Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug-resistant epilepsy.

OBJECTIVE: Differentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)-based metabolomics could differentiate AE from drug-resistant epilepsy (DRE), and stratify AE subtypes. METHODS: This study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin-associated protein-like 2 (CASPR2), 29 with leucine-rich glioma inactivated 1 (LGI1) and 20 with N-methyl-d-aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS-DA). RESULTS: The OPLS-DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS-DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high-density lipoprotein (HDL, -(CH2)n-, -CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype-specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, -CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR-antibody patients. INTERPRETATION: This study presents the first non-antibody-based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.

Isolated headache is not a reliable indicator for brain cancer: the 2-week wait pathway for suspected CNS malignancies.

INTRODUCTION: The UK uses the 2-week-wait (2WW) pathway for rapid access to cancer services. It is unclear whether this is effective for brain cancer. METHODS: We retrospectively analysed all 2WW referrals for brain cancer between 2009 and 2016 in a district general neurology department. We compared clinical presentations to national guidelines and diagnoses of brain cancer. RESULTS: Of the 153 cases analysed, four brain cancers were identified: two glioblastomas and two metastases. Headaches were the most common referral. The end diagnosis was mostly migraine. The highest positive predictive value was for behavioural/personality change (5.3%) and sub-acute neurological deficit (3.2%). There was no significant association between any symptom(s) and brain cancer. CONCLUSION: The 2WW pathway is not effective in the diagnosis of brain cancer. Resources are better directed towards clinical research and treatment trials. Headache remains the most common reason for referral although it is not yet a reliable indicator of brain cancer.

Acoustic neuroma presenting as a hypnic headache.

Hypnic headache (HH) is a rare, primary headache syndrome that invariably occurs during sleep and wakes the patient. Acoustic neuroma (AN) is a benign tumour that uncommonly presents with isolated headache. Here, we describe a patient with AN that presented with an HH-like syndrome. A 40-year-old woman presented with 4 months of generalised, throbbing, nocturnal headaches that woke her from sleep. Neurological examination was unremarkable. Retrospectively, she reported a 4-year history of mild, bilateral tinnitus. Neuroimaging demonstrated a large, left-sided AN in the cerebellopontine angle without obstructive hydrocephalus. Gamma knife radiosurgery controlled tumour growth. One year after radiosurgery, she became nocturnal headache-free. AN has not previously been described as presenting with an HH-like syndrome. There are four previous reports of an HH-like syndrome secondary to intracranial masses. In all cases, patients became headache-free following surgery. This advocates for neuroimaging to exclude structural causes.

Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells.

BACKGROUND: The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. OBJECTIVE: To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. METHODS: A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. RESULTS: Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. CONCLUSIONS: Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.

Cortical excitability correlates with seizure control and epilepsy duration in chronic epilepsy.

OBJECTIVE: Cortical excitability differs between treatment responders and nonresponders in new-onset epilepsy. Moreover, during the first 3 years of epilepsy, cortical excitability becomes more abnormal in nonresponders but normalizes in responders. Here, we study chronic active epilepsy, to examine whether cortical excitability continues to evolve over time, in association with epilepsy duration and treatment response. METHODS: We studied 28 normal subjects, 28 patients with moderately controlled epilepsy (≤4 seizures per year) and 40 patients with poorly controlled epilepsy (≥20 or more seizures per year). Resting motor threshold (RMT), active motor threshold (AMT), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and cortical silent period (CSP) were measured, using transcranial magnetic stimulation (TMS). Disease and treatment covariates were collected (age at onset of epilepsy, epilepsy duration, number of drugs prescribed, total drug load, sodium channel drug load). RESULTS: RMT and AMT were higher in patients than in normal subjects; RMT and AMT were higher in poorly controlled than moderately controlled patients. ICF at 12 msec and 15 msec were lower in poorly controlled patients than in normal subjects. Long-interval intracortical inhibition (LICI) at 50 msec was higher in poorly controlled compared to moderately controlled patients. These differences were not explained by antiepileptic drug (AED) treatment or duration of epilepsy. RMT and AMT increased with duration in the poorly controlled group, but did not increase with duration in the moderately controlled group. INTERPRETATION: Cortical excitability differs markedly between moderately controlled and poorly controlled patients with chronic epilepsy, not explained by disease or treatment variables. Moreover, the evolution of cortical excitability over time differs, becoming more abnormal in the poorly controlled group.

Motor evoked potential polyphasia: a novel endophenotype of idiopathic generalized epilepsy.

OBJECTIVE: We compared the motor evoked potential (MEP) phases using transcranial magnetic stimulation in patients with idiopathic generalized epilepsy (IGE), their relatives, and healthy controls, hypothesizing that patients and their unaffected relatives may share a subtle pathophysiologic abnormality. METHODS: In a cross-sectional study, we investigated 23 patients with IGE, 34 first-degree relatives, and 30 matched healthy controls. Transcranial magnetic stimulation was performed to produce a series of suprathreshold single-pulse MEPs. A semiautomated method was used to count phases. We compared between groups the mean number of MEP phases, the stimulus-to-stimulus variability in MEP phases, and the proportion of polyphasic MEPs within subjects. RESULTS: Patients with IGE and their relatives had a significantly increased number of MEP phases (median for patients 2.24, relatives 2.17, controls 2.01) and a significantly higher proportion of MEPs with more than 2 phases than controls (median for patients 0.118, relatives 0.088, controls 0.013). Patients had a greater stimulus-to-stimulus variability in number of MEP phases than controls. There were no differences between patients and relatives. CONCLUSION: Increased MEP polyphasia in patients with IGE and their first-degree relatives may reflect transient abnormal evoked oscillations. The presence of polyphasic MEPs in relatives as well as patients suggests that MEP polyphasia is not related to treatment, and is in isolation insufficient to predispose to epilepsy. Polyphasic MEP may be a novel endophenotype in IGE.