Frances A. Booth

International headache society criteria and childhood headache.

The objective of this study was to determine whether the intuitive clinical diagnosis of a headache type made by paediatric neurologists would also have fulfilled International Headache Society (IHS) criteria for that type. Clinical information was recorded on data sheets. The neurologists made clinical diagnoses without referring to a fixed set of criteria. An independent physician then used the information on the data sheets to classify the childs headache by IHS criteria. Complete data sheets were available for 72 children, aged between four and 18 years. The intuitive clinical diagnosis was completely concordant with the criterion diagnosis of the IHS in 61 per cent, partially concordant in 31 per cent and at complete variance in 8 per cent. These data suggest that the IHS criteria can be applied to a majority of children in a referral‐based population such as this, but that minor revisions to the criteria are necessary to make them even more applicable to children.

Primary Antiphospholipid Syndrome with Moyamoya-Like Vascular Changes

We describe a young girl with antiphospholipid syndrome (APS) and moyamoya-like cerebrovascular changes which reversed after anticoagulation. Although there was a risk of hemorrhage from collateral vessels, we speculate that this treatment may have prevented progression of the vascular abnormalities, while resolution of the thrombus resulted in improved cerebrovascular circulation.

GLUT1 Deficiency Without Epilepsy: Yet Another Case

Glucose transporter type 1 (GLUT1) deficiency syndrome is a metabolic disorder characterized by a low cerebrospinal fluid glucose level caused by decreased activity of the glucose transporter protein. Of approximately 100 patients described with this syndrome in the published literature to date, only 3 patients have had intermittent ataxia as the initial manifestation. This case report describes a 13-year-old boy with a longstanding history of intermittent ataxia who was diagnosed as having GLUT1 deficiency syndrome after the onset of seizures at age 11 years. This case highlights the importance of a carefully organized lumbar puncture in the investigation and management of any child with neurodevelopmental delay and intermittent ataxia with or without seizures.

Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia

Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.

Inter-observer agreement in the diagnosis of childhood headache.

SYNOPSIS

Cardioembolic Stroke in Children: A Clinical Presentation and Outcome Study

BACKGROUND Cardiac disease is a common cause of ischemic stroke in children. Limited information is available about its incidence and long-term outcome. METHODS We undertook a retrospective study of children (age 0-17 years) with cardioembolic arterial ischemic stroke, occurring between 1992 and December 2007. Study subjects were observed at the Winnipeg Childrens Hospital and identified using multiple databases and disease code searches. RESULTS We identified 84 children with arterial ischemic stroke, 17 (20%) of which were cardioembolic stroke (15 non-neonates; 10 females; mean age 4.6 years). The crude annual incidence rate for cardioembolic stroke was estimated to be 0.39 and mortality rate of 0.046 per 100,000 person-years. Stroke occurred commonly in children <5 years (65%) and during hospitalization (65%). Initial presenting symptoms were focal deficits 12 (71%), altered consciousness 5 (29%), seizures 5 (29%), and headache 3 (18%). The mean stroke severity measured by Pediatric National Institutes of Health Stroke Scale was 14.5 (range 2-40) at presentation and 3.7 (range 0-9) at discharge, with mean acute recovery from stroke presentation to discharge of 9.94 (0-32). At 2 years, poor outcome was evident in 10 (59%) children: 2 or >2 Pediatric Stroke Outcome Measure score in 6 (35%), death in 2 (12%), and recurrent stroke in 2 (12%). Factors associated with poor outcome included headache (P = 0.048), high Pediatric National Institutes of Health Stroke Scale at presentation (r = 0.57; P = 0.05) and discharge (r = 0.58; P = 0.05), and high Pediatric Stroke Outcome Measure at discharge (r = 0.77; P = 0.0008). CONCLUSION Our cohort provides hospital-based incidence estimates for children with cardioembolic stroke. Pediatric National Institutes of Health Stroke Scale performed at different time points can be a helpful tool in measuring stroke recovery and needs to be further explored.

Dissecting hematoma of intracranial internal carotid artery in an 8-year-old girl

BACKGROUND An 8-year-old girl had a minor fall without head trauma and she collapsed the following day while playing. She was awake but mute with focal neurologic signs when admitted to hospital. Radiologic imaging studies showed a progressive left cerebral infarct with left hemisphere vascular narrowing and beading. She died on the third hospital day. METHODS Autopsy including exploration of neck vessels and neuropathological examination was performed. Postmortem studies included immunostaining for immunoglobulins and fixed complement. RESULTS Subtotal subintimal dissections of both proximal supraclinoid internal carotid arteries were found microscopically. On the left, the subintimal dissection extended into the major branches of the left internal carotid artery as dissecting hematomas with a major compromise of the arterial lumina. Specific IgM deposition at the dissection sites was found. A literature review shows that subintimal dissection of the intracranial internal carotid artery or its branches occurs rarely, it is often fatal, and it is present in patients with a mean age of 17.5 years in cases studied pathologically. Trauma and physical exertion are the most common associated factors. CONCLUSIONS Among the causes of ischemic stroke in young individuals, dissecting hematomas of the intracranial portions of the internal carotid artery system rank low. Few reported cases have identifiable pre-existing pathology. The pathogenesis of dissecting hematomas in this region is reviewed and expanded with speculation regarding relevant developmental, anatomical, flow stress and possibly humoral factors that are involved in the disruption of the arterial elastica and subsequent development and extension of a subintimal hematoma resulting in luminal closure and often death.

Early-Onset Neurodegenerative Disease of the Cerebellum and Motor Axons

We describe a novel hereditary neurodegenerative disease of infancy affecting an Aboriginal family from northern Manitoba, Canada. The parents are nonconsanguineous, without a family history of neurodegenerative diseases. Four of 10 siblings (three males and one female) presented with neurologic abnormalities including arthrogryposis, seizures, and severe developmental delay shortly after birth. In two children, cerebellar atrophy and mild cerebral atrophy were documented on neuroimaging. Two children, a boy who died at age 40 months and a girl who died at age 22 months, underwent muscle biopsies at 3 weeks and 4 months of age, respectively. The biopsies revealed fiber-size variability in the boy, and grouped atrophy with fiber-type grouping in the girl. Two boys who died at ages 7.5 and 37 months underwent autopsies that indicated severe atrophy of the cerebellar hemispheres (especially the inferior lobules and vermis), hypomyelination of white-matter fascicles in the striatum, severe atrophy of corticospinal tracts in the brainstem and spinal cord, and atrophy of the anterior spinal roots. In the spinal cord, motor neuron cell bodies and the posterior columns were spared. This clinical entity likely represents a novel neurodegenerative disease of the cerebellum and long motor axons.

MITOCHONDRIAL NADH-CoQ OXIDOREDUCTASE (COMPLEX I) DEFICIENCY IN MAN

Two brothers, aged 11 and 13 years, have seizures, growth and developmental delay and intellectual regression. Physical findings include mild facial coarseness, bilateral ptosis, sensorineural hearing loss, hypotonia, weakness, incoordination, and hyporeflexia. Their mother has late onset sensorineural hearing loss but is otherwise normal. Abnormal laboratory results include elevated plasma and CSF alanine and lactate (4-6mM), low dibasic and neutral amino acids and mild cerebral atrophy; muscle from the younger boy contains ragged red fibers. Lactate to pyruvate ratios in fibroblasts incubated with glucose were normal (Dr. Brian Robinson). Dr. Thomas Perry of Vancouver has ruled out lysinuric protein intolerance or renal tubular dysfunction. In the younger boys fibroblast mitochondria, ATP synthesis with pyruvate and malate was undetectable (<1% of control) and with succinate, 70% of control, suggesting deficient activity of Complex I of the electron transport chain. In another child with hypotonia, necrotic lesions of the cerebral cortex, hepatomegaly with severe fatty change, lactic acidosis and early death, we found Complex I activity to be 20% of control, as did Dr. Robinson. These patients demonstrate the clinical and biochemical heterogeneity of disorders involving the electron transport chain in man and the utility of mitochondrial studies in fibroblasts.

Ataxia with oculomotor apraxia type 2 in the Canadian aboriginal population.

To the Editor: Ataxia with oculomotor apraxia type 2 (AOA2) (OMIM 606002) is an autosomal recessive disorder, representing approximately 8% of non-Friedreich autosomal recessive cerebellar ataxias. It is characterized by ataxia onset between 11 and 22 years, and associated with oculomotor apraxia and elevated serum alpha fetoprotein. It was first described in Japanese (1), Pakistani (2) and French Canadian patients (3). We report on affected siblings from a consanguineous family of Ojibwe Canadian Aboriginal descent. The proband presented at age 16 years with insidious and protracted balance difficulties since age 11 years. By 16 years, his symptoms advanced to a noticeably unsteady gait with occasional falls and deterioration in manual dexterity. He was born to healthy parents who are second cousins. His older sister had similar gait abnormality. Reportedly, a paternal first cousin and two maternal first cousins once removed have a similar phenotype. The parents of these individuals are second cousins. These relatives have not presented for a formal evaluation. On examination, his speech was dysarthric and scanning. There was ocular apraxia with initiation of saccades with a head thrust maneuver. He had sustained gaze-evoked nystagmus with lateral gaze. There were no conjunctival telangiectasias. The fine finger and rapid alternating movements were impaired. He displayed symmetric dysmetria on finger-nose-finger and heel-to-shin testing. His gait and stance were broad in base. He was unable to perform tandem walking. The work up included serum alpha fetoprotein (AFP) which was elevated at 20 μg/l (normal 0.0–7.0 μg/l). Brain magnetic resonance imaging revealed cerebellar atrophy affecting the vermis. Chromosome breakage studies did not show evidence of chromosome instability. Mutation analysis of the SETX gene (Prevention Genetics, Marshfield, WI) was performed by polymerase chain reaction amplification of genomic DNA followed by automated sequencing of all the coding exons, as well as 50 bases of flanking non-coding sequences. This revealed a homozygous c.1406A>G (NM_015046.5) mutation predicted to result in the amino acid substitution p.His469Arg. His affected sister was also homozygous for this mutation. Since the early reports of AOA2 in Japanese (1), Pakastani (2) and French Canadian (3) families, it has now been reported in a wide range of populations. This report is the first to document the disease presence in the Canadian Aboriginal population. To date more than 75 mutations have been identified in more than 100 reported patients worldwide. The vast majority of these mutations are distributed across the entire gene without any reported hot spots. Our patients were homozygous for a c.1406A>G, a mutation that has been reported to be causative of AOA2 in a consanguineous family from Southern Italy (4). This substitution was not found in 200 Italian control chromosomes (4) nor did we identify this change in any of the population databases, including dbSNP, 1000Genomes and Exome Aggregation Consortium. In silico analysis using PolyPhen-2, SIFT and MutationTaster predict p.His469Arg change to be ‘probably damaging’, ‘not tolerated’ and ‘disease causing’, respectively (5–7). Based on the recent ACMG guidelines for interpreting sequence variants (8), the c.1406A>G is likely pathogenic. Consanguinity in this family favors the idea of a founder mutation. The presence of the same mutation in the family from Southern Italy is likely a recurrent event and not derived from a single ancestral mutation. This report supports the panethnic presence of AOA2.