Biomedical subjects
Publications and source records attributed to I J Butler.
Two children with achondroplasia and neurologic sequelae secondary to foramen magnum compression were found to have syringomyelia. In one patient, the cyst was associated with a subependymal glioma. These findings suggest that foramen magnum stenosis may lead to irreversible spinal cord damage.
Twenty-three patients with achondroplasia were evaluated using short-latency somatosensory evoked potentials (SEPs) of median and peroneal nerves. Abnormal studies were found in 61%. All patients with neurologic signs or symptoms had abnormal SEPs, with good correlation between SEP results and the level of the lesion determined clinically and radiographically. SEPs were abnormal in 44% of neurologically intact achondroplasts, several of whom had CTs confirming significant foramen magnum stenosis. SEPs are an important noninvasive means of evaluating patients with achondroplasia and are particularly valuable in children to document neurologic compromise before significant and perhaps irreversible clinical impairment develops.
Tourette's syndrome is a chronic tic disorder in which motor and vocal tics begin in childhood, persist to adulthood, and occur predominantly in males, often in a familial setting. Following the delineation of the characteristic clinical features of TS, and as a result of increased educational efforts, there has been a heightened awareness of the frequency of this neurologic disorder in childhood and adolescence. Furthermore the demographic and other clinical neurophysiologic factors, coupled with the frequent and dramatic response of the tics to treatment with haloperidol, have strongly indicated an underlying disorder of neurotransmitter metabolism. One such hypothesis suggests that there is a relative overactivity of dopamine receptors, and findings from recent clinical and experimental studies are consistent with a defect in the ontogeny of the mesocortical group of dopamine neurons. New neuroimaging techniques applied to patients with TS may help to localize these overactive dopamine receptors and lead to different and more specific treatment strategies.
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A distinct syndrome with continuous motor neuron discharges apparently developed in seven members of a single family, involving both sexes and spanning three generations. Persistent vermiform twitching and episodic stiffness predominantly in lower extremity muscles occurred in early childhood and tended to be less severe in adulthood. In 2 patients the clinical manifestations improved with oral phenytoin and carbamazepine but not with parenteral diazepam. Insertional activity was normal, and continuous, rhythmical, normal-appearing muscle discharges were observed on electromyography. The cerebrospinal fluid levels of homovanillic acid and 5-hydroxyindoleacetic acid were increased in the proband. The disappearance of continuous muscle discharges during spinal anesthesia and the lack of response to diazepam indicated generation of the discharges from the proximal portion of the motor unit.
A 22-year-old woman with type I Ehlers-Danlos syndrome had severe radicular pain in the lower back. A laterally herniated lumbar disk was seen on myelography. Pain and walking improved after lumbar laminectomy. A chronic focal seizure disorder was associated with CT evidence of a congenital structural defect of the brain.
A prospective clinical and biochemical study on the effects of treatment with haloperidol has been performed in seven patients with Tourette syndrome. Pretreatment cerebrospinal fluid levels of homovanillic acid (CSF HVA) were significantly reduce in all patients, whereas 5-hydroxyindoleacetic acid was reduced in only two. With haloperidol treatment, symptoms decreased in all cases (21 to 88%) and clinical improvement was associated with an increased level of CSF HVA, often returning to the normal range. Optimal therapeutic response was found with serum levels of haloperidol between 1 and 4 ng/ml; however, disturbing side effects also occurred within this range. These results support the hypothesis that Tourette syndrome may result from a supersensitivity of dopaminergic receptors.
Norepinephrine and dopamine were examined in 19 discrete brain areas from the telencephalon, diencephalon, and mesencephalon of nutritionally rehabilitated adult rats following postnatal undernutrition from birth through 21 days of age. Following rehabilitation, catecholamine levels were not significantly different from control values in any of the areas examined. Catecholamine concentrations in young, undernourished rats are generally elevated (either from stress or from nutritional insufficiency). Data presented here show that whichever case is true, the early effect of undernourishment is transient and that normal values are restored by nutritional rehabilitation.
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Germ-cell tumors arising in the neuraxis have similar histopathological characteristics to those germ-cell tumors occurring in the gonads and other midline body sites. As a rare cause of intracranial neoplasm, germ-cell tumors affect predominantly the diencephalon and in particular the pineal region and suprasellar structures. Clinical features are due to local infiltration of these areas by tumor and hydrocephalus. Germinomas or mixed-cell tumors with a germinoma component make up the majority of these tumors and are very responsive to irradiation and chemotherapy. Early clinical recognition of a diencephalic tumor and determination of the specific tumor-cell type may result in curative treatment by surgery, irradiation and chemotherapy.
Our studies have demonstrated that TS patients show a high degree of sensitivity to butyrophenone blockade of dopaminergic receptors. The clinical response to extremely low serum levels of haloperidol includes sedating side effects, as well as therapeutic effects. These clinical changes are associated with significant increases in CSF HVA levels, which were abnormally decreased before treatment. CSF HIAA levels tended to be normal and did not change with haloperidol treatment. These results lend additional support to the hypothesis that TS is related to supersensitivity of dopaminergic receptors.
The disordered biosynthesis of dopamine, norepinephrine, and serotonin in brain in untreated PKU is corrected by dietary restriction of phenylalanine. Low levels of biogenic amine metabolites were measured in cerebrospinal fluid from three patients with classical PKU; metabolite concentrations increased after dietary treatment. In a variant of hyperphenylalaninemia caused by deficiency of dihydropteridine reductase, there is defective metabolism of biogenic amines despite dietary restriction of phenylalanine. Two siblings with DHPR deficiency had low amine metabolite values in CSF; in one patient the metabolic defect was corrected by administration of hydroxylated amino acid precursors. Defective biosynthesis of biogenic amines in brain in disorders associated with hyperphenylalaninemia and evaluation of specific dietary treatments can be determined by analysis of neurotransmitter metabolites in CSF.
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A female newborn infant with Marfan-like habitus experienced lethargy and hypothermia associated with tyrosinemia that was not corrected by the administration of ascorbic acid at 50 mg/day but that subsequently responded to ascorbic acid at 500 mg/day. Cerebrospinal fluid analysis for neurotransmitter metabolites showed elevated concentrations of homovanillic acid and 5-hydroxyindoleacetic acid when the child was symptomatic and normal concentrations after successful ascrobic acid therapy. These observations suggest that a high level of tyrosine in serum can affect the metabolism in the brain of dopamine and serotonin.
In a detailed investigation of a family with musculoskeletal abnormalities observed in four generations, the proband and his mother were found to have central cores and multicores on histochemical and electron microscopic studies of biopsied muscle. A male sibling experienced a malignant hyperthermic reaction during hand surgery, and although similar reactions had not been observed in other family members, unexplained ventricular dysrhythmias did occur in the proband during surgery. The proband and his mother were subsequently shown to be susceptible to malignant hyperthermia by abnormal in vitro muscle contractures in the presence of halothane or caffeine. Physicians and dentists caring for patients with central core disease should be aware of its possible association with malignant hyperthermia. Complete evaluation of patients with central core disease should include in vitro muscle contracture studies for malignant hyperthermia since many of patients require surgery for musculoskeletal defects.
Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in lumbar cerebrospinal fluid from a group of patients ranging in age from 1 week to 45 years. Quantitation of these biogenic amine metabolites was achieved using a gas chromatographic/mass spectrometric technique. The subjects had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided. The results indicated a strong inverse correlation in children between CSF HVA and 5-HIAA concentrations and age. The decline in these metabolites with age appeared to be exponential. No significant age effect was observed for MHPG. The results indicate the importance of comparing CSF metabolite levels in children with values in age-matched controls.
Biogenic amine metabolism in the central nervous system of 9 children with Tourette syndrome was evaluated by quantitation of their metabolites in cerebrospinal fluid by a gas chromatographic/mass spectrometric method. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in CSF before and after oral administration of probenecid. Dopamine metabolism appeared defective, as both baseline and accumulated levels of HVA after probenecid were decreased. Serotonin metabolism also appeared defective in some patients with low baseline and low accumulated levels of 5-HIAA after probenecid. Taken together with other clinical features of this disease, the results suggest an underlying disorder of dopamine and serotonin metabolism in Tourette syndrome.
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