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BACKGROUND AND PURPOSE Myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) is an inflammatory autoimmune condition of the central nervous system. However, data on pain and depression have remained scarce. The aim of this study was to assess features of chronic pain and depression as well as their impact on health-related quality of life (hr-QoL) in MOGAD. METHODS Patients with MOGAD were identified in the Neuromyelitis Optica Study Group registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory-Short Form, McGill Pain Questionnaire-Short Form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items. RESULTS Twenty-two of 43 patients suffered from MOGAD-related pain (11 nociceptive, eight definite neuropathic, three possible neuropathic) and 18 from depression. Patients with neuropathic pain had the highest pain intensity and most profound activities of daily living (ADL) impairment. Fifteen patients reported spasticity-associated pain, including four with short-lasting painful tonic spasms. Later disease onset, profound physical impairment, and depression were associated with chronic pain. Physical QoL was more affected in pain sufferers (p

Background Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. Case presentation The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred. Conclusion We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.ResultsPatients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Therapy of autoimmune diseases of the central and peripheral nervous system with intravenous IgG immunoglobulin (IVIg) is well established. Since IVIg is produced from pooled human plasma, autoantibodies can be found in IVIg products and, accordingly, in patient sera after transfusion. The de novo evidence or disappearance of anti-neural autoantibodies after IVIg treatment has so far not been systematically examined. We screened 50 neurological patients before and after IVIg treatment for classical onconeural and the most common neurological surface autoantibodies as well as for ganglioside autoantibodies and 23 different antinuclear autoantibodies using immunoblot or cell-based indirect immunofluorescence assays. Furthermore, we screened 31 neurological patients with previously known seropositivity for disappearance of the corresponding antibody after treatment. After IVIg treatment, 90% of all sera were de novo positive for antinuclear antibodies, especially for Ro-52. In contrast, 94% of all sera did not show any de novo-positive anti-neural antibodies. In the remaining three cases, titers were very low. Importantly, 12.9% of all tested sera of patients with known antibody positivity turned false negative after IVIg treatment and titers were falsely low in 37% of the remaining sera. Here, we present for the first time results of a broad screening for clinically relevant autoantibodies before and after IVIg treatment in neurological patients. We identified a high specificity but reduced sensitivity for anti-neural antibody testing after IVIg transfusion. In contrast, antinuclear antibody testing is not reliable after IVIg treatment. These results are of high practical importance for diagnostic of neuroimmunological diseases.

Background and ObjectivesTo evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD).MethodsIn this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database.ResultsTwo hundred twelve patients (80% women, median age 50 [19–83] years, median disease duration 7 [0–43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0–8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225–68,293 or US dollars [USD] 70,297, 95% CI 60,445–80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65–0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45–0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946–160,336 or USD 153,031, 95% CI 120,296–189,196). The HRQoL revealed a negative correlation to disease severity (ρ = −0.69, 95% CI −0.76 to −0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13–0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL.DiscussionThese German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.

ObjectivesTo evaluate prevalence, clinical characteristics, and predictors of pain, depression, and their impact on the quality of life (QoL) in a large neuromyelitis optica spectrum disorder (NMOSD) cohort.MethodsWe included 166 patients with aquaporin-4–seropositive NMOSD from 13 tertiary referral centers. Patients received questionnaires on demographic and clinical characteristics, PainDetect, short form of Brief Pain Inventory, Beck Depression Inventory–II, and Short Form 36 Health Survey.ResultsOne hundred twenty-five (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR = 1.27, p = 0.018) and involved upper thoracic segments (OR = 1.31, p = 0.018) were the only predictive factors for chronic pain. The latter was specifically associated with spasticity-associated pain (OR = 1.36, p = 0.002). More than a third (39.8%) suffered from depression, which was moderate to severe in 51.5%. Pain severity (OR = 1.81, p < 0.001) and especially neuropathic character (OR = 3.44, p < 0.001) were associated with depression. Pain severity and walking impairment explained 53.9% of the physical QoL variability, while depression and walking impairment 39.7% of the mental QoL variability. No specific medication was given to 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain. Two-thirds (64.2%) of patients with symptomatic treatment still reported moderate to severe pain.ConclusionsMyelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.

Antibody-mediated encephalomyelitis, such as neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and glial fibrillary acidic protein (GFAP) antibody-associated astrocytopathy belong to a group of newly described autoimmune diseases.Presentation of the treatment of antibody-mediated encephalomyelitis with a focus on NMOSD and MOGAD.Selective literature search in PubMed taking the consultation version of the S2k guidelines of the German Society of Neurology (DGN) on the diagnosis and treatment of multiple sclerosis (MS), NMOSD and MOG IgG-associated diseases into account.Acute relapses are treated with high-dose steroid pulse therapy or apheresis therapy (plasma exchange or immunoadsorption). It is crucial to start treatment as quickly as possible and apheresis therapy can also be used as first-line treatment under certain conditions. For prophylactic immunotherapy, steroids, classical immunosuppressants and monoclonal antibodies with specific mechanisms of action are used. Eculizumab, inebilizumab and satralizumab are the first drugs approved for NMOSD. Symptomatic treatment and neurorehabilitation are important complementary measures.Treatment of antibody-mediated encephalomyelitis differs from treatment of multiple sclerosis and requires specific measures.HINTERGRUND: Antikörpervermittelte Enzephalomyelitiden wie die Neuromyelitis-optica-Spektrumerkrankung (NMOSD), die Myelooligodendrozytenglykoprotein-Antikörper-assoziierte Erkrankung (MOGAD) und die saures-Gliafaserprotein(GFAP)-Antikörper-assoziierte Astrozytopathie gehören zu einer Gruppe neu beschriebener Autoimmunerkrankungen.Die Therapie antikörpervermittelter Enzephalomyelitiden wird mit Fokus auf NMOSD und MOGAD dargestellt.Es wurde eine selektive Literaturrecherche in PubMed unter Berücksichtigung der Konsultationsfassung der S2k-Leitlinie der Deutschen Gesellschaft für Neurologie „Diagnose und Therapie der Multiplen Sklerose (MS), NMOSD und MOG-IgG-assoziierte Erkrankungen“ durchgeführt.Akute Schübe werden mit einer hoch dosierten Steroidpulstherapie oder Plasmaaustauschverfahren (Plasmapherese oder Immunadsorption) behandelt. Ein möglichst rascher Therapiebeginn ist entscheidend, Plasmaaustauschverfahren können unter bestimmten Voraussetzungen auch als Erstlinientherapie eingesetzt werden. Zur prophylaktischen Immuntherapie werden Steroide, klassische Immunsuppressiva und monoklonale Antikörper mit verschiedenen, spezifischen Wirkmechanismen eingesetzt. Mit Eculizumab, Inebilizumab und Satralizumab existieren erstmals zugelassene Medikamente für die NMOSD. Symptomatische Therapien und Neurorehabilitation sind wichtige ergänzende Maßnahmen.Die Therapie antikörpervermittelter Enzephalomyelitiden unterscheidet sich von der Therapie der Multiplen Sklerose und erfordert spezifische Maßnahmen.

We thank Dr. Chen for his comment. We included neuromyelitis optica spectrum disorder (NMOSD) patients with longitudinal visual-evoked potential (VEP) data covering ≥3 months. We calculated the changes per year using regression analysis. For eyes with

Background New-generation cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). Objective To describe systematically the CSF profile in MOG-EM. Material and methods Cytological and biochemical findings (including white cell counts and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgA/IgM fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster (MRZ) reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF l-lactate) from 163 lumbar punctures in 100 adult patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. Results Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in almost 90% of samples (N = 151), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 62). If present, intrathecal IgG (and, more rarely, IgM) synthesis was low, often transient and mostly restricted to acute attacks. CSF WCC was elevated in > 50% of samples (median 31 cells/μl; mostly lymphocytes and monocytes; > 100/μl in 12%). Neutrophils were present in > 40% of samples; activated lymphocytes were found less frequently and eosinophils and/or plasma cells only very rarely (< 4%). Blood–CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 48% of all samples and at least once in 55% of all patients (N = 88) tested. The frequency and degree of CSF alterations were significantly higher in patients with acute myelitis than in patients with acute ON and varied strongly depending on attack severity. CSF l-lactate levels correlated significantly with the spinal cord lesion load in patients with acute myelitis (p < 0.0001). Like pleocytosis, blood–CSF barrier dysfunction was present also during remission in a substantial number of patients. Conclusion MOG-IgG-positive EM is characterized by CSF features that are distinct from those in MS. Our findings are important for the differential diagnosis of MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

The conversion of relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) cannot be defined by a sharp threshold determined by event-based measures, but rather represents a gradual process. In consequence, there may exist a transitional phase between RRMS and clearly established SPMS. So far, transitional MS has been poorly characterized in terms of patient properties, course of disease and therapeutic interventions that may delay conversion to SPMS. Furthermore, the pathogenesis of transitional MS is incompletely understood, and no definitive imaging or laboratory test informs when exactly a patient has entered the transitional MS phase. Here we review the current knowledge and evidence characterizing the transitional phase of MS and propose potential designs and criteria for a prospective clinical study in patients with transitional MS.

Background New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD). Objective To describe systematically the CSF profile in children with MOG-EM. Material and methods Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF l-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively. Results Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6–256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF l-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF l-lactate (p < 0.0003) during acute attacks with age. Conclusion MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.

\(\bf Objective\) To report the course of 3 recent Japanese and European cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) and to analyze its risk factors and increased incidence in Japan. \(\bf Methods\) Case series and literature review. \(\bf Results\) Fingolimod-associated PML may cause both supratentorial and infratentorial lesions and a pronounced disability. Diagnosis can be challenging because PML lesions (especially infratentorial) can be initially misdiagnosed as extensive MS lesions. Immune reconstitution inflammatory syndrome (IRIS) develops a few weeks after fingolimod discontinuation and is usually mild. Age factor and therapy duration seem to be relevant because most reported patients were older than 45 years and were treated with fingolimod for more than 3 years. Combined IgG/IgM deficiency has been identified as a possible further predisposing condition in 1 case. Another patient developed an endogenous fungal skin infection, as a sign of generally compromised cellular immune response, shortly before PML. None of the reported patients had lymphocyte counts below 200/μl. Two of the 3 reported and 4 of the 21 (19%) registered fingolimod-PML cases occurred in Japan (estimated risk of 0.652 per 1,000 compared with 0.083 per 1.000 worldwide). \(\bf Conclusions\) The risk of PML under fingolimod is low, but there are no reliable predictors. Despite a mild IRIS phase, it causes profound disability. Patients older than 45 years, especially with known comorbid immunodeficiencies or manifestation of other opportunistic infections, should be monitored more closely. Increased surveillance and identification of further risk factors are urgently needed in Japan.

Introduction Reduced echogenicity of the brainstem raphe nuclei (BRN) was demonstrated in major depression, possibly indicating serotonergic dysfunction. Postulating that migraine may constitute a “chronic low serotonin syndrome,” we aimed to evaluate the echogenicity of midbrain structures, including serotonergic BRN in episodic migraine. Methods Transcranial sonography was performed in 39 patients with episodic migraine (median age 35, interquartile range (IQR): 27–47 years; 27 women) and 35 controls (median age 31, IQR: 29–47 years; 19 women). Individuals with concomitant depression were excluded. Echogenicity of BRN, substantia nigra (SN) and third ventricle width was evaluated according to an internationally established examination protocol. Results Hypoechogenicity of BRN was depicted in 23.1% of migraine patients and 20% of controls, showing no significant difference. Migraine patients with hypoechogenic BRN had significantly higher attack frequency (median 3, IQR 2–5 vs. 1.5, IQR 1–2 days/month; p = 0.029) and a trend toward earlier disease manifestation. The rate of hyperechogenic SN and width of the third ventricle were similar between both groups. We did not observe any differences between migraine patients with and without aura. Conclusion Sonographic findings did not differ between migraine patients and controls. Hypoechogenic BRN correlated to a higher migraine attack frequency, probably indicating more severe disease activity.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired, chronic progressive or relapsing immune mediated disorder of the peripheral nervous system. Thickening of cranial nerves as a sign of central nerve involvement is increasingly reported in the last years. Our aim was to assess systematically for the first time the frequency of optic nerve hypertrophy in patients with CIDP by means of transorbital sonography (TOS). Thirty-four optic nerves of 17 patients with CIDP (age=60.8±13.3y, range=39-82y; 7 female) were examined by TOS. The diameter of Optic nerve (OND) as well as the intern and extern diameters of the sheath (ONDSi, ONSDe) was measured 3mm behind the optic disc. Findings were compared to the data of 15 healthy controls. CIDP-patients showed a mean OND of 2.8±0.4mm, an ONSDi of 4.7±0.7mm, and an ONSDe of 6.3±0.9mm. No papilledema was detectable. There was no significant difference to the healthy control group. Our study revealed no evidence for a frequent optic nerve involvement in CIDP. Reported cases seem to represent exceptions. Transorbital sonography could be a useful tool in these rare cases with optic nerve hypertrophy.

Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer. A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies. IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0447-3) contains supplementary material, which is available to authorized users.

Background Headache is common in patients with Moyanoya angiopathy (MMA), but usually underestimated in its management and not well characterized. Methods A validated self-administered headache screening questionnaire and a telephone interview were used in order to investigate headache characteristics, frequency and pain intensity in a large cohort of 55 German patients with MMA. Results Thirty-seven patients (67.3%) had suffered from headache in the past year. Headache intensity was rated 3.2 ± 1.3 on a verbal rating scale from 0 to 10. Seventeen patients (47.9%) reported migraine-like headache, 10 patients (27.0%) reported tension type-like headache and 10 patients (27.0%) had a combination of both. The majority of patients with migraine-like headache ( n = 10, 58.8%) described migrainous aura. Headache frequency and intensity improved significantly after revascularization surgery; however, nine patients developed new-onset headache postoperatively. Conclusion Headache is very common in MMA, often with a migraine-like phenotype. Tension type-like headache was also found in 27% of patients, which is a new finding that has not been reported before.

Background and purpose The study evaluated headache-attributed burden and its impact on productivity and quality of life (QoL) in Russia. Its purpose was to support recommendations for change. Methods A countrywide population-based random sample of 2725 biologically unrelated adults (aged 18–65 years) in 35 cities and nine rural areas of Russia were interviewed in a door-to-door survey. The structured questionnaire enquired into symptom burden, functional disability, lost productive time and QoL (applying the WHOQoL-8 question set), as well as willingness to pay (WTP) for adequate headache treatment, if it were available. Results Mean lost paid-work days due to headache in the previous 3 months were 1.9 ± 4.2, and mean lost household work days were 3.4 ± 5.7. The estimated annual indirect cost of primary headache disorders was USD 22.8 billion, accounting for 1.75% of gross domestic product. QoL was reduced by all types of primary headaches. According to WHOQoL-8, it was significantly lower in those with headache on ≥15 days/month than in those with episodic headache (24.7 ± 4.6 vs. 28.1 ± 5.0; P

We investigated the effect of chronic administration of different pain medications on the activity of the serotonin transporter (SERT) in patients with medication overuse headache (MOH). We measured the kinetic of platelet 5-HT uptake (maximal velocity, Vmax and the Michaelis–Menten constant, Km) in patients with overuse of triptans (tMOH, n = 15) or analgesics (aMOH, n = 14) before and after drug withdrawal, as well as in headache-free healthy subjects (n = 15) and patients with episodic migraine (EM, n = 16). Vmax was increased similarly in both, tMOH and aMOH compared to healthy subjects and patients with EM and normalized after withdrawal in parallel to the improvement of headache frequency. Average Km was similar in all groups at baseline and not affected by the withdrawal. The data demonstrate a transient increase of SERT activity in patients with analgesic and triptan induced MOH but do not allow to differentiate whether the increase of serotonin uptake is caused by regular intake of analgesics or triptans or is a consequence of frequent headache attacks.

Importance Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. Objective To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. Design, Setting, and Participants Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab–seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). Main Outcomes and Measures Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. Results Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) ( P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) ( P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers ( P = .02) and pain levels ( P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. Conclusions and Relevance Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.

Background.—Electrophysiological techniques such as laser and contact heat evoked pain-related potentials are very useful for studying trigeminal and somatic pain transmission in humans. These methods are, however, partly invasive, expensive, and therefore not available for broad clinical use. We recently proposed a novel technique of noninvasive transcutaneous electrical stimulation. Objective.—To elicit pain-related evoked potentials (PREP) by using a concentric planar electrode and demonstrate their nociceptive specificity. Methods.—We registered PREP following stimulation of the forehead and hand in 14 healthy volunteers. Latencies, peak-to-peak amplitudes, and conduction velocities of nociceptive fibers have been estimated. Effects of temporal and spatial summation and of cutaneous anesthesia were evaluated. Results.—Stimulation with the concentric planar electrode produced pinprick-like painful sensation. Cutaneous anesthesia led to abolishment of PREP responses. Estimated mean conduction velocity was 11.61 ± 5.12 m/s, which corresponded well with conduction via A-delta fibers. Spatial as well as temporal summation resulted in a parallel increase of perceived pain intensity and PREP amplitudes. Conclusion.—The technique is noninvasive, affordable, and easy to perform and allows quantitative assessment of human nociceptive pathways.

Trigeminal and somatic nociceptive systems were studied in controls ( n = 15), episodic migraine ( n = 16), analgesics ( n = 14) and triptan-induced medication overuse headache (MOH) ( n = 15) before and after withdrawal. Patients with MOH and comorbid depressive symptoms and depression without headache were studied to investigate the influence of depression. Trigeminal nociception was studied by simultaneous registration of pain-related cortical potentials (PREP) and nociceptive blink reflex (nBR) following nociceptive-specific electrical stimulation of the forehead. Somatic nociception was evaluated using PREP of upper limbs. We found facilitation of both trigeminal and somatic PREP but not of nBR in MOH, which normalized after withdrawal. No differences were found comparing analgesics vs. triptan MOH. No differences were observed between controls and patients with episodic migraine and depression without headache. A transient facilitation was found of trigeminal and somatic nociceptive systems in MOH, which was more pronounced on a supraspinal level.

We present a 77-year-old previously well patient with facial asymmetry and progressive weakness of the lower extremities. An initial MRI revealed slight contrast enhancement of the meninges. Three consecutive cerebrospinal fluid examinations demonstrated low glucose concentration, marked elevation of total protein and moderate pleocytosis. No tumor cells, fungi, acid-fast bacilli or mycobacterial DNA were found. The patient's level of consciousness deteriorated dramatically, and follow-up MRI showed widespread extensive cortical hyperintensities. The lesions showed restricted diffusion on diffusion-weighted images as well as low values on the corresponding apparent diffusion coefficient maps, the changes consistent with diffuse cytotoxic edema. Neuropathological examination findings were of leptomeningeal carcinomatosis (LMC) with diffuse continuous infiltration of the cerebral cortex, cerebellum and spinal cord. The autopsy revealed a subcentimetre adenocarcinoma of the lung. To our knowledge, this is the first report demonstrating extensive cortical involvement in adenocarcinomatous LMC.

Optic neuritis (ON) is a key feature of neuromyelitis optica (NMO). Recently, NMO patients of predominantly Afro-Brazilian origin were evaluated by visual evoked potentials (VEPs) and showed marked amplitude reductions. Here, we analyzed VEPs in a predominantly Caucasian cohort, consisting of 43 patients with definite NMO, 18 with anti-aquaporin (AQP) 4 antibody-seropositive NMO spectrum disorders and 61 matched healthy controls. We found reduced amplitudes in only 12.3%, prolonged latencies in 41.9% and a lack of response in 14.0% of NMO eyes. Delayed P100 latencies in eyes without prior ON suggested this was a subclinical affection. The data indicate heterogenous patterns in NMO, warranting further investigation.

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced ( p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients.

Objective Persistent postural-perceptual dizziness (PPPD) is the most common vestibular disorder in the age group between 30 and 50 years. It is considered to be based on a multisensory maladjustment involving alterations of sensory response pattern including vestibular, visual and motion stimuli. Previous data supported a link between vestibular and pain mechanism. The aim of the study was to investigate whether other sensory inputs such as pain stimuli might be altered in terms of a more widespread central perception dysfunction in this disorder. Methods Nociceptive blink reflex was measured in 27 patients with PPPD and compared with 27 healthy, age and gender matched controls. The habituation of the R2 component of the blink reflex was evaluated as the percentage area-under-the curve (AUC) decrease in ten consecutive blocks of five averaged rectified responses. Additionally, clinical characteristics were evaluated. Results In patients with PPPD a lack of habituation was observed compared to healthy controls. Relative AUC decreased between the first and the tenth block by 19.48% in PPPD patients and by 31.63% (p = 0.035) in healthy controls. There was no correlation between clinical data (course of disease, comorbid depression, medication, trigger factors) or electrophysiological data (perception threshold, pain threshold, stimulus intensity) and habituation pattern. No trigeminal sensitization in terms of facilitation of absolute values could be detected. Conclusion Our study results supports the hypothesis of the multisensory dimension of impaired sensory processing in patients with PPPD extends beyond vestibular/visual motion stimuli and reflexive postural/oculomotor control mechanisms to other sensory inputs such as pain perception in terms of a more generalized disturbed habituation pattern.

Objective To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). Design Retrospective case series. Setting Neurology department at a tertiary referral center. Patients Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. Main Outcome Measures Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. Results We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4–positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. Conclusions Interleukin 6 receptor–blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.