Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

BACKGROUND: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). OBJECTIVE: To assess cognitive performance and changes over time in NMOSD. METHODS: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. RESULTS: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. CONCLUSIONS: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

A smart peek: Processing of rapid visual displays is disturbed in newly diagnosed, cognitively intact MS patients and refers to cognitive performance and disease progression in late stages.

BACKGROUND: MS can reduce the speed of information processing (IPS) leading to a variable pattern of cognitive impairment. To better understand this deficit, a separate evaluation of the sensory, cognitive, and motor speed component is required. Tests using rapid visual displays allow for assessment of separate components of information uptake. We utilized such a test to compare deficit profiles at the earlier and later stage of MS and their relation to cognitive ability and disease progression. METHOD: Two groups were evaluated: "Early MS" comprised N = 24 patients with disease durations <2 years; "late MS" N = 45 with disease durations >12 years. Rapid visual displays of letters were utilized to derive individual profiles of visual information uptake according to the 'theory of visual attention' (TVA). The resulting data was then compared with measures of disability, fatigue, depression, IPS, visual-spatial ability, verbal and visual memory. RESULTS: In the EMS group, where cognitive impairment was the exception, three of the four main parameters of visual information uptake were already modified, i.e. processing rate C, storage capacity K, and iconic memory µ. In LMS an additional elevation of the fourth parameter, i.e., the perceptual threshold t0 was evident. Threshold values were related to most clinical and cognitive measures. CONCLUSIONS: An early deficit pattern of visual information uptake can be detected at a stage, when performance in tests of IPS is still well-preserved. At later disease stages, a single parameter reflecting the threshold of conscious visual perception may provide a valid estimate of cognitive performance and disease progression.

Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.

We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10-17 , OR = 13.66 [7.50-24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10-16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 2018;83:863-869.

Information processing deficits as a driving force for memory impairment in MS: A cross--sectional study of memory functions and MRI in early and late stage MS.

BACKGROUND: Memory impairment (MI) is a common symptom of MS. Previous studies were conflicting in respect to the possible existence of early MI and the role of hippocampal atrophy. The objective of this study was to investigate MI and structural MRI correlates in homogenous groups of early and late MS, controlling for a potential information-processing speed (IPS) deficit, and utilizing multiple memory test paradigms. METHODS: 152 individually matched subjects were recruited: early MS (EMS, N = 25, disease duration 1.0 ± 0.8 years), late MS (LMS, N = 52, 16.5 ± 5.2 years), and corresponding controls. Five memory tests were utilized to account for differences in learning material (verbal, visual), encoding (incidental, intentional), and retrieval (free recall, recognition, recurring recognition). Performance was related to IPS, memory-specific (hippocampal volumes), and unspecific MRI measures (T1/T2LL, brain volume, cortical thickness). RESULTS: Memory was impaired across all tests in LMS, but not in EMS. LMS-patients were also significantly impaired in IPS which was correlated with several memory scores. Regression analyses revealed IPS and cortical thickness as predictors for visual MI, and IPS, sex, and left hippocampal volume as predictors for verbal MI. CONCLUSION: Additionally to direct destructions in memory specific tracts such as the hippocampus, memory decline in MS may also be related to a general factor comprising slowed information-processing and global tissue loss.

Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis.

BACKGROUND/OBJECTIVE: Fatigue, cognitive, and affective disorders are relevant symptoms in multiple sclerosis (MS). The treatment with Natalizumab has a positive effect on physical disabilities in patients with relapsing-remitting MS (RRMS). Some studies describe improvements in cognition and fatigue over 1 year of treatment. Only little is known about longer treatment effects especially on fatigue, and also on cognition and mood. Therefore, the present retrospective open label observational study investigates the effect of Natalizumab on fatigue, attention, and depression over a treatment period of 2 years. METHODS: About 51 RRMS patients who were treated with Natalizumab (male = 11, female = 40; mean age: 33. 9 ± 9. 1 years) were included. The neuropsychological assessment consisted of different tests of attention (TAP: alertness, divided attention, flexibility, SDMT, PASAT), fatigue (WEIMuS, FSMC), and depression (CES-D). The assessments occurred immediately before the first administration of Natalizumab, after 1 and 2 years of treatment. RESULTS: Significant improvements were found in aspects of attention and depression from baseline to follow-up 1 [alertness: reaction time (RT) cued, p < 0.05; divided attention: visual RT, p < 0.05; SDMT: p = 0.05; CES-D: p < 0.05] and from baseline to follow-up 2 (divided attention: visual RT: p < 0.001; errors: p < 0.01, omissions: p < 0.05; flexibility: RT, p < 0.05; SDMT: p < 0.01; CES-D: p < 0.05). No significant changes were detected in fatigue, probably because of the small sample size, especially in the second year of treatment (WEIMuS: N = 16, FSMC: N = 8). CONCLUSION: The results show a positive effect of Natalizumab on attention in patients with RRMS, and for the first time, also in depression after 2 years of observation, and support the efficacy of the treatment over 2 years. More research is needed for fatigue.

How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis?

BACKGROUND: Prevalence rates of cognitive impairment (CI) in multiple sclerosis (MS) vary between 40% and 80%. Differences in classification criteria for CI may explain this variance. OBJECTIVE: This study reviewed and compared classification criteria for CI in patients with early and late MS. METHODS: The paper consists of two parts: a systematic review of published classification criteria and the presentation of new data. Criteria were reviewed in respect to percentage of abnormal parameters and cut-offs concerning standard deviations. Thereafter, criteria were applied to cognitive data of 25 patients with early MS (duration ≤ 2 y), 52 matched patients with late MS (≥ 12 y), and 75 matched controls. The test battery assessed alertness, divided attention, mental flexibility, verbal and visual learning, memory, and visuospatial abilities. RESULTS: Seventy classification criteria were revealed and grouped into 20 distinct approaches that can be subdivided into three basic classification strategies. Most commonly, CI was defined as performing 1.5 SD or 2 SD below the normative mean in 18-30% of test parameters (n=42). Other criteria utilized cognitive domains (n=6), composite indices (n=8), or combinations of cut-offs and strategies. The stringency of the criteria was correlated with the prevalence rate of CI (r=-.43) and disease duration (r=.48). In the new data, a substantial effect of classification criteria was found with a prevalence rate ranging from 0 to 68% in early and 4 to 81% in late MS. Increased rates of CI in patients vs. controls were found following 18 out of 20 criteria in the sample of late MS. In early MS, an increased rate of CI was only found following a liberal 1.5 SD cut-off criterion. Inter-rater reliability between all criteria was moderate. However, between criteria of comparable stringency the inter-rater reliability was found to be strong. CONCLUSION: Classification based on different published criteria is not fully comparable and criteria need to be better homogenized.

Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients.

BACKGROUND: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. OBJECTIVE: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. METHODS: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). RESULTS: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. CONCLUSION: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Early development of spasticity following stroke: a prospective, observational trial.

This study followed a cohort of 103 patients at median 6 days, 6 and 16 weeks after stroke and recorded muscle tone, pain, paresis, Barthel Index and quality of life score (EQ-5D) to identify risk-factors for development of spasticity. 24.5% of stroke victims developed an increase of muscle tone within 2 weeks after stroke. Patients with spasticity had significantly higher incidences of pain and nursing home placement and lower Barthel and EQ-5D scores than patients with normal muscle tone. Early predictive factors for presence of severe spasticity [modified Ashworth scale score (MAS) >or=3] at final follow-up were moderate increase in muscle tone at baseline and/or first follow-up (MAS = 2), low Barthel Index at baseline, hemispasticity, involvement of more than two joints at first follow-up, and paresis at any assessment point. The study helps to identify patients at highest risk for permanent and severe spasticity, and advocates for early treatment in this group.

Cognition in the early stage of multiple sclerosis.

OBJECTIVE: Cognitive dysfunctions may contribute to limitation of everyday activities of patients with multiple sclerosis (MS). Recent studies have demonstrated that 45 to 65% of MS-patients are cognitively impaired. The profile of MS-related cognitive dysfunctions varies greatly. It includes memory and learning deficits, attention deficits, executive dysfunctions and visuo-spatial deficits. Most studies of cognition in MS examined patients in later stages, often including MS-patients with marked physical disabilities. Studies of cognitive dysfunctions in the early stage of the disease are rare. This study specifically aimed at evaluating and characterizing cognitive impairments in the early stage of MS, and determining specific patterns of cognitive dysfunction. METHODS: 21 MS patients, experiencing their first neurological symptoms not more than two years previously, and 22 healthy controls were compared. A comprehensive neuropsychological test-battery was used to evaluate MS-related cognition. The battery consisted of memory and learning tests, executive functioning tests and a visuo spatial functioning test. A computerized attention test-battery was also included, which assess accuracy and speed of test responses. In addition depression and intellectual capabilities were assessed. RESULTS: Compared with healthy controls, MS-patients in the early stage of the disease performed significantly lower on each neuropsychological assessment, except for verbal short-term memory. In particular, MS-patients showed a lengthened reaction time for simple and focused attention (19-38%), impaired non-verbal memory function (RVDLT recognition: 33%) and a planning deficit (24%). Associations between information processing speed and disease course and the employment situation were additionally found. However, patients did not have clinically relevant depression rates on the ADS-L and visuo spatial abilities remain preserved. CONCLUSION: Our findings revealed discrete cognitive dysfunction in MS-patients within the early stage of the disease.