Huned S. Patwa

Evidence-based guideline: Intravenous immunoglobulin in the treatment of neuromuscular disorders: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Objective: To assess the evidence for the efficacy of IV immunoglobulin (IVIg) to treat neuromuscular disorders. Methods: The MEDLINE, Web of Science, and EMBASE databases were searched (1966–2009). Selected articles were rated according to the American Academy of Neurologys therapeutic classification of evidence scheme; recommendations were based on the evidence level. Results and Recommendations: IVIg is as efficacious as plasmapheresis and should be offered for treating Guillain-Barré syndrome (GBS) in adults (Level A). IVIg is effective and should be offered in the long-term treatment of chronic inflammatory demyelinating polyneuropathy (Level A). IVIg is probably effective and should be considered for treating moderate to severe myasthenia gravis and multifocal motor neuropathy (Level B). IVIg is possibly effective and may be considered for treating nonresponsive dermatomyositis in adults and Lambert-Eaton myasthenic syndrome (Level C). Evidence is insufficient to support or refute use of IVIg in the treatment of immunoglobulin M paraprotein–associated neuropathy, inclusion body myositis, polymyositis, diabetic radiculoplexoneuropathy, or Miller Fisher syndrome, or in the routine treatment of postpolio syndrome or in children with GBS (Level U). IVIg combined with plasmapheresis should not be considered for treating GBS (Level B). More data are needed regarding IVIg efficacy as compared with other treatments/treatment combinations. Most studies concluded IVIg-related serious adverse effects were rare. Given the variable nature of these diseases, individualized treatments depending on patient need and physician judgment are important.

The effect of prednisone on the progression from ocular to generalized myasthenia gravis.

Fifty percent of ocular myasthenia gravis (OMG) patients will progress to generalized myasthenia, 90% within 3 years from the onset of ocular symptoms. This study was performed to determine whether treatment with oral prednisone initiated and completed within 2 years from the onset of ocular symptoms would affect the progression of ocular myasthenia to generalized myasthenia gravis (GMG). Fifty-six patients were included in this review, with 27 patients in the prednisone-treated group and 29 patients in the untreated group. The treated group was initiated on 60 mg of prednisone daily with a slow taper over 3-6 months. At 2 years, significantly fewer patients in the treated group (3 of 27) progressed to generalized myasthenia when compared to the untreated group (10 of 29) (chi(2), p=0.04). Our results suggest that the early use of steroids may decrease progression of ocular to generalized myasthenia gravis. The decision to use steroids should be considered early in the course of patients diagnosed with ocular myasthenia gravis. This study should be considered preliminary and a prospective trial is warranted to confirm our observations.

Use of fiberoptic endoscopic evaluation of swallowing (FEES) in patients with amyotrophic lateral sclerosis.

This study investigated the use of fiberoptic endoscopic evaluation of swallowing (FEES) to both diagnose pharyngeal dysphagia and make treatment recommendations in 17 consecutive patients with a new diagnosis of amyotrophic lateral sclerosis (ALS) and complaints of dysphagia. Ten of 17 (59%) patients exhibited pharyngeal dysphagia with aspiration or aspiration risk with clear liquids, i.e., 5 of 8 (63%) limb and 5 of 9 (56%) bulbar. If depth of bolus flow was a problem, thickened liquids and single, small bolus sizes were recommended. If bolus retention was a problem, a small clear liquid bolus after each puree or solid bolus was recommended to aid pharyngeal clearing. Five of 17 (30%) patients required multiple FEES evaluations because of disease progression. For the first time in patients with ALS, FEES was shown to be successful in assessing preswallow anatomy and physiology, diagnosing pharyngeal dysphagia, and providing objective data for appropriate therapeutic interventions to promote safer oral intake. Visual biofeedback provided by FEES was successful for both patient and family education and to investigate individualized therapeutic strategies that, if successful, can be implemented immediately. Serial FEES allows for objective monitoring of dysphagia symptoms and timely implementation of diet changes and/or therapeutic strategies to continue safer oral intake and maintain optimum quality of life.

Rituximab in the management of refractory myasthenia gravis.

Myasthenia gravis (MG) is an immune‐mediated disorder with a variable response to treatment. In this study, patients with refractory MG who were treated with rituximab were identified. A review of patients referred to the Yale Neuromuscular Clinic was performed. Patients with refractory MG who were treated with rituximab were reviewed for response to treatment. Patients who had muscle‐specific kinase (MuSK+) or acetylcholine receptor (AChR+) antibodies were included. Six patients were identified who met the criteria described. All patients tolerated rituximab without side effects and had a reduced need for immunosuppressants and/or improvement in clinical function. Patients with refractory MG appeared to respond to rituximab in this small, retrospective study. This result suggests that a larger, prospective trial is indicated. Muscle Nerve, 2009

Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody–Positive Myasthenia Gravis

Importance Myasthenia gravis (MG), an autoimmune disorder of neuromuscular transmission, is treated by an array of immunotherapeutics, many of which are nonspecific. Even with current therapies, a subset of patients has medically refractory MG. The benefits of B-cell–targeted therapy with rituximab have been observed in MG; however, the duration of these benefits after treatment is unclear. Objective To evaluate the durability of response to rituximab in the treatment of acetylcholine receptor autoantibody–positive (AChR+) generalized MG. Design, Setting and Participants This retrospective case series study included 16 patients with AChR+ MG referred to an MG clinic from January 1, 2007, to December 31, 2015. The patients were treated with rituximab and followed up for 18 to 84 months after treatment. Main Outcomes and Measures Assessment of long-term clinical response, durability of response and/or relapse rate, AChR autoantibody levels, adverse effects, and inflammatory markers. Results In the 16 patients (6 men and 10 women; median age, 42 [range, 18-69] years), clinical improvement was observed in parallel with complete withdrawal or reduction of other immunotherapies, with all patients achieving complete stable remission, pharmacologic remission, or minimal manifestations based on the Myasthenia Gravis Foundation of America postintervention status criteria. Nine patients (56%) had a relapse during a mean follow-up of 36 (range, 24-47) months. Seven patients (44%) remained relapse free with a mean follow-up of 47 (range, 18-81) months since the last rituximab treatment. All values were normalized to a pretreatment anti-AChR antibody level of 100% and the mean levels after each rituximab cycle were calculated. A 33% decrease was seen after cycle 1 of rituximab treatment (100% vs 67%; P = .004); 20% after cycle 2 (compared with cycle 1) (67% vs 47%; P = .008); and 17% after cycle 3 (compared with cycle 2) (47% vs 30%; P = .02). However, the serum cytokine levels measured were found to be unchanged. Conclusions and Relevance Rituximab therapy appears to be an effective option in patients with refractory AChR+ MG, who were observed to have a durable response after treatment. Identification of markers of disease relapse and sustained remission are critical next steps in the development of pathophysiology-relevant, evidence-based practice parameters for rituximab in the treatment of MG.

Independent home use of a brain-computer interface by people with amyotrophic lateral sclerosis

Objective To assess the reliability and usefulness of an EEG-based brain-computer interface (BCI) for patients with advanced amyotrophic lateral sclerosis (ALS) who used it independently at home for up to 18 months. Methods Of 42 patients consented, 39 (93%) met the study criteria, and 37 (88%) were assessed for use of the Wadsworth BCI. Nine (21%) could not use the BCI. Of the other 28, 27 (men, age 28–79 years) (64%) had the BCI placed in their homes, and they and their caregivers were trained to use it. Use data were collected by Internet. Periodic visits evaluated BCI benefit and burden and quality of life. Results Over subsequent months, 12 (29% of the original 42) left the study because of death or rapid disease progression and 6 (14%) left because of decreased interest. Fourteen (33%) completed training and used the BCI independently, mainly for communication. Technical problems were rare. Patient and caregiver ratings indicated that BCI benefit exceeded burden. Quality of life remained stable. Of those not lost to the disease, half completed the study; all but 1 patient kept the BCI for further use. Conclusion The Wadsworth BCI home system can function reliably and usefully when operated by patients in their homes. BCIs that support communication are at present most suitable for people who are severely disabled but are otherwise in stable health. Improvements in BCI convenience and performance, including some now underway, should increase the number of people who find them useful and the extent to which they are used.

Relationship Between Cerebrospinal Fluid Protein Levels and Electrophysiologic Abnormalities in Guillain-Barré Syndrome.

Objectives: The cerebrospinal fluid (CSF) protein level is known to be elevated in patients with Guillain–Barré syndrome (GBS). This report correlates the degree of CSF protein elevation with the number of electrophysiologic abnormalities on nerve conduction study (NCS). Methods: We reviewed 38 patients admitted to our institution with a diagnosis of GBS and had both a measured CSF protein level and a NCS within 24 hours of each other. Results: CSF protein level correlates with the number of NCS demyelination criteria, as described by Cornblath, in patients with GBS. Conclusions: This retrospective study is the first to demonstrate a relationship between the CSF protein level and the electrophysiologic abnormalities that accompany GBS.

Current and emerging therapies for multiple sclerosis.

Huned S. Patwa, MD In this issue of Clinical Therapeutics, we review current and emerging therapies for multiple sclerosis (MS). MS is the fourth leading cause of neurologic disability in the United States. The condition commonly begins in the second or third decade of life and has a female preponderance. Given the young age of onset, patients often deal with the effects of MS for decades. The relapsing-remitting form of MS is the most common and affects 80% of patients; a more progressive course is seen in 20% of subjects. There are a broad number of immunologic agents available to treat patients with MS, with other promising therapies in development. Although early descriptions of MS date back to the 14th century, it was Jean-Martin Charcot, who has been called the “Father of Neurology,” who made the correlation between the clinical features and pathologic changes seen postmortem. Charcot described the characteristic “plaques” in the brain of a young woman with tremor, dysarthria, and eye movement abnormalities. He used many of the treatments of the day such as strychnine and injections of gold and silver, with no luck. In the 1960s, MS was recognized as an autoimmune disorder and, over the next decade, steroids were used for the treatment of MS attacks. The first disease-modifying therapy was introduced in 1993 (interferon β-1b); since then, numerous other therapies have been discovered. In addition to the number of new therapies approved for the treatment of MS, there are others in development, presenting patients with a range of therapeutic options. In this issue of Clinical Therapeutics, Carrithers provides an excellent overview of the clinical trial data for the disease-modifying therapies. In addition, he discusses the limitations due to their adverse effects, as well as other challenges of current treatments. Moreover, he reminds us that even the most current therapies have a limited effect on cumulative disability. Despite the proven benefit of many of the therapies, the long duration of illness and treatment over decades lead to challenges of adherence to therapy. Interferon β-1a is administered via subcutaneous injections, and patients report discomfort with injections or local site reactions. In their observational study on “real-life setting” patients, Hupperts and colleagues describe low injection site reactions with the use of serum-free interferon β-1a. This option, in turn, led to better adherence, which presumably accounts for the reduced annualized relapse rate observed in this study. Reduction of relapse rates and lesions on magnetic resonance imaging is a key measure of success in MS treatment trials and is often used as a primary outcome measure. The impact of MS on quality of life cannot be underestimated and is an important measure of benefit. Kita and colleagues used existing data from 2 large studies of dimethyl fumarate, the DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) and CONFIRM (Comparator and an Oral Fumarate in RRMS), to assess health-related quality of life in patients with MS. Dimethyl fumarate was shown to improve neuroradiologic and relapse rate

Commentaries on the Current Treatment of Selected Neurologic Diseases

Huned S. Patwa The “Decade of the Brain” in the 1990s was meant to “to enhance public awareness of the benefits to be derived from brain research.” Earlier this year, President Obama announced a new research initiative funded by the federal government to study the human brain. In his announcement, the president stated, “Now, as humans, we can identify galaxies light years away. We can study particles smaller than an atom, but we still haven’t unlocked the mystery of the three pounds of matter that sits between our ears.” There is clearly great interest in diseases affecting the nervous system. The common neurologic disorders affect a large proportion of the population. Alzheimer’s disease is the most common cause of age-related dementia. In addition to the devastating effects of Alzheimer’s in individuals with this disorder, there is an additional burden on the caregivers of people with this condition. Similarly, Parkinson’s disease, with the hallmarks of resting tremor, postural instability, bradykinesia, and rigid tone, occurs at higher rates in the elderly population. Those at greatest risk for cerebrovascular disease have vascular risk factors, such as hypertension, atrial fibrillation, smoking, and elevated cholesterol. Although the clinical characteristics of stroke vary considerably, the rate of disability is significant, accounting for one of the leading causes of disability worldwide. Multiple sclerosis can have a variable clinical course and is classified as relapsing, remitting, secondary progressive, or primary progressive. The peak age of onset is around 30 years of age, with increased risk in the European and North American populations. All together, these conditions represent a high burden of neurologic disease. Although there is still much more work to be done, the treatment armamentarium for these neurologic disorders has grown, and many are now well known: (1) cholinomimetic agents to slow progression of cognitive decline in some forms of dementia; (2) dopamine-enhancement therapies for the relief of motor symptoms in Parkinson’s disease; (3) antiplatelet agents and risk factor modification for the secondary prevention of stroke; and (4) disease-modifying biologics to reduce the number of relapses in multiple sclerosis. These and other advances in neuroscience make the future of treatment of neurologic disease promising. In this inaugural Topic Issue for Neurology and Neuroscience in Clinical Therapeutics, we have assembled authors who provide reviews of the current use of existing therapies and assessments of newer therapies, emphasizing their risks and benefits for the above-mentioned neurologic conditions. We believe their insights will be useful to both neurologic and generalist clinicians. Dr. Nygaard provides an overview of current and future therapies for Alzheimer’s disease. The cholinesterase inhibitors and memantine have been approved for the treatment of Alzheimer’s Dimmentia Immunotherapy, although with some disappointing clinical trials, still holds some promise. Other therapies aimed at blocking the effects of the A-β and τ proteins are reviewed. Malloy et al review the literature on the use of antiplatelet therapy for the secondary prevention of noncardioembolic stroke. Although “more is better” when it comes to combination antiplatelet therapy, it is not surprising that more also leads to higher rates of hemorrhagic conversion. Malloy reminds us that the use of

Veterans Health Administration Information Systems as a Resource for Rare Disorders Research: Creutzfeldt–Jakob Disease as a Paradigm

OBJECTIVE To illustrate the application of Veterans Health Administration (VHA) information systems in both clinical and epidemiologic investigations of a rare disease, our specific aims were: (1) to determine the number and incidence of Creutzfeldt-Jakob disease (CJD) diagnoses in the VHA from fiscal year (FY) 1997 through FY 2010 and (2) to describe the relevant clinical features associated with those diagnoses. METHODS The VHA Medical SAS Datasets were queried for all unique, incident CJD diagnoses between FY 1997 and 2010. Electronic health records were then reviewed to validate diagnoses using modified criteria. RESULTS During the study period, 115 CJD diagnoses (43 definite, 27 probable, 19 possible, and 26 suspected) were identified. Annual incidence ranged between 0.8 per million (95% CI, 0.3-1.7) in FY 2009 and 3.7 per million (95% CI, 2.1-6.4) in FY 1997. Dementia was documented in 111 cases (96.5%) and myoclonus in 73 (63.5%). Discharges consistent with CJD were noted in 31 of 78 patients (39.7%) with documented electroencephalography. CONCLUSIONS For certain rare diseases, VHA information systems can be used to assemble a substantive case series for clinical study. However, the VHAs distinctive demographic characteristics and population dynamics may limit the external validity of epidemiologic investigations.