Hanna Kolski

A 12-Year Prospective Study of Childhood Herpes Simplex Encephalitis: Is There a Broader Spectrum of Disease?

OBJECTIVE. The purpose of this study was to review the experience with herpes simplex encephalitis at the Hospital for Sick Children over the past 12 years. METHODS. All patients who were admitted to our institution with acute encephalitis between January 1994 and December 2005 were enrolled prospectively in an encephalitis registry. Children from the registry with herpes simplex encephalitis were included in this study; we detailed the clinical presentations, laboratory findings, electroencephalographic findings, diagnostic imaging findings, treatments, and outcomes for all cases. RESULTS. Of 322 cases of acute encephalitis, 5% were caused by herpes simplex virus. Initially negative herpes simplex virus cerebrospinal fluid polymerase chain reaction results were found in 2 cases (13%), but results became positive in repeat cerebrospinal fluid analyses. Classic clinical presentations were seen in 75% of cases, cerebrospinal fluid pleocytosis was found in 94%, elevated cerebrospinal fluid protein levels were found in 50%, electroencephalographic changes were observed in 94%, and diagnostic imaging abnormalities were noted in 88%. All patients were treated with intravenous acyclovir. Neurologic sequelae occurred in 63% of cases, including seizures in 44% and developmental delays in 25%. There were no deaths in this study group. CONCLUSIONS. Herpes simplex encephalitis continues to be associated with poor long-term neurologic outcomes despite appropriate therapy. Cerebrospinal fluid polymerase chain reaction results may be negative early in the course of herpes simplex encephalitis; therefore, repeat cerebrospinal fluid analysis should be considered if herpes simplex encephalitis is suspected. Atypical forms of herpes simplex virus central nervous system disease may occur in children.

Mutation update and genotype-phenotype correlations of novel and previously described mutations in TPM2 and TPM3 causing congenital myopathies.

Mutations affecting skeletal muscle isoforms of the tropomyosin genes may cause nemaline myopathy, cap myopathy, core‐rod myopathy, congenital fiber‐type disproportion, distal arthrogryposes, and Escobar syndrome. We correlate the clinical picture of these diseases with novel (19) and previously reported (31) mutations of the TPM2 and TPM3 genes. Included are altogether 93 families: 53 with TPM2 mutations and 40 with TPM3 mutations. Thirty distinct pathogenic variants of TPM2 and 20 of TPM3 have been published or listed in the Leiden Open Variant Database (http://www.dmd.nl/). Most are heterozygous changes associated with autosomal‐dominant disease. Patients with TPM2 mutations tended to present with milder symptoms than those with TPM3 mutations, DA being present only in the TPM2 group. Previous studies have shown that five of the mutations in TPM2 and one in TPM3 cause increased Ca2+ sensitivity resulting in a hypercontractile molecular phenotype. Patients with hypercontractile phenotype more often had contractures of the limb joints (18/19) and jaw (6/19) than those with nonhypercontractile ones (2/22 and 1/22), whereas patients with the non‐hypercontractile molecular phenotype more often (19/22) had axial contractures than the hypercontractile group (7/19). Our in silico predictions show that most mutations affect tropomyosin–actin association or tropomyosin head‐to‐tail binding.

Cooperative International Neuromuscular Research Group Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy.

Introduction: Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). Methods: This investigation was a cross‐sectional cross‐sectional analysis of clinical data from the multi‐institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2–28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Results: Two hundred thirty‐one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. Conclusions: We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort. Muscle Nerve 50:250–256, 2014

Clinical Characteristics of Pediatric Myasthenia: A Surveillance Study

OBJECTIVE: To evaluate the incidence, clinical features, diagnostic, and treatment trends of pediatric myasthenia in Canada. METHODS: Through established Canadian Pediatric Surveillance Program methodology, physicians were anonymously surveyed for cases of pediatric myasthenia using a standardized clinical questionnaire containing deidentified data. Inclusion criteria were any child <18 years old with ≥1 of the following: (1) fluctuating ptosis or extraocular weakness, (2) skeletal muscle weakness or fatigue, and (3) any of the following supportive tests: clinical response to acetylcholinesterase inhibitor, positive antibodies, abnormal slow repetitive nerve stimulation, or single-fiber electromyography. RESULTS: In 2 years of surveillance, 57 confirmed cases were reported. There were 34 generalized and 18 ocular reports of juvenile myasthenia gravis plus 5 congenital myasthenic syndrome cases. There were 14 incident cases in 2010 and 6 in 2011. Age of onset ranged from “birth” to 17 years for the generalized form compared with 18 months to 11 years for the ocular subtype. Positive acetylcholine receptor titers were found in 22 (67%) of 33 generalized cases and 8 (44%) of 18 ocular patients. Of patients started on pyridostigmine, improvement was noted in 33 (100%) of 33 generalized cases and 15 (88%) of 17 ocular cases. CONCLUSIONS: This study represents the largest descriptive series of pediatric myasthenia in North America and provides valuable information about clinical characteristics. A high index of suspicion is important for this treatable disease. Children generally respond promptly to readily available therapies.

Exon skipping for nonsense mutations in Duchenne muscular dystrophy: too many mutations, too few patients?

Introduction: Duchenne muscular dystrophy (DMD), one of the most common and lethal genetic disorders, is caused by mutations of the dystrophin gene. Removal of an exon or of multiple exons using antisense molecules has been demonstrated to allow synthesis of truncated ‘Becker muscular dystrophy-like’ dystrophin. Areas covered: Approximately 15% of DMD cases are caused by a nonsense mutation. Although patient databases have previously been surveyed for applicability to each deletion mutation pattern, this is not so for nonsense mutations. Here, we examine the world-wide database containing notations for more than 1200 patients with nonsense mutations. Approximately 47% of nonsense mutations can be potentially treated with single exon skipping, rising to 90% with double exon skipping, but to reach this proportion requires the development of exon skipping molecules targeting some 68 of dystrophins 79 exons, with patient numbers spread thinly across those exons. In this review, we discuss progress and remaining hurdles in exon skipping and an alternative strategy, stop-codon readthrough. Expert opinion: Antisense-mediated exon skipping therapy is targeted highly at the individual patient and is a clear example of personalized medicine. An efficient regulatory path for drug approval will be a key to success.

A population-based study of dystrophin mutations in Canada.

INTRODUCTION We carried out a population-based study of dystrophin mutations in patients followed by members of the Canadian Paediatric Neuromuscular Group (CPNG) over a ten-year period. OBJECTIVES We aimed to describe the changes in diagnostic testing for dystrophinopathy and to determine the frequency of dystrophin mutations from 2000 to 2009. METHODS De-identified data containing the clinical phenotypes, diagnostic methods, and mutational reports from dystrophinopathy patients followed by CPNG centres from January 2000 to December 2009 were analyzed using descriptive statistics. RESULTS 773 patients had a confirmed diagnosis of dystrophinopathy based on genetic testing (97%), muscle biopsy (2%), or family history (1%). 573 (74%) had complete deletion/duplication analysis of all 79 exons or whole gene sequencing, resulting in 366 (64%) deletions, 64 (11%) duplications, and 143 (25%) point mutations. The percentage of patients who were diagnosed using currently accepted genetic testing methods varied across Canada, with a mean of 63% (SD 23). 246 (43%) mutations involved exons 45 to 53. The top ten deletions (n=147, 26%) were exons 45-47, 45-48, 45, 45-50, 45-55, 51, 45-49, 45-52, 49-50, and 46-47. 169 (29%) mutations involved exons 2 to 20. The most common duplications (n=29, 5.1%) were exons 2, 2-7, 2-17, 3-7, 8-11, 10, 10-11, and 12. CONCLUSION This is the most comprehensive report of dystrophin mutations in Canada. Consensus guidelines regarding the diagnostic approach to dystrophinopathy will hopefully reduce the geographical variation in mutation detection rates in the coming decade.

Symptomatic dystrophinopathies in female children.

Although manifesting female carriers of dystrophinopathies have been documented in adults, there are few reports of females presenting with symptomatic dystrophinopathies during childhood. The Canadian Pediatric Neuromuscular Group identified and characterized nine cases of female children 16 years or younger with genetically and/or histologically confirmed symptomatic dystrophinopathy, with an age range of 2-10 years at presentation. Presenting symptoms included proximal muscle weakness (6/9), calf pseudohypertrophy (5/9), abnormal gait (5/9) and myalgias (5/9). Five patients were noted to have significant behavioural and learning issues. The patients had a delay in diagnosis of 4 years from symptom onset. Skewed X inactivation was noted in 5/9 patients, while one patient had X inactivation levels in the normal range. Two of the patients were found to have X/autosome translocation, one of whom also had skewed X-inactivation. Increased awareness of manifesting females with dystrophinopathies will allow for earlier diagnosis and appropriate management for this rare group of patients.

Long-Term Effects of Glucocorticoids on Function, Quality of Life, and Survival in Patients with Duchenne Muscular Dystrophy: A Prospective Cohort Study.

BACKGROUND Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.

Pentoxifylline as a rescue treatment for DMD: A randomized double-blind clinical trial

Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). Methods: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. Results: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. Conclusion: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. Classification of evidence: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

CINRG Duchenne Natural History Study demonstrates insufficient diagnosis and treatment of cardiomyopathy in Duchenne muscular dystrophy

Introduction: Cardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD). Methods: This investigation was a cross‐sectional cross‐sectional analysis of clinical data from the multi‐institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2–28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%. Results: Two hundred thirty‐one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy. Conclusions: We found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort. Muscle Nerve 50:250–256, 2014