Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease).

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.

Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy.

Carbamyl phosphate synthetase I is a urea cycle enzyme. Severe deficiency of carbamyl phosphate synthetase I presents in the neonatal period as hyperammonemic encephalopathy with altered consciousness and occasional seizures after feeding begins. Episodes of altered consciousness with or without seizures and focal neurologic deficits are seen later with patients of partial carbamyl phosphate synthetase I deficiency. Fatal cerebral edema with brain herniation may develop on occasion. Three patients presenting with carbamyl phosphate synthetase I deficiency are reported with neuroimaging and pathologic findings illustrating the destructive encephalopathy with acute cerebral edema, followed by diffuse cerebral atrophy and occasional cystic encephalomalacia. The deterioration in carbamyl phosphate synthetase I deficiency occurs during the hyperammonemic crises. This deficiency may be difficult to treat despite the current advances in treatment strategies, especially in neonatal-onset patients with low carbamyl phosphate synthetase I activity.

Diffusion-weighted imaging in neonatal cerebral infarction: clinical utility and follow-up.

We describe the clinical utility of echo-planar diffusion-weighted imaging in neonatal cerebral infarction. Eight full-term neonates aged 1 to 8 days referred for neonatal seizures were studied. Patients were followed for a mean of 17 months with detailed neurologic examinations at regular intervals. Head computed tomography (CT) and conventional magnetic resonance (MRI) and diffusion-weighted images were obtained. Percent lesion contrast was evaluated for 19 lesions on T2-weighted and diffusion-weighted images. Follow-up conventional MRIs were obtained in seven patients. The findings on diffusion-weighted imaging were correlated with CT and conventional MRI findings as well as with short-term neurodevelopmental outcome. Four patients had focal cerebral infarctions. Four patients had diffuse injury consistent with hypoxic-ischemic encephalopathy. Percent lesion contrast of all 19 lesions was significantly higher on diffusion-weighted images when compared with T2-weighted images. In five patients, there were lesions visualized only with diffusion-weighted imaging. In all patients, there was increased lesion conspicuity and better definition of lesion extent on the diffusion-weighted images compared with the CT and T2-weighted MR images. In seven of eight patients follow-up imaging confirmed prior infarctions. Short-term neurologic outcome correlated with the extent of injury seen on the initial diffusion-weighted imaging scans for all patients. Diffusion-weighted imaging is useful in the evaluation of acute ischemic brain injury and seizure etiology in neonates. In the acute setting, diffusion-weighted imaging provides information not available on CT and conventional MRI. This information correlates with short-term clinical outcome.

Aicardi syndrome: prenatal sonographic findings. A report of two cases.

The prenatal sonographic findings in two children with Aicardi syndrome are reported.

Prader-Willi syndrome associated with fetal goiter: a case report.

We describe a unique case of a newborn with Prader-Willi syndrome who presented with fetal goiter as well as neonatal thyroid abnormalities, marked hypotonia, and thrombocytopenia. These new clinical observations may correlate with the uniparental monodisomy form of inheritance of this genetic condition.

Fosphenytoin in infants.

In comparison with phenytoin preparations, which have a pH value of 11, fosphenytoin, a phosphorylated prodrug of phenytoin, has a pH value of only 8.6, which decreases the risk of cardiovascular and cutaneous side effects. The near-neutral pH value of fosphenytoin allows effective intravenous or intramuscular administration. A 1-mg phenytoin equivalent (PE) of fosphenytoin is converted to 1 mg of phenytoin in adults. We describe four infants whose seizures were treated with intravenous fosphenytoin. We had difficulty maintaining therapeutic serum phenytoin levels of 10 to 20 microg/mL on doses of 5 to 8 mgPE/kg/day, and many bolus doses of 5 to 10 mgPE/kg or maintenance doses of more than 10 mgPE/kg/day were given. Despite increased doses in three out of the four patients, a therapeutic serum phenytoin level was not maintained. From our experience, careful and individual dosing of fosphenytoin in this age group can be considered.

Molecular analysis and prenatal diagnosis of human fumarase deficiency.

Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.

Delayed myelination in infants and young children: radiographic and clinical correlates.

Magnetic resonance imaging (MRI) is the best method for assessing myelination in infants and young children. Although delayed myelination is a common neuroradiologic diagnosis, there are few or no data regarding the reliability of this diagnosis or radiographic and clinical findings in cohorts of such patients. We evaluated the cranial MRI scans of 109 patients from age 0 to 36 months, without knowledge of any patient's age or previous clinical or radiologic diagnosis. For each cranial MRI, seven neuroradiologic landmarks were evaluated and established criteria used to assess the state of myelination. We found that in 12 of 109 patients, delayed myelination was misdiagnosed, whereas the diagnosis of delayed myelination was missed in four other patients. Lack of familiarity with the myelination milestones of infancy was the most common reason for a misdiagnosis of delayed myelination. Failure to recognize delayed myelination was due to a failure to appreciate the forceps minor as a landmark. Overall, the diagnosis of delayed myelination was inaccurately applied or missed in 15% of the patients in this series. Of the 14 patients identified as having delayed myelination, 10 had other central nervous system structural abnormalities seen on MRI, most commonly cortical atrophy. Developmental delay was the most common clinical correlate of delayed myelination and was documented in 12 of the 14 patients. To increase the reliability of neuroradiologic assessments in young children, we propose that central nervous system myelin maturation be evaluated and expressed as a myelination age equivalent, analogous to the assessment of pediatric bone age using conventional radiographs.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure to clinically predict NICU hearing loss.

Neonatal intensive care unit (NICU) survivors demonstrate handicapping sensorineural hearing loss up to 50 times more frequently than normal newborns, yet little is known about the etiology of the hearing loss. Theoretically, accurate identification and triage of a particular infant based on a clinical profile would be useful. Forty NICU graduates of The Massachusetts General Hospital were selected for a detailed retrospective chart review evaluating prenatal, perinatal, and NICU medical conditions and treatment. Twenty-three patients identified with hearing loss and 17 infants with normal hearing were compared clinically. Univariate and multivariate analysis was performed on a subpopulation of patients (20 with hearing loss and 16 with normal hearing). A history of ventilation was associated with hearing loss (P = .0023), but this factor was not absolute. No other clinical parameters were convincingly linked to hearing loss. We conclude that reliance on risk factors is an inadequate clinical method to select a patient for a hearing test and that each NICU survivor deserves audiometric evaluation.

Management of generalized tonic-clonic status epilepticus.

The steps to be taken in the management of GTC status are outlined in Table 2. Once the GTC status is brought under control, prevention of recurrent seizures must be considered. The specific etiology must be sought. Those patients who require long-term prophylactic anticonvulsant therapy include those with structural brain abnormalities, progressive neurological disorders, and patients with idiopathic epilepsy.

Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up.

The EEG features and clinical correlates were investigated before, directly after, and on long-term follow-up after initiation of pyridoxine therapy in 6 patients with B6-dependent epilepsy. At each phase, the EEG provided important diagnostic and prognostic information. Pre-B6 3 neonates manifested a unique EEG pattern of generalized bursts of 1-4 Hz sharp and slow activity. This pattern has not been previously described in neonates with B6 dependency and in this age group appears to be highly suggestive of the diagnosis. Five patients experienced an apparent initial response to traditional antiepileptics. The parenteral pyridoxine test, performed in all 5, and repeated in 3, proved to be a highly reliable and reproducible diagnostic test. After 50-100 mg of B6 there was cessation of clinical seizures within minutes and of paroxysmal discharges within hours. On long-term follow-up (3-28 years) all 6 patients were seizure free on B6 (10-100 mg/day) monotherapy. Recurrences of seizures and of specific sequential EEG changes (background slowing, photoparoxysmal response, spontaneous discharges, stimulus-induced myoclonus, generalized seizures) occurred upon B6 withdrawal. Long-term prognosis correlated with the EEG. Two patients had persistently abnormal EEG backgrounds and were moderately to severely retarded, while 4 had normal EEGs with normal or near normal development.

The epidemiology of germinal matrix hemorrhage during the first half-day of life.

The personal and maternal characteristics of 27 babies with early-onset germinal matrix hemorrhage (EGMH) were compared with those of 280 babies with normal cranial ultrasonograms, studied in a separate clinical trial. None of the mothers of the babies with EGMH had high blood pressure or pre-eclampsia during pregnancy. Gestational age less than 30 weeks and initial pH less than 7.2 indicated increased risks of EGMH, and maternal receipt of steroids indicated reduced risk of EGMH. Thus prenatal and immediately perinatal factors appear to convey much of the information about the risk of EGMH.

Periventricular-intraventricular hemorrhage, sonographic localization, phenobarbital, and motor abnormalities in low birth weight infants.

A total of 228 low birth weight (less than 1750 g), mechanically ventilated infants with and without periventricular-intraventricular hemorrhage were examined at 18 months corrected age to assess the relationship between cranial ultrasonographic findings and specific motor abnormalities. All infants were previously enrolled in a double-blind, randomized, prospective clinical trial of phenobarbital prophylaxis against periventricular-intraventricular hemorrhage. Ultrasonographic abnormalities on the scans performed between 7 and 13 days of life were categorized as germinal matrix hemorrhage, lateral ventricular hemorrhage, parenchymal hemorrhage, ventriculomegaly, and any hemorrhage. Regardless of anatomical location, periventricular-intraventricular hemorrhage was associated with an increased risk for developing motor abnormalities. Hypertonia and hyperreflexia/ankle clonus were most common. No abnormal motor findings distinguished unilateral from bilateral germinal matrix hemorrhage and lateral ventricular hemorrhage or between phenobarbital and placebo treatment. None of the 5 infants with parenchymal hemorrhage had spastic cerebral palsy. Ventriculomegaly was associated with a fivefold increase in risk for spastic cerebral palsy and delayed walking and a threefold increase for hypertonia and hyperreflexia/clonus. The results suggest that ventriculomegaly, observed even as early as the first week of life, might be a significant antecedent of later motor abnormalities among the survivors of periventricular-intraventricular hemorrhage.