Acute flaccid myelitis in childhood: a retrospective cohort study.

BACKGROUND AND PURPOSE: Clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM. METHODS: This was a retrospective cohort study. RESULTS: Eight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total). CONCLUSIONS: Acute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

In vivo and in vitro correction of the mdx dystrophin gene nonsense mutation by short-fragment homologous replacement.

Targeted genetic correction of mutations in cells is a potential strategy for treating human conditions that involve nonsense, missense, and transcriptional splice junction mutations. One method of targeted gene repair, single-stranded short-fragment homologous replacement (ssSFHR), has been successful in repairing the common deltaF508 3-bp microdeletion at the cystic fibrosis transmembrane conductance regulator (CFTR) locus in 1% of airway epithelial cells in culture. This study investigates in vitro and in vivo application of a double-stranded method variant of SFHR gene repair to the mdx mouse model of Duchenne muscular dystrophy (DMD). A 603-bp wild-type PCR product was used to repair the exon 23 C-to-T mdx nonsense transition at the Xp21.1 dys locus in cultured myoblasts and in tibialis anterior (TA) from male mdx mice. Multiple transfection and variation of lipofection reagent both improved in vitro SFHR efficiency, with successful conversion of mdx to wild-type nucleotide at the dys locus achieved in 15 to 20% of cultured loci and in 0.0005 to 0.1% of TA. The genetic correction of mdx myoblasts was shown to persist for up to 28 days in culture and for at least 3 weeks in TA. While a high frequency of in vitro gene repair was observed, the lipofection used here appeared to have adverse effects on subsequent cell viability and corrected cells did not express dystrophin transcript. With further improvements to in vitro and in vivo gene repair efficiencies, SFHR may find some application in DMD and other genetic neuromuscular disorders in humans.

Benign acute childhood myositis: laboratory and clinical features.

BACKGROUND: Benign acute myositis of childhood is a disorder of midchildhood, typically affecting boys. Symptoms include calf pain and difficulty walking after a viral illness. There is an epidemiologic association with influenza. OBJECTIVES: To describe the clinical and laboratory features of benign acute myositis. RESULTS: Thirty-eight children (32 boys, 6 girls) were seen with 41 episodes of myositis between 1978 and 1997. Two were siblings and three had recurrent episodes. Mean age at onset of symptoms was 8.1 years. Children remained ambulant during 33 of 41 episodes. Two characteristic gaits were noted: toe-walking in 13, with a wide-based stiff-legged gait in another 7. Muscle tenderness was isolated to the gastrocnemius-soleus muscles in 82% of episodes. Recovery occurred within 1 week. Creatine kinase levels were elevated during all episodes. Viral studies were positive in 10 of 24 episodes, 5 because of influenza B. CONCLUSION: Benign acute myositis is a syndrome of midchildhood that can be differentiated from more serious causes of walking difficulty by the presence of calf tenderness, normal power, intact tendon reflexes, and elevated creatine kinase. The gait patterns noted may minimize power generation of the calf muscles by splinting the ankles. Onset in childhood may reflect an age-related response to viral infection, and occurrence primarily in boys may reflect a genetic predisposition or an as-yet unknown metabolic defect.

Selective staining of the cerebellar molecular layer by serum IgG in Miller-Fisher and related syndromes.

During 1 year, we used immunocytochemical staining of human cerebellum to screen 1,488 serums for IgG autoantibodies to Hu and Yo antigens. Three serums had none of the classically described patterns of IgG binding but instead, selectively stained the cerebellar molecular layer. Evaluation of clinical data showed that the patients had either typical Miller Fisher syndrome (MFS) or Guillain-Barré syndrome with ophthalmoplegia. Further analysis by ELISA, assay showed that all three serums had high titers of IgG anti-GQ1b autoantibodies. IgG autoantibody staining of human cerebellum, which is used for the diagnosis of paraneoplastic disorders, may have additional specificity for other, presumably autoimmune, syndromes such as MFS. The specificity of the serum IgG autoantibody binding to the cerebella molecular layer may be related to the ataxia that often occurs in these patients.

Distal lower motor neuron syndrome with high-titer serum IgM anti-GM1 antibodies: improvement following immunotherapy with monthly plasma exchange and intravenous cyclophosphamide.

Motor neuropathies associated with electrodiagnostic evidence of motor conduction block often improve after treatment with immunotherapy, but there is less evidence about the responsiveness of lower motor neuron (LMN) syndromes without conduction block. In this study we treated four patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 ganglioside antibodies but without conduction block on electrodiagnostic testing. Treatment courses consisted of five to seven repeated monthly regimens of plasma exchange on 2 consecutive days followed, on day 3, by intravenous cyclophosphamide (1 g/m2). The results of treatment were quantitatively measured using hand-held dynamometry. We found that all four patients showed progressive improvement in strength over the 6 to 24 months following treatment. Improvement was documented by both objective muscle testing and patient reports of increased strength and less fatigability. We conclude that immunotherapy may be followed by useful functional benefit in selected patients with an asymmetric, predominantly distal LMN syndrome associated with high serum titers of IgM anti-GM1 antibodies. Gradual improvement often begins as late as 6 to 9 months after the onset of treatment and may persist for 1 to 2 years, or longer, after immunosuppressive treatment is stopped.

Anti-MAG antibodies: major effects of antigen purity and antibody cross-reactivity on ELISA results and clinical correlation.

There is controversy regarding the relationship of polyneuropathy syndromes to the presence of serum antibody binding to myelin-associated glycoprotein (MAG). Using standard ELISA methodology, we identified 74 sera that appeared to have high titers of IgM binding to MAG and found that only 34% of these sera stained MAG using Western blot methodology. Follow-up studies showed that two factors greatly influence concordance between ELISA and Western blot testing for anti-MAG antibodies. Sera with high titers of binding to both MAG and histone H3 identified by ELISA rarely stain MAG on Western blot. In addition, sera analyzed by ELISA often bind to impurities in the semipure MAG that is frequently used in ELISA assays. Further purifications to separate MAG from other contaminants improved concordance between ELISA and Western blot results to 85% to 90% in a retrospective analysis, as well as in a prospective study of 49 additional sera. Patients with a polyneuropathy and serum IgM binding to MAG preparations by ELISA but not by Western blot methodology had several different clinical syndromes, including gait disorders and asymmetric motor neuropathies. Patients with IgM binding to MAG by both assay methods usually had a distal, sensory-motor, symmetric polyneuropathy with some features of demyelination on electrodiagnostic testing.

Childhood chronic inflammatory demyelinating neuropathies: clinical course and long-term follow-up.

Chronic inflammatory demyelinating neuropathy (CIDP) is a rare disease in childhood. We reviewed the clinical characteristics, response to therapy, and long-term prognosis in 13 children (1.5 to 16 years of age) diagnosed with CIDP at Washington University Medical Center, St. Louis, and the Royal Children's Hospital, Melbourne, Australia, between 1979 and 1994. The most common presenting symptom (in 11/13 [85%]) was lower extremity weakness associated with difficulty in walking. Preceding events within 1 months of onset, mostly intercurrent infections or vaccinations, occurred in seven children (54%). The disease was monophasic in three children (23%). One relapse occurred in four (30%) and multiple relapses in six (46%). All patients had at least short-term response to steroids. Three children (23%) recovered completely during the first year. Ten children (77%) had residual weakness after an average follow-up of 6 years. There seems to be two populations of children with CIDP. One subgroup, with a favorable prognosis, progressed to peak disability over less than 3 months; these children often have a monophasic course with complete resolution of symptoms and signs and withdrawal from all medications by 1 year after onset. A second subgroup progressed for 3 months or longer; these children all required substantial does of prednisone for prolonged periods and had considerable long-term morbidity with persistent weakness.

Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children.

OBJECTIVE: To identify the clinical and neuroradiologic features of acute disseminated encephalomyelitis (ADEM) in childhood. METHODS: A retrospective review was conducted of the medical records and MRI of children who presented to the Royal Children's Hospital in Melbourne with ADEM between January 1993 and December 1998. RESULTS: Of the 31 patients included in this study, 22 (71%) experienced a prodromal illness. Two patients (6%) had received hepatitis B vaccine 3 to 6 weeks before developing their illness. Symptoms and signs typically evolved over several days. Ataxia was the most common presenting feature, occurring in 20 patients (65%). MRI findings were variable, but lesions were most commonly seen bilaterally and asymmetrically in the frontal and parietal lobes. The authors found a high incidence of the corpus callosal and periventricular changes more typically associated with MS, but they also found a high rate of deep gray matter involvement (61% of patients). The use of high-dose IV methylprednisolone was usually associated with rapid recovery. Eighty-one percent of patients recovered completely, with only mild sequelae recorded in the remaining children. CONCLUSION: In the absence of a biological marker, the distinction between ADEM and MS cannot be made with certainty at the time of first presentation, but the authors suggest that a viral prodrome, early-onset ataxia, high lesion load on MRI, involvement of the deep gray matter, and absence of oligoclonal bands are more indicative of ADEM.

CD45 fraction bone marrow cells as potential delivery vehicles for genetically corrected dystrophin loci.

Targeted correction of mutations in muscle can be delivered by direct i.m. injection of corrective DNA to the dystrophic muscle or by autologous injection of cells that have been genetically corrected after isolation from the individual with the dystrophic muscle. The successful application of chimeraplasty and short fragment homologous replacement to correct the exon 23 nonsense mdx transition at the mouse dys locus has opened up the possibility that with further development, targeted gene correction may have some future application for the treatment of muscular dystrophies. In vitro, application of targeted gene correction at the mdx dys locus results in better correction efficiencies than when applied directly to dystrophic muscle. This suggests that at least for the time being, a strategy involving ex vivo correction may be advantageous over a direct approach for delivery of gene correction to dystrophic muscle. This, particularly in view of recent developments indicating that bone-marrow-derived cells are able to systemically remodel dystrophic muscle, whilst penetration of DNA introduced to muscle is limited to individually injected muscles. Application of targeted gene correction to Duchenne dystrophy needs to account for the fact that about 65% of Duchenne muscular dystrophy cases involve large frame-shift deletion of gene sequence at the dys locus. Traditionally, whilst targeted gene correction is able to restore point mutations entirely, it remains to be seen as to whether a strategy for the 'correction' of frame shift deletions may be engineered successfully. This communication discusses the possibility of applying targeted gene correction to dystrophic muscle in Duchenne dystrophy.

Serum antibodies to heparan sulfate glycosaminoglycans in Guillain-Barré syndrome and other demyelinating polyneuropathies.

We tested for serum antibodies to glycosaminoglycans (GAGs), including heparan sulfate, in patients with Guillain-Barré syndrome (GBS) and other disorders. We used ELISA methods that optimize immunoglobulin binding to carbohydrate antigens to measure serum antibodies to heparan sulfate GAGs in GBS, and control neuromuscular and immune disorders. We found serum IgM or IgG antibodies to heparan sulfate GAGs in 34% of patients with GBS. Serum IgM binding to heparan sulfate GAGs was also found in some chronic demyelinating polyneuropathies, with the highest frequency (33%) in patients with IgM anti-MAG M-proteins. Antibodies to heparan sulfate GAGs were rare (1%) in control serums from patients with other disorders. This result is the first demonstration of high titer serum antibodies to a specific antigen in a substantial group of, and with some specificity for, patients with the classically described GBS syndrome of acute-onset, motor-sensory polyneuropathy with demyelinating features.

IgM anti-sulfatide autoantibodies: patterns of binding to cerebellum, dorsal root ganglion and peripheral nerve.

Anti-sulfatide antibodies are associated with polyneuropathies having a prominent sensory component, but with variable degrees of motor and sensory loss, gait dysfunction and demyelination. In this study, we asked whether patterns of IgM binding to neural tissue in anti-sulfatide serums also demonstrated heterogeneity. We used immunocytochemical methods to examine IgM binding to peripheral nerve, dorsal root ganglion, and cerebellum in 41 serums with high titers of IgM anti-sulfatide antibodies. Our results showed that there were several different patterns of IgM binding to neural tissues in anti-sulfatide serums. In peripheral nerve the most common targets of IgM were axons, resident macrophages or Schwann cell cytoplasm. In the cerebellum, IgM bound to neuronal nuclei, white matter, or neuropil in molecular and granule cell layers. There was little binding of IgM to structures in the dorsal root ganglion. Patterns of IgM binding to peripheral nerve and cerebellum were related. Binding to neuronal nuclei in the cerebellum was usually found in serums that recognized peripheral nerve axons or macrophages. Serums with binding of IgM to cerebellar white matter usually recognized Schwann cell cytoplasm. We conclude that IgM anti-sulfatide antibodies may have several different tissue binding patterns in the peripheral and central nervous systems. These differences may be related to the variation in clinical neuropathy syndromes associated with apparently similar anti-sulfatide antibodies.

Anti-myelin associated glycoprotein antibodies: variability in patterns of IgM binding to peripheral nerve.

We previously found that serums with anti-sulfatide antibodies have several different patterns of binding to neural tissue. In this study, we asked whether serums with anti-myelin associated glycoprotein (MAG) antibodies also have similar variations in patterns of tissue binding. We examined binding to peripheral nerve in 49 serums with IgM anti-MAG antibodies and 13 serums with IgM anti-sulfoglucuronyl paragloboside (SGPG) antibodies but no MAG binding. We correlated patterns of binding with titers of IgM binding to MAG and SGPG measured by ELISA methods. Our results show that IgM in most anti-MAG serums stained areas of non-compact myelin, including the periaxonal and outer myelin membranes and Schmidt-Lanterman incisures. However, other patterns included IgM binding to areas of compact myelin and to non-myelin structures including axons and endoneurial macrophages. IgM in anti-SGPG serums bound to axons or macrophages, but rarely to myelin-related structures. A total of 11/62 (18%) of serums had IgM binding to axons, six with anti-MAG antibodies and five with anti-SGPG antibodies. The majority of these serums (73%) had SGPG titers greater than MAG titers when measured by ELISA. We conclude that anti-MAG serums have several different binding patterns to neural tissue, including axonal binding, especially when anti-MAG antibodies cross-react with SGPG. These different binding patterns may relate to the ability of anti-MAG serum IgM to bind both MAG and SGPG or to other molecules with a sulfated glucuronic acid epitope that are present in peripheral nerve.

An extended phenotype of an early-onset inherited nonprogressive cerebellar ataxia syndrome.

A father and son with presumed dominantly inherited, nonprogressive, early-onset cerebellar ataxia are reported. The clinical features are similar to those in other reports of this rare disorder, but magnetic resonance imaging revealed generalized atrophy of the cerebellum and not localized vermal atrophy as previously noted. This family illustrates either an extended phenotype of the previously reported disorder or possibly an unique type of autosomal dominant cerebellar ataxia.

Subacute sclerosing panencephalitis presenting as simple partial seizures.

Subacute sclerosing panencephalitis is reported in a 16-year-old girl with a 2 1/2-year history of right-sided simple partial sensory and motor seizures. The seizures were verified with video-electroencephalographic monitoring, showing left frontal epileptic activity. After an initial response to antiepileptic medication, her seizures became intractable, and mild, right-hemisphere signs developed. Magnetic resonance imaging showed an extensive right-hemisphere infiltrative lesion, thought to be a neoplasm. Cortical brain biopsy raised the possibility of subacute sclerosing panencephalitis, and this was confirmed serologically. The case highlights the importance of considering subacute sclerosing panencephalitis in the differential diagnosis of intractable seizures and demonstrates that strikingly asymmetrical magnetic resonance imaging abnormalities are not inconsistent with this diagnosis.

Congenital muscular dystrophy, white-matter abnormalities, and neuronal migration disorders: the expanding concept.

The congenital muscular dystrophies are a heterogeneous, recessively inherited group of disorders that have been subclassified on the basis of clinical central nervous system involvement. We report two children with "pure" congenital muscular dystrophy, one merosin negative and one merosin positive with extensive white matter and occipital cortical neuromigration abnormalities on magnetic resonance imaging (MRI). The first patient (merosin-negative congenital muscular dystrophy) presented with hypotonia and weakness in the neonatal period and subsequently was found to have a leukoencephalopathy and occipital cortical dysplasia on magnetic resonance imaging. The second patient presented with developmental delay without definite weakness. Initial investigations revealed a leukoencephalopathy and cortical dysplasia, but the patient subsequently was shown to have merosin-positive congenital muscular dystrophy. These patients illustrate that white-matter changes are not specific for merosin-negative congenital muscular dystrophy alone and that extensive cortical abnormality can be found in both groups of patients. In addition, our second patient illustrates a nonmuscular mode of congenital muscular dystrophy presentation that should be considered in patients with a "nonprogressive leukodystrophy."

Stroke and fibromuscular dysplasia: confirmation by renal magnetic resonance angiography.

Childhood stroke is uncommon and may require extensive evaluation to elucidate an underlying cause. A 9-year-old boy had clinical and magnetic resonance imaging (MRI) features of an ischemic event in the left middle cerebral artery territory. Magnetic resonance angiography (MRA) revealed beading of the left middle cerebral artery, consistent with irregular blood flow secondary to turbulence or luminal narrowing. Conventional angiography of the cerebral vessels confirmed the findings of cerebral MRA and raised further the suspicion of fibromuscular dysplasia (FMD). MRA of the renal vessels was subsequently performed, revealing beading of the left renal artery and confirming the diagnosis of FMD. MRA, a rapid and less invasive technique associated with far less morbidity and mortality as compared with conventional angiography, may prove to be as sensitive as conventional angiography in detecting the changes of FMD. MRA of the renal arteries should be performed with initial cranial MRI and MRA in children who present with cerebral infarction of possible vascular origin. This may obviate the need to perform further investigations and may make early diagnosis possible at the first MRI scan and under a single general anesthetic.

Observations of body mass index in Duchenne muscular dystrophy: a longitudinal study.

BACKGROUND/OBJECTIVES: Nutritional issues that are associated with Duchenne muscular dystrophy (DMD) remain poorly understood. The aim of this analysis was to describe and explore longitudinal observations of body mass index (BMI) in a cohort of children with DMD. SUBJECTS/METHODS: Anthropometric and clinical characteristics were collected retrospectively and longitudinally for boys with DMD seen in two large neuromuscular clinics. BMI Z-scores were determined using the Centers for Disease Control and Prevention reference values for children (2000). RESULTS: Medical records (n=193) were examined from which 75% were included for analysis. The mean age of the cohort at the time of data collection was 11.9 years, with 72% of patients currently or previously using steroids. The highest prevalence of obesity based on the BMI Z-score was 50% at the age of 10 years. Longitudinally, BMI Z-scores from the age of 2 to 12 years plot approximately one s.d. above the mean, after which there is a marked and progressive decline. BMI gainers were identified for whom BMI Z-score increased by 1.65 units compared with the 0.09 units in non-gainers. BMI gainers were younger when they had their first BMI measurement (5.9 vs 7.2 years), and this measure was significantly lower compared with the non-gainers (BMI Z-score: 0.04 vs 1.17). In this cohort, BMI was associated with age, ambulatory status and lung function. CONCLUSIONS: This study demonstrates that boys with DMD using steroid therapy experience shifts in BMI. A declining BMI appears to be associated with increasing age. Interpretation of growth patterns is limited here by a lack of normative growth references in DMD.

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy.

OBJECTIVE: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). METHODS: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. RESULTS: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. CONCLUSIONS: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.