Monoclonal antibodies and progressive multifocal leukoencephalopathy.

Monoclonal antibodies have become an important treatment option for a number of serious conditions. Concerns have arisen about the potential association of these products with progressive multifocal leukoencephalopathy (PML). A list of monoclonal antibodies authorized for sale was derived from the Health Canada Drug Product Database. Case reports of PML after exposure to a monoclonal antibody authorized for use in Canada were retrieved by searching Canada Vigilance and WHO adverse event databases and through a Pub MED/Medline literature search. 182 adverse event case reports were retrieved (adalimumab -1 case, alemtuzumab-14, bevacizumab -3, cetuximab -1, efalizumab - 8, ibritumomab tiuxetan-5, infliximab-4, natalizumab-32, and rituximab-114). The Canadian Product Monographs for natalizumab and ritiximab contain box warnings for PML. A natalizumab registry has been established.

Outcome of secondary high-grade glioma in children previously treated for a malignant condition: a study of the Canadian Pediatric Brain Tumour Consortium.

BACKGROUND AND PURPOSE: Reports of secondary high-grade glioma (HGG) in survivors of childhood cancer are scarce. The aim of this study was to review the pattern of diagnosis, the treatment, and outcome of secondary pediatric HGG. PATIENTS AND METHODS: We performed a multi-center retrospective study among the 17 paediatric institutions participating in the Canadian Pediatric Brain Tumour Consortium (CPBTC). RESULTS: We report on 18 patients (14 males, 4 females) treated in childhood for a primary cancer, who subsequently developed a HGG as a second malignancy. All patients had previously received radiation therapy +/- chemotherapy for either acute lymphoblastic leukaemia (n=9) or solid tumour (n=9). All HGG occurred within the previous radiation fields. At the last follow-up, 17 patients have died and the median survival time is 9.75 months. CONCLUSION: Although aggressive treatment seems to provide sustained remissions in some patients, the optimal management is still to be defined. Further documentation of such cases is necessary in order to better understand the pathogenesis, the natural history and the prevention of these tumours.

A systematic review of the use of the ketogenic diet in childhood epilepsy.

The ketogenic diet has been used in the treatment of intractable childhood epilepsy since the 1920s. A systematic review of the efficacy, adverse reactions, and costs associated with using the diet was performed. PubMed and Ovid searches were performed using the keywords epilepsy/therapy, dietary therapy, ketogenic diet, adverse events, and costs. Cochrane library was searched. Bibliographies of papers located by searches and review articles were compiled. Papers published after 1990 were selected if they were written in either English or French and reported on the use of classic ketogenic diet in patients under age 18 years of age with medically refractory epilepsy. Outcome measures were degree of seizure control, duration patient remained on diet, and occurrence of adverse events. Twenty-six studies were found. No prospective-controlled studies were found. Fourteen studies met all criteria for inclusion. The studies indicated that some children report reduction in seizure frequency. The estimated rate for obtaining complete seizure control was 15.6% (95% confidence interval 10.4-20.8%) with 33% (95% confidence interval 24.3-41.8%) reporting greater than 50% reduction in seizures. Adverse events were not frequent; however, 16 cases of death occurring while on the diet were found. No cost/benefit studies were located. There is evidence to support the cautious use of ketogenic diet in children with refractory epilepsy.

Neonatal death: Case definition & guidelines for data collection, analysis, and presentation of immunization safety data.

More than 40% of all deaths in children under 5 years of age occur during the neonatal period: the first month of life. Immunization of pregnant women has proven beneficial to both mother and infant by decreasing morbidity and mortality. With an increasing number of immunization trials being conducted in pregnant women, as well as roll-out of recommended vaccines to pregnant women, there is a need to clarify details of a neonatal death. This manuscript defines levels of certainty of a neonatal death, related to the viability of the neonate, who confirmed the death, and the timing of the death during the neonatal period and in relation to immunization of the mother.

Cognitive changes in children treated for acute lymphoblastic leukemia with chemotherapy only according to the Pediatric Oncology Group 9605 protocol.

The purpose of this study was to examine cognitive functioning and neuroimaging in children with leukemia treated with the Pediatric Oncology Group 9605 protocol at the Children's Hospital of Eastern Ontario. Mean age at diagnosis was 4.88 +/- 2.54 years. The mean (n = 24) Wechsler Verbal and Performance IQ fell in the low-average range (87.33 +/- 15.69 and 84.83 +/- 19.11, respectively). Mean (n = 20) Verbal and Visual Memory Indexes of 82.95 +/- 15.46 and 88.30+/- 10.80, respectively, were obtained. The proportion of scores on measures of intelligence and memory falling > 1 SD below the normative mean was substantially higher than expected. Paired t-test suggested that Wechsler Verbal IQ and memory remained stable, whereas Wechsler Performance IQ declined significantly. The results of growth curve analyses replicated these findings and suggested a significant adverse effect of cumulative dosage of intrathecal methotrexate on estimated Wechsler Performance IQ. Although only two children experienced seizures, 78% of the group showed leukoencephalopathy on at least one magnetic resonance image. Reliance on seizures as a predictor of leukoencephalopathy might underestimate the incidence of neurotoxicity.

Inventory of pediatric neurology "manpower" in Canada.

OBJECTIVE: To review the demographics and workload characteristics of pediatric neurology in Canada. METHOD: A standardized survey questionnaire was mailed out to practicing pediatric neurologists in Canada in 2001. Variables examined were age, gender, hours on call, regular hours worked per week, type of practice and projected changes in practice over next five to ten years. Results were compared to the 1994 Pediatric Neurology Manpower Survey which had used the same survey instrument. RESULTS: Fifty-six (70%) pediatric neurologists practicing in Canada returned the survey. As was the case in 1994, no significant differences in workload were found based on age or gender. The average age of the practicing pediatric neurologist in 2001 was 51 years compared to 45 years in 1994. The proportion of physicians over 55 years in 2001 was 35% compared to 25% in 1994. CONCLUSIONS: Pediatric neurology in Canada is an aging specialty needing a significant recruitment of new members

Functional MRI study of verbal fluency in a patient with subcortical laminar heterotopia.

RATIONALE: Double cortex syndrome is a malformation in which there is a band of subcortical heterotopic grey matter separated from the cortex by white matter. The functional activity of the heterotopic neurons is unclear. PATIENT: A 13-year-old female was evaluated for seizures. The EEG showed bifrontal spike wave disturbance. Band heterotopia, in association with mild reduction of sulcation of the cerebral hemispheres, was found on MRI. Psychological assessment indicated the presence of variable cognitive abilities, with verbal IQ [82] generally better than nonverbal IQ [59], and specific difficulties in language comprehension and mathematics. METHOD: Functional MRI was used to localize the areas of language and motor activation. The language activation paradigm was a visual verb generation task with a visual fixation baseline. The motor paradigm consisted of alternating blocks of sequential finger tapping and rest. Coronal functional and anatomical images were obtained. RESULTS: The motor paradigm produced activation of the primary motor cortex, the band heterotopia and the supplementary motor cortex. The language paradigm produced activation of the left inferior frontal gyrus and left supplementary motor area, but not of the band heterotopia. CONCLUSIONS: The activation of heterotopic grey matter during a motor task demonstrates a hemodynamic association with motor activity and suggests that this tissue may be functional. Such association was not seen with the language task. We speculate that later maturing functions such as language are restricted in their development to the normal situated superficial cortex in our patient.

Surveillance for progressive intellectual and neurological deterioration in the Canadian paediatric population.

OBJECTIVES: To conduct active surveillance of the Canadian paediatric population for children who have a progressive intellectual and neurological deterioration to detect the occurrence of cases of Creutzfeldt-Jakob disease or variant Creutzfeldt-Jakob disease. CASE DEFINITION: Any child who is less than or equal to 18 years of age, who had a progressive loss of already attained intellectual/developmental abilities and development of abnormal neurological signs of greater than three months duration was eligible for inclusion. DURATION: July 1999 to July 2001. METHOD: Enhanced active surveillance system for progressive intellectual and neurological deterioration was implemented to detect, prospectively, among the Canadian paediatric population. Each month, all paediatricians and paediatric neurologists in Canada were mailed a reporting form. All reported cases were reviewed by the principal investigator who classified the cases into one of four predetermined categories. Cases where there was evidence of neurological and intellectual regression without known cause were reviewed by a panel. Reported cases were reviewed for the possibility of classic or variant Creutzfeldt-Jakob disease. RESULTS: Over 2200 physicians took part in this program. There was more than an 80% monthly return rate of the initial report form. Ninety-nine possible cases of progressive neurological and intellectual deterioration were reported. Sixty cases were classified as having a progressive neurological syndrome associated with intellectual deterioration. Fourteen cases were duplicates. One case of Creutzfeldt-Jacob disorder was found but no cases of the variant form of Creutzfeldt-Jacob disorder. Fifteen cases were felt not to meet the above-mentioned entry criteria.

Cognitive sequelae in children with posterior fossa tumors.

Late effects of radiotherapy on intellectual functioning have been well documented in children treated for posterior fossa tumors. Other aspects of cognitive functioning, such as memory, have not been adequately assessed in this population. This retrospective review reports on 15 children diagnosed with medulloblastoma or cerebellar astrocytoma who were administered a norm-referenced standardized test of memory functioning (i.e., Wide Range Assessment of Memory and Learning) an average of 3.5 years after treatment. Analyses revealed that sample means of IQ and memory were significantly lower than those of the normative population. No significant differences were found between the verbal and nonverbal IQ, or verbal and visual memory. Age at diagnosis accounted for a significant proportion of variability in the intelligence ratings but not in the memory indexes. The IQ scores of children less than 6 years of age at diagnosis were significantly lower than those of children diagnosed when over 6 years of age. Given the substantial variability within the older age group, there was insufficient power to detect true differences between memory index means for children by age at diagnosis. Follow-up assessments over 5 years may better identify the long-term effects of radiotherapy on memory functioning.

Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report.

INTRODUCTION: Supratentorial primitive neuroectodermal tumors (SPNET) are rare tumors accounting for only 2.5% of childhood brain tumors. The purpose of this study was to describe the range of treatment regimens used to treat pediatric SPNET in Canada and to identify prognostic factors for overall survival in this population. METHODS: This study was a retrospective clinical analysis of SPNET patients treated over the last 10 years in Canada. A questionnaire was developed and distributed to all institutions in Canada who treat pediatric patients. Data were collected for patients <19 years of age who were diagnosed and treated for SPNET between 1995 and 2005. RESULTS: Data were obtained for 48 eligible patients. The stages of patients for whom complete data were provided were 80, 3, and 16% for metastatic stage M0, M1, and M2/3, respectively. The best responses to therapy included complete response in 44%, partial response in 8%, still on therapy in 2%, progressive disease in 31%, toxic death in 2%, and no therapy given in 12%. The 4-year survival was 37.7 +/- 7.6%. The factors associated with an increase in survival were the use of radiation therapy and chemotherapy, and age >2 years. Overall survival was not affected by metastatic disease at diagnosis, tumor site, or degree of initial resection. CONCLUSIONS: Survival is poor in SPNET patients but highest in those who received chemotherapy and radiation therapy. Further studies are needed to improve the survival of these patients.

Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia.

A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later.

Vascular complications of cranial radiation.

OBJECTIVES: Cerebral vascular disease has been reported as a long-term complication of cranial radiotherapy. The purpose of this study was to examine the frequency and risk factors associated with development of cerebral vascular disease in children after cranial radiation. MATERIALS AND METHODS: A retrospective chart review of all cancer patients treated between 1985 and 2003 who were under the age of 18 years at the time of initial radiotherapy was performed. Variables examined include diagnosis and site of malignancy, age at the time of radiotherapy, sex, total radiation dosage, number of fractions, duration, and whether the patient had proven cerebral vascular event. RESULTS: Two hundred and forty-four patients met the study criteria. One hundred and 13 cases involved tumors of the central nervous system. The remaining patients had systemic neoplastic disease. Post radiation cerebral vascular disease occurred in 11 (5%) patients, and all but one patient had a tumor involving the central nervous system (mainly in the posterior fossa and supratentorial midline). CONCLUSION: There is an increased risk of cerebral vascular disease after radiation therapy in childhood, especially in children who received high dose radiation at the posterior fossa and supratentorial axial region.

A survey of behavior problems in children with epilepsy.

Over a period of 3 consecutive months, a cross-sectional, descriptive survey was made of the frequency of behavior problems and needs, as reported by their caregivers, of 6- to 18-year-old epileptic children attending two neurology clinics, using the Child Behavior Checklist. Caregivers of 175 children were approached to take part in the study; 158 (90%) completed the Child Behavior Checklist. The mean age of the children was 11.3 (range, 6-18). t scores >70 were obtained for 15.9% of the group for total behavior, 12.7% of the group for internalized behavior and 11.4% of the group for externalized behavior. Compared with those with normal scores, children with elevated t scores were more likely to have learning difficulties and to require the use of more community services.

Psychosocial functioning following surgical treatment for intractable epilepsy in childhood.

METHODS: Psychosocial functioning was examined in 13 children who had undergone surgical treatment for intractable epilepsy. The ratings of each child's social, emotional and behavioural problems were obtained via parent and teacher reports made an average of 2 years post-operatively. RESULTS: Parents viewed their children as having greater social difficulties than reported in standardisation samples. Although the overall level of difficulty fell below clinically significant cut-offs, the proportion of children who were rated as having clinically significant levels of difficulties approached significance. Teachers rated these children as displaying more symptoms of anxiety and depression, although the levels remained subclinical. DISCUSSION: These results are discussed in view of the complex interaction between neurological and environmental variables involved in social-emotional functioning following surgical treatment for epilepsy.

Are there changes in intelligence and memory functioning following surgery for the treatment of refractory epilepsy in childhood?

MATERIALS AND METHODS: A retrospective review of the neuropsychological and medical variables of 26 children who underwent a cortical resection as part of the management of their medically refractory epilepsy was conducted. Neuropsychological variables included pre- and postoperative measures of intelligence (Wechsler Scales) and memory functioning (Wide Range Assessment of Memory and Learning). Medical variables included age at onset of seizures, age at surgery, site of resection, and degree of seizure control postoperatively. RESULTS: Twenty patients had temporal resections (13 left-sided). Six had extratemporal resections. In this series, cortical resection as treatment of epilepsy in children did not result in a significant change in performance on measures of intelligence or memory functioning. No significant correlation was found between the medical variables and the neuropsychological outcome.