG-positive patient who presented with recurrent psychotic symptoms but no cerebellar ataxia. In addition, low-titer acetylcholine receptor antibodies, voltage-gated potassium channel complex antibodies (but no LGI1 or CASPR2 antibodies) and anti-nuclear antibodies of unknown specificity were detected, suggesting a general autoimmune predisposition. Thymectomy revealed mild thymic nodular hyperplasia. CONCLUSION: This case indicates that the clinical spectrum of ARHGAP26-related autoimmunity might be broader than expected. Studies on the prevalence of anti-Ca/ARHGAP26 in patients with suspected limbic encephalitis seem warranted.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity.

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab(-)). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50 %) had LGI1-Abs, three (16 %) had CASPR-2-Abs; and six (33 %) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab(+) patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26 months), thirteen (72 %) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab(+) patients, but in none of the CASPR-2-Ab(+) or LGI/CASPR-2-Ab(-) patients (p = 0.003). While all subgroups improved, memory scores only normalized in six patients (33 %) and LGI1-Ab(+) patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab(+)-LE.

Paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes are immune-mediated erroneous attacks on the central or peripheral nervous systems, or both, directed originally against the tumour itself. They have been known for more than 40 years, but recently the discovery of new subgroups of paraneoplastic encephalitis syndromes with a remarkably good response to immune therapy has ignited new clinical and scientific interest. Knowledge of these subgroups and their associated autoantibodies is important in therapeutic decision-making. However, the abundance of new autoantibodies and syndromes can be confusing. This review paper summarizes current knowledge and new developments in the field of paraneoplastic neurological syndromes, their classification, pathophysiology and treatment.

Seroprevalence and specificity of NMO-IgG (anti-aquaporin 4 antibodies) in patients with neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric manifestations are present in 30-40% of patients with systemic lupus erythematosus (SLE). Recently, antibodies to aquaporin-4 (termed AQP4-Ab, or NMO-IgG), a water channel protein, were reported to be present in a subset of patients with SLE and neurological involvement. To evaluate the syndrome specificity and prevalence of serum NMO-IgG/anti-AQP4 antibodies in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Sera of 76 patients with SLE and neurological symptoms, 50 of whom met the ACR case definitions of NPSLE, were tested for AQP4-Ab in an indirect immunofluorescence assay employing HEK293 cells transfected with recombinant human AQP4. Only one of the examined sera was positive for NMO-IgG/AQP4-Ab. This patient suffered from TM, ranging over two vertebral segments on spinal MRI. None of the 75 NPSLE without TM was found to be seropositive for NMO-IgG/AQP4-Ab. NMO-IgG/AQP4-Ab in NPSLE were present only in a patient with TM and were not detectable in NPSLE patients with other neurological manifestations. Testing for NMO-IgG/AQP4-Ab positivity should be considered in patients presenting with SLE and TM. Non-longitudinally extensive lesions do no not exclude NMO-IgG/AQP4-Ab in patients presenting with SLE and TM.

IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment.

OBJECTIVE: To report that antibodies to synaptic proteins may occur in association with slow, progressive cognitive decline. METHODS: A total of 24 patients with progressive cognitive dysfunction of unclear etiology were examined for onconeuronal and synaptic receptor antibodies. The effect of serum was examined in cultures of dissociated mouse hippocampal neurons. RESULTS: Seven patients had immunoglobulin A (IgA), but no immunoglobulin G (IgG), antibodies against NMDA receptor (NMDAR). Anti-NMDAR IgA positive patients' serum, but not serum from control individuals, caused dramatic decrease of the levels of NMDAR and other synaptic proteins in neurons, along with prominent changes in NMDAR-mediated currents. These effects correlated with the titer of IgA NMDAR antibodies and were reversed after removing patients' serum from the culture media. When available, comprehensive clinical assessment and brain metabolic imaging showed neurologic improvement after immunotherapy. CONCLUSIONS: A subset of patients with slowly progressive cognitive impairment has an underlying synaptic autoimmunity that decreases the density of NMDAR and other synaptic proteins, and alters synaptic currents. This autoimmunity can be demonstrated examining patients' serum and CSF for NMDAR IgA antibodies, identifying possible candidates for immunotherapy.

Immune monitoring of Trichuris suis egg therapy in multiple sclerosis patients.

Initial clinical trials using Trichuris suis eggs (TSO) in autoimmune diseases such as inflammatory bowel disease, revealed a striking suppressive effect on the autoimmune response. Here, we analysed the effect of TSO therapy on the course of multiple sclerosis (MS), as a Th1/Th17-associated autoimmune disease. Different immunological parameters in four patients with secondary progressive MS were surveyed during a 6-month therapy with TSO, focusing on the modulation of T-cell Th1-Th2 balance as well as on the innate immune response. We are able to show a slight downregulation of the Th1-associated cytokine pattern, especially relevant in interleukin (IL)-2 (P < 0.05 after 2 months of therapy), with a temporary increase of Th2-associated cytokines such as IL-4. Furthermore, mild eosinophily and changes in CD4+ and CD8+T cells and natural killer (NK) CD56 bright cell numbers were observed. The findings observed in this group of patients suggest that TSO therapy has a moderate immunomodulatory impact in MS.

Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.

BACKGROUND: Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly non-Caucasians. OBJECTIVE: To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature. METHOD: Retrospective study. RESULTS: In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors' own files (n = 10) and the previous literature (n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3-32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients. CONCLUSION: Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.

Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature.

Neuromyelitis optica (NMO) is associated with antibodies to aquaporin-4 (termed NMO-IgG or AQP4-Ab) in 60-90% of cases. Little is known about the aetiology of NMO in NMO-IgG/AQP4-Ab negative patients. Here we report on CV2/CRMP5 antibodies in a 69-year-old male patient with NMO-IgG/AQP4-Ab negative NMO. The association of CV2/CRMP5-Ab with prostate cancer suggests a paraneoplastic aetiology of NMO in our patient. Our report strengthens the case of antibodies other than AQP4-Ab being involved in the immunopathogenesis in a subset of patients with NMO. We conclude that CV2/CRMP5-Ab should be included in the differential diagnosis of NMO, in particular if AQP4-Ab are negative and irrespective of whether a tumour is known or not. We recommend that recombinant tests, which are increasingly used because of their higher sensitivity and specificity, should always be accompanied by standard indirect immunofluorescence employing brain tissue sections in order to avoid CV2/CRMP5-Ab or other paraneoplastic antibodies being overlooked. In addition, we provide a comprehensive review of all patients with CV2/CRMP5-Ab and NMO-like disease published in the English literature so far.

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.

[Susac syndrome: an interdisciplinary challenge]. / Susac-Syndrom : Eine interdisziplinäre Herausforderung.

Susac syndrome, named after John Susac, the first to describe this condition, is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. Although certainly a rare disease, Susac syndrome needs to be considered in the differential diagnosis of a broad variety of diseases. The pathogenesis is not yet clear. Autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI. Usually, immunosuppressive therapy is required, though controlled therapy trials are missing so far. The intention of this review article is to raise awareness of this disease among neurologists, psychiatrists, ophthalmologists, and ENT specialists as a high number of unreported cases probably exists. Accordingly, the focus is on the clinical presentation and the diagnostic approach.

Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin.

BACKGROUND: Anti-NMDA-receptor (NMDAR) encephalitis is a severe disorder that occurs in association with antibodies to the NR1 subunit of the NMDAR and results in a characteristic syndrome. OBJECTIVE: To determine in a single institution setting whether patients previously diagnosed with encephalitis of unknown origin had anti-NMDAR encephalitis. METHODS: Charts of 505 patients aged 18 to 35 years admitted to the intensive care unit (ICU) during a 5-year period were retrospectively reviewed for criteria of encephalitis of unknown etiology. These included encephalitic signs with psychiatric symptoms (agitation, paranoid thoughts, irritability, or hallucinations); seizures; CSF inflammation; and exclusion of viral or bacterial infection. Archived serum and CSF samples of patients fulfilling these criteria were examined for NMDAR antibodies. Follow-up visits allowed the analysis of the natural disease course and estimation of prognosis. RESULTS: Seven patients (all women) fulfilled the indicated criteria; 6 of them had NMDAR antibodies. Ovarian teratomas were detected in 2 patients, in one 3 years after the onset of encephalitis. Outcome was favorable in all patients. One patient without teratoma improved spontaneously along with disappearance of NMDAR antibodies. CONCLUSIONS: Anti-NMDAR encephalitis represented 1% of all young patients' admissions to the ICU. Six of 7 cases with the indicated clinical criteria had anti-NMDAR encephalitis. NMDAR antibodies should be tested in all patients with encephalitis who fulfill these criteria.