Clinical and genetic spectrum of SCN2A-associated episodic ataxia.

BACKGROUND: Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches. RESULTS: We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1-2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype-phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not. CONCLUSIONS: Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.

The use and effectiveness of temozolomide in children with central nervous system tumours: a survey from the Canadian Paediatric Brain Tumour Consortium.

OBJECTIVE: To describe the use of temozolomide (tmz) in Canadian children treated for brain tumours and to evaluate survival and predictors of survival for children treated with this agent. METHODS: A survey was conducted within the Canadian Paediatric Brain Tumour Consortium (cpbtc), a group of tertiary care centres in pediatric neuro-oncology (n = 16) in Canada that are involved in the treatment of children with central nervous system tumours. RESULTS: In 10 of the 16 participating pediatric oncology centres of the cpbtc, 137 children with brain tumours were treated with tmz between January 2000 and March 2006. Although 33% of the children were enrolled into a clinical trial, 67% were treated outside open studies. Most patients (72%) received tmz treatment on recurrence of their brain tumour (first or subsequent). The most commonly administered regimen was single-agent tmz 150-200 mg/m(2) administered on 5 consecutive days every 28 days. The median duration of tmz treatment was 141 days (range: 4-1102 days). Response data were provided for 127 of the 137 patients, of whom 6 showed a complete response. Sixteen patients experienced a minor or partial response, 53 had stable disease, and 52 had progressive disease. Of 32 patients alive at last follow-up, 19 had a diagnosis of low-grade glioma. CONCLUSIONS: Temozolomide is used in a variety of pediatric brain tumours, often at the time of recurrence. The lack of insight into clear indications for this agent in pediatric brain tumours-used either alone or in combination therapy-may be a result of suboptimal design of phase i and ii studies and a lack of phase iii trials in the pediatric brain tumour population.

Concurrent carbogen and radiation therapy in children with high-risk brainstem gliomas.

In an attempt to improve local control, we assessed the feasibility of the addition of 4 min of carbogen inhalation (as a radiosensitizer) to daily fractionated radiotherapy in pediatric patients with high grade and/or diffuse brainstem gliomas. Ten patients inhaled carbogen for >90% of the radiation treatments. Median survival time from start of therapy was 0.80 years. Carbogen inhalation did not appear to improve the dismal prognosis.

Isolated sulfite oxidase deficiency in the newborn: lactic acidaemia and leukoencephalopathy.

We report a newborn with progressive leukoencephalopathy and lactic acidaemia, diagnosed with isolated sulfite oxidase deficiency. We show that low plasma total homocysteine (PTHcy) is a valuable early indicator of sulfite oxidase dysfunction, providing a crucial first-line screen, whereas plasma cystine is not always informative in the first few days of life.

Asynchronous burst-suppression in a child with callosal Ki-1 anaplastic large cell lymphoma.

A 13-year-old girl with Ki-1 anaplastic large cell lymphoma (Ki-1ALCL) bulky deposits in the brain developed raised intracranial pressure and coma associated with asynchronous burst-suppression following standard dose cranial irradiation. Supportive care, steroids, and chemotherapy resulted in clinical improvement. Burst-suppression coma may be reversible when secondary to tumor, decrease in steroids, or radiation effects; the asynchrony localizes the lesion to cortical interconnections such as the corpus callosum.

Intratumoral therapy with bleomycin for cystic craniopharyngiomas in children.

Surgical removal of cystic craniopharyngiomas in children is associated with significant operative morbidity and recurrence rates. The purpose of this study was to review our experience with a less invasive therapy, namely, intratumoral bleomycin, in the treatment of predominantly cystic craniopharyngiomas. All children with craniopharyngiomas treated at a tertiary care pediatric neurosurgical center since 1994, when bleomycin was first used, were reviewed retrospectively. Seven patients received intratumoral bleomycin therapy. Patients received 2-5 mg bleomycin per dose, 3 times per week, for 3-5 weeks as an initial course. Mean follow-up of these patients was 3 years. In 4 patients, treatment resulted in a significant decrease (>50%) in tumor size, which has remained stable. Two patients' tumors progressed and underwent resection, and 1 patient had surgical removal because of persistent headaches, although no growth of residual tumor had been noted. One patient developed peritumoral edema as a result of bleomycin therapy. Intratumoral bleomycin is a useful alternative therapy for cystic craniopharyngiomas, and may control tumor growth and delay potentially harmful resection and/or radiotherapy in young children.

Hyperbaric oxygen therapy for cerebral palsy: two complications of treatment.

There is growing interest in the use of hyperbaric oxygen therapy (HBO(2)) for children with cerebral palsy. Although there is no rigorous evidence to support this management, private hyperbaric centers have been established throughout the United States and Canada. There is likely to be increasing pressure on pediatricians and other health professionals to prescribe HBO(2). We describe 2 children with cerebral palsy who suffered significant morbidity immediately after treatment with hyperbaric oxygen. Both the temporal association and pathologic findings suggest that the hyperbaric treatment is likely to have been responsible for the resulting complications. As with any new therapy, we suggest waiting for the results of a randomized, controlled trial before recommending this treatment.

Treatment of intracranial ependymoma by surgery alone.

OBJECTIVE: This study aimed to determine the safety of deferring radiotherapy in pediatric intracranial ependymoma following a radiographically confirmed gross total resection in patients with localized disease. METHODS: Children over age 3 were recruited prospectively from 1990 to 1997, following a surgical impression and radiologic confirmation of a gross total resection of an intracranial ependymoma. RESULTS: 10/32 cases of intracranial ependymomas were both eligible and gave consent. 7 remain free of disease without further intervention. 3 recurred, 2 were salvaged with surgery and radiotherapy, none died. CONCLUSIONS: Deferral of radiotherapy following gross total resection alone is a safe option in supratentorial ependymomas. The pattern of recurrence is usually local and patients may be salvaged with additional surgery with or without radiotherapy.

Clinical manifestations of childhood ependymoma: a multitude of syndromes.

Over 90% of childhood ependymomas arise within the cranium, two-thirds below and one-third above the tentorium, and they comprise 8-10% of all childhood CNS neoplasms. This is in contradistinction to the presentation in adults where over 75% of the ependymomas arise within the spinal canal. The incidence of 2.2 cases per million appears to be increasing over the past 30 years. The biology of the disease resembles that of a low-grade glioma where local control measures are most important and less than 5% of children present with metastatic disease. Thus, total resection is the optimum therapy. The value of adjuvant therapy for children with no postoperative residual disease is unclear. Adjuvant radiotherapy is reserved for children with postoperative residual disease and appears to prolong survival. A brief review of our current understanding of the incidence, sites of origin, clinical presentations, prognostic factors and controversial treatment issues will be presented.

Encephalopathy complicating Henoch-Schönlein purpura: reversible MRI changes.

A 10-year-old boy with Henoch-Schönlein purpura complicated by encephalopathy, transient cortical blindness, and a secondary generalized seizure is reported. Reversible changes in the posterior white and gray matter were seen on magnetic resonance imaging. Our patient illustrates uncommon neurologic manifestations of Henoch-Schönlein purpura. The nature and location of the lesions and the normalization of the patient's magnetic resonance imaging is consistent with a posterior predominant parieto-occipital encephalopathy and suggests that cerebral edema from blood-brain barrier breakdown may play a central role in the pathophysiology of the central nervous system symptomatology in some patients.

Case-control study of primary human herpesvirus 6 infection in children with febrile seizures.

RATIONALE: Human herpesvirus 6 (HHV-6) has been demonstrated to be the causative agent in roseola infantum. It has been suggested that HHV-6 may have neurotropic properties and be involved in the pathogenesis of febrile seizures in infants. We describe a case-control study to examine the hypothesis that acute HHV-6 infection occurs more commonly in children with febrile seizures than in controls. METHODS: Patients presenting with a first or second febrile seizure between 6 months and 2 years of age were entered in the study. Control patients did not have a seizure but had similar inclusion and exclusion criteria. Specimens were obtained for HHV-6 viral serology and polymerase chain reaction in the acute stage and approximately 2 weeks later. A diagnosis of HHV-6 infection was based on HHV-6-specific IgM and IgG serology and HHV-6 polymerase chain reaction of peripheral blood mononuclear cells and saliva. RESULTS: Eighty-six patients (45 with febrile seizures; 41 controls) were enrolled. The HHV-6 infection status could be determined in only 68 patients (35 with febrile seizures; 33 controls). Acute HHV-6 infection was identified in 15 of 35 febrile seizure patients and in 15 of 33 controls. Evidence of past HHV-6 infection was demonstrated in 13 febrile seizure patients and in 8 controls. CONCLUSIONS: The incidence of primary HHV-6 infection is similar in patients with febrile seizures and age-matched controls. HHV-6 does not seem to be a major factor in the pathogenesis of first and second febrile seizures.

Basal ganglia infarction associated with HHV-6 infection.

A 6 year old boy presented with meningoencephalitis and was found to have serological evidence of acute human herpes virus-6 (HHV-6) infection. He did not develop symptomatic seizures or the rash of exanthum subitum (roseola). His course was marked by severe spastic quadriparesis associated with radiological evidence of basal ganglia infarction. HHV-6 infection should be considered in any child with acute meningoencephalitis.

Reye syndrome associated with subclinical varicella zoster virus and influenza A infection.

An association is reported between Reye syndrome and varicella zoster virus (VZV) infection in a 10-year-old boy who had serologic evidence of coinfection with VZV and influenza A H3N2, and exposure to salicylates. He developed VZV reinfection without skin lesions after family exposure and influenza A was community-acquired. Recent chickenpox contact should initiate VZV serologic studies in Reye syndrome patients, regardless of the chickenpox history or evidence of infection with other viruses.