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BackgroundIt remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course.MethodsThis large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis.ResultsIn total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015).ConclusionsIn RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Background and objectivesThe diagnosis of neurosyphilis (NS) lacks a true ‘gold standard’, making the diagnosis challenging while consequences of a misdiagnosis are potentially severe. The aim of this study was to evaluate the diagnostic performance of measuring an antibody index (AI) for the intrathecal synthesis of specific anti-Treponema pallidum(T. pallidum) IgG for the diagnosis of NS.MethodsSpecific anti-T. pallidumIgG were measured simultaneously in paired cerebrospinal fluid (CSF)–serum samples collected retrospectively and prospectively between 2007 and 2022, from patients suspected of NS, in Switzerland. An AI was calculated to account for blood–brain barrier integrity. Area under the receiver operating characteristic curve, sensitivity/specificity and positive/negative predictive values of AI test were estimated. Two NS definitions were used: NS1 included patients with NS suspicion presenting with neurological symptoms and/or acute neurosensory signs, and positive T. PallidumHemagglutinations Assay (TPHA)/T. pallidumparticle agglutination assay (TPPA) serology and CSF-TPHA/TPPA ≥320, and either CSF-leucocytes >5 cells/mm3and/or CSF-protein >0.45 g/L and/or a reactive CSF-venereal disease research laboratory (VDRL)/rapid plasma reagin (RPR) test. NS2 included patients with suspected NS presenting with acute ocular and/or otologic symptoms, and positive TPHA/TPPA serology, and a favourable response to NS treatment. Controls were patients diagnosed with any other central nervous system (CNS) pathologies and with positive TPHA/TPPA serology.ResultsThe study included 71 NS (43 NS1 and 28 NS2) and 110 controls. With a threshold of ≥1.7, sensitivity and specificity of the specific AI test were 90.7% (CI 77.7 to 97.4) and 100% (CI 96.7 to 100.0), respectively, for NS1 and 14.3% (CI 4 to 32.7) and 100% (CI 96.7 to 100.0) for NS2. In patients suspected of NS with a CNS involvement (NS1 group), NS could be confirmed by the positivity of this specific AI.ConclusionsMeasurement of an intrathecal synthesis index of specific anti-T. pallidumIgG in patients with CSF inflammatory signs appears to be a valuable diagnostic test. However, in otic or ocular syphilis, presenting few CSF abnormalities, AI is not sufficient alone to confirm NS diagnosis.Trial registrationSwiss Association of Research Ethics Committees number 2019-00232.

IMPORTANCE: Mechanisms contributing to disability accumulation in multiple sclerosis (MS) are poorly understood. Blood neurofilament light chain (NfL) level, a marker of neuroaxonal injury, correlates robustly with disease activity in people with MS (MS); however, data on the association between NfL level and disability accumulation have been conflicting. OBJECTIVE: To determine whether and when NfL levels are elevated in the context of confirmed disability worsening (CDW). DESIGN, SETTING, AND PARTICIPANTS: This study included 2 observational cohorts: results from the Expression, Proteomics, Imaging, Clinical (EPIC) study at the University of California San Francisco (since 2004) were confirmed in the Swiss Multiple Sclerosis Cohort (SMSC), a multicenter study in 8 centers since 2012. Data were extracted from EPIC in April 2022 (sampling July 1, 2004, to December 20, 2016) and SMSC in December 2022 (sampling June 6, 2012, to September 2, 2021). The study included 2 observational cohorts in tertiary MS centers. All participants of both cohorts with available NfL results were included in the study, and no eligible participants were excluded or declined to participate. EXPOSURE: Association between NfL z scores and CDW. MAIN OUTCOME MEASURES: CDW was defined as Expanded Disability Status Scale (EDSS) worsening that was confirmed after 6 or more months and classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR). Visits were classified in relation to the disability worsening events into CDW(−2) for 2 visits preceding event, CDW(−1) for directly preceding event, CDW(event) for first diagnosis of EDSS increase, and the confirmation visit. Mixed linear and Cox regression models were used to evaluate NfL dynamics and to assess the association of NfL with future CDW, respectively. RESULTS: A total of 3906 EPIC visits (609 participants; median [IQR] age, 42.0 [35.0-50.0] years; 424 female [69.6%]) and 8901 SMSC visits (1290 participants; median [IQR] age, 41.2 [32.5-49.9] years; 850 female [65.9%]) were included. In CDW-R (EPIC, 36 events; SMSC, 93 events), NfL z scores were 0.71 (95% CI, 0.35-1.07; P < .001) units higher at CDW-R(−1) in EPIC and 0.32 (95% CI, 0.14-0.49; P < .001) in SMSC compared with stable MS samples. NfL elevation could be detected preceding CDW-NR (EPIC, 191 events; SMSC, 342 events) at CDW-NR(−2) (EPIC: 0.23; 95% CI, 0.01-0.45; P = .04; SMSC: 0.28; 95% CI, 0.18-0.37; P < .001) and at CDW-NR(−1) (EPIC: 0.27; 95% CI, 0.11-0.44; P < .001; SMSC: 0.09; 95% CI, 0-0.18; P = .06). Those findings were replicated in the subgroup with relapsing-remitting MS. Time-to-event analysis confirmed the association between NfL levels and future CDW-R within approximately 1 year and CDW-NR (in approximately 1-2 years). CONCLUSIONS AND RELEVANCE: This cohort study documents the occurrence of NfL elevation in advance of clinical worsening and may hint to a potential window of ongoing dynamic central nervous system pathology that precedes the diagnosis of CDW.

IMPORTANCE: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). OBJECTIVE: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. DESIGN, SETTING, AND PARTICIPANTS: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab). EXPOSURES: Patients received standard immunotherapies or were untreated. MAIN OUTCOMES AND MEASURES: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. RESULTS: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (−1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [−0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Type 2 diabetes (T2D) is characterized by β-cell dysfunction and the subsequent depletion of insulin production, usually in a context of increased peripheral insulin resistance. T2D patients are routinely treated with oral antidiabetic agents such as sulfonylureas or dipeptidyl peptidase-4 antagonists, which promote glucose-and incretin-dependent insulin secretion, respectively. Interestingly, insulin secretion may also be induced by neural stimulation. Here we report the expression of Nogo-A in β-cells. Nogo-A is a membrane protein that inhibits neurite outgrowth and cell migration in the central nervous system. We observed that Nogo-A-deficient mice display improved insulin secretion and glucose clearance. This was associated with a stronger parasympathetic input and higher sensitivity of β-cells to the cholinergic analog carbachol. Insulin secretion was also improved in diabetic db/db mice treated with neutralizing antibody against Nogo-A. Together, these findings suggest that promoting the vagal stimulation of insulin secretion through the selective inhibition of Nogo-A could be a novel therapeutic approach in T2D., The relative or absolute lack of insulin is responsible for diabetes. In type 1 diabetes, β-cell loss is due in most cases to an autoimmune reaction, but not exclusively (1). [...]

IMPORTANCE: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. OBJECTIVE: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. DESIGN, SETTING, AND PARTICIPANTS: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. EXPOSURES: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. MAIN OUTCOMES AND MEASURES: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. RESULTS: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, −0.36; 95% CI, −0.60 to −0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, −0.18; 95% CI, −0.34 to −0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. CONCLUSIONS AND RELEVANCE: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

The authors conducted a prospective and descriptive pilot study in 14 healthy medical students, investigating whether a psychologically stressful event (final examination) may modify serum tumor necrosis factor alpha (TNF-[alpha]) levels. There was a dramatic and sustained decrease of phytohemagglutinin (PHA)-induced TNF-[alpha] several weeks before and the day of the examination, followed by a significant increase of TNF-[alpha] starting the next day. Examination-induced stress was confirmed by both elevated urinary cortisol concentration and significant increase in stress scale scores. Extending these results to patients suffering from multiple sclerosis (MS) leads to the hypothesis that psychological stress may influence the course of MS by substantially altering TNF-[alpha] levels, and suggests the need for further studies in MS patients exposed to stressful conditions.

Nous présentons un cas remplissant les critères de MOGAD, avec atteinte inflammatoire du tronc cérébral et titre élevé d’anti-MOG, qui se révèlera être une pathologie granulomateuse.

This pilot study was designed to compare the levels of interleukin-8 (IL-8), a pro-inflammatory chemokine, in the cerebrospinal fluid (CSF) of patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), non-inflammatory polyneuropathy (PNP), and other non-inflammatory neurological diseases (functional syndrome or migraine). The results show elevated CSF IL-8 levels in GBS compared to the other groups (p < 0.05). IL-8 could be considered a potential biomarker to differentiate GBS from CIDP. This distinction could be relevant in terms of therapeutic decisions and functional prognosis.

Evoked potentials (EPs) are a powerful and cost-effective tool for evaluating the integrity and function of the central nervous system. Although imaging techniques, such as MRI, have recently become increasingly important in the diagnosis of neurological diseases, over the past 30 years, many neurologists have continued to employ EPs in specific clinical applications. This review presents an overview of the recent evolution of ‘classical’ clinical applications of EPs in terms of early diagnosis and disease monitoring and is an extension of a previous review published in this journal in 2005 by Walsh and collaborators. We also provide an update on emerging EPs based on gustatory, olfactory and pain stimulation that may be used as clinically relevant markers of neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and cortical or peripheral impaired pain perception. EPs based on multichannel electroencephalography recordings, known as high-density EPs, help to better differentiate between healthy subjects and patients and, moreover, they provide valuable spatial information regarding the site of the lesion. EPs are reliable disease-progression biomarkers of several neurological diseases, such as multiple sclerosis and other demyelinating disorders. Overall, EPs are excellent neurophysiological tools that will expand standard clinical practice in modern neurology.

•Pachymeningitis can cause optic neuropathy as onset symptom.•A patient with extra-pulmonary TB presented with optic neuropathy due to pachymeningitis of the orbit.•Worsening on anti-TB treatment with recovery on steroids suggests that the pachymeningitis was due not to primary TB infection but to antiphospholipid syndrome secondary to the TB.•Antiphospholipid antibodies may provoke inflammatory changes in dura microvessels.

Recently, an association between painful tonic spasms (PTS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) was established.

Brain MRI in a 65-year-old woman with headache, sensory ataxia, and tick exposure revealed leptomeningeal and cranial nerve enhancement and T2-hyperintense symmetrical pontine lesions resembling the “owl-eyes” sign, a radiologic finding described in ischemic or compressive myelopathy (Figure, A–C).1CSF analysis revealed pleocytosis (163/µL) and intrathecal production of anti-BorreliaIgG (CSF/serum index 21, N < 2). Workup was negative for alternative causes. The patient fully recovered after 21 days of ceftriaxone (Figure, D–F).

•In SSc patients neurological involvement of inflammatory origin has been reported.•Autoimmune encephalitis can occur in SSc patients in a period of quiescent SSc.•Possibility of a “neuro-scleroderma” can have important consequences for treatment escalation.•In SSc patients with autoimmune encephalitis, the introduction of an immunotherapy is justified.•Multiple autoimmune illnesses is not rare in patients with history of autoimmune disease.

We investigated whether uptake of 18fluoro-2-deoxy-d-glucose (18FDG) positron emission tomography–computed tomography (PET-CT) correlated to clinical symptoms and presence of microembolic signals (MES) detected by transcranial Doppler in patients with carotid stenosis.

OBJECTIVE To increase the recognition of glutamic acid decarboxylase autoantibodies–related encephalitis in childhood. DESIGN Case report and review of the literature. PATIENT A 6-year-old girl who had developed refractory seizures, developmental regression, and type 1 diabetes mellitus at age 25 months. INTERVENTIONS Blood analysis, electroencephalogram, cerebral magnetic resonance imaging, positron emission tomography scan, lumbar puncture, and measurement of glutamic acid decarboxylase activity were performed. Treatment with repeated plasmapheresis and rituximab, with concomitant antiepileptic drugs, was administered. RESULTS Highly elevated titers of glutamic acid decarboxylase autoantibodies were found in the serum, as well as in the cerebrospinal fluid. Major clinical improvement in parallel with a decrease in the levels of serum and cerebrospinal fluid antibodies was observed with treatment. CONCLUSIONS Encephalitis associated with glutamic acid decarboxylase autoantibodies is a severe epileptic disorder that occurs in young children as well as adults. It may be partially reversible with aggressive immunomodulatory treatment, including plasmapheresis and rituximab. Studies are warranted to determine whether early treatment leads to complete remission.

BACKGROUND Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females. OBJECTIVE To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies. DESIGN Case report. SETTING Geneva University Hospital. PATIENT A 23-year-old woman with opsoclonus-myoclonus syndrome. RESULTS Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient's condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid. CONCLUSIONS Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.Arch Neurol. 2010;67(1):118-121--

•Safety data on rabies vaccination in persons with multiple sclerosis (MS) are lacking.•It is unknown whether MS patients have an increased for relapse after RV.•A self-controlled retrospective cohort of 55 MS patients was followed in the year before and the year after prophylactic RV.•There were fewer relapses in the year after vaccination, including the three-month post-vaccination exposure period, than in the year before.•Rabies vaccination was not associated with MS relapse.

BACKGROUND Corneal nerves can be examined using in vivo confocal microscopy (IVCM). This new technique permits sequential observation of the corneal subbasal nerve plexus and detects early signs of diabetic peripheral neuropathy. OBJECTIVE To describe a patient with autoimmune peripheral neuropathy followed up using corneal IVCM. DESIGN Case report. SETTING Clinic of neurology, Geneva, Switzerland. PATIENT A 56-year-old man with peripheral neuropathy diagnosed as anti–myelin-associated glycoprotein neuropathy. His symptoms initially worsened despite the administration of intravenous immunoglobulins and plasma exchange. Evolution was eventually favorable after rituximab and corticosteroids were given. At 1-year follow-up, clinical recovery was almost complete, and the patient was stable according to the results of clinical and electrophysiologic assessments. MAIN OUTCOME MEASURE Corneal nerve measurement by IVCM. RESULTS Examination of corneal nerves using IVCM at 2 different times during the patient's clinical evolution (peak disease and recovery phase) demonstrated histologic signs that correlated with the results of clinical and electrophysiologic assessments. CONCLUSION This observation supports the hypothesis that corneal IVCM could also be helpful for the early detection or follow-up of autoimmune peripheral neuropathy.Arch Neurol. 2009;66(3):403-405--

L’encéphalite limbique (EL) est souvent associée à des auto-anticorps spécifiques. L’association d’anticorps anti-γ-Aminobutyrique-acide-B (GABAB1) et anti-acid-glutamique-decarboxylase (GAD) est rare, et fréquemment paranéoplasique.

Le mécanisme physiopathologique du syndrome de Guillain-Barré (SGB) demeure encore d’indéterminé. Il existe des arguments parlant en faveur d’un rôle des cytokines inflammatoires dans l’atteinte des nerfs périphériques.

•The differential diagnosis of a MS relapse and a TIA is rarely questionable.•This is a very atypical case in its clinical manifestation and MRI finding.•Acute MRI of brain could have been misleading.