Warren D. Grover

Case Study: Corticosteroid Treatment of Language Regression in Pervasive Developmental Disorder

The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. A single-photon emission computed tomography scan and steady-state auditory evoked potentials suggested bitemporal and left frontal pathophysiology. The overall profile resembled Landau-Kleffner syndrome, but no electroencephalographic disturbance was evident. Corticosteroid treatment resulted in amelioration of language abilities and behavior. These findings suggest that the factors underlying language regression in pervasive developmental disorder can, in special circumstances, be amenable to pharmacological treatment.

Copper infusion therapy in trichopoliodystrophy

The effect of repeated intravenous infusions of cupric salts was studied in two patients (cousins) with trichopoliodystrophy identified at the ages of 3 days and 2 and-one-half mo, respectively. The intravenous doses of copper were gradually increased and normal or near-normal serum values were achieved after 150 mug/Cu2+/kg were administered daily for 5 days. At that time the hepatic concentration of copper in the two patients increased from 14 to 38 mug/gm of dry weight from 7 to 45 mug/gm of dry weight, respectively, and the muscle homogenate exhibited the capacity to oxidize pyruvate-3-14C. Continued infusions of cupric salts in doses of 190-220 mug/kg/day once or twice weekly were necessary to maintain elevated hepatic and serum concentrations of copper. At 6 mo of age the younger infant had reached a functioning level of 4 mo. The older infant demonstrated progressive loss of neurologic functions and died at 15 mo of age. These observations suggest that the neurologic and biochemical dysfunctions of trichopoliodystrophy may be altered by infusion of cupric salts early in the course of the disease.

Biochemical studies and therapy in subacute necrotizing encephalomyelopathy (Leigh's syndrome)

The clinical course, biochemical abnormalities, and the effects of vitamin therapy in subacute necrotizing encephalomyelopathy are described in a patient who was serially evaluated from birth. Important features include increased cerebrospinal protein, elevated blood lactic acid values, and abnormal macular morphology detected when the patient was asymptomatic. Renal tubular acidosis and alaninemia were noted shortly after the onset of symptoms. No clinical improvement was noted with pharmacologic doses of biotin, thiamine (hydrochloride or propyldisulfide), or lipoic acid. Hepatic pyruvate carboxylase was within the range of control values early in the disease but was negligible in postmortem material. The clinical and biochemical course suggests that low levels of hepatic pyruvate carboxylase in postmortem material were secondary effects of an otherwise as yet unknown biochemical process. Decreased cerebral pyruvate carboxylase activity at autopsy was documented for the first time.

Neuropathologic changes in ataxia‐telangiectasia

The neuropathologic findings in a 17-year-old boy with ataxia-telangiectasia are described. In agreement with previous reports, pathologic changes were present in the cerebellum, spinal cord, dorsal root ganglia, and striated muscle. The lesions in the spinal cord and dorsal root ganglia were more severe than previously described. Abnormalities were also seen in several brain stem nuclei, including the mesencephalic nucleus of the trigeminus and the substantia nigra. In addition, a small hamartomatous tumor was found in the thalamus.

Serum copper concentrations in sick and well preterm infants

In order to define the range of serum copper concentrations in preterm infants and to determine the effect of growth upon these values, serial serum copper concentrations were measured in 26 preterm infants over their first six weeks of life. Fourteen healthy, growing preterm infants (Group I) had mean serum copper concentrations below 32 microgram/dl throughout the study. Clinical and hematologic signs of copper deficiency which responded promptly to the oral administration of copper sulfate were noted in five of these 14 infants. Twelve ill preterm infants (Group II-A), who received parenteral nutrition without supplemental copper and had slow rates of growth, had mean serum copper concentrations above 50 micrograms/dl after the first week of life. Seven surviving from Group II-A (Group II-B) had a decrease in mean serum copper concentrations to values similar to those in Group I after two weeks of oral feedings and resumption of normal growth. Our findings suggest that preterm infants who have normal growth while receiving oral feedings are at significant risk for developing copper deficiency.

Ocular Histopathologic and Biochemical Studies of the Cerebrohepatorenal Syndrome (Zellweger's Syndrome) and its Relationship to Neonatal Adrenoleukodystrophy

The eyes of three infants with cerebrohepatorenal disease (Zellwegers syndrome) who died demonstrated ganglion cell loss, gliosis of the nerve fiber layer and optic nerve, optic atrophy, and changes resembling those of retinitis pigmentosa in the retina and pigment epithelium. Ultrastructural examination showed bileaflet inclusions identical to those seen in neonatal adrenoleukodystrophy in the pigment epithelium and in pigmented macrophages, but these were absent in the cornea. Biochemical analysis of tissues demonstrated an excessive amount of very-long-chain fatty acids in the ocular tissues, an abnormality also found in adrenoleukodystrophy. These histopathologic and biochemical results demonstrated that the cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy are similar in regard to ocular abnormalities and the presence of saturated very-long-chain fatty acids.

Diagnostic Value of Pediatric Outpatient Video-EEG

Outpatient video-electroencephalography (OVEEG) was performed in 100 infants, children, and adolescents with diagnosed (group I, n = 64) or suspected (group II, n = 36) epilepsy. Median monitoring duration was 4 hours. Indications for OVEEG in group I were classification of seizures, reported seizure exacerbation, or onset of new signs. OVEEG indications in group II were repetitive paroxysmal and stereotyped signs of myoclonic movements, fixed gaze, abnormal behavior, or nonmyoclonic motor activity. In group I patients, symptomatic events were recorded in 89%, half of which were seizures. Among group II patients, events were recorded in 67% and were seizures in 22%. Overall, OVEEG was successful in 83% of patients. Compared to a 24-hour inpatient admission for video-EEG monitoring, OVEEG represented cost reductions of 55-80% per patient. We conclude that OVEEG is a cost-effective, useful alternative to continuous inpatient video-EEG monitoring in the investigation of selected infants, children, and adolescents with diagnosed or suspected epilepsy.

Mitochondrial activity in pompe’s disease

Mitochondrial oxidative metabolism was examined in two infants with Pompes disease. The clinical diagnosis was confirmed by the demonstration of intralysosomal glycogen accumulation and a deficiency of acid alpha-D-glucosidase in muscle biopsies. Light and electron microscopy studies demonstrated a normal number of mitochondria with normal ultrastructure. Spectrophotometric measurements revealed that the specific activities of citrate synthase and the partial reactions of electron transport were markedly elevated in the skeletal muscle homogenates prepared from both infants with Pompes disease when calculated as micromoles per minute per gram wet weight of tissue. However, when respiratory chain enzyme activities were expressed relative to citrate synthase as a marker mitochondrial enzyme, a different pattern emerged, in which all Pompe muscle respiratory enzymes, except complex IV, were decreased relative to control subjects. These observations demonstrate that caution should be exercised when analyzing and interpreting data obtained from tissue homogenates in general and, in particular, in those prepared from tissues in which the wet weight of tissue may be altered, for example, by pathologic accumulation of carbohydrate or lipid.

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

Extract: Proximal renal tubular acidosis has been observed in two infants who had lactic acidosis associated with subacute necrotizing encephalomyelitis. Reduced renal thresholds for bicarbonate (18–19.2 mM/liter) were found in both, in conjunction with the ability to excrete normal quantities of acid. In order to raise the level of serum bicarbonate, increasing rates of infusion of solutions containing bicarbonate were required, because of a progressive increase in serum lactate from 18 to 54 mg/dl. The infusion of sodium bicarbonate expanded the extracellular space, as measured by an increase in chloride space of 12.9%. Volume expansion was associated with a progressive fall in bicarbonate reabsorption from a maximum of 1.91 to 1.02 mM/100 ml glomerular filtration rate. In addition, the tubular reabsorption of phosphate fell from 80 to 60%, urate clearance increased from 8.7 to 20 ml/min/1.73 m2, lactate clearance increased from 0.23 to 22.9 ml/min/1.73 m2, and chloride excretion increased from 0.7 to 3.14 μEq/min/1.73 m2. At autopsy, reduced activity of renal pyruvate carboxylase was demonstrated for the first time in this disease.Speculation: As a reflection of impaired lactate metabolism in subacute necrotizing encephalomyelitis (SNE), generation of ATP may be reduced in the renal cortex. This reduced supply of energy might be expected to impair reabsorption of normal quantities of filtered bicarbonate; proximal renal tubular acidosis may be the result. The fact that other evidence of proximal tubular dysfunction was not observed in the normohydrated state further suggests that failure to reabsorb filtered sodium bicarbonate may be the initial abnormality observed when the supply of energy diminishes in the renal cortex.The changes in the chloride space observed during bicarbonate infusions may provide data useful in the interpretation of changes in the renal threshold both for bicarbonate and for other solutes.Finally, it appears that subacute necrotizing encephalomyelitis may include a spectrum of biochemical abnormalities, and that only certain forms may be associated with renal tubular acidosis.

Long-Term Computer-Assisted Outpatient Electroencephalogram Monitoring in Children and Adolescents

The aims of this study were (1) to define the role of long-term computer-assisted outpatient electroencephalographic monitoring (COEEG) in children and adolescents with known or suspected epilepsy, and (2) to compare COEEG data with routine interictal electroencephalograms (EEG). We performed 18-channel COEEG in 84 children and adolescents with diagnosed (group 1, n = 49) or suspected (group 2, n = 35) epilepsy. Mean recording time was 1.4 days. Overall, COEEG was useful in 87% of patients. In group 1, events were recorded in 73% of patients and were electrographic seizures in 45%. In group 2, events were detected in 86% of patients and were electrographic seizures in 17%. Nocturnal and partial seizures predominated. Seizure diagnosis and classification by COEEG was concordant with interictal EEG findings in 19% and discordant in 63% of patients. COEEG is a useful technique for the diagnosis of epileptic and nonepileptic events among selected children and adolescents. When compared to routine interictal EEG, COEEG could offer additional accuracy in the classification of seizures in pediatric patients. (J Child Neurol 2000;15:49-55).