Peter Humphreys

Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities

Rett syndrome (RTT) is characterized by specific motor, cognitive, and behavioral deficits. Because several of these abnormalities occur in other disease states associated with alterations in aminergic neurotransmitters, we investigated the contribution of such alterations to RTT pathogenesis. We found that both individuals with RTT and Mecp2-null mice have lower-than-normal levels of aminergic metabolites and content. Deleting Mecp2 from either TH-positive dopaminergic and noradrenergic neurons or PET1-positive serotonergic neurons in mice decreased corresponding neurotransmitter concentration and specific phenotypes, likely through MeCP2 regulation of rate-limiting enzymes involved in aminergic neurotransmitter production. These data support a cell-autonomous, MeCP2-dependent mechanism for the regulation of aminergic neurotransmitter synthesis contributing to unique behavioral phenotypes.

The efficacy and efficiency of a self-administered treatment for adolescent migraine☆

&NA; Migraine headaches are frequent in adolescents. Although many adolescents are adequately treated palliatively with analgesics, an important subgroup requires prophylactic treatment. Medical treatments for adolescents with frequent severe headaches is often problematic. Prophylactic pharmacological treatments are often shunned by adolescents and their parents because of concern over drug usage. Moreover, propranolol, the most widely used prophylactic drug with adults, is frequently not effective. Psychological interventions are effective but are costly and often not available. A randomized controlled trial was undertaken to evaluate the efficacy and efficiency of a predominantly self‐administered treatment that could be delivered in a very cost‐efficient format. Eighty seven adolescents (63 females and 24 males) ranging in age from 11 to 18 years were randomly assigned to receive a self‐administered treatment, the same treatment delivered by a therapist or a control treatment. Self‐administered and clinic treatment were equally effective and superior to the control treatment. However, the self‐administered treatment was substantially more efficient. Both active treatments were durable at 1‐year follow‐up.

Cognitive and relaxation treatment of paediatric migraine

&NA; The present study compared the efficacy of two active treatments, relaxation training and cognitive coping, with a non‐specific placebo control in the treatment of 42 children and adolescents with migraine. The first treatment is a simplified version of progressive deep muscle relaxation; the second, a form of cognitive restructuring involving the alteration of dysfunctional thought processes. The results demonstrated that each active treatment was superior to the non‐specific intervention in reducing overall headache activity and frequency but not duration or intensity. There were no differences between the experimental groups, and both continued to improve through a 16‐week follow‐up period, but the control group did not. Initial level of headache severity was an important factor in treatment outcome, with children with severe headaches responding better than those with milder headaches. Possible reasons for the differential treatment effects are discussed, and the implications for future research are considered.

Children's drawings of their pain

Abstract Children and adolescents with recurrent migraine headaches or musculo‐skeletal pain were asked to draw a picture of their pain and another picture of themselves in pain. The drawings were categorized according to content and color. No differences in content or dominant color of drawings was found for sex and there were no changes with age (5–18 years). Children with recurrent migraine more often drew themselves doing something to relieve their pain, than did children with musculoskeletal pain. Implications for the use of pain drawings in the treatment of chronic and recurrent pain are discussed.

RELAXATION PROPHYLAXIS FOR CHILDHOOD MIGRAINE: A RANDOMIZED PLACEBO-CONTROLLED TRIAL

A randomized controlled trial was used to evaluate the effectiveness of relaxation training in the treatment of paediatric migraine. Relaxation training was compared with two control groups (psychological placebo and ‘own best efforts’) in a total of 99 children and adolescents with frequent migraine. Daily recording of the headaches following treatment, three months after treatment and at the one‐year follow‐up indicated that all three treatments were equally effective. The importance of the use of adequate control conditions which generate equivalent expectancies in pain treatment research was confirmed.

Validity of the Headache Diary for Children

SYNOPSIS

Incidence of Guillain-Barré syndrome in Ontario and Quebec, 1983-1989, using hospital service databases.

To determine the incidence of Guillain-Barré syndrome (GBS) in the Canadian provinces of Ontario and Quebec during 1983–1989 and to demonstrate the feasibility of measuring the incidence of GBS through internal record linkage of Canadian hospital service data, we conducted a record linkage study. This study used the databases of the Hospital Medical Records Institute and the Ministere de la sante et des services sociaux du Quebec. We extracted records containing the International Classification of Diseases, 9th revision, code for GBS or a diagnosis likely to harbor misclassified GBS cases from each database and linked them internally using computerized algorithms. We identified a total of 1,302 and 1,031 incident cases of GBS admitted to Ontario and Quebec hospitals, respectively. The calculated mean annual GBS incidence rate in each province, after age and sex standardization to the 1986 Canadian census population, was 2.02 per 100,000 person-years in Ontario and 2.30 per 100,000 person-years in Quebec. Chart reviews revealed that the false-positive diagnosis rate might be as high as 0.26 per 100,000 person-years in Ontario and 0.21 per 100,000 person-years in Quebec. With adjustment for these false-positive rates, the incidence rate of GBS becomes 1.51 per 100,000 person-years and 1.78 per 100,000 person-years in Ontario and Quebec, respectively. In both provinces, the incidence rate was higher in older age strata (70–80 years) and in males. We saw no seasonal or geographic pattern.

Arteriopathy Diagnosis in Childhood Arterial Ischemic Stroke Results of the Vascular Effects of Infection in Pediatric Stroke Study

Background and Purpose Although arteriopathies are the most common cause of childhood arterial ischemic stroke (AIS), and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with AIS.Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (&kgr;=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Clinical guidelines for management of bone health in Rett syndrome based on expert consensus and available evidence

Objectives We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. Methods An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. Results Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. Conclusion A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.

Clobazam as an Add-on Drug in the Treatment of Refractory Epilepsy of Childhood

We report the results of a double-blind cross-over study comparing clobazam and placebo in the treatment of refractory childhood epilepsy. Fifty-two percent of patients had greater than 50% reduction in their seizure frequency when taking the clobazam. During the placebo phase no patient recorded a greater than 50% reduction in seizure frequency. Sex, age, seizure type, intellect did not appear to differentiate clobazam responsive from nonresponsive patients. Only 2/21 patients had behavioral changes on the drug sufficiently severe to require the patient to drop out of the study prematurely. Drug interactions between clobazam and the other anticonvulsant medicines did not occur.