Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis.

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

Personalized extended interval dosing of natalizumab in MS: A prospective multicenter trial.

OBJECTIVE: To determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: This was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase. RESULTS: Sixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%-7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%-7.4%) or relapses (95% CI 0%-7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0-5.0) and after follow-up (3.0, IQR 2.0-5.0). CONCLUSION: Personalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.

[Post-traumatic benign paroxysmal positional vertigo; an underdiagnosed cause of dizziness following trauma]. / Posttraumatische benigne paroxymale positieduizeligheid.

Dizziness is a frequently reported symptom following head trauma. Although often ascribed to concussion, post-traumatic benign paroxysmal positional vertigo (BPPV) must be included in the differential diagnosis. In this article, three patients who attended a neurology outpatient clinic with persistent dizziness following head trauma were ultimately diagnosed with post-traumatic BPPV. Dizziness lessened substantially once a canalith repositional manoeuvre was performed. Patients with post-traumatic BPPV are generally younger, report more severe symptoms and have a higher rate of relapse. Diagnosing post-traumatic BPPV can be challenging due to the presence of more urgent injuries in the initial phase and the habitual attribution of symptoms to concussion. A timely diagnosis is crucial, however, since treatment is easy to perform, non-invasive and effective.

[The invisible burden of cognitive problems in patients with multiple sclerosis]. / De onzichtbare last van cognitieve problemen bij multipele sclerose.

Approximately 34-65% of patients with multiple sclerosis (MS) are confronted with cognitive problems sooner or later. These include problems with the speed of information processing, memory, attention and executive functioning. Cognitive problems in patients with MS are currently often not examined on a routine basis and therefore remain unrecognised, or are not recognised in time. This may have a negative impact on their work and lead to social problems. In this article, we talk about the importance of early recognition of cognitive problems in patients with MS. Routine questioning about cognitive problems and the use of a short screening test are first steps in the right direction.

Cerebrospinal Venous Outflow in Multiple Sclerosis Patients versus Fatigue and/or Depression.

BACKGROUND: Endovascular treatment of impaired cerebrospinal venous outflow has been suggested to improve the overall quality of life in multiple sclerosis (MS) patients. Fatigue and depression are key factors in measuring the quality of life in MS patients. OBJECTIVE: In the present study, we investigated the correlation between anomalous venous outflow and the seriousness of fatigue and depression in MS patients and healthy controls. METHODS: Five cerebrospinal venous outflow parameters were measured in 20 MS patients and age- and sex-matched controls using extra- and transcranial Colour Doppler sonography. All patients and volunteers filled out the Fatigue Severity Scale (FSS) and Hospital Anxiety Depression Subscale (HADS). RESULTS: Nine abnormal parameters were found in 8 MS patients, whereas five abnormal parameters were found in 3 healthy controls (no significant difference). Only 1 MS patient met the criteria for chronic cerebrospinal venous insufficiency compared to 2 healthy controls. No significant differences were found in the FSS and HADS scores between patients with and without abnormal cerebrospinal venous outflow parameters. CONCLUSIONS: We found no significantly impaired cerebrospinal venous outflow in patients with MS versus sex- and age-matched controls. Furthermore, we did not find any correlation between anxiety or depression and impaired venous outflow in MS patients.

Validity of maximal exercise testing in people with multiple sclerosis and low to moderate levels of disability.

BACKGROUND: Cardiopulmonary exercise testing can be considered the gold standard for assessing cardiorespiratory fitness. Little is known about the criteria for maximal exercise testing in people with multiple sclerosis (MS) and how these criteria behave across different levels of neurological disability. OBJECTIVE: The study objectives were to determine the criteria for maximal exercise testing across various levels of disability and to assess concomitant subgroup differences in measures related to the participant, disease, and function. DESIGN: This was a cross-sectional study. METHODS: Cardiopulmonary exercise testing was conducted with a sample of 56 participants with MS. Analysis of variance was used to assess the criteria in participants with MS and low, mild, and moderate levels of disability. RESULTS: Mean peak oxygen consumption (V̇o2peak) was 21.4 (SD=7.1) mL·kg(-1)·min(-1). An oxygen consumption (V̇o2) plateau was seen in 37.5% of participants. A respiratory exchange ratio of 1.10 or greater was achieved by 69.6% of the participants, a maximal heart rate within 90% of their age-predicted maximal heart rate was achieved by 48.2% of the participants, and 23.2% of the participants perceived their exertion to be 18 or greater on the Borg Scale of Perceived Exertion (scores of 6-20). The values for achieved heart rate and incidence of a V̇o2 plateau were significantly lower in participants with moderate levels of disability than in those with mild levels of disability. LIMITATIONS: The primary limitations of this study were its cross-sectional nature and relatively small sample of participants with moderate levels of disability. CONCLUSION: The findings suggest that the outcome of cardiopulmonary exercise testing in people with MS and low to mild levels of disability (Expanded Disability Status Scale scores of ≤4.0) is a valid measure of cardiorespiratory fitness, whereas the outcome in people with moderate levels of disability (Expanded Disability Status Scale scores of >4.0) is most likely symptom limited.

Median nerve neuropraxia by a large false brachial artery aneurysm.

Peripheral nerve compression is a rare complication of an iatrogenic false brachial artery aneurysm. We present a 72-year-old patient with median nerve compression due to a false brachial artery aneurysm after removal of an arterial catheter. Surgical exclusion of the false aneurysm was performed in order to release traction of the median nerve. At 3-month assessment, moderate hand recovery in function and sensibility was noted. In the case of neuropraxia of the upper extremity, following a history of hospital stay and arterial lining or catheterization, compression due to pseudoaneurysm should be considered a probable cause directly at presentation. Early recognition and treatment is essential to avoid permanent neurological deficit.

Outcome measurement in multiple sclerosis: detection of clinically relevant improvement.

Because the development of new treatments in multiple sclerosis as well as the awareness of the importance of patient-oriented measures have become more important in the last two decades, new outcome measures have been developed with the aim of being more responsive to change and more clinically relevant to patients. The ability to detect improvement is sparsely studied. In the present study we evaluate the responsiveness of the Expanded Disability Status Scale and two quantitative tests (the timed 25-foot walk test and the nine-hole peg test) separately and in combination, to detect improvement after intravenous methylprednisolone. The Expanded Disability Status Scale, the timed 25-foot walk test and the nine-hole peg test were assessed in 112 multiple sclerosis patients before and 6 weeks after intravenous methylprednisolone. In addition patients were asked to rate their change as an anchor to evaluate the performance of the tests. Combining the timed 25-foot walk test and the nine-hole peg test turned out to be the optimal combination of measures to predict patient perceived improvement (positive predictive value of 67% and a negative predictive value of 59%, likelihood ratio of positive test 2.31 (95% confidence interval 1.08-4.95)). In the higher Expanded Disability Status Scale range (4.5 and higher), for all measures a significant change was more often perceived as clinically relevant than in the lower disability range. The Expanded Disability Status Scale seems not to be the preferred outcome of choice to detect patient perceived improvement in multiple sclerosis, especially in the lower Expanded Disability Status Scale range. Combining the timed walk test and the nine-hole peg test can improve the sensitivity to detect clinically relevant changes without conceding with respect to specificity.

Relation between objective and subjective measures of bladder dysfunction in multiple sclerosis.

The authors studied 297 patients with multiple sclerosis (MS), correlating urinary symptoms (bowel/bladder Functional System [FS] score of the Expanded Disability Status Scale [EDSS] and bladder dysfunction score of the Guy's Neurological Disability Scale [GNDS[) vs objective measurement of bladder dysfunction (postmicturition residual volume). EDSS and GNDS were of no value for predicting the presence of a clinically relevant postvoiding volume. Therefore, the authors recommend ultrasound scanning of residual volume in every patient with MS, even in the absence of subjective urinary symptoms.

INTERMED: a measure of biopsychosocial case complexity: one year stability in Multiple Sclerosis patients.

The 1-year temporal stability of the INTERMED in a sample of patients with relatively stable care needs, patients with established Multiple Sclerosis (MS) was analyzed. Seventy MS patients underwent an interview to assess the INTERMED by a trained nurse, and two examinations of disability, EDSS and GNDS by medical doctors. At the following appointment with the nurse, approximately 1 year later, a second INTERMED assessment was done. Spearman correlations and change scores between the INTERMED assessments were calculated. Correlations between the two assessments were considerable: 0.75 for the total score and 0.55-0.74 for the domain scores (all P <.05). Median change of all four INTERMED domain scores and total score were 0. Changes in INTERMED total scores tended to be associated with changes in EDSS scores over time (P = 0.09), but not with changes in GNDS scores (P = 0.67). Patients with INTERMED scores above 20 on at least one of the two assessments had longer disease duration (P < 0.01), were more frequently suffering from a chronic form of MS (P < 0.01), and had more disability on EDSS (P < 0.01) and GNDS (P < 0.01) assessments. In a sample of patients with an established diagnosis of MS, INTERMED scores remained fairly stable over the period of a year. Implementing the INTERMED in routine care of patients with chronic conditions may help the clinician to structure interdisciplinary care.

A study validating changes in the multiple sclerosis functional composite.

OBJECTIVE: To prospectively characterize the relation between 1-year changes in neurologist ratings of abnormalities as measured by means of the Expanded Disability Status Scale (EDSS) and changes in observations of functional impairment as measured by means of the Multiple Sclerosis Functional Composite (MSFC) in the clinical assessment of multiple sclerosis (MS). METHODS: One hundred twenty patients with MS were recruited at our outpatient clinic. Impairment and disability at baseline and follow-up were assessed using the EDSS and MSFC. We studied correlations between change (Delta) in the EDSS, MSFC, and MSFC components for the total population and different subgroups and analyzed the contribution of change in MSFC components to change in the EDSS and MSFC. RESULTS: Median EDSS score at baseline was 4.5; at follow-up, 5.0. Mean MSFC score at baseline was -0.00; at follow-up, -0.04. Good cross-sectional correlations were found between the EDSS and MSFC at baseline (-0.72) and follow-up (-0.73). Only weak correlations were found between DeltaEDSS and DeltaMSFC. Although DeltaEDSS showed the strongest correlations with change in leg function and weak or no correlation with change in cognitive function or arm function, DeltaMSFC showed the highest correlation with change in arm function and cognitive function. CONCLUSION: Our longitudinal data indicate that the MSFC reflects change from different dimensions of neurologic functions, which is a favorable characteristic when compared with the EDSS.