Objective: We describe a large cohort of contactin-associated protein 2 (Caspr2) patients with this disorder and provide a framework for patient recognition.
Background: Caspr2 is a membrane protein closely related to the voltage-gated potassium channel (VGKC). The clinical spectrum of Caspr2 antibodies is diverse and poorly known. Recognition of this disorder is important because it is treatable.
Methods: Clinical information and patients’ serum and CSF samples were assessed at two neuroimmunology centers in Barcelona or Rotterdam. Antibody studies were investigated using previously reported brain immunohistochemistry and cell-based assays. Clinical information was obtained by the authors or provided by treating physicians after patients’informed consent.Results: Thirty-eight patients were included, 89[percnt] were male. The median age at symptom onset was 66 years. The nadir of the disease was reached at a median of 4 months, but in 30[percnt] of the patients was reached after 1 year. The most frequent syndromes included Morvan’s syndrome (29[percnt]), limbic encephalitis (LE) with additional symptoms (26[percnt]) or LE (16[percnt]). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy, cerebellar symptoms, peripheral nervous hyperexcitability, autonomic dysfunction, insomnia, neuropathic pain and weight loss. The presence of an underlying tumor (usually thymoma) occurred in 19[percnt] of the patients. IgG4 subclass antibodies were present in 94[percnt] of the patients. Full or partial response to treatment occurred in 93[percnt] of the patients; overall, 73[percnt] had a favorable outcome. Relapses occurred in 25[percnt] of the patients.
Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients, but usually includes a set of well-established symptoms. The recognition of this spectrum of symptoms and the consideration of a protracted clinical course are essential for the early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.
				
				 Disclosure: Dr. Sonderen has nothing to disclose. Dr. Arino has nothing to disclose. Dr. Petit-Pedrol has nothing to disclose. Dr. Leypoldt has received personal compensation for activities with Grifols as a speaker. Dr. Kortvelyessy has nothing to disclose. Dr. Lancaster has nothing to disclose. Dr. Wirtz has nothing to disclose. Dr. Schreurs has nothing to disclose. Dr. Sillevis Smitt has nothing to disclose. Dr. Graus has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity from the board of Up-To-Date. Dr. Dalmau has received royalty payments from Memorial Sloan-Kettering Cancer Center. Dr. Dalmau has received research support from Euroimmun. Dr. Titulaer has nothing to disclose.

The Clinical Spectrum of Caspr2-Antibody Associated Disease (S12.008)

Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.

Infectious immunity in the central nervous system and brain function.

Summary Background Surgery is a widely accepted treatment option for drug-resistant focal epilepsy A detailed analysis of longitudinal postoperative seizure outcomes and use of antiepileptic drugs for different brain lesions causing epilepsy is not available We aimed to analyse the association between histopathology and seizure outcome and drug freedom up to 5 years after epilepsy surgery, to improve presurgical decision making and counselling Methods In this retrospective, multicentre, longitudinal, cohort study, patients who had epilepsy surgery between Jan 1, 2000, and Dec 31, 2012, at 37 collaborating tertiary referral centres across 18 European countries of the European Epilepsy Brain Bank consortium were assessed We included patients of all ages with histopathology available after epilepsy surgery Histopathological diagnoses and a minimal dataset of clinical variables were collected from existing local databases and patient records The primary outcomes were freedom from disabling seizures (Engel class 1) and drug freedom at 1, 2, and 5 years after surgery Proportions of individuals who were Engel class 1 and drug-free were reported for the 11 main categories of histopathological diagnosis We analysed the association between histopathology, duration of epilepsy, and age at surgery, and the primary outcomes using random effects multivariable logistic regression to control for confounding Findings 9147 patients were included, of whom seizure outcomes were available for 8191 (89·5%) participants at 2 years, and for 5577 (61·0%) at 5 years The diagnoses of low-grade epilepsy associated neuroepithelial tumour (LEAT), vascular malformation, and hippocampal sclerosis had the best seizure outcome at 2 years after surgery, with 77·5% (1027 of 1325) of patients free from disabling seizures for LEAT, 74·0% (328 of 443) for vascular malformation, and 71·5% (2108 of 2948) for hippocampal sclerosis The worst seizure outcomes at 2 years were seen for patients with focal cortical dysplasia type I or mild malformation of cortical development (50·0%, 213 of 426 free from disabling seizures), those with malformation of cortical development-other (52·3%, 212 of 405 free from disabling seizures), and for those with no histopathological lesion (53·5%, 396 of 740 free from disabling seizures) The proportion of patients being both Engel class 1 and drug-free was 0–14% at 1 year and increased to 14–51% at 5 years Children were more often drug-free; temporal lobe surgeries had the best seizure outcomes; and a longer duration of epilepsy was associated with reduced chance of favourable seizure outcomes and drug freedom This effect of duration was evident for all lesions, except for hippocampal sclerosis Interpretation Histopathological diagnosis, age at surgery, and duration of epilepsy are important prognostic factors for outcomes of epilepsy surgery In every patient with refractory focal epilepsy presumed to be lesional, evaluation for surgery should be considered Funding None

/pdf/seizure-outcome-and-use-of-antiepileptic-drugs-after-1ddutfx2vu.pdf

Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study

http://www3.med.unipmn.it/intranet/papers/2014/LWW/2014-03-10_lww/Nocardiosis_of_the_Central_Nervous_System_.3.pdf

Nocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature.

Parkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body–confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.

Identification of TMEM230 mutations in familial Parkinson's disease

Central nervous system (CNS) involvement, one of the most devastating clinical manifestations of tuberculosis (TB) is noted in 5 to 10% of extrapulmonary TB cases, and accounts for approximately 1% of all TB cases. Definitive diagnosis of tuberculous meningitis (TBM) depends upon the detection of the tubercle bacilli in the CSF. Every patient with TBM should preferably be evaluated by imaging with contrast enhanced CT either before or within the first 48 hours of treatment. An extra-neural focus of tuberculosis should be sought clinically and radiologically in all patients with CNS TB as it may indicate safer and more accessible sites for diagnostic samplings. A minimum of 10 months treatment is warranted, prompted by the uncertain influences of disease severity, CNS drug penetration, undetected drug resistance and patient compliance. All patients with TB meningitis may receive adjunctive corticosteroids at presentation regardless of disease severity even for those with HIV infection. Drug resistance is strongly associated with previous treatment. The key principle of managing drug-resistant TB is never to add a single drug to a failing regimen. Early ventriculo-peritoneal shunting should be considered in those with hydrocephalus failing medical management. The single most important determinant of outcome is the stage of tuberculous meningitis at which treatment has been started.

/pdf/central-nervous-system-tuberculosis-nzbpr4e6xr.pdf

Central nervous system tuberculosis

Hyperglycemia-induced hemichorea can show T1 hyperintensity of the contralateral striatum on MRI. This is thought to be due to petechial hemorrhages or gemistocytic astrocyte accumulation. This study explores the utility of susceptibility-weighted imaging (SWI) and diffusion-weighted imaging (DWI) in identifying the nature of these lesions. Three patients underwent MR imaging of the brain with SE T1, F SE T2, DWI, and SWI. T1 images showed hyperintensity predominantly involving the contralateral striatum, where mild (two cases) to moderate (one case) restricted diffusion (low apparent diffusion coefficient [ADC]) was detected on DWI. SWI demonstrated bilateral symmetrical hypointensities in the first two cases, suggesting age associated mineralization. In addition, increased susceptibility change (hypointensity) was also noted in the right putamen in the first and the third cases, suggesting paramagnetic mineral deposition. T1 hyperintensity may be from the protein hydration layer inside the cytoplasm of swollen gemistocytes appearing after an acute cerebral injury. These astrocytes also express metallothionein with zinc, which is thought to be the cause of asymmetric hypointensity of the posterior putamen on SWI. ADC values were thought to be useful for prognostication; however, they should be interpreted cautiously in the presence of susceptibility changes.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/jmri.21672

Concepts and controversies in nonketotic hyperglycemia-induced hemichorea: further evidence from susceptibility-weighted MR imaging.

Less than a quarter century after the discovery of SNCA as the first attributable gene in Parkinson's disease (PD), our knowledge of the genetic architecture underlying this disease has improved by leaps and bounds. About 5-10% of all patients suffer from a monogenic form of PD where mutations in autosomal-dominant (AD) genes-SNCA, LRRK2, and VPS35 and autosomal recessive (AR) genes-PINK1, DJ-1, and Parkin cause the disease. Whole-exome sequencing has described AR DNAJC6 mutations not only in predominantly atypical, but also in patients with typical PD. Majority of PD is genetically complex, caused by the combination of common genetic variants in concert with environmental factors. Genome-wide association studies have identified twenty six PD risk loci till date; however, these show only moderate effects on the risk for PD. The validation of novel genes and its association with PD remains extremely challenging as families harboring rare genetic variants are sparse and globally widespread. This review article aims to provide a comprehensive overview on PD genetics.

Ajith Cherian

Papers

Central nervous system tuberculosis

Concepts and controversies in nonketotic hyperglycemia-induced hemichorea: further evidence from susceptibility-weighted MR imaging.

Genetics of Parkinson's disease.

Oxcarbazepine induced worsening of seizures in Jeavons syndrome: lessons learnt from an interesting presentation.

Surgery for "Long-term epilepsy associated tumors (LEATs)": Seizure outcome and its predictors.