Bjorn Oskarsson

Motor neuron involvement in multisystem proteinopathy: Implications for ALS

Objective: To explore the putative connection between inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) and motor neuron disease (MND). Methods: Clinical, genetic, and EMG characterization of 17 patients from 8 IBMPFD families. Results: Limb weakness was the most common clinical manifestation (present in 15 patients, median onset age 38 years, range 25–52), with unequivocal evidence of upper motor neuron dysfunction in 3. EMG, abnormal in all 17, was purely neurogenic in 4, purely myopathic in 6, and mixed neurogenic/myopathic in 7. Cognitive/behavioral impairment was detected in at least 8. Mutations in VCP (R155H, R159G, R155C) were identified in 6 families, and in hnRNPA2B1 (D290V) in another family. The genetic cause in the eighth family has not yet been identified. Conclusion: Mutations in at least 4 genes may cause IBMPFD, and its phenotypic spectrum extends beyond IBM, Paget disease, and frontotemporal dementia (FTD). Weakness, the most common and disabling manifestation, may be caused by muscle disease or MND. The acronym IBMPFD is, therefore, insufficient to describe disorders due to VCP mutations or other recently identified IBMPFD-associated genes. Instead, we favor the descriptor multisystem proteinopathy (MSP), which encompasses both the extended clinical phenotype and the previously described prominent pathologic feature of protein aggregation in affected tissues. The nomenclature MSP1, MSP2, and MSP3 may be used for VCP-, HNRNPA2B1-, and HNRNPA1-associated disease, respectively. Genetic defects in MSP implicate a range of biological mechanisms including RNA processing and protein homeostasis, both with potential relevance to the pathobiology of more common MNDs such as amyotrophic lateral sclerosis (ALS) and providing an additional link between ALS and FTD.

Cognitive-behavioral screening reveals prevalent impairment in a large multicenter ALS cohort

Objectives: To characterize the prevalence of cognitive and behavioral symptoms using a cognitive/behavioral screening battery in a large prospective multicenter study of amyotrophic lateral sclerosis (ALS). Methods: Two hundred seventy-four patients with ALS completed 2 validated cognitive screening tests and 2 validated behavioral interviews with accompanying caregivers. We examined the associations between cognitive and behavioral performance, demographic and clinical data, and C9orf72 mutation data. Results: Based on the ALS Cognitive Behavioral Screen cognitive score, 6.5% of the sample scored below the cutoff score for frontotemporal lobar dementia, 54.2% scored in a range consistent with ALS with mild cognitive impairment, and 39.2% scored in the normal range. The ALS Cognitive Behavioral Screen behavioral subscale identified 16.5% of the sample scoring below the dementia cutoff score, with an additional 14.1% scoring in the ALS behavioral impairment range, and 69.4% scoring in the normal range. Conclusions: This investigation revealed high levels of cognitive and behavioral impairment in patients with ALS within 18 months of symptom onset, comparable to prior investigations. This investigation illustrates the successful use and scientific value of adding a cognitive-behavioral screening tool in studies of motor neuron diseases, to provide neurologists with an efficient method to measure these common deficits and to understand how they relate to key clinical variables, when extensive neuropsychological examinations are unavailable. These tools, developed specifically for patients with motor impairment, may be particularly useful in patient populations with multiple sclerosis and Parkinson disease, who are known to have comorbid cognitive decline.

Using the Frontal Assessment Battery to identify executive function impairments in amyotrophic lateral sclerosis: A preliminary experience.

Up to 50% of persons with amyotrophic lateral sclerosis (ALS) develop cognitive impairments, particularly of executive function (EF). The Frontal Assessment Battery (FAB) provides a method for rapid assessment of EF. We investigated the FAB as an assessment of cognitive impairment among 16 subjects with ALS, and evaluated their performance on the FAB and the Mini-Mental State Examination (MMSE). Raw FAB and MMSE scores were Z-transformed using published age- and education-based norms. FAB Z-scores were significantly lower than MMSE Z-scores (p<0.03). Eight subjects (50%) were impaired (Z ≤ −2) on the FAB while no subjects were impaired on the MMSE. MMSE and FAB scores did not vary as function of disease duration, laterality of onset, or Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Further study of the suitability of the FAB as a domain-specific screening measure of executive dysfunction for ALS is warranted.

Potential Environmental Factors in Amyotrophic Lateral Sclerosis

The causes of amyotrophic lateral sclerosis (ALS) are largely unknown, and may always be multiple, including environmental factors. Monogenetic determinants of ALS are involved in roughly 20% of all cases (including 10% familial cases). Less well understood multigenetic causes may contribute to another 20% to 80%. Environmental factors likely play a role in the development of ALS in susceptible individuals, but proved causation remains elusive. This article discusses the possible factors of male gender (males are selectively exposed to different influences, or genetically predisposed to be susceptible), smoking, military service, exercise, electrical exposure, heavy metals, agricultural chemicals, and geographic clusters.

ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS): Study methodology, recruitment, and baseline demographic and disease characteristics

Abstract In a multicenter study of newly diagnosed ALS patients without a reported family history of ALS, we are prospectively investigating whether markers of oxidative stress (OS) are associated with disease progression. Methods utilize an extensive structured telephone interview ascertaining environmental, lifestyle, dietary and psychological risk factors associated with OS. Detailed assessments were performed at baseline and at 3–6 month intervals during the ensuing 30 months. Our biorepository includes DNA, plasma, urine, and skin. Three hundred and fifty-five patients were recruited. Subjects were enrolled over a 36-month period at 16 sites. To meet the target number of subjects, the recruitment period was prolonged and additional sites were included. Results showed that demographic and disease characteristics were similar between 477 eligible/non-enrolled and enrolled patients, the only difference being type of health insurance among enrolled patients. Sites were divided into three groups by the number of enrolled subjects. Comparing these three groups, the Columbia site had fewer ‘definite ALS’ diagnoses. This is the first prospective, interdisciplinary, in-depth, multicenter epidemiological investigation of OS related to ALS progression and has been accomplished by an aggressive recruitment process. The baseline demographic and disease features of the study sample are now fully characterized.

Myopathy: Five New Things

Published with permission from Bjorn Oskarsson, MD This brief review touches on 5 relatively new things that ought to be useful for neurologists in general practices. The chosen topics include common conditions, techniques that are rapidly growing in utilization, and new developments that mandate new paradigms of treatment. Furthermore, all topics have had important developments in the last 5 years. The first section discusses the very common myalgias, myopathies, and rare rhabdomyolysis occurring with statin use. Next, the recently established necrotizing myopathy associated with statins is described. The third topic is muscle imaging with MRI and ultrasound, which are techniques used in conjunction with neuromuscular examination, EMG, and muscle biopsies, all of which remain the mainstay of diagnostic studies for muscle disease. The fourth topic reviewed is the myositis-specific autoantibodies and their relationship to the inflammatory myopathies. Finally, enzyme replacement therapy for Pompe disease is reviewed. This is the first limb-girdle syndrome for which we have a specific treatment and this has increased the importance of firmly establishing the underlying diagnosis in patients with these phenotypes. Before proceeding, it should be acknowledged that the review will not cover other interesting developments in the field of muscle diseases, particularly the muscular dystrophies and mitochondrial muscle diseases, where huge steps in our understanding of these conditions have been made. Also, while the term myositis is often used interchangeably with myopathy in both clinical practice and in the literature, in this review the term myositis will be used exclusively for the inflammatory myopathies. It is important to be aware that the term often is used to refer to all myopathies, inflammatory or not, and that it can not be taken to imply an inflammatory etiology. Statin drugs are being used more and more frequently, with up to 29.7 million people using them in …

ALS untangled no. 20: The Deanna protocol

ISSN 2167-8421 print/ISSN 2167-9223 online

Muscle Biopsy Evaluation in Neuromuscular Disorders

This article reviews the indications for a muscle biopsy, and then gives a step-by-step description of the processes of muscle selection through to interpreting the biopsy report. The article aims to aid the clinician in preparing for a muscle biopsy procedure to avoid common pitfalls and obtain optimal results from this minimally invasive procedure. The basic anatomic structure of normal muscle is reviewed to provide a foundation for understanding common patterns of pathologic change observed in muscle disease and common and disease-specific histopathologic findings are presented, focusing on a select group of neuromuscular diseases.

Myasthenia gravis exacerbation after discontinuing mycophenolate: A single-center cohort study.

Objective: To determine whether discontinuation or marked reduction of mycophenolate mofetil (MMF) in patients with myasthenia gravis (MG) causes MG exacerbations. Methods: We identified 88 patients with MG who took MMF during the 5-year period 2007–2011 at our MG clinic. We then performed detailed chart reviews and recorded all MG exacerbations and their relationship to MMF and other treatment changes. We also recorded demographic data and disease characteristics (including antibody status and Myasthenia Gravis Foundation of America status). Results: There were 14 patients who had an MG exacerbation during the study period. Of these, 13 had discontinued MMF therapy, with a median time until exacerbation of 16 weeks after discontinuation (9 patients) or marked dose reduction (4 patients) of MMF therapy (exacerbation in the absence of change in any other component of the immunosuppressive regimen). Using the cluster option in a Cox regression analysis, the MMF coefficient was −5.32, with a standard error of 1.05 and a p value of 0.0002, corresponding to an estimated hazard ratio of 204. Conclusions: This retrospective cohort study suggests that discontinuation/marked reduction of MMF therapy may increase the risk of MG exacerbation many fold, supporting the hypothesis that MMF plays a role in the maintenance of MG remission/minimal manifestation status. Classification of evidence: This study provides Class IV evidence that in patients with MG taking MMF, discontinuation or marked reduction of MMF causes MG exacerbation.

Upper extremity 3-dimensional reachable workspace assessment in amyotrophic lateral sclerosis by Kinect sensor

Introduction: Reachable workspace is a measure that provides clinically meaningful information regarding arm function. In this study, a Kinect sensor was used to determine the spectrum of 3‐dimensional reachable workspace encountered in a cross‐sectional cohort of individuals with amyotrophic lateral sclerosis (ALS). Methods: Bilateral 3D reachable workspace was recorded from 10 subjects with ALS and 17 healthy controls. The data were normalized by each individuals arm length to obtain a reachable workspace relative surface area (RSA). Concurrent validity was assessed by correlation with scoring on the ALS Functional Rating Score—revised (ALSFRSr). Results: The Kinect‐measured reachable workspace RSA differed significantly between the ALS and control subjects (0.579 ± 0.226 vs. 0.786 ± 0.069; P < 0.001). The RSA demonstrated correlation with ALSFRSr upper extremity items (Spearman correlation ρ = 0.569; P = 0.009). With worsening upper extremity function, as categorized by the ALSFRSr, the reachable workspace also decreased progressively. Conclusions: This study demonstrates the feasibility and potential of using a novel Kinect‐based reachable workspace outcome measure in ALS. Muscle Nerve 53: 234–241, 2016