Jonathan L. Carter

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Effects of Acute and Chronic Denervation on Release of Acetylcholinesterase and Its Molecular Forms in Rat Diaphragms

Abstract: Hemidiaphragms were removed from rats at various times after intrathoracic transection of the left phrenic nerve and were incubated in organ baths containing 1.5 ml of oxygenated, buffered physiologic saline solution, with added glucose and bovine serum albumin. After incubation, the acetylcholinesterase (AChE; EC 3.1.1.7) activities of the bath fluid and of the muscle were determined. Innervated left hemidiaphragms were found to release 107 units of AChE over a 3‐h period, corresponding to 1.9% of their total AChE activity. Denervation led to a rapid loss of AChE from the muscle coincident with a transient increase in the outpouring of enzyme activity into the bath fluid. Thus, 1 day after nerve transection the left hemidiaphragm contained only 68% of the control amount of AChE activity, but released 140% as much as control. After 3 or 4 days of denervation, the AChE activity of the diaphragm stabilized at 35% of the control value. Release also fell below control by this time, but not as far. One week after denervation the release, 69 units per 3 hr, corresponded to 3.3% of the reduced content of AChE activity in the muscle, indicating that denervation caused an increase in the proportion of AChE released. Sucrose density gradient ultracentrifugation showed that 10S AChE accounted for more than 80% of the released enzyme activity at all times. The results did not rule out the possibility, however, that the released enzyme originally stemmed from 4S or 16S AChE in the diaphragm.

Therapy of relapsing multiple sclerosis. Treatment approaches for nonresponders

There is increasing impetus to begin disease-modifying therapy for relapsing multiple (R-MS) early, before the development of irreversible tissue damage and resultant permanent disability. However, all of the currently-approved therapies for relapsing multiple sclerosis are only partially effective for patients as a group. Treatment failure can be due to noncompliance with therapy, intolerable adverse effects, the development of neutralizing antibodies, or non-responsive disease. Neurologists managing patients on disease-modifying therapy for R-MS must remain vigilant for these issues and take appropriate action when necessary.

Autonomic symptom burden is associated with MS-related fatigue and quality of life

BACKGROUND Nonspecific symptoms such as fatigue and dizziness are common in multiple sclerosis (MS), even in patients with normal exams. Little is known about the relationship of autonomic dysfunction with these symptoms and quality of life. OBJECTIVE Assess the association of autonomic symptom burden with fatigue, clinical status and quality of life. METHODS Subjects completed an autonomic symptom (COMPASS-31), quality of life (MSQOL-54) and fatigue (FSS) questionnaire at their routine MS clinic follow-up. Demographic and clinical data were collected from the medical record. Pearson correlations were assessed between autonomic symptoms and fatigue, quality of life, disability and disease duration. RESULTS One-hundred subjects completed the study (mean age 48 years; 78% female; 84% relapsing-remitting), mean disease duration was 14.7 years and mean EDSS 2.5. MSQOL-54 composite scores were 58 physical and 65 mental. COMPASS-31 correlated with MSQOL-54 (Physical R= -0.60; Mental -0.54; p<0.001) and FSS (R=0.51; p<0.001). There was no relationship between COMPASS-31 and EDSS (R=0, p=0.97) or disease duration (R= -0.02, p=0.84). CONCLUSIONS Autonomic symptom burden is correlated with decreased quality of life and increased fatigue. Autonomic symptoms are present early in the disease and at low disability and may reflect aspects of disease burden that are not well-captured by current disability measures.

Rational Clinical Immunotherapy for Multiple Sclerosis

In this article, we assess the roles and the efficacy of immunopharmacologic agents in the treatment of multiple sclerosis (MS) and other demyelinating disease syndromes. The initial clinical manifestations of demyelinating disease, immunotherapeutic goals, efficacy of individual agents, and specific immunopharmacologic recommendations are discussed. MS and other idiopathic demyelinating disease syndromes can be effectively managed with immunotherapy. Exacerbations are treatable, and the frequency and severity of exacerbations can be reduced. Although some agents have a minor effect on progression of disability, current approaches have not proved to have a major influence on treatment of progressive MS. Immunotherapy for inflammatory demyelinating disease necessitates a high degree of clinical certainty about the diagnosis. Because all available therapeutic agents have limitations and significant toxic effects, careful consideration is necessary before use. Treatment should be individualized on the basis of the clinical course of the disease and the degree of patient disability.

Alliance for Clinical Education Perspective Paper: Recommendations for Redesigning the “Final Year” of Medical School

Background: Although medical school typically lasts 4 years, little attention has been devoted to the structure of the educational experience that takes place during the final year of medical school. Summary: In this perspectives paper, we outline goals for the 4th year of medical school to facilitate a transition from undergraduate to graduate medical education. We provide recommendations for capstone courses, subinternship rotations, and specialty-specific schedules, and we conclude with recommendations to medical students and medical schools for how to use the recommendations contained in this document. Conclusions: We provide an overview of general competencies and specialty specific recommendations to serve as a foundation for medical schools to develop robust 4th-year curricula and for medical students to plan their 4th-year schedules.

Do Cannabinoids Reduce Multiple Sclerosis-Related Spasticity?

Background:The plant Cannabis sativa contains numerous cannabinoids, which are aromatic hydrocarbons that have central nervous system effects mediated through specific cannabinoid receptors. Some patients with multiple sclerosis (MS) report symptomatic relief from spasticity, pain, and other symptoms when using smoked cannabis, and small trials have suggested some symptomatic benefit. Objective:Do cannabinoids improve spasticity in patients with MS? Methods:We addressed the question through the development of a structured, critically appraised topic. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarian, and clinical content experts in the field of MS. Participants started with a clinical scenario and a structured question, devised search strategies, located and compiled the best evidence, performed a critical appraisal, synthesized the results, summarized the evidence, provided commentary, and declared bottom-line conclusions. Results:The largest randomized, placebo-controlled trial of oral cannabinoid therapy detected no improvement for MS-related spasticity as measured by the Ashworth scale. However, subjective participant reports indicated improvement in spasticity (P = 0.01), spasms (P = 0.038), sleep quality (P = 0.025), and pain (P = 0.002) without detriment to depression, fatigue, irritability, or walk time. A second randomized controlled trial, which used subjective participant report as the primary outcome, revealed the same discrepancy between subjective and objective spasticity outcome measures. Conclusion:Randomized controlled trials have failed to confirm objective evidence for a beneficial effect of cannabinoids on MS-related spasticity. However, improvement in subjective assessments of spasticity and other related symptoms have been consistently noted, raising questions about the sensitivity and validity of current objective outcome instruments. Further research is warranted with regards to both outcome instrument development and the effects of cannabinoids on MS-related spasticity.

Are corticosteroids efficacious for preventing or treating neutralizing antibodies in multiple sclerosis patients treated with beta-interferons?: A critically appraised topic

Background:Persistent, high-titer neutralizing antibodies (NAbs) reduce or eliminate the biologic activity of interferon-beta (IFNB) therapies for multiple sclerosis (MS) and are associated with reduction in efficacy. Most patients who develop NAbs have preceding detectable binding antibodies. There is no consensus on prevention or management of NAb-positive patients but switching to noninterferon therapy and use of immunosuppressive strategies, especially corticosteroids, has been proposed. Objective:To evaluate the evidence supporting the efficacy of corticosteroid therapy for (a) reducing the incidence of NAbs; and (b) improving markers of interferon bioavailability, reducing NAbs titers, and improving clinical outcomes in NAb-positive patients with MS receiving IFNB therapy. Methods:The objective was addressed through the development of a structured critically appraised topic. This included a case scenario, structured question, search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and content experts in the fields of neuroimmunology and multiple sclerosis. Results:We selected 4 papers for detailed review, all of which used pulsed methylprednisolone therapy, either alone or in combination with another immunosuppressive therapy. A randomized open-label trial showed that monthly intravenous methylprednisolone initiated at INFB therapy onset was associated with a lower risk of an ever-positive NAb result but was insufficiently sensitive to detect an effect on more clinically meaningful high-titer NAbs. A randomized controlled trial for patients with active disease despite IFNB therapy showed that baseline NAb titers were reduced by subsequent intravenous methylprednisolone treatment, but the incidence of NAbs was too small to assess clinical relevance. Small open-label observational studies suggest that pulse methylprednisolone, alone or in combination with azathioprine, does not restore the bioavailability of IFNB. Conclusions:Pulse methylprednisolone therapy may reduce the risk of developing NAbs (but possibly not high-titer NAbs of clinical importance) when coadministered with newly initiated IFNB therapy. However, current evidence suggests that methylprednisolone therapy does not restore IFNB biologic response in established NAB-positive MS patients.

Status of neurology medical school education Results of 2005 and 2012 clerkship director survey

Objective: To survey all US medical school clerkship directors (CDs) in neurology and to compare results from a similar survey in 2005. Methods: A survey was developed by a work group of the American Academy of Neurology Undergraduate Education Subcommittee, and sent to all neurology CDs listed in the American Academy of Neurology database. Comparisons were made to a similar 2005 survey. Results: Survey response rate was 73%. Neurology was required in 93% of responding schools. Duration of clerkships was 4 weeks in 74% and 3 weeks in 11%. Clerkships were taken in the third year in 56%, third or fourth year in 19%, and fourth year in 12%. Clerkship duration in 2012 was slightly shorter than in 2005 (fewer clerkships of ≥4 weeks, p = 0.125), but more clerkships have moved into the third year (fewer neurology clerkships during the fourth year, p = 0.051). Simulation training in lumbar punctures was available at 44% of schools, but only 2% of students attempted lumbar punctures on patients. CDs averaged 20% protected time, but reported that they needed at least 32%. Secretarial full-time equivalent was 0.50 or less in 71% of clerkships. Eighty-five percent of CDs were “very satisfied” or “somewhat satisfied,” but more than half experienced “burnout” and 35% had considered relinquishing their role. Conclusion: Trends in neurology undergraduate education since 2005 include shorter clerkships, migration into the third year, and increasing use of technology. CDs are generally satisfied, but report stressors, including inadequate protected time and departmental support.

Disease Modifying Therapies for Multiple Sclerosis

SummaryOver the last few decades the treatment of multiple sclerosis (MS) has been approached from a number of different perspectives. The initial successes in MS therapy involved the use of corticosteroid treatments to induce short term improvements in neurological function, and symptomatic therapies for some of the complications of MS. More recently, with improved understanding of the immunological events occurring during progression of the disease, therapies that modify the natural history of the disease have become available. Interferon beta-1b (‘Betaseron’) is the first new treatment for MS to be licensed by the US Food and Drug Administration (FDA) in the last 30 years. In a multicentre, double-blind, placebo-controlled trial, the drug reduced the exacerbation rate and magnetic resonance imaging (MRI) evidence of disease activity. Other interferon preparations are currently undergoing clinical testing, and a second recombinant interferon beta has also shown evidence of clinical efficacy in a recently completed trial. Copolymer-1 has also reduced relapse rate in patients with replasing-remitting MS.Global immunosuppression with azathioprine and cyclophosphamide has been utilised with varying benefit in Europe and North America for several decades. In addition, there have been recent reports of beneficial effects of immunosuppressive agents such as methotrexate and cladribine in patients with chronic progressive MS.Clinical trial methodology (including more sensitive clinical outcome measures and the use of serial quantitative MRI) and serial cognitive testing have evolved to provide more convincing evidence of efficacy of MS therapies. In addition, the mechanism of action of older therapies, such as corticosteroids, has been elucidated by these advances. In the future, increasingly more specific immunotherapies will become available, and combinations of therapy may provide greater efficacy than current single agent approaches.