Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis.

BACKGROUND: Intrathecal IgM synthesis is reported to be associated with a worse prognosis in adults with multiple sclerosis (MS). OBJECTIVE: To study the predictive value of intrathecal IgM synthesis for the clinical course of pediatric MS. METHODS: Seventy children with onset of MS before the age of 16 years and followed for a median period of 10.4 years (range: 0.4-22.8 years) were studied. The two subgroups with (n=44) or without (n=26) intrathecal IgM synthesis were distinguished by a new, very sensitive, evaluation of quantitative analysis in cerebrospinal fluid (CSF)/serum quotient diagrams (Reibergrams). The clinical course and EDSS (Expanded Disability Status Scale) scores at five and ten years were compared with IgM frequencies between both groups with a new statistics program for CSF data. RESULTS: The cohort of children without intrathecal IgM production had higher numbers of attacks in the first two years and shorter time intervals between first and second attack, although this was not statistically significant (p=0.04, p=0.15 respectively). In addition there was also a trend for girls without intrathecal IgM synthesis to have a higher EDSS score after 10 years compared with the group with IgM synthesis. CONCLUSION: Intrathecal IgM synthesis is not associated with a more rapid progression of disability in pediatric MS. Reevaluation of data from previous reports about the negative predictive value of intrathecal IgM synthesis in adult MS with a CSF statistics tool show that the apparent contradiction is due to a methodological bias in the qualitative detection of 'oligoclonal' IgM or linear IgM index.

Paediatric and adult multiple sclerosis: age-related differences and time course of the neuroimmunological response in cerebrospinal fluid.

We investigate common pathophysiology in paediatric and adult multiple sclerosis (MS) by comparison of cerebrospinal fluid (CSF) data. We compared cerebrospinal fluid (CSF) data from eight patient groups with onset of MS at 7 to 29 years (n = 184). A new statistics program allows sensitive detection, quantifies the mean amount of intrathecal Ig synthesis in groups based on the 96% reference range of 4100 non-inflammatory controls, corrects for age-related increase of blood-derived albumin and immunoglobulins in CSF, and presents graphical data interpretation in Reibergrams. Already at onset of MS before puberty (< or =10 years) the frequency of intrathecal IgG synthesis (oligoclonal IgG) was 100% like in adults with 98%, but the amount of intrathecal IgG increases twofold during puberty. Intrathecal IgM synthesis is most frequent before and during puberty (in 57-67% of patients) compared with 41% in adults. The amount of intrathecal IgM synthesis before puberty is only 30% of that in adults. IgG and IgM Index are biased evaluations not suitable for characterizing age-related dynamics. A twofold age-related increase of the albumin quotient, Q(Alb), as a measure of the blood-CSF barrier function, represents normal physiological growth. Cell counts in CSF are low. The pre-puberty gender ratio is about 1:1. Intrathecal antibodies against measles, rubella and/or varicella zoster virus are detected in 73% of patients before puberty compared with 89% of adults. Individual paediatric patients (n = 17), with sequential punctures over 2-5 years, show constant quantities of intrathecal IgM and specific antibodies. In conclusion, paediatric MS already at first clinical manifestation shows the complete, neuroimmunological data pattern in CSF, i.e. inflammatory signs are not gradually evolving. Paediatric and adult MS differ quantitatively but not qualitatively in neuroimmunological patterns which does not allow for discrimination between 'early' and 'late' onset MS. CSF analysis may help to discriminate between acute and mono-symptomatic chronic inflammatory disease already at earliest clinical manifestation.

Chronic relapsing opsoclonus-myoclonus syndrome: combination of cyclophosphamide and dexamethasone pulses.

Opsoclonus-myoclonus syndrome (OMS) is a rare and debilitating disorder of unknown etiology affecting children and adults. Outcome is unfavourable; approximately 80% of children with OMS suffer from mild to severe neurological handicaps, mainly cognitive impairment. A standard therapy does not exist. Due to the possible immune-mediated mechanisms, treatment with steroids, ACTH, plasmapheresis and immunoglobulins can be successful. However, some children become steroid dependent and symptoms may reoccur after treatment has been finished. We present two girls with OMS, who had a prolonged clinical course lasting 4 and 9 years with many relapses. Both children developed symptoms around the age of two years. Diagnostic work-up to exclude neuroblastoma was negative. Several treatment modalities including oral steroids, dexamethasone pulses, immunoglobulin and cyclosporine were used without lasting success. In addition, cognitive impairment developed in both children. In order to prevent further clinical and mental deterioration, 6 pulses of cyclophosphamide in combination with dexamethasone pulses every 4 weeks were administered. Both children showed significant improvement of OMS symptoms. One girl is still symptom free 18 months after treatment, mild ataxia developed in the other after 12 months. Both children are mentally handicapped and in special need schools. We conclude that combination of cyclophosphamide pulses and dexamethasone pulse therapy is a therapeutic option even after a long clinical course to improve symptoms of OMS.

Proton MRS of a child with Sandhoff disease reveals elevated brain hexosamine.

Sandhoff disease (gangliosidosis type 0) is a lysosomal storage disorder with a deficiency of hexosaminidases A and B. After an initially normal development the clinical course of affected children is severe and rapidly progressive leading to spastic tetraparesis, epileptic seizures and early death. In a 10-month-old girl with enzymatically established diagnosis of Sandhoff disease MRI of the brain showed signal changes in the periventricular white matter, pyramidal tract, basal ganglia, and cerebellar hemispheres. Proton MR spectroscopy (MRS) at the age of 13 months revealed a reduction of total N-acetylaspartate (neuroaxonal marker) as well as strongly elevated inositol (glial marker) in white matter, gray matter, and basal ganglia. A new resonance at 2.07 ppm was detected in all regions and ascribed to N-acetylhexosamine with highest concentrations in white matter and thalamus. While conventional MRS findings are in line with neuroaxaonal damage and pronounced astrocytosis, the observation of N-acetylhexosamine appears as a specific marker of Sandhoff disease indicating accumulation of hexosamine-containing oligosaccharides. This interpretation is supported by a recent in vitro MRS study of a Sandhoff mouse model. In conclusion, proton MRS of cerebral metabolites offers specific insights into the pathopysiologic processes of children with Sandhoff disease and may prove to represent another disease specific MRS pattern of the brain.

High seroprevalence of Epstein-Barr virus in children with multiple sclerosis.

We studied seroprevalence and concentrations of Epstein-Barr virus (EBV) antibodies in 147 pediatric patients with multiple sclerosis (MS) and paired controls. The children with MS showed a near-complete seropositivity for EBV antibody against virus capsid antigen (98.6% vs 72.1% in controls, p = 0.001) but did not display serologic evidence for a recent EBV infection. EBV antibody concentrations of pediatric patients with MS were significantly higher vs controls.

Baló's concentric sclerosis associated with primary human herpesvirus 6 infection.

BACKGROUND: Baló's concentric sclerosis (BCS) is a demyelinating disorder believed to be a rare variant of multiple sclerosis (MS). Human herpesvirus 6 (HHV-6) is a highly neurotropic virus causing severe central nervous system (CNS) infections predominantly following reactivation of latent HHV-6 in immunocompromised individuals. Primary infection with HHV-6 usually occurs in early childhood manifesting as exanthema subitum. The clinical spectrum of primary infection in adolescents or adults has not yet been evaluated. CASE REPORT: A previously healthy 13 year old girl developed acute hemianopsia and anomia 5 days after an episode of fever and malaise of unknown origin. Cerebral MRI revealed three white matter lesions, one with ring-like contrast enhancement. Lumbar puncture showed mononuclear pleocytosis of 30 cells/microl, oligoclonal IgG, and a normal protein level. Follow up cerebral MRI scans revealed lamellar concentric hemispheric lesions characteristic of BCS. The first neurological symptoms of the patient coincided with primary HHV-6 CNS infection, diagnosed by a positive PCR test of the CSF together with seroconversion. Response to antiviral and corticosteroid treatment was only temporary, but immunoglobulin treatment has so far been followed by clinical stability for 30 months. CONCLUSIONS: To our knowledge, this is the first report both of an association between HHV-6 and BCS and of immunoglobulin treatment of BCS. A late primary infection with HHV-6 might be associated with BCS. Further studies in patients with this rare disease are needed to confirm this association and to evaluate the efficacy of antiviral and immunoglobulin treatment.

Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination.

BACKGROUND: Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive neurologic disorder caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The associated depletion of PLP and severe reduction of other major myelin proteins results in dysmyelination. MRI reveals loss of T1 contrast between gray and affected white matter and T2 hyperintensities of white matter due to elevated water content. METHODS: In vivo proton magnetic resonance spectroscopy (MRS) was used to determine cerebral metabolite patterns in five patients with genetically proven PMD. Absolute metabolite concentrations were obtained in cortical gray matter, affected white matter, and basal ganglia and compared to age-matched control values. RESULTS: In comparison to age-matched controls, MRS of affected white matter resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate (tNAA), glutamine (Gln), myo-inositol (Ins), and creatine and phosphocreatine. Most remarkably, the concentration of choline-containing compounds was reduced. Parietal gray matter and basal ganglia appeared normal but showed a tendency for elevated tNAA, Gln, and Ins. CONCLUSIONS: Magnetic resonance spectroscopy (MRS)-detected alterations are consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia. These disturbances in cellular composition are in close agreement with the histopathologic features characteristic of dys- and hypomyelination. The proton MRS profile of Pelizaeus-Merzbacher disease (PMD) differs from the pattern commonly observed in demyelinating disorders and allows PMD to be distinguished from other leukodystrophies.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

CSF characteristics in early-onset multiple sclerosis.

The authors studied CSF characteristics in 136 patients with multiple sclerosis (MS) with a disease onset before age 16. In the initial diagnostic lumbar puncture, CSF-pleocytosis was observed in 66%, blood-CSF barrier dysfunction in 13%, and oligoclonal IgG in 92% of the early-onset MS (EOMS) patients. CSF oligoclonal IgG supports the early diagnosis of MS in childhood with a sensitivity similar to adult-onset MS.

Stroke-like pattern in DTI and MRS of childhood mitochondrial leukoencephalopathy.

In a 13-month-old boy with recurrent motor deterioration provoked by fever MRI and proton MRS detected a leukoencephalopathy with reduced cerebral metabolites and elevated lactate. At follow-up 6 and 16 months later these abnormalities improved gradually. Serial diffusion tensor imaging revealed a stroke-like pattern with an initial strong reduction of the apparent diffusion coefficient followed by elevated values 6 months later. The relative diffusion anisotropy remained reduced. Muscle biopsy confirmed a mitochondrial encephalomyopathy.

CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children.

Hemophagocytic lymphohistiocytosis is a rare and fatal disorder of early infancy, which affects predominantly the mononuclear phagocyte system and is characterized by the presence of fever, hepatosplenomegaly and cytopenia. Neurological symptoms can be extremely variable, ranging from irritability, and convulsions to focal neurological signs. They often develop during disease progression, but can also be the leading initial symptoms. Early diagnosis is mandatory, because new treatments, including bone marrow transplantation, appear to be promising. Here we present the clinical, neuroradiological and histopathological findings from two children with progressive CNS disease as the main clinical manifestation of hemophagocytic lymphohistiocytosis. Both children died and diagnosis was only obtained in retrospect after careful review of the histopathological material.

Quantitative proton magnetic resonance spectroscopy of children with adrenoleukodystrophy before and after hematopoietic stem cell transplantation.

About 35-40 % of boys with X-linked adrenoleukodystrophy (ALD) develop a rapidly progressive cerebral form which leads to severe neurologic disability and death within 3-5 years after onset of clinical symptoms. Because previous proton magnetic resonance spectroscopy (MRS) studies of ALD identified metabolite patterns characteristic of demyelination, gliosis, and neuroaxonal loss, this work tested the hypothesis that MRS--apart from indicating disease progression--provides criteria for the outcome after hematopoietic stem cell transplantation (HSCT) which has been promising at an early stage of the active disease. Follow-up quantitative proton MRS was performed in frontal and occipital white matter of ALD patients (n = 12) before and up to 5 years after HSCT. The observed metabolite alterations were retrospectively correlated with the clinical outcome representing either a stable condition (n = 5), a further deterioration (n = 5), or death (n = 2). While disease progression of patients before HSCT was mainly characterized by a further increase of elevated choline-containing compounds (Cho) as an indicator of active demyelination, a positive outcome after HSCT was correlated with high N-acetylaspartate (tNAA) levels in affected white matter before HSCT yielding positive and negative predictive values for tNAA of 80 %. Although to be confirmed in a larger cohort of patients, the present findings suggest the preservation of neuroaxonal integrity as a prerequisite for an arrested course. Conversely, the combination of increased Cho with markedly reduced tNAA before HSCT apparently reflects a degree of tissue degeneration which precludes a successful therapeutic intervention.

Clinical and genetic heterogeneity in megalencephalic leukoencephalopathy with subcortical cysts (MLC).

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) was recently localized on chromosome 22q (tel) and 26 different mutations of the gene MLC1 have been found. We report three siblings of non-consanguineous parents who presented with characteristic features of MLC, but did not have MLC1 mutations. MEYHODS: Clinical, laboratory and neuro-imaging findings of the siblings are described and similar patients with MLC are reviewed. RESULTS: All three siblings suffered from ataxia, progressive severe tetraparesis, dysarthria, dysphagia and epilepsy. Generalized dystonia occurred in one patient. Mental deterioration progressed more slowly than motor deterioration. The youngest male was the most severely affected and died at the age of 23 years. The two older females are now 34 and 35 years old. Our patients are among the oldest described with this clinical entity. No mutation of the MLC1 gene was found in our siblings and linkage with the MLC1 locus was excluded. CONCLUSIONS: The genetic findings in our patients suggest at least a second gene locus for MLC.

[The Levy-Hollister syndrome: a syndrome of dysplasias with ENT-manifestations]. / Das Levy-Hollister-Syndrom: Ein Dysplasiesyndrom mit HNO-Manifestationen.

The Levy-Hollister syndrome is characterized by a highly variable expression of dysplasia in different organ systems. Autosomal-dominant inheritance is recognised, but most cases are sporadic. In the field of otorhinolaryngology, xerostomia can be found due to aplasia of the major salivary glands, as well as congenital sensorineural, conductive or combined hearing loss and dysplasia of the auricles, mostly appearing as cup-shaped ears. Here we report on a 2-year-old boy with severe xerostomia. The disease was found to be caused by bilateral aplasia of the parotid and submandibular glands. There were also slight dysplasias of both auricles and a bilateral inner ear malformation as the origin of sensorineural hearing loss. Due to its highly variable expression, Levy-Hollister syndrome is often difficult to distinguish from other diseases and syndromes, so that the cooperation of different departments is necessary for an accurate diagnosis. Because of its dominant inheritance, a genetic consultation should be recommended to the patient. Auricular dysplasia and conductive hearing loss can possibly be treated surgically.

Chlamydia pneumoniae in children with MS: frequency and quantity of intrathecal antibodies.

The authors investigated the frequency and quantity of intrathecal antibody synthesis against Chlamydia pneumoniae and the presence of C pneumoniae antigen in 25 children with MS. C pneumoniae genome was present in two children. In seven children an intrathecal synthesis of C pneumoniae antibodies was detected, representing only a small part of the total intrathecal immunoglobulin G, suggesting that this intrathecal synthesis is part of a polyspecific, oligoclonal immune response.

Striking improvement of muscle strength under creatine therapy in a patient with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Creatine monohydrate given orally led to a long-lasting improvement of muscular weakness and ataxia in a girl with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Megalencephalic leukoencephalopathy with subcortical cysts in an adult: quantitative proton MR spectroscopy and diffusion tensor MRI.

A 37-year-old macrocephalic woman was investigated for increasing gait disturbance due to longstanding spasticity and ataxia. MRI showed widespread bilateral increase in signal from cerebral white matter on T2-weighted images. Numerous subcortical cysts were visible in anterior-temporal and parietal regions. These clinical and neuroradiological features are those of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a recently delineated white-matter disease with onset in childhood. Quantitative localised proton MR spectroscopy of white matter revealed marked reduction of N-acetylaspartate, creatine, and choline with normal values for myo-inositol, consistent with axonal loss and astrocytic proliferation. Diffusion tensor imaging showed an increased apparent diffusion coefficient and reduced anisotropy in affected white matter pointing to reduced cell density with an increased extracellular space. These findings are in line with histological changes alterations known to occur in MLC.