B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes.

BACKGROUND: Although many lines of evidence suggest an autoimmune etiology, the pathophysiology of opsoclonus-myoclonus syndrome (OMS) remains poorly understood and no immunologic abnormalities have correlated with neurologic severity. Conventional immunotherapies often do not prevent relapse or permanent sequelae. OBJECTIVE: To test the cellular immune hypothesis of OMS in a cross-sectional study and determine if CSF lymphocyte subset analysis provides biomarkers of disease activity. METHODS: The expression of lymphocyte surface antigens was investigated in CSF and blood of 36 children with OMS and 18 control subjects, using a comprehensive panel of monoclonal antibodies to adhesion and activation proteins in combination with anti-CD3 and anti-CD45 antibodies in four-color fluorescence-activated cell sorting. RESULTS: Although most children with OMS had normal CSF cell counts, they exhibited expansion of CD19+ B-cell (up to 29%) and gammadelta T-cell (up to 26%) subsets and a lower percentage of CD4+ T-cells and CD4/CD8 ratio, which persisted even years after disease onset and conventional treatments. The percentage of activated CSF T-cells was also higher. Abnormalities correlated with neurologic severity, as scored blinded from videotapes using a 12-item motor scale, and disease duration. No significant differences were found between tumor and no-tumor groups. In children with neuroblastoma, tumor resection or cancer chemotherapy did not alter immunologic abnormalities. CONCLUSIONS: CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.

Myopathy with muscle spindle excess: A new congenital neuromuscular syndrome?

An infant presented with congenital weakness, hypotonia, arthrogryposis, atrial tachycardia, and a left intra-abdominal neuroblastoma. Muscle biopsy revealed marked excess of muscle spindles with atrophy of extrafusal fibers. The patient expired at age 14 months from progressive cardiorespiratory failure. Postmortem examination demonstrated muscle-spindle excess in other muscles, along with hypertrophic obstructive cardiomyopathy and organomegaly. Muscle spindle excess has previously been reported in two patients with Noonan syndrome and progressive hypertrophic cardiomyopathy. Muscle spindle excess with hypertrophic cardiomyopathy, organomegaly, and, possibly, congenital neuroblastoma suggests a syndromic association and may represent an unusual form of congenital myopathy.

Lissencephaly: fetal pattern of glucose metabolism on positron emission tomography?

BACKGROUND: In classical lissencephaly, the cerebral cortex is four-layered, containing neurons that have failed to complete their migration between 12 and 16 weeks of gestation. METHODS: The authors studied the functional activity of lissencephalic cortex using 2-deoxy-2[(18)F]fluoro-D-glucose PET (FDG PET) in eight patients (six girls and two boys, mean age 7.5 years) with isolated lissencephaly sequence. RESULTS: The PET scans revealed a remarkably similar and bilaterally symmetric pattern of glucose metabolism in all eight patients. The cerebral cortex of lissencephaly showed two layers that could be differentiated based on metabolic activity. The inner layer, which probably corresponds to the inner cellular layer of lissencephalic cortex, showed 8 to 63% higher glucose utilization rate than the outer layer, which probably represents a composite of the molecular, outer cellular, and cell-sparse layers. Patients with a higher metabolic ratio between the cortical layers (inner/outer) showed greater delay in communication (p = 0.007) and socialization (p = 0.03). CONCLUSIONS: These findings are consistent with [(14)C]-2-deoxyglucose autoradiography studies in fetal sheep that have shown that before the development of significant numbers of axons, dendrites, and synapses, glucose metabolism appears to be highest in regions with the highest density of cell bodies, compared to the more mature state when glucose metabolism is highest in areas of greatest dendritic arborization. FDG PET studies of classical lissencephaly provide a different perspective in the analysis of brain gyral anomalies than those with traditional neuroanatomic imaging techniques.

XY sex reversal and a nonprogressive neurologic disorder: a new syndrome?

We report a patient with a unique combination of clinical findings: XY sex reversal, spastic paraplegia, mental retardation, dysmorphism, and infantile-onset olivopontocerebellar hypoplasia. The phenotype of our patient did not coincide with any of the described forms of XY reversal syndromes, hereditary or sporadic spastic paraplegias, or congenital or infantile-onset cerebellar or olivopontocerebellar atrophies or hypoplasias. The disorder of this patient likely represents a genetic condition with pleiotropic effects on brain development and sex determination and adds further evidence for the heterogeneity of spastic paraplegia/infantile olivopontocerebellar hypoplasia syndromes and sex reversal syndromes.

Otocerebral anomalies associated with topical tretinoin use.

Topical preparations of tretinoin are used for the treatment of various skin conditions and for rejuvenation of the skin. Published information on pregnancy outcome following maternal exposure to topical tretinoin is limited to three case reports. We report a case of a patient with anomalies involving the ear and central nervous system with exposure to topical tretinoin during the first trimester. Though the potential link between the use of topical tretinoin and the existence of fetal malformations remains to be further documented by animal as well as epidemiological studies, we strongly recommend that the use of topical tretinoin during pregnancy should be discouraged, and effective contraception should be used in patients of childbearing age.

High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis.

Autoimmune neurologic disease management has been significantly modified by the use of high-dose intravenous immunoglobulin (HDIVIG) during the past 15 years. Venous access, readily available IgG (until recently), and the relative lack of serious identifiable complications have prompted its use in myasthenia gravis. In adults, its effectiveness has been inconsistent, with variable acetylcholine receptor (AChR) antibody responses. Ten children were evaluated for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. The HDIVIG dosage was 2 gm/kg body weight, infused at variable rates of 2 gm/kg for 1 day, 0.66 gm/kg daily for 3 days, and 0.5 g/kg daily for 4 days; in one patient the total dose was 0.8 gm/kg to correct to the ideal body weight. All children but one tolerated HDIVIG without complications. Eight patients exhibited definite improvement in functional strength after HDIVIG, but a decreasing response to HDIVIG was evident after multiple monthly treatments, warranting the additional use of corticosteroids in two patients. A decrease in anti-AChR antibody levels was observed in the three patients tested, but this decrease was constant in one patient. No correlation was observed between clinical response and antibody titers. HDIVIG is safe and effective in most patients for short-term management of juvenile myasthenia gravis, in myasthenic crises, and in preparing patients for surgery but appears to be of limited long-term benefit.

Muscle and nerve biopsy in the evaluation of neuromuscular disorders: the surgeon's perspective.

BACKGROUND/PURPOSE: A muscle biopsy frequently is requested by the neurologist evaluating a child with neuromuscular symptoms. However, there are no reports discussing the preoperative evaluation for, and diagnostic yield of, this procedure. The authors reviewed our experience over a 10-year period to obtain these data. METHODS: The records of 153 patients who underwent muscle biopsy were reviewed with particular attention to the cardiology evaluation, the pathology report, and any resultant change in diagnosis and treatment of the child. RESULTS: All 153 specimens contained adequate tissue for complete histological analysis. Preoperative cardiology consults were obtained in 82% of the children, with abnormalities found in 9%. Severe cardiac dysfunction was found in three children, all of whom had a previously diagnosed cardiomyopathy or dysrhythmia. No pathological abnormality was found in 41% of the muscle biopsy specimens, and nonspecific pathological findings were described in 23%. A specific diagnosis was made in 36%. Only 19% of the children had their treatment changed by the results of the muscle biopsy. CONCLUSIONS: Muscle biopsies can be performed safely without routine preoperative cardiac evaluation. A specific diagnosis, however, may be made in less than half of the patients with a change in therapy available for even fewer.

The timing of congenital brachial plexus injury: a study of electromyography findings in the newborn piglet.

OBJECTIVE: Permanent congenital brachial plexus palsy is a recognized serious complication associated with shoulder dystocia. The timing and etiology of this injury remains controversial. Previous authorities have used adult-derived, non-brachial plexus data to extrapolate the anticipated timing for electromyographic denervation changes to date such injuries in the newborn. With use of a domestic swine model, this investigation tests the hypothesis that electromyographic evidence of brachial plexus denervation in the newborn is temporally different than that in the adult. STUDY DESIGN: Five healthy 2-day-old and two adult pigs underwent unilateral sharp transection of the brachial plexus. Daily electromyographic studies were performed in brachial plexus innervated muscle groups on the involved and contralateral (control) front limbs. Postmortem measurements of the transected nerve segments were obtained in one piglet and one adult animal. Representative hard copy recordings of individual electromyographic studies were collected. RESULTS: Immediately after surgical transection of the brachial plexus, no electromyographic evidence of denervation was observed. Uniformly in the newborn piglets, at 24 hours after transection, denervation in the form of fibrillation potentials, positive sharp waves, and complex repetitive discharges was seen. Serial testing demonstrated proximal to distal gradients of denervation over the next 24 to 48 hours. A delay in electromyographic evidence of denervation was observed in the two adult pigs until days 5 and 8, respectively. Control limb studies remained normal throughout the study period. Nerve length measurements for individual muscle groups were as follows for the adult and newborn pigs, respectively: deltoid 11.4 cm, 2.5 cm; cleidobrachialis 16.0 cm, 4.0 cm; triceps 15.5 cm, 4.5 cm; forelimb flexors 26.0 cm, 6.5 cm; and extensor carpi radialis 31.0 cm, 9.0 cm. CONCLUSION: Electromyographic evidence of brachial plexus denervation after surgical transection differs between the newborn and the adult pig. Consistent with wallerian degeneration, a correlation exists between length of the distal nerve segment and timing for electromyographic signs of denervation. These findings suggest it would be inappropriate to extrapolate the anticipated timing for electromyographic changes in the newborn on the basis of previously established adult non-brachial plexus data.

A variant of adrenomyeloneuropathy in a family with adrenoleukodystrophy and adrenomyeloneuropathy.

A 31-year-old man was seen with addisonian crisis, followed by the abrupt onset of spastic paraparesis and peripheral neuropathy. A workup revealed adrenal insufficiency, for which the patient was aggressively treated. The workup also revealed an increase in very-long-chain fatty acids consistent with the diagnosis of adrenomyeloneuropathy. Abnormal pituitary dysfunction improved with treatment of the Addison's disease. A review of the patient's pedigree revealed two family members in whom multiple sclerosis had been diagnosed but which, in retrospect, was thought to be adrenomyeloneuropathy. No other family member was found to have Addison's disease. A sibling died at age 8 of Schilder's disease, confirming the presence of adrenoleukodystrophy as well as adrenomyeloneuropathy within this family.

Preradiation chemotherapy in advanced medulloblastoma. A Pediatric Oncology Group pilot study.

BACKGROUND: Children diagnosed with medulloblastoma whose tumor involves the brain stem or has spread through the cerebrospinal fluid pathways to other areas of the brain or spinal cord have a poor prognosis despite therapy with surgery, craniospinal irradiation (CSI), and chemotherapy. Preradiation chemotherapy may improve the outlook for these patients. METHODS: To further study the role and feasibility of preradiation chemotherapy, children between the ages of 4 and 21 years diagnosed with advanced medulloblastoma and measurable disease were enrolled in the Pediatric Oncology Group 8695 study. Patients were treated with a 9-week course of vincristine, cisplatin, and cyclophosphamide followed by CSI. Imaging films were reviewed centrally for eligibility and response to chemotherapy. Toxicity to chemotherapy and radiation as well as delays and modifications in subsequent CSI were recorded. RESULTS: Thirteen of 30 fully evaluable patients achieved complete or partial response (43%) to chemotherapy. Toxicity was mostly fever and neutropenia after cyclophosphamide, which is predictable and tolerable. Radiation therapy was delivered in full doses and volumes in most patients but was delayed in its start in most patients. Central review of films revealed frequent use of different imaging modalities at baseline and after therapy, making accurate assessment of tumor response difficult. CONCLUSION: Preradiation chemotherapy with vincristine, cisplatin, and cyclophosphamide is active in patients with advanced medulloblastoma but should be modified to minimize the risk of progressive disease while on therapy and to avoid delays in starting radiation therapy. Consistent use of the same neuroimaging modality is essential in documenting response.

Genetic and radiation hybrid mapping of the hyperekplexia region on chromosome 5q.

Hyperekplexia, or startle disease (STHE), is an autosomal dominant neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to sudden, unexpected acoustic or tactile stimuli. STHE responds dramatically to the benzodiazepine drug clonazepam, which acts at gamma-aminobutyric acid type A (GABA-A) receptors. The STHE locus (STHE) was recently assigned to chromosome 5q, on the basis of tight linkage to the colony-stimulating factor 1-receptor (CSF1-R) locus in a single large family. We performed linkage analysis in the original and three additional STHE pedigrees with eight chromosome 5q microsatellite markers and placed several of the most closely linked markers on an existing radiation hybrid (RH) map of the region. The results provide strong evidence for genetic locus homogeneity and assign STHE to a 5.9-cM interval defined by CSF1-R and D5S379, which are separated by an RH map distance of 74 centirays (roughly 2.2-3.7 Mb). Two polymorphic markers (D5S119 and D5S209) lie within this region, but they could not be ordered with respect to STHE. RH mapping eliminated the candidate genes GABRA1 and GABRG2, which encode GABA-A receptor components, by showing that they are telomeric to the target region.

Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death.

Nitrazepam was used in the treatment of resistant myoclonic epilepsy in 38 children. After the occurrence of nitrazepam-associated swallowing incoordination, high-peaked esophageal peristalsis and related bronchospasm in one patient, we initiated a prospective study of esophageal manometry using a station pull-through technique with a pediatric 4-channel continuous perfusing system. Three more patients were found to have delayed cricopharyngeal relaxation and high-peaked esophageal peristaltic waves. The initial patient developed severe respiratory distress and bronchospasm necessitating ventilatory support while on nitrazepam and improved dramatically with subsequent normal manometric study following nitrazepam discontinuation. Nitrazepam was reintroduced for its anticonvulsant and cognitive benefits and was tolerated at a reduced dosage. We postulate a central nervous system effect of nitrazepam promoting parasympathetic overactivity or vagotonia which can cause potentially fatal respiratory distress. Care must be exercised in nitrazepam use and esophageal manometry may be helpful in defining patients at greater risk for sudden death.

Clinical improvement of the myopathy in eosinophilia-myalgia syndrome with steroids and rehabilitative therapy.

The authors report a case of eosinophilia-myalgia syndrome with a progressive neuromyopathy. Progressive weakness, myalgia, and dermatitis developed in the patient described after chronic ingestion of high-dose L-tryptophan for insomnia. Laboratory, electrophysiologic, and muscle biopsy results support the diagnosis of an inflammatory myopathy consistent with that of eosinophilia-myalgia syndrome. The patient's weakness led to wheelchair dependency. A review of the literature regarding this disorder shows inconsistent results with steroid and other modes of therapy. After a course of high-dose steroids with long-term tapering and vigorous inpatient and outpatient rehabilitation, the patient was able to walk and function independently within 2 months.

Hyperekplexia and sudden neonatal death.

Fifteen patients with hyperekplexia were identified in 3 families; diagnostic clinical characteristics were defined which allowed for early recognition and treatment. During the first 24 hours of life, spontaneous apnea and sluggish feeding effort were observed. After the first 24 hours, surviving infants exhibited the hyperekplexic startle response to nose tapping. This startle response is characterized by sudden muscular rigidity, feeding-induced oropharyngeal incoordination, and poor air exchange often with apnea, persisting with repetitive nose tapping. Untreated infants experienced recurring apnea until 1 year of age. Three of 15 patients died unexpectedly during the neonatal period. Patients treated with clonazepam (0.1-0.2 mg/kg/day) had no serious apneic episodes and startle reflexes were diminished. The pathophysiologic mechanism for hyperekplexia remains obscure. Electroencephalographic studies were consistently normal. The response to and tolerance of benzodiazepines are striking in newborns and infants and suggest an aberrant central nervous system reflex as the etiology; therefore, hyperekplexia should be considered in the evaluation of neonates and infants with apnea, aspiration pneumonia, episodic muscular rigidity, hyperexcitability, and near-miss sudden infant death syndrome. The need for immediate monitoring of at-risk infants, observation for signs of hyperekplexia, and initiation of clonazepam in these patients are emphasized. Hyperekplexic startle response to nose tapping should be included in the routine examination of all newborns.

Metastatic hypopharyngeal carcinoma mimicking necrotizing vasculitis of the skin.

Clinical features of cutaneous necrotizing vasculitis were the presenting signs of a hypopharyngeal carcinoma in a forty-three-year-old man. A definite diagnosis was established by examination of fine-needle aspiration biopsy and scalpel biopsy specimens. Among the dermatoses simulated by metastatic pharyngeal carcinoma, necrotizing vasculitis has not, to our knowledge, been reported previously.

X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.

Seven boys with an apparently X-linked syndrome of dilated cardiomyopathy, growth retardation, neutropenia, and persistently elevated urinary levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate were studied. The natural history of the disorder was characterized by severe or lethal cardiac disease and recurrent infections during infancy and early childhood but relative improvement in later childhood. The initial presentation of the syndrome varied from congenital dilated cardiomyopathy to infantile congestive heart failure to isolated neutropenia without clinical evidence of heart disease. The excretion of 3-methylglutaconate and 3-methylglutarate appeared to be independent of the metabolism of leucine, the presumed precursor of these organic acids in humans. Although the cause of the organic aciduria remains obscure, the constellation of biochemical and clinical abnormalities forms a distinct syndrome that may be a relatively common cause of dilated cardiomyopathy or neutropenia in boys during infancy and childhood.

Colpocephaly in identical twins.

Colpocephaly is congenital disproportionately enlarged occipital horns of the lateral ventricles. It is easily recognized on computed tomography, magnetic resonance imaging or cerebral ultrasonography. The first report of colpocephaly in identical twins is presented. This is also the first reported instance of above normal intelligence occurring in conjunction with colpocephaly. The associated anomalies found as mirror images in these twins imply a genetic basis for their colpocephaly.

Relapsing lumbosacral plexus neuropathy. Report of two cases.

Primary lumbosacral plexus neuropathy (LSPN) is a well-defined syndrome characterized by pain, weakness and atrophy in the distribution of the lumbosacral plexus. Previous reports of LSPN have stressed the benign nature of the syndrome. Patients generally have a nearly complete recovery in months to years following the initial event. Two patients presenting with a relapsing form of LSPN are reported. The diagnosis of LSPN was based on clinical and electromyographic features, and no underlying cause was found on initial evaluation or subsequent follow-up over a 6- to 8-year period. We suggest that these patients represent a clinically and possibly pathologically distinct subgroup of LSPN.

Beevor's sign and facioscapulohumeral dystrophy.

We have frequently observed that Beevor's sign was present in patients with facioscapulohumeral dystrophy (FSHD) but absent in patients with other neuromuscular disorders. To determine the significance of this observation we prospectively evaluated 30 patients with FSHD and 40 patients with other neuromuscular disorders. Beevor's sign was present in 27 of 30 patients with FSHD but absent in all 40 control patients. We conclude that Beevor's sign is a common finding in patients with FSHD even before functional weakness of abdominal wall muscles is apparent. Testing for Beevor's sign is a simple screening test that may help in distinguishing FSHD from other forms of facioscapulohumeral syndrome.