MRI characteristics of neuromyelitis optica spectrum disorder An international update

Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti–aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti–aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD.

Neurology 2015

Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy

Objective: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy.

Methods: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators' discretion. Seizure frequency was determined using daily seizure diaries.

Results: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (≥50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years (p < 0.001).

Conclusion: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population.

Classification of evidence: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.

Neurology 2015

Neurogenetics The expanding horizons of diagnosis and disease pathogenesis

To an increasing extent, the desire to catalog and categorize neurologic disorders based on genotype–phenotype correlations is challenged by frequent departures from the syndromic categorizations that were commonplace in the pregenomic era. This challenge is not limited to the recent striking revelations concerning diseases attributable to noncoding, nonconventional mutations, such as repeat expansions in C9ORF72. There are abundant examples of conventional mutations, identified using nonbiased, whole-exome sequencing, that lead to unanticipated phenotypes in the world of hereditary motor system disorders. The report by Pfeffer et al. Further the supports the idea that, as targeted sequencing based on clinical phenotype moves toward nonbiased sequencing, we must be prepared to expect surprises that link genetic abnormalities to unanticipated clinical syndromes.

Neurology 2015

Defects of mutant DNMT1 are linked to a spectrum of neurological disorders

We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43–75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18–51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

Brain 2015

Expanding the phenotype of GMPPB mutations

Dystroglycanopathies are a heterogeneous group of diseases with a broad phenotypic spectrum ranging from severe disorders with congenital muscle weakness, eye and brain structural abnormalities and intellectual delay to adult-onset limb-girdle muscular dystrophies without mental retardation. Most frequently the disease onset is congenital or during childhood. The exception is FKRP mutations, in which adult onset is a common presentation. Here we report eight patients from five non-consanguineous families where next generation sequencing identified mutations in the GMPPB gene. Six patients presented as an adult or adolescent-onset limb-girdle muscular dystrophy, one presented with isolated episodes of rhabdomyolysis, and one as a congenital muscular dystrophy. This report expands the phenotypic spectrum of GMPPB mutations to include limb-girdle muscular dystrophies with adult onset with or without intellectual disability, or isolated rhabdomyolysis.

Brain 2015

Comparing language outcomes in monolingual and bilingual stroke patients

Post-stroke prognoses are usually inductive, generalizing trends learned from one group of patients, whose outcomes are known, to make predictions for new patients. Research into the recovery of language function is almost exclusively focused on monolingual stroke patients, but bilingualism is the norm in many parts of the world. If bilingual language recruits qualitatively different networks in the brain, prognostic models developed for monolinguals might not generalize well to bilingual stroke patients. Here, we sought to establish how applicable post-stroke prognostic models, trained with monolingual patient data, are to bilingual stroke patients who had been ordinarily resident in the UK for many years. We used an algorithm to extract binary lesion images for each stroke patient, and assessed their language with a standard tool. We used feature selection and cross-validation to find ‘good’ prognostic models for each of 22 different language skills, using monolingual data only (174 patients; 112 males and 62 females; age at stroke: mean = 53.0 years, standard deviation = 12.2 years, range = 17.2–80.1 years; time post-stroke: mean = 55.6 months, standard deviation = 62.6 months, range = 3.1–431.9 months), then made predictions for both monolinguals and bilinguals (33 patients; 18 males and 15 females; age at stroke: mean = 49.0 years, standard deviation = 13.2 years, range = 23.1–77.0 years; time post-stroke: mean = 49.2 months, standard deviation = 55.8 months, range = 3.9–219.9 months) separately, after training with monolingual data only. We measured group differences by comparing prediction error distributions, and used a Bayesian test to search for group differences in terms of lesion-deficit associations in the brain. Our models distinguish better outcomes from worse outcomes equally well within each group, but tended to be over-optimistic when predicting bilingual language outcomes: our bilingual patients tended to have poorer language skills than expected, based on trends learned from monolingual data alone, and this was significant (P < 0.05, corrected for multiple comparisons) in 13/22 language tasks. Both patient groups appeared to be sensitive to damage in the same sets of regions, though the bilinguals were more sensitive than the monolinguals.

Brain 2015

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10−11). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10−5 using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10−6 for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10−8). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10−9 using Poser criteria; P = 5.6 × 10−11 for McDonald criteria) and more rapid development of disability (P = 1.8 × 10−10). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Brain 2015