N. Paul Rosman

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

BACKGROUND Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

A controlled trial of diazepam administered during febrile illnesses to prevent recurrence of febrile seizures

Background Phenobarbital, once widely prescribed to prevent febrile seizures, is now in disfavor because of its side effects and lack of efficacy. Diazepam, administered only during episodes of fever, may be a safe, effective agent to prevent the recurrence of febrile seizures. Methods We conducted a randomized, double-blind, placebo-controlled trial among 406 children (mean age, 24 months) who had at least one febrile seizure. Diazepam (0.33 mg per kilogram of body weight) or placebo was administered orally every eight hours during all febrile illnesses. Results During a mean follow-up of 1.9 years (a period during which 90 percent of febrile seizures recur), our intention-to-treat analysis showed a reduction of 44 percent in the risk of febrile seizures per person-year with diazepam (relative risk = 0.56; 95 percent confidence interval, 0.38 to 0.81; P = 0.002). A survival analysis of the length of time to the first recurrent febrile seizure did not show a significant difference between the treatment gr...

The Neurology of Benign Paroxysmal Torticollis of Infancy: Report of 10 New Cases and Review of the Literature

Benign paroxysmal torticollis is an under-recognized cause of torticollis of early infancy. The attacks usually last for less than 1 week, recur from every few days to every few months, improve by age 2 years, and end by age 3. There very frequently is a family history of migraine. We did a detailed analysis of 10 cases of benign paroxysmal torticollis, seen over 5 years, and compared our findings with those in the 103 cases in the literature. Detailed neurodevelopmental assessments, available only in our cases, showed accompanying gross motor delays in 5/10 children, with additional fine motor delays in 3/5. As the benign paroxysmal torticollis improved, so did the gross motor delays in 3/5, and the fine motor delays in 1/3. In all of our cases, at least 2 other family members had migraine. Benign paroxysmal torticollis is likely an age-sensitive, migraine-related disorder, commonly accompanied by delayed motor development.

Argininemia: A Treatable Genetic Cause of Progressive Spastic Diplegia Simulating Cerebral Palsy: Case Reports and Literature Review

Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized. (J Child Neurol 1997;12:301-309).

Farber's lipogranulomatosis. Report of a case and demonstration of an excess of free ceramide and ganglioside.

Abstract The tenth case of Farbers lipogranulomatosis is reported. The clinical and pathologic features closely resemble those previously described except that in this patient the macula was also involved, there was nerve cell loss and neuronal storage in the cerebral cortex, and there was a strong family history of rheumatoid arthritis. The foam cells within the granulomas as well as certain of the neurons contained periodic acid-Schiff positive cytoplasmic material with the histochemical properties of an acidic glycolipid. Biochemical studies demonstrated an excess of gangliosides, roughly in proportion to the accumulation of the periodic acid-Schiff-positive material. The excess gangliosides were found to consist mainly of hematoside, the visceral ganglioside. Lymph nodes, liver, kidney and lung contained a ten- to sixtyfold excess of free ceramide, and similar very high levels of free ceramide were present in a subcutaneous nodule. In rats, subcutaneous injection of ceramide produced granulomas which resembled those found in the patients with the lipogranulomatosis syndrome. It is suggested that the lipogranulomatosis syndrome represents an inborn error of lipid metabolism. Its enzymatic basis is as yet undetermined.

Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome.

Two families are presented in which siblings of children affected with Hallervorden-Spatz syndrome exhibited characteristic cranial magnetic resonance imaging changes before developing clinical features of the disease. Linkage to a major locus on chromosome 20p supported the diagnosis of Hallervorden-Spatz syndrome. In some patients with Hallervorden-Spatz syndrome, iron is radiographically evident before the onset of clinical symptoms.

Rectal diazepam gel for treatment of acute repetitive seizures

The purpose of these investigations was to determine from combined data the response to rectal diazepam (DZP) gel (Diastat [Athena Neurosciences, South San Francisco, CA]) in home treatment of children with episodes of acute repetitive seizures (ARS). A subset of patients aged 2-17 years were selected from two prospective placebo-controlled studies of children and adults. In both studies a prospective, double-blind, placebo-controlled design was used. The treatment groups (68 DZP; 65 placebo) did not differ significantly in age, race, seizure type or etiology, or in the median number of ARS episodes per month before study entry. DZP-treated children demonstrated a significant reduction in median seizure frequency compared with the placebo group (0.00 vs 0.25 seizures per hour, P = 0.001). Significantly more DZP-treated children remained seizure free during the observation period (40 vs 20, P = 0.001). Somnolence was the only adverse effect present significantly more often in the DZP-treated children (25.0% vs 7.7%, P = 0.0095). There were no instances of serious respiratory depression. Rectal DZP was demonstrated to be an effective and safe treatment to abort an episode of ARS in a child and, additionally, lessened the likelihood of seizure recurrence within the next 12 hours.

Developmental Correlates of Head Circumference at Birth and Two Years in a Cohort of Extremely Low Gestational Age Newborns

OBJECTIVES To evaluate the developmental correlates of microcephaly evident at birth and at 2 years in a cohort born at extremely low gestational age. METHODS We assessed development and motor function at 2 years of 958 children born before the 28th week of gestation, comparing those who had microcephaly at birth or 2 years with children with normal head circumference while considering the contribution of neonatal cranial ultrasound lesions. RESULTS A total of 11% of infants in our sample had microcephaly at 2 years. Microcephaly at 2 years, but not at birth, predicts severe motor and cognitive impairments at 2 years. A total of 71% of children with congenital microcephaly had a normal head circumference at 2 years and had neurodevelopmental outcomes comparable with those with normal head circumference at birth and 2 years. Among children with microcephaly at 2 years, more than half had a Mental Developmental Index <70, and nearly a third had cerebral palsy. The risks were increased if the child also had cerebral white matter damage on a cranial ultrasound scan obtained 2 years previously. CONCLUSION Among extremely low gestational age newborns, microcephaly at 2 years, but not at birth, is associated with motor and cognitive impairment at age 2.

Neurologic sequelae of experimental febrile convulsions

A study was designed to investigate the effects of experimentally produced hyperthermic seizures on the brain of the developing rat. Seventy-nine newborn Sprague-Dawley white rats were divided into five groups and exposed to one of the following: Nonseizure-producing hyperthermia at 5 or 15 days (febrile controls), seizure-producing hyperthermia at 5 or 15 days, or no hyperthermia (afebrile controls). As the animals matured, seven developmental reflexes were tested and there were no differences found among the five groups in the ages at which these reflexes were acquired. At age 31/2 months, the ability of rats to adapt to a maze, and later to solve 12 maze problems, was studied. Although there was no significant difference in the amount of time required for any of the groups to adapt to the maze, there was a significant difference in the number of maze errors made by the different groups of rats. The mean error score for the control group was 118.5, compared with 183.0 (p < 0.00l), for rats with seizures at 5 days and 161.4 (p < 0.001), for rats which convulsed at 1 5 days. It is apparent that experimental induction of a single hyperthermic seizure in the young rat interferes significantly with the animals maze-solving ability at a later age.

Basilar artery occlusion in children: misleading presentations, "locked-in" state, and diagnostic importance of accompanying vertebral artery occlusion.

Basilar artery occlusion in children is rare. The clinical diagnosis of basilar artery occlusion is often difficult because the initial neurologic findings, most frequently hemiparesis, involuntary movements, or headache, are often transient and can suggest complicated migraine, seizures, or both. We have reviewed 37 previously reported pediatric cases of basilar artery occlusion and present 3 additional ones. In the 40 cases, basilar artery occlusion alone occurred in 22; in the other 18, there was accompanying vertebral artery occlusion. In the cases of pure basilar artery occlusion, the most common causes were trauma and arteritis, but in most such cases, the etiology could not be determined. The cause was found much more often in cases of basilar artery occlusion with accompanying vertebral artery occlusion, with trauma being the most frequent etiology, especially in boys between 6 and 14 years. Of the 37 previously reported pediatric cases of basilar artery occlusion, 7 were “locked in” early in the course (mute, quadriparetic, aware, and communicative with eye movements), as were our 3 cases. In most cases of basilar artery occlusion that are locked in, the basilar artery occlusion involves its midportion, sparing the anterior inferior cerebellar and superior cerebellar arteries. (J Child Neurol 2003;18:450—462).