Zaeem A. Siddiqi

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis

Background: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). Methods: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. Results: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). Conclusions: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Antiepileptic drugs and liver disease

Antiepileptic drugs (AEDs) are no longer restricted to the treatment of epilepsy. These are widely used in a broad spectrum of psychiatric and neurological disorders. Liver plays a major role in the metabolism of a majority of these drugs. Hepatotoxicity is rare, but a real concern when initiating therapy. Likewise, liver disease can adversely affect the biotransformation of some of these drugs. This manuscript addresses the significance of elevated liver enzymes associated with AED use, the role of therapeutic drug monitoring, pharmacokinetics during liver disease and potential risk of hepatotoxicity.

A genome-wide association study of myasthenia gravis

IMPORTANCE Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Peripheral neuropathy in Krabbe disease Electrodiagnostic findings

Background: Krabbe disease (KD) is associated with marked central and peripheral demyelination and nerve conduction studies (NCS) typically show a mixed sensorimotor demyelinating peripheral neuropathy (PN). Objectives: To further characterize the PN in a large cohort of patients with KD and to assess the diagnostic sensitivity of NCS in this condition. Methods: The authors report the results of electrodiagnostic studies performed in 27 children with KD, ranging in age from 1 day to 8 years, whose diagnosis was confirmed by leukocyte lysosomal enzyme analysis. Results: Based on age-adjusted normative values, 25 of 27 patients had abnormal NCS (sensitivity > 90%) when at least one motor and one sensory nerve were tested in a lower and an upper extremity. Of the 24 patients with the early infantile form of the disease, 23 had abnormal NCS (sensitivity > 95%). Abnormal sural sensory responses (SNR) (82%), F-wave latencies (FWL) (85%), motor conduction velocities (CV) (82%), and distal motor latencies (DL) (76%) were the most sensitive indices. In the lower extremities the sensitivity of motor CV, FWL, and motor DL was 79%, 79%, and 57%, respectively, while in the upper limbs the corresponding sensitivities were 80%, 87%, and 73%. No conduction block was detected and there was uniform slowing of CV. SNR was unobtainable or abnormal in 82% of patients. The compound muscle action potential amplitudes were within normal limits in >70% of lower limb and >45% of upper limb responses. Marked NCS abnormalities were found in a 1-day-old and two 3-week-old neonates, the youngest patients reported to date. NCS were abnormal in 5/9 children with normal EEG or evoked potentials. The severity of the demyelination on NCS correlated well with the clinical severity of the disease. Conclusions: Peripheral neuropathy occurs very early in Krabbe disease and affects the nerves uniformly. Nerve conduction studies may provide a highly sensitive tool to screen this patient population.

Lessons from Two Trials of Mycophenolate Mofetil in Myasthenia Gravis

Two randomized controlled trials of mycophenolate mofetil (MMF) in the treatment of myasthenia gravis (MG) were recently completed. Although neither study demonstrated efficacy of MMF in the population of patients studied, there are valuable lessons in the way these studies were developed and performed. After reviewing the design and results of these trials, we discuss possible reasons leading to negative results and the lessons learned, which should be useful for future clinical trials in MG.

Cervical electromyogram profile differences between patients of neck pain and control.

Study Design. A comparative analysis of electromyogram (EMG) signals of patients of cervical pain and normal controls. Objectives. To determine the differences between frequency and time domain parameters of EMG signals of patients of cervical pain and normal controls. Summary of Background Data. No diagnostic technique has emerged as a satisfactory tool for identification of spinal pain. Method. Seventeen male and 17 female chronic neck pain patients without cervical radiculopathy were recruited through neurology EMG clinic. The controls consisted of 30 male and 33 female subjects with no history of neck pain in the past 12 months. All subjects performed flexion, left anterolateral flexion, left lateral flexion, left posterolateral extension, and extension to pain threshold/20% maximum voluntary contraction and pain tolerance/maximum voluntary contraction in random order. The descriptive statistics for body weight normalized strength, normalized peak EMG, time to onset, time to peak, median frequency, mean power frequency, and frequency bands were calculated. These variables were subjected to analysis of variance and logistic regression to distinguish between patients and controls. Results. The normalized peak EMG of patients was significantly greater than those of controls in both maximal and submaximal exertions (P < 0.01). Whereas there was no consistent pattern in time to peak EMG, the time to onset of EMG revealed that the left sternocleidomastoid was always recruited before the onset of torque. A lack of significant difference in the median frequency of the 2 samples indicates that the pain did not disturb the muscle conduction velocity. Using discriminant logistic regression on frequency domain and time domain parameters, up to 97% of patients and controls were correctly classified with the resubstitution method. Conclusion. Surface EMG can be used successfully in distinguishing chronic pain patients and controls, and efficacy of treatment regimes.

Use of specialized coagulation testing in the evaluation of patients with acute ischemic stroke

Objective: To investigate the use and appropriateness of specialized coagulation tests in the evaluation of patients with acute ischemic stroke and identify factors that influence test ordering. Background: Coagulation abnormalities are a rare but recognized cause of ischemic stroke. Methods: Patient demographics, stroke risk factors, history of venous thrombosis or miscarriage, family history of stroke, and the results of specialized tests for coagulation disorders were recorded for a consecutive series of ischemic stroke patients over age 18 admitted to an academic medical center over 3 years (n = 674). Factors associated with testing were identified with univariate analyses in a random sample of two-thirds of the patients (n = 450). Multivariate logistic regression modeling was then used to identify variables independently associated with testing and then validated in the remaining patients (n = 224). Results: Of the 31% of patients (n = 208) tested for coagulopathies, 29% (n = 60) were tested when the result was unlikely to influence therapeutic decisions. Historical factors associated with an increased incidence of a coagulopathy, such as history of venous thrombosis or miscarriage, were not commonly documented. The absence of small-artery atherosclerosis (OR 0.36, 95% CI 0.17 to 0.76) and younger age (OR 0.89 per year, 95% CI 0.87 to 0.92) were independently related to the frequency of specialized coagulation testing. Conclusions: One-third of specialized coagulation tests were ordered when the test results were unlikely to affect therapeutic decisions. Age was the only clinical factor increasing the likelihood of a coagulopathy that appeared to influence ordering of specialized coagulation tests.

Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up.

We examined the clinical effectiveness of rituximab in fourteen patients with refractory myasthenia gravis (MG). Manual muscle testing (MMT) score was recorded at baseline and followed during the course of the study. Steroid dose, frequency of intravenous immunoglobulin (IVIG) infusions, and plasma exchange (PLEX) were also monitored throughout the duration of the study. All patients responded dramatically to rituximab, as measured by a change in MMT score, prednisone dose, or the frequency of IVIG infusions or PLEX. Rituximab appears safe and effective for the treatment of refractory MG. It should be considered as a therapeutic option in refractory patients.

Improving patient selection for coagulopathy testing in the setting of acute ischemic stroke.

To improve patient selection for specialized coagulation testing in the setting of ischemic stroke, the authors sought to identify factors associated with the presence of hypercoagulable states. Of 208 patients with ischemic stroke tested, undetermined stroke subtype was significantly associated with the presence of coagulopathy, but only 60% were treated with warfarin. The frequency of coagulopathy in selected patients with ischemic stroke (5%) is low, and establishing the diagnosis did not uniformly influence treatment.

CRYPTOCOCCAL MENINGOENCEPHALITIS IN IMMUNOCOMPETENT PATIENTS: CHANGING TRENDS IN CANADA

Cryptococcosis can range from asymptomatic pulmonary colonization to life-threatening meningitis and disseminated disease. Most infections occur in immunodeficiency states, though recent reports suggest that immunocompetent individuals may be at risk with some varieties of the yeast. Cryptococcus neoformans var grubii and Cryptococcus neoformans var neoformans infect immunocompromised individuals,1 whereas Cryptococcus neoformans var gattii occurs predominantly in immunocompetent patients and has a strong male preponderance. This variety is found in the tropics in the decaying heartwood of a number of tree species and the outbreak in 2002 on Vancouver Island suggests this region to be the primary ecologic niche of the organism in Canada.2 To date, no cases of C neoformans var gattii in immunocompetent patients have been reported outside British Columbia. We describe clinical features of 3 such patients from Edmonton, Alberta. ### Case reports. #### Case 1. A 52-year-old previously healthy man presented with a 2-day history of fever, drowsiness, and neck stiffness. In the previous month, he had experienced new onset headaches, excessive daytime sleepiness, decreased mobility, and occasional disorientation, though routine investigations, including brain CT scan, had been normal. His family had moved from British Columbia in 2006. His HIV serology and chest X-ray were normal. CSF had lymphocytic pleocytosis. Brain CT showed hypodensities in basal ganglia, which appeared as multiple septated cysts (cryptococcoma) on MRI with no enhancement or surrounding edema (figure, A–F). CSF India ink stain was positive for cryptococcus and cultures grew C neoformans var gattii . Induction therapy with amphotericin B and flucytosine was instituted with daily lumbar punctures for raised …