Maartje Boon

Prognostic factors after a first attack of inflammatory CNS demyelination in children

Objective: To identify clinical, radiologic, or CSF factors that predict conversion to multiple sclerosis (MS) after a first attack of inflammatory demyelination in children. Methods: In this nationwide retrospective multicenter study in the Netherlands, 117 children below age 16 were included. Fifty-four children presented with a monofocal clinically isolated syndrome (CIS) and 63 children with a polyfocal CIS (PCIS). Results: A second MS-defining attack occurred in 43% of the CIS cases, compared to 21% of the patients with PCIS onset (p < 0.006). Basal ganglia and thalamic lesions and lesions larger than 2 cm on MRI (considered typical of ADEM) were observed during PCIS, irrespective of the presence of encephalopathy. No significant difference in developing MS was found in children with PCIS with or without encephalopathy. Elevated IgG index and presence of oligoclonal CSF bands were more often observed in children who developed MS. Both Barkhof and KIDMUS MRI criteria shared a high specificity and had a high positive predictive value for conversion to MS. In children under the age of 10, the Barkhof criteria had a higher sensitivity than the KIDMUS criteria, but still lower than in older children. Conclusions: Barkhof and KIDMUS MRI criteria share a high specificity and positive prognostic value for conversion to multiple sclerosis (MS). Sensitivity of these criteria is poor, especially in children below 10 years of age. Basal ganglia lesions can occur in patients who later develop MS. A substantial number of patients presenting with polyfocal onset and no encephalopathy remained monophasic.

The management of multiple sclerosis in children: a European view

About 3—5% of all patients with multiple sclerosis experience the onset of their disease under the age of 16. A significant proportion of paediatric multiple sclerosis patients develop significant cognitive disturbances and persistent physical disability. The high relapse rate and the morbidity in the paediatric multiple sclerosis population has triggered the use of disease-modifying therapies that have been shown to reduce relapse rate, disease progression and cognitive decline in adult patients with multiple sclerosis. Hard evidence for the right treatment and its appropriate timing is scarce in paediatric multiple sclerosis. Nevertheless, expertise in this field has grown thanks to recent open-label trials and experience generated in specialized centres. In spring 2009, a first meeting was held in Rotterdam with clinicians from 11 European countries (one from Canada) that are all active in the management of paediatric multiple sclerosis. One of the aims was to generate a common view on the management of paediatric multiple sclerosis patients. The result of this meeting is presented here to help standardize treatment and to support clinicians with less experience in this field.

PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions

Objective: To describe the phenotypes and penetrance of paroxysmal kinesigenic dyskinesia (PKD), a movement disorder characterized by attacks of involuntary movements occurring after sudden movements, infantile convulsion and choreoathetosis (ICCA) syndrome, and benign familial infantile convulsions (BFIC), caused by PRRT2 mutations. Methods: We performed clinical and genetic studies in 3 large families with ICCA, 2 smaller families with PKD, and 4 individuals with sporadic PKD. Migraine was also present in several individuals. Results: We detected 3 different PRRT2 heterozygous mutations: the recurrent p.Arg217Profs*8 mutation, previously reported, was identified in 2 families with ICCA, 2 families with PKD, and one individual with sporadic PKD; one novel missense mutation (p.Ser275Phe) was detected in the remaining family with ICCA; and one novel truncating mutation (p.Arg217*) was found in one individual with sporadic PKD. In the 2 remaining individuals with sporadic PKD, PRRT2 mutations were not detected. Importantly, PRRT2 mutations did not cosegregate with febrile convulsions or with migraine. The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was considered; however, if infantile convulsions were also taken into account, the penetrance was nearly complete. Considering our findings and those reported in literature, 23 PRRT2 mutations explain ∼56% of the families analyzed. Conclusions: PRRT2 mutations are the major cause of PKD or ICCA, but they do not seem to be involved in the etiology of febrile convulsions and migraine. The identification of PRRT2 as a major gene for the PKD-ICCA-BFIC spectrum allows better disease classification, molecular confirmation of the clinical diagnosis, and genetic testing and counseling.

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Fatigue and depression in children with multiple sclerosis and monophasic variants

BACKGROUND Fatigue is an important symptom in adult multiple sclerosis (MS) and it is likely to occur in children with MS. It is currently unknown whether children who experienced a monophasic inflammatory demyelinating event of the central nervous system in the past also suffer from fatigue. METHODS We studied the presence and severity of fatigue in 32 children (18 boys, 14 girls) between 11-17 years old (mean: 14 years, 10 months) with a monophasic inflammatory demyelinating disease (n=22) or definite MS (n=10). This was measured with the Checklist Individual Strength. A score of >or=40 on the severity of fatigue subscale indicated the presence of severe fatigue. We also examined the relation between fatigue and depression (assessed by the Child Depression Inventory). Additionally we measured the health-related quality of life (HRQoL), using the TNO-AZL Child Quality of Life child form. We compared the scores of the MS and monophasic patients with the scores of healthy Dutch children. RESULTS The highest scores on the fatigue scales subjective fatigue and physical activity were found in the children with MS. Only 1 of the monophasic patients suffered from severe fatigue in contrast to 4 of the MS patients. In the MS group fatigue and depression were correlated. MS patients experienced a lower HRQoL on the scales locomotor functioning, cognitive functioning and interaction with peers. CONCLUSION The occurrence of fatigue is very rare after a monophasic inflammatory demyelinating event in the past. As expected, fatigue occurs more frequent in paediatric MS patients.

Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment.

Plantar lipomatosis, unusual facies, and developmental delay : Confirmation of Pierpont syndrome

In 1998 , Pierpont et al. reported on two unrelated boys with plantar lipomatosis, unusual facial phenotype, and developmental delay as a possible new MR/MCA syndrome. Here we report on a 2‐year‐old boy with similar manifestations: axial hypotonia in the first few months, prolonged feeding problems, moderate developmental delay, no speech development, deep palmar and plantar grooves, fat pads at the anteromedial aspect of the heels, and a distinct facial phenotype (high forehead, high anterior hairline, mild midfacial hypoplasia, remarkably narrow and upward slanted palpebral fissures, broad nasal ridge and tip, broad philtrum, bowed upper lip, “pouting” lower lip, full cheeks, and flat occiput). Brain MRI and MR spectroscopy studies showed relatively small frontal lobes, some widening of the lateral and third ventricles, and increased choline levels in the frontal white matter. Cytogenetic studies in lymphocytes and skin fibroblasts and whole genome micro‐array CGH failed to show abnormalities. The present patient has a phenotype almost identical to that of the earlier reported children (Pierpont et al. [ 1998 ]: Am J Med Genet 75:18–21), which thereby validates this as a separate MR/MCA syndrome, appropriately designated Pierpont syndrome. The cause of the entity remains uncertain, the most likely etiologies being X‐linked recessive or autosomal dominant genes.

1H chemical shift imaging, MRI, and diffusion-weighted imaging in vanishing white matter disease

Sir, Leukoencephalopathy with vanishing white matter (OMIM no. 603896, VWM) is characterized by ataxia, spasticity and epileptic seizures. The course is chronic progressive with episodes of rapider deterioration after febrile illness or minor head injury. Underlying mutations are found in eukaryotic translation initiation factor 2B (eIF2B) [1]. The MRI signal intensity of cerebral white matter approaches that of CSF and decreased amounts of the normal brain metabolites (choline, creatine, N-acetylaspartate) are observed by H magnetic resonance spectroscopy (MRS), coupled with the appearance of lactate and glucose signals. Previous studies disagree on whether or not gray matter shows abnormalities on MRS. This is the first study mapping white and gray matter spectra in one overview. A 15-month-old boy presented with progressive leukoencephalopathy after fever and vomiting. After investigations with either acute disseminated encephalomyelitis or VWM as differential diagnosis, corticosteroids were given (initially 2 mg prednisone/kg, later 5 mg/day). The patient recovered nearly completely but relapsed 1 month later after a minor head injury. The diagnosis of VWM disease was confirmed by DNA investigation. (The initial improvement after administration of corticosteroids remains unexplained; prolonged treatment with corticosteroids might even be contraindicated, since the concomitant increased sensitivity to infections could influence the disease course negatively.) Subsequent MRI and H MRS examination, at age 19 months, included axial diffusion-weighted images with b=0, 500 and 1,000 s/mm and an apparent diffusion coefficient (ADC) map, and automated hybrid point-resolved spectroscopy 2D chemical shift imaging with a repetition time of 1,500 ms and an echo time of 135 ms [2]. Figure 1 shows spectra of a 1×1×2 cm white matter voxel and of gray matter near the interhemispheric fissure. The gray matter spectra are, in disagreement with others [3], normal and the white matter spectra show reduced levels of inositol, choline, creatine, glutamate and N-acetylaspartate. The white matter spectra show lactate signals, the inverted doublet at a frequency of 1.32 ppm, and α-glucose multiplet peaks around 3.8 ppm. Figure 2 shows increased white matter MRI signal intensity on T2 fast spin-echo (Fig. 2a), and decreased signal on fluid-attenuated inversion recovery and inversion P. E. Sijens (*) . L. C. Meiners . M. Oudkerk Department of Radiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands e-mail: p.e.sijens@rad.umcg.nl Tel.: +31-50-3613534

Barkhof Magnetic Resonance Imaging Criteria Predict Early Relapse in Pediatric Multiple Sclerosis

We sought to identify clinical and radiologic features predicting early relapse after a diagnosis of multiple sclerosis in children. In this nationwide retrospective multicenter study in The Netherlands, we included 28 children with multiple sclerosis with onset before age 16 years. Magnetic resonance images and clinical features at the onset of disease were evaluated. The mean follow-up time was 55 months. Twenty children (71%) had a relapse during follow-up. We found that the presence of at least three of four Barkhof magnetic resonance imaging criteria at the onset of multiple sclerosis signs is predictive of early relapse after a diagnosis of multiple sclerosis in children (P<0.05).

MR spectroscopy and diffusion tensor imaging of the brain in Sjögren-Larsson syndrome.

Diffusion tensor imaging (DTI) is reported for the first time in a patient with Sjögren-Larsson syndrome, an autosomal recessive neurocutaneous disorder. Magnetic resonance spectroscopy (MRS) revealed normal levels of choline, creatine and N-acetyl aspartate (NAA) and the characteristic lipid signals in the white matter brain tissue. Conventional MRI showed increased signal intensity around the lateral ventricles indicating abnormal myelination. DTI revealed normal apparent diffusion coefficient (ADC) values, but reduced fractional anisotropy (FA) in the white matter. After co-registration of the parameters obtained with DTI with the results of MRS (36 voxels), significant correlations were obtained of lipid content with FA (r=0.81), ADC (r=-0.62), choline (r=0.51), and NAA (r=0.44) (P<0.01, all). These results suggest that in Sjögren-Larsson syndrome, the white matter lipid signals originate from the neurons, with NAA and choline reflecting neuron density and myelination. The comparatively high FA/low ADC values in these lipid-rich locations, indicate a loss of diffusion in directions perpendicular to the fibers. The overall loss of FA in the white matter may reflect a loss of brain tissue water content in SLS patients compared with controls and precede the formation of atrophy.