Validation of the finding of hypertrophy of the clava in infantile neuroaxonal dystrophy/PLA2G6 by biometric analysis.

INTRODUCTION: Infantile neuroaxonal dystrophy (INAD), an autosomal recessive neurodegenerative disorder due to PLA2G6 mutation, is classified both as a PLA2G6-associated neurodegeneration (PLAN) disorder and as one of the neurodegeneration with brain iron accumulation (NBIA) disorders. Age of onset and clinical presentation in INAD is variable. Typically described imaging features of cerebellar atrophy, cerebellar cortex bright FLAIR signal, and globus pallidus iron deposition are variable or late findings. We characterize clinical and neuroimaging phenotypes in nine children with confirmed PLA2G6 mutations and show a useful imaging feature, clava hypertrophy, which may aid in earlier identification of patients. Measurements of the clava confirm actual enlargement, rather than apparent enlargement due to volume loss of the other brain stem structures. METHODS: A retrospective clinical and MRI review was performed. Brain stem measurements were performed and compared with age-matched controls. RESULTS: We identified nine patients, all with novel PLA2G6 gene mutations. MRI, available in eight, showed clava hypertrophy, regardless of age or the absence of other more typically described neuroimaging findings. Brain autopsy in our cohort confirmed prominent spheroid bodies in the clava nuclei. CONCLUSION: Clava hypertrophy is an important early imaging feature which may aid in indentification of children who would benefit from specific testing for PLA2G6 mutations.

Development of a standardized MRI scoring tool for CNS demyelination in children.

BACKGROUND AND PURPOSE: The degree to which MR imaging is useful in the diagnosis of MS is predicated on standardized and reliable evaluation of MR imaging parameters. We aimed to devise items for an MR imaging scoring tool that would have high inter-rater agreement and would be straightforward to apply. MATERIALS AND METHODS: On the basis of a literature search and consensus of an expert panel, we identified 48 parameters that describe acute CNS demyelination, predict MS diagnosis, or characterize demyelinating disorder mimics. MR images of children with clinically confirmed MS, monophasic ADEM, and angiography-negative biopsy-positive small-vessel primary angiitis of the CNS were scored by 2 neuroradiologists independently, using the preliminary 48-parameter tool. Parameters with Cohen κ ≥ 0.6 and deemed important in predicting diagnosis were retained. Parameters not visualized on routine clinical imaging or not important in differentiating MS, ADEM, and SV-cPACNS were discarded. RESULTS: Of 65 eligible patients, 55 children were enrolled (16 with monophasic ADEM, 27 with MS, 12 with SV-cPACNS); 10 were excluded (6 had hard-copy films, 4 did not meet MR imaging quality requirements). Of the 48 parameters, 16 were retained in the final scoring tool. The remaining 28 parameters were discarded: 4 had κ < 0.6 and were not deemed useful in predicting diagnosis; 9 were not visible on routinely acquired clinical images; and 15 had inter-rater agreement ≥0.6 but were not useful in differentiating monophasic ADEM, MS, and SV-cPACNS. CONCLUSIONS: We propose a 16-parameter MR imaging scoring tool that is straightforward to apply in the clinical setting and demonstrates high inter-rater agreement.

Cyclophosphamide therapy in pediatric multiple sclerosis.

OBJECTIVE: To review our multicenter experience with cyclophosphamide in the treatment of children with multiple sclerosis (MS). METHODS: Retrospective chart review of children with MS treated with cyclophosphamide. Demographic, clinical, treatment, and MRI parameters were collected. RESULTS: We identified 17 children with MS treated with cyclophosphamide. All but one had worsening of Expanded Disability Status Scale scores or multiple relapses prior to treatment initiation. Children were treated with one of three regimens: 1) induction therapy alone; 2) induction therapy with pulse maintenance therapy; or 3) pulse maintenance therapy alone. Treatment resulted in a reduction in relapse rate and stabilization of disability scores assessed 1 year after treatment initiation in the majority of patients. Longer follow-up was available for most cases. Cyclophosphamide was well tolerated in most patients. However, side effects included vomiting, transient alopecia, osteoporosis, and amenorrhea. One patient developed bladder carcinoma that was successfully treated. CONCLUSIONS: Cyclophosphamide is an option for the treatment of children with aggressive multiple sclerosis refractory to first-line therapies. Recommendations regarding patient selection, treatment administration, and monitoring are discussed.

Role of MRI in the differentiation of ADEM from MS in children.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is typically a monophasic demyelinating disorder. However, a clinical presentation consistent with ADEM can also be the first manifestation of multiple sclerosis (MS), particularly in children. Quantitative analyses of MRI images from children with monophasic ADEM have yet to be compared with those from children with MS, and MRI criteria capable of distinguishing ADEM from MS at onset have yet to be derived. METHODS: A retrospective analysis of MRI scans obtained at first attack from 28 children subsequently diagnosed with MS and 20 children with ADEM was performed. T2/fluid-attenuated inversion recovery hyperintense lesions were quantified and categorized according to location, description, and size. T1-weighted images before and after administration of gadolinium were evaluated for the presence of black holes and for gadolinium enhancement. Mean lesion counts and qualitative features were compared between groups and analyzed to create a proposed diagnostic model. RESULTS: Total lesion number did not differentiate ADEM from MS, but periventricular lesions were more frequent in children with MS. Combined quantitative and qualitative analyses led to the following criteria to distinguish MS from ADEM: any two of 1) absence of a diffuse bilateral lesion pattern, 2) presence of black holes, and 3) presence of two or more periventricular lesions. Using these criteria, MS patients at first attack could be distinguished from monophasic ADEM patients with an 81% sensitivity and a 95% specificity. CONCLUSIONS: MRI diagnostic criteria are proposed that may be useful in differentiating children experiencing the first attack of multiple sclerosis from those with monophasic acute disseminated encephalomyelitis.

MRI in the diagnosis of pediatric multiple sclerosis.

BACKGROUND: MRI diagnostic criteria have not yet been adopted for pediatric multiple sclerosis (MS). MRI plays a pivotal role in supporting the diagnosis of MS in adults. We sought to quantitatively define the MRI features of pediatric MS, to determine features that distinguish MS from nondemyelinating relapsing childhood neurologic disorders, and to propose MRI criteria for lesion dissemination in space in children with MS. METHODS: A retrospective analysis of MRI scans from 38 children with clinically definite MS and 45 children with nondemyelinating diseases with relapsing neurologic deficits (migraine, systemic lupus erythematosus) was performed. For each scan, T2/FLAIR hyperintense lesions were quantified and categorized according to location and size. Mean lesion counts in specific locations were compared between groups to derive diagnostic criteria. Validation of the proposed criteria was performed using MRI scans from a second independent MS cohort (n = 21). RESULTS: MRI lesion location and size categories differed between children with MS and nondemyelinating controls with a medium to large effect size for most variables. The presence of at least two of the following-five or more lesions, two or more periventricular lesions, or one brainstem lesion-distinguished MS from other nondemyelinating disease controls with 85% sensitivity and 98% specificity. CONCLUSIONS: We propose modifications to the currently established McDonald MRI criteria for lesion dissemination in space that will enhance the diagnostic accuracy of these criteria for multiple sclerosis in children.

A case of Horner syndrome with intermittent mydriasis in a patient with hypoplasia of the internal carotid artery.

We report a rare case of hypoplasia of the right internal carotid artery (ICA) with ipsilateral congenital Horner syndrome. The etiology and pathogenesis of hypoplasia of the ICA is not well understood. Multiple types of collateral flow have been reported to develop to maintain blood supply to the ipsilateral cerebral hemisphere. Although collateral flow may allow these patients to remain asymptomatic, we postulate that the enlarged posterior communicating artery (PcomA) in our patient caused mass effect on the cisternal segment of cranial nerve III causing intermittent mydriasis apart from Horner syndrome.