Pentoxifylline as a rescue treatment for DMD: a randomized double-blind clinical trial.

OBJECTIVE: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). METHODS: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (~20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. RESULTS: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. CONCLUSION: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Common viruses associated with lower pediatric multiple sclerosis risk.

BACKGROUND: Because common viruses are encountered during childhood, pediatric multiple sclerosis (MS) offers a unique opportunity to investigate the influence of these viruses on disease susceptibility and the interactions between seroprevalence and select HLA genotypes. We studied seroprevalence for Epstein-Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV) type 1 and HLA-DRB1*1501/1503 status as predictors of pediatric MS. METHODS: This was a retrospective analysis of prospectively collected demographic, clinical, and biologic data in subjects up to 18 years of age with early MS, control subjects seen at the same regional referral pediatric MS clinics, and additional healthy pediatric control subjects. RESULTS: Patients with early pediatric MS (n=189) and pediatric control subjects (n=66) were tested. Epstein-Barr nuclear antigen-1 seropositivity was associated with an increased odds of MS (odds ratio [OR] 3.78, 95% confidence interval [CI] 1.52-9.38, p=0.004) in analyses adjusted for age, sex, race, ethnicity, and HLA-DRB1*1501/1503 status. In multivariate analyses including EBV status, a remote infection with CMV (OR 0.27, 95% CI 0.11-0.67, p=0.004) was associated with a lower risk of developing MS. Although a remote infection with HSV-1 was not associated with an increased odds of MS, a strong interaction was found between HSV-1 status and HLA-DRB1 in predicting MS (p<0.001). HSV-1 was associated with an increased risk of MS in those without a DRB1*15 allele (OR 4.11, 95% CI 1.17-14.37, p=0.03), whereas the effect was reversed in those who were DRB1*15-positive (OR 0.07, 95% CI 0.02-0.32, p=0.001). CONCLUSIONS: These findings suggest that some infections with common viruses may in fact lower MS susceptibility. If this is confirmed, the pathways for risk modification remain to be elucidated.

Younger children with MS have a distinct CSF inflammatory profile at disease onset.

BACKGROUND: The clinical and MRI presentation differs between earlier- and later-onset pediatric multiple sclerosis (MS), whereas the effect of age on the CSF inflammatory profile is unknown and may contribute to delayed diagnosis. OBJECTIVES: To compare the CSF cellular and immunoglobulin G (IgG) profiles between earlier- and later-onset pediatric MS. METHODS: We queried the databases of 6 pediatric MS centers for earlier-onset (onset <11 years) and later-onset (> or = 11 and <18 years) patients with MS or clinically isolated syndrome who underwent CSF analysis within the first 3 months of presentation (observational study). We compared CSF white blood cell (WBC) differential count, IgG index, and IgG oligoclonal bands between age groups. RESULTS: We identified 40 earlier-onset (mean age at onset = 7.2 +/- 2.7 years, 60% females) and 67 later-onset pediatric MS patients (15.1 +/- 1.7 years, 63% females). Although WBC count tended to be higher in earlier-onset patients (median = 9/mm(3) [0-343] vs 6 [0-140], p = 0.15), they had a lower proportion of lymphocytes (70% [0-100] vs 93% [0-100] of WBCs, p = 0.0085; difference = +3% per 1-year increase of age, p = 0.0011) and higher proportion of neutrophils than later-onset patients (0.5% [0-75] vs 0% [0-50] of WBCs, p = 0.16; difference = -1% per 1-year increase of age, p = 0.033). In earlier-onset disease, fewer patients had an elevated IgG index than in the later-onset group (35% vs 68% of patients, p = 0.031). CONCLUSION: Age modifies the CSF profile at pediatric multiple sclerosis (MS) onset, which may mislead the diagnosis. Our findings suggest an activation of the innate rather than the adaptive immune system in the earlier stages of MS or an immature immune response.

CNS aquaporin-4 autoimmunity in children.

BACKGROUND: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. METHODS: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. RESULTS: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). CONCLUSIONS: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Contrasting effects of IFNbeta and IVIG in children with central and peripheral demyelination.

Reported are three children with MS who responded dramatically to interferon-beta (IFNbeta) therapy. While on immunomodulatory therapy, they developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) that responded to IV immunoglobulin (IVIG) administration. These cases emphasize two interesting observations: 1) IFNbeta treatment did not prevent development of CIDP; 2) CIDP in the context of MS responded to IVIG, even though IVIG had no therapeutic effect on the central demyelinating disease.

Newborn hearing screening in Hawaii.

Hawaii has been a pioneer and national leader in implementing universal newborn hearing screening. In fact, Hawaii is one of only two states (Rhode Island is the other) which have a statewide newborn hearing screening program in which 95% or more of all newborns are screened. Hawaii is the best example of a truly integrated system of services to provide effective intervention for all infants and toddlers who are identified as having a hearing loss. The success of the newborn hearing screening program is measurable in two ways: 1) all available information indicates that not a single infant with hearing loss has been missed by the screening process and not a single infant has been misdiagnosed as having a hearing loss; and 2) many of the children identified with hearing loss by the newborn hearing screening program have transitioned out of the early intervention program with age-appropriate developmental and communication skills. The success of Hawaii's program is a tribute to the enthusiastic support and collaboration of legislators, pediatricians, hospital staff, and DOH personnel.

Therapeutic play and bone marrow transplantation.

Constructive, therapeutic play is an essential part of the care of children with long-term hospitalizations. The O'Connor theoretical framework supports the importance of play in ensuring the emotional, developmental, and physical health of children. The negative effects of long-term hospitalization are particularly evident for children who have undergone bone marrow transplants and must be kept in germ-free environment and isolation for extended periods of time. This article describes a successful play therapy program in a Bone Marrow Transplant Unit, using a play cabinet designed to provide readily available, sterilized toys that are appropriate for each of four age groups. Two cases are presented that show the efficacy of the use of the play cabinet in play therapy programs.

The electrophysiologic profile of Dejerine-Sottas disease (HMSN III).

Electrophysiologic studies in 11 patients with Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III, HMSN III) showed median and ulnar motor nerve conduction velocities less than 6 m/sec in all but 1 patient. Marked temporal dispersion without conduction block was present in all patients. Uniform slowing in adjacent motor nerves was consistent with other studies of inherited neuropathies, although marked temporal dispersion may make HMSN III more difficult to distinguish from acquired neuropathies than other hereditary conditions. The electrophysiologic features of HMSN III patients were significantly different from a series of patients with other hereditary neuropathies chosen because of very slow nerve conduction velocity.

Nerve conduction studies in infants and children.

The electrophysiologic evaluation of peripheral nerves may provide critically important information, both with respect to diagnosis and prognosis, in the child with a suspected neuromuscular disorder. However, special attention to various technical considerations is necessary to avoid misleading results. Utilizing these techniques, both hereditary and acquired neuropathies may be identified and characterized. The latter has become especially important in view of recent advances in the treatment of acquired demyelinating neuropathies.

Chronic idiopathic anhidrosis.

We describe the cases of eight patients with chronic idiopathic anhidrosis. These patients were heat intolerant and became hot, flushed, dizzy, dyspneic, and weak but did not sweat when the ambient temperature was high or when they exercised. Four patients had preganglionic sudomotor lesions and in the remaining 4 the lesion appeared to be postganglionic. The patients did not have orthostatic hypotension, other evidence of generalized autonomic failure, or symptomatic somatic neuropathy. One patient regained thermoregulatory sweat function and no patient's condition progressed to generalized autonomic failure. Chronic idiopathic anhidrosis appears to be distinctly different from other autonomic neuropathies that tend to carry much poorer prognoses.

Tuberous sclerosis, early onset of seizures, and mental subnormality: study of discordant homozygous twins.

In two sets of male homozygous twins with tuberous sclerosis, one twin in each set suffered frequent generalized seizures from early life, and the second either had no seizures or had only short-lived seizures. One twin of each pair is of normal intelligence, and the other is mentally subnormal. We propose that generalized seizures occurring in early life are an important mechanism in an apparently progressive dementing process in some infants and children with tuberous sclerosis. If our assumption is correct, an early attempt to control generalized seizures in these patients is indicated even in the presence of the cortical, subcortical, and subependymal pathologic changes characteristic of cerebral tuberous sclerosis.