Alexander Rae-Grant

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo- controlled, randomized phase II trial

In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Practice guideline update summary: Mild cognitive impairment: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective To update the 2001 American Academy of Neurology (AAN) guideline on mild cognitive impairment (MCI). Methods The guideline panel systematically reviewed MCI prevalence, prognosis, and treatment articles according to AAN evidence classification criteria, and based recommendations on evidence and modified Delphi consensus. Results MCI prevalence was 6.7% for ages 60–64, 8.4% for 65–69, 10.1% for 70–74, 14.8% for 75–79, and 25.2% for 80–84. Cumulative dementia incidence was 14.9% in individuals with MCI older than age 65 years followed for 2 years. No high-quality evidence exists to support pharmacologic treatments for MCI. In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. Major recommendations Clinicians should assess for MCI with validated tools in appropriate scenarios (Level B). Clinicians should evaluate patients with MCI for modifiable risk factors, assess for functional impairment, and assess for and treat behavioral/neuropsychiatric symptoms (Level B). Clinicians should monitor cognitive status of patients with MCI over time (Level B). Cognitively impairing medications should be discontinued where possible and behavioral symptoms treated (Level B). Clinicians may choose not to offer cholinesterase inhibitors (Level B); if offering, they must first discuss lack of evidence (Level A). Clinicians should recommend regular exercise (Level B). Clinicians may recommend cognitive training (Level C). Clinicians should discuss diagnosis, prognosis, long-term planning, and the lack of effective medicine options (Level B), and may discuss biomarker research with patients with MCI and families (Level C).

Outcome of severe brain injury: a multimodality neurophysiologic study.

We screened all head-injured trauma patients admitted to Lehigh Valley Hospital during a 2-year period. From 725 screened patients, 69 patients in a coma on the second day after trauma were entered into this study. During the first week, these patients underwent electroencephalography (EEG), evoked potentials, ocular pneumoplethysmography, and transcranial Doppler (TCD) sonography. Clinical examinations were undertaken 2 and 7 days after trauma. Test results were correlated with functional clinical outcome at 6 months. In a multiple regression analysis, EEG was the major independent variable that significantly predicted 6-month outcome based on Glasgow Outcome Scale score. Transcranial Doppler sonography contributed a small additional component. Though EEG was the most significant predictive factor in this neurophysiological battery, it did not add significantly to the predictive power of Glasgow Coma Scale score determined at day 7. These findings suggest that in neurophysiologic testing in this type of patient is not useful in improving predictive outcome data.

Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). Methods A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine–compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus–based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. Results Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.

Quality improvement in neurology: Multiple sclerosis quality measures: Executive summary.

All clinicians believe they provide quality care, yet most clinicians do not directly measure quality parameters in their practice to provide verifiable health care outcomes.1 Quality measures related to a chronic disease provide reportable and repeatable measures that can either document performance of quality care or identify gaps in care for future action/improvement. Disease-specific quality measures in neurology provide a framework that can assist clinicians in practice measurement and modification; these have the potential to benefit both subspecialist and generalist alike. Multiple sclerosis (MS) is a common, chronic, and ultimately disabling disease with multiple potential clinical intervention points during its course. It is therefore appropriate to have quality measures specific for this condition that span the course of the disease.

A technical approach to dissecting and assessing cadaveric veins pertinent to chronic cerebrospinal venous insufficiency in multiple sclerosis

Abstract Objective: To establish a detailed technical procedure for studying the anatomical correlates of chronic cerebrospinal venous insufficiency in cadavers of multiple sclerosis and control subjects, and to present our findings of the normal anatomic venous structures, with reference to previous descriptions from the literature. Methods: This study examined the internal jugular veins (IJVs), the brachiocephalic veins, and the azygos vein from 20 cadavers (10 control and 10 multiple sclerosis). These veins were exposed, isolated by clamps from the rest of the venous system, flushed with water, and then injected with fluid silicone from the superior ends of both IJVs. After the silicone cured to its solid state, the venous tree was removed en bloc and dissected longitudinally to expose the luminal surface. All vein segments were analyzed for anatomic variation. Anatomical analysis for this manuscript focused on normal vein architecture and its variants. Results: Thirty-seven of 40 IJVs contained valves: 29 bicuspid, 6 tricuspid, and 2 unicuspid. The average circumferences of the right and left IJVs were 2·2 and 1·8 cm, respectively. Thirteen of 20 azygos veins contained a valve, located on average 3·6 cm away from the superior vena cava junction. Nine of the 13 azygos valves were bicuspid; four were tricuspid. Only one of the 40 brachiocephalic veins contained a valve. Discussion: We detailed a technical approach for harvesting cadaveric neck and thoracic veins with relevance to chronic cerebrospinal venous insufficiency. The anatomy of the venous system has significant variability, including differing number of valves in different regions and variable characteristics of the valves. Average vein circumference was less than that typically reported in imaging studies of live patients.

Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective To review evidence on starting, switching, and stopping disease-modifying therapies (DMTs) for multiple sclerosis (MS) in clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and progressive MS forms. Methods Relevant, peer-reviewed research articles, systematic reviews, and abstracts were identified (MEDLINE, CENTRAL, EMBASE searched from inception to November 2016). Studies were rated using the therapeutic classification scheme. Prior published Cochrane reviews were also used. Results Twenty Cochrane reviews and an additional 73 full-text articles were selected for data extraction through an updated systematic review (completed November 2016). For people with RRMS, many DMTs are superior to placebo (annualized relapses rates [ARRs], new disease activity [new MRI T2 lesion burden], and in-study disease progression) (see summary and full text publications). For people with RRMS who experienced a relapse on interferon-β (IFN-β) or glatiramer acetate, alemtuzumab is more effective than IFN-β-1a 44 μg subcutaneous 3 times per week in reducing the ARR. For people with primary progressive MS, ocrelizumab is probably more effective than placebo (in-study disease progression). DMTs for MS have varying adverse effects. In people with CIS, glatiramer acetate and IFN-β-1a subcutaneous 3 times per week are more effective than placebo in decreasing risk of conversion to MS. Cladribine, immunoglobulins, IFN-β-1a 30 μg intramuscular weekly, IFN-β-1b subcutaneous alternate day, and teriflunomide are probably more effective than placebo in decreasing risk of conversion to MS. Suggestions for future research include studies considering comparative effectiveness, usefulness of high-efficacy treatment vs stepped-care protocols, and research into predictive biomarkers.

A Systematic Review of Stress-Management Interventions for Multiple Sclerosis Patients

BACKGROUNDnThe objective of this study was to identify stress-management interventions used for people with multiple sclerosis (MS) and systematically evaluate the efficacy of these interventions.nnnMETHODSnSeveral strategies were used to search for studies reported in articles published up to 2013.nnnRESULTSnOur initial search retrieved 117 publications, of which 8 met our criteria for review. Of the eight studies, one provided Class I evidence, five provided Class III evidence, and two provided Class IV evidence for the efficacy of stress-management interventions according to the evidence classification established by the American Academy of Neurology. Most studies showed positive changes in outcomes assessed; however, the range of methodological quality among the published studies made it difficult to draw conclusions.nnnCONCLUSIONSnThe promising findings for stress-management interventions highlight the need for future studies. Additional large, prospective, multicenter studies will help to define the role of stress-management interventions in the treatment and course of MS. Furthermore, including outcome measures based on biological and clinical markers of disease will prove useful in understanding potential underlying mechanisms.

Clinical utility of seropositive voltage-gated potassium channel-complex antibody.

Background:Antibodies against voltage-gated potassium channel (VGKC)–complex are implicated in the pathogenesis of acquired neuromyotonia, limbic encephalitis, faciobrachial dystonic seizure, and Morvan syndrome. Outside these entities, the clinical value of VGKC-complex antibodies remains unclear. Methods:We conducted a single-center review of patients positive for VGKC-complex antibodies over an 8-year period. Results:Among 114 patients positive for VGKC-complex antibody, 11 (9.6%) carrying the diagnosis of limbic encephalitis (n = 9) or neuromyotonia (n = 2) constituted the classic group, and the remaining 103 cases of various neurologic and non-neurologic disorders comprised the nonclassic group. The median titer for the classic group was higher than the nonclassic group (p < 0.0001). A total of 90.9% of the patients in the classic and 21.4% in the nonclassic group possessed high (>0.25 nM) VGKC-complex antibody levels (p < 0.0001). A total of 75.0% of the patients in the high-level group had definite or probable autoimmune basis, while nonautoimmune disorders were seen in 75.6% of patients from the low-level group (p < 0.0001). A total of 26.3% of patients were found with active or remote solid organ or hematologic malignancy, but no antibody titer difference was observed among subgroups of absent, active, or remote malignancy. Compared to age-matched US national census, rates of active cancer in our cohort were higher in patients older than 45 years. Conclusions:High VGKC-complex antibody titers are more likely found in patients with classically associated syndromes and other autoimmune conditions. Low-level VGKC-complex antibodies can be detected in nonspecific and mostly nonautoimmune disorders. The presence of VGKC-complex antibody, rather than its level, may serve as a marker of malignancy.

Quality improvement in neurology: Multiple sclerosis quality measures: Executive summaryAuthor Response

Editors Note: In reference to “Quality improvement in neurology: Multiple sclerosis quality measures: Executive summary,” Dr. McDonnell suggests several additions based on existing guidelines. The authors reply and discuss the Work Group process. Responding to “Association between job strain and risk of incident stroke: A meta-analysis,” Dr. Bianchi argues that the link between job stress and stroke may be overestimated when job-unrelated stress is not taken into account. The authors reaffirm their results but agree that more integrative studies are needed. —Megan Alcauskas, MD, and Robert C. Griggs, MD nnRae-Grant et …