Ischemic stroke and rhabdomyolysis in a 15-year-old girl with paraganglioma due to an SDHB exon 6 (Q214X) mutation.

BACKGROUND: We report a 15-year-old girl with a recent diagnosis of type 2 diabetes mellitus who presented in malignant hypertensive crisis (BP 210/120 mm Hg). Abdominal CT showed an 8.2 x 4.7 x 7.0 cm mass in the region of the organ of Zuckerkandl. MIBG scan showed a single paraganglioma without metastatic foci. Plasma total metanephrines were 232,176.4 pmol/l [263-1052] with normetanephrine predominance. Pre-operative course was complicated by ischemic stroke in the left MCA and right thalamic regions, acute renal failure, rhabdomyolysis and congestive heart failure. She required massive doses of propranolol, phenoxybenzamine, doxazosin and metyrosine prior to surgery. RESULTS: Pathology showed a Zellballen pattern, negative tumor margins and benign para-aortic lymph nodes. Mutation analysis of the succinate dehydrogenase type B (SDHB) gene revealed a heterozygous change of C to T at position 640 in exon 6 (Q214X) predicting an amino acid change to a stop codon. CONCLUSION: We report a severe clinical phenotype in a patient with a paraganglioma affecting multiple organ systems, due to an SDHB mutation. SDHB mutation warrants close follow up and investigation of the family due to high malignant potential and risk of familial occurrence.

Pedigree analysis in families with febrile seizures.

Febrile seizures are the most common form of seizures, occurring in an estimated 2-5% of North American children. We carried out a systematic pedigree study of febrile seizure probands. Forty of 52 probands (77%) in a referral population selected for increased severity had more than one case per family: one family had 10 cases, one family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fit the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. Because the cases were selected for increased severity, this represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies. Simulated lod scores showed adequate power for a linkage study in the absence of heterogeneity. Individual families had simulated average lod scores as high as 2.1. However, with potential heterogeneity, assuming only 70% of families share the same disease locus, average lod scores were marginal, and a high density map of marker loci and additional families would be required to document linkage.

Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus.

The occurrence of febrile seizures (FSs) in large autosomal dominant FS kindreds makes possible accurate delineation of the pure clinical phenotype of hereditary FS among secondary FS cases, and the identification of gene loci causing susceptibility to FS. Recently FS gene loci on chromosomes 8 and 19 were identified. We studied the phenotype of FS in four large families in which FS is an autosomal dominant trait. Among 30 affected secondary FS cases, mean age of onset was 16.3 months (range 4 to 36 months), sex ratio was equal, and 43% were complex (13 of 30). Among these 30 secondary FS cases, the mean number of FSs was 2.1, half had only a single FS, and none had afebrile seizures. Penetrance was 0.67, approximately the same as in our previous larger group of 40 multicase FS families (0.64). The occurrence of DPT encephalopathy in a sib of a patient with FS raises the possibility that these two etiologies are related. Linkage studies showed that one of the four families (Family 1) was linked to chromosome 19p markers, none of the families was linked to chromosome 8q markers, and the largest FS family (Kindred 6) was unlinked to either 19p or 8q markers, supporting the hypothesis of genetic heterogeneity for FS.

Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group.

The long-term effects of monotherapy with levodopa or the dopamine agonist pergolide on the motor/sensory, behavioral, and cognitive variables in seven children with restless legs syndrome/periodic limb movements in sleep (RLS/PLMS) and attention-deficit-hyperactivity disorder (ADHD) were investigated. Five of the seven children had previously been treated with stimulants that had either been determined to be ineffective or to have intolerable side effects. Dopaminergic therapy improved the symptoms of RLS and reduced the number of PLMS per hour of sleep (P = 0.018) and associated arousals (P = 0.042) for the entire group. After treatment, three children no longer met the criteria for ADHD, and three reverted to normal on the Test of Variable Attention. ADHD improved in all seven as measured by the Connors parent rating scale (P<0.04) and the Child Behavior Checklist (P<0.05). A significant improvement also occurred in the visual, but not verbal, memory scores on the Wide Range Assessment of Memory and Learning (P<0.001). Five of seven children continue on dopaminergic therapy 3 years after treatment initiation, with good response. We postulate that the improvement in ADHD may be the result of the amelioration of RLS/PLMS and its associated sleep disturbance. Alternatively, ADHD and RLS/PLMS may share a common dopaminergic deficit.

Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci.

Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine.

The effect of seizure type and medication on cognitive and behavioral functioning in children with idiopathic epilepsy.

Antiepileptic drugs have been reported to have a variety of adverse effects on behavior and performance in children with epilepsy. Previous studies investigating these side effects, however, have not controlled for the baseline status of the child (e.g. underlying neurological condition, seizure type, socioeconomic status, family variables), making it difficult to determine whether changes in function are attributable to the use of medication. We investigated the cognitive and behavioral profiles of 43 children, aged from 4 to 16 years, with new onset, idiopathic seizures. Twenty-six of these children participated in a 6-month follow-up study, and 12 in a 12-month follow-up study, investigating the effects of antiepileptic medications on psychological functioning. The children were of average intelligence (mean IQ 108) and had not previously been treated with antiepileptic medication. Children were classified as having either generalized convulsive, generalized non-convulsive (absence), simple partial, or complex partial seizures. Prior to the initiation of treatment, children with partial seizures were found to perform better than children with generalized seizures on measures of cognitive functioning. Children with convulsive seizures obtained significantly higher cognitive scores than those with non-convulsive seizures. Children with generalized non-convulsive seizures had lower cognitive scores than subjects with other types of seizure. No differences were found between groups at baseline prior to the initiation of antiepileptic medications. Analysis of subjects' performance after 6 and 12 months of antiepileptic therapy showed no significant deterioration attributable to medication. The differences in cognitive performance of the four seizure groups at baseline were not apparent at the time of follow-up. These results indicate that intrinsic and environmental variables may play a more significant role in predisposing certain children to cognitive and learning problems than do antiepileptic medications.

Serial neuropsychological follow-up of a child following craniospinal irradiation.

Serial neuropsychological examinations were made of an eight-year-old girl following diagnosis and treatment of a pineocytoma. The tumor was resected and she received intensive radiation therapy to the entire neuraxis, with a boost to the pineal region. A battery of neuropsychological tests was administered every six to eight weeks, beginning before and continuing for 48 weeks after radiation therapy. Parental questionnaires on the patient's everyday behavior were obtained, as well as past and present school records. MRI studies were performed seven weeks, nine months and 14 months after treatment had ended. The only functional area showing deterioration over the follow-up period was memory, both verbal and spatial. The MRIs showed no abnormalities related either to the tumor or to the radiation therapy.

Attention deficit hyperactivity disorder associated with orbitofrontal epilepsy in a father and a son.

The authors report on a father and son with frontal lobe epilepsy and symptoms of attention deficit hyperactivity disorder (ADHD). Attention deficit hyperactivity is a syndrome defined by criteria that include inattention, impulsive behavior, impaired concentration and motor restlessness. It does not require medical or neurobehavioral evaluation to determine an underlying etiology. The father is a 45-year-old man evaluated for possible ADHD. His referral came after the diagnosis of ADHD in his 6-year-old son who responded well to treatment with methylphenidate HCL. Neurobehavioral evaluation of the father suggested frontal lobe dysfunction. Magnetic resonance imaging and electroencephalography (EEG) were normal. Brain 99mTc HMPAO single-photon emission computed tomography (SPECT) revealed left orbitofrontal hypoperfusion. Additional history from his wife revealed episodic symptoms suggestive of nonconvulsive epilepsy that included nonresponsive staring, complex automatic behavior, and amnesic lacunas. Treatment of the father with carbmazepine produced dramatic improvement. Subsequent evaluation of his son, currently on maintenance treatment with methylphenidate HCL for ADHD, elicited a history consistent with atonic and simple motor partial epilepsy. The son's brain SPECT revealed bilateral orbitofrontal hypoperfusion defects. Attention deficit hyperactivity disorder is a syndrome that may be caused by frontal lobe lesions or epilepsy. In the setting of possible ADHD, neurological evaluation is warranted. Although overreliance on structural imaging or EEG in such an evaluation must be discouraged, brain SPECT may be useful to evaluate patients with symptoms of attention disorders for frontal epilepsy.

SSPE, measles virus, and the matrix protein: report of a case with unusual immunochemical findings.

We report a case of atypical subacute sclerosing panencephalitis (SSPE) in which the diagnosis was confirmed by a new radioimmunoprecipitation method. Antimeasles antibody was absent in the cerebrospinal fluid (CSF) when measured by conventional immunoassay techniques, there was no clinical response to isoprinosine, and the patient showed a selective absence of CSF antibody response to the matrix protein and only a partial serum antibody response to this measles polypeptide. The value of this sensitive immunoprecipitation method in profiling the selective antibody responses to the several measles polypeptides and the advisability of using isoprinosine, an immunopotentiating agent, to treat SSPE are discussed.

Topographic mapping of brain potentials in the newborn infant: the establishment of normal values and utility in assessing infants with neurological injury.

AIM: To demonstrate that quantitative EEG (qEEG) can be used as a non-invasive measure of brain injury by establishing normative data in term infants and contrasting it with other modalities of brain imaging. DESIGN: qEEG during quiet sleep was performed on 13 healthy full-term infants comprising a normal group and on 10 infants with neurological abnormalities identified on brain imaging studies (abnormal group) at 36-47 wk postconceptional age. Quantitative analysis was performed and topographic maps were produced for each patient. The EEG data from the normal group, after spectral analysis, yielded power data in the delta, theta, alpha, and beta frequency bands and coherence information, which then formed the normative database. qEEG from the infants in the abnormal group was then compared to this normative data. RESULTS: The normal group's mean absolute power in the delta, theta, alpha, and beta bands for all EEG leads combined were 278.48+/-83.83, 31.71+/-10.12, 29.20+/-2.04, and 35.76+/-11.35 uv2, respectively. The median frequency was 1.49+/-0.07, 5.45+/-3.46, 9.74+/-5.11, and 18.01+/-3.38 Hz, respectively. The qEEG was abnormal in all 10 study infants, while abnormalities were noted in the clinical EEG in 4 of 10, in the neuroultrasound in 5 of 10, in the CT in one of 6, and in the MRI in 2 of 2 tested. CONCLUSIONS: qEEG appears to be a useful non-invasive method for measuring brain injury as it correlates well with other modalities of brain imaging and, if corroborated by further study, may, in fact, be more sensitive in determining abnormalities in brain function.

Functional role of serotonergic neuromodulation in Aplysia.

The serotonergic metacerebral cell (MCC) of the mollusk Aplysia produces slow synaptic potentials in motor neurons of the buccal muscle, and increases the rate of ongoing rhythmic burst output of the buccal ganglion. In addition, the MCC acts peripherally to enhance the strength of buccal muscle contractions that are produced by firing of motor neurons. The potentiation of contraction is not associated with any detectable changes of resting membrane potential of muscle cells. Although MCC activity produces a small enhancement of excitatory junctional potentials, several experiments clearly indicate that the MCC has a direct potentiating effect on excitation-contraction coupling. The data suggest that potentiation of contraction might be mediated by cAMP. For example, activity of the MCC enchances the rate of accumulation of cAMP in buccal muscle, application of phosphodiesterase resistant analogs of cAMP potentiates muscle contraction, and a phosphodiesterase inhibitor enhances the effect of MCC stimulation. Recordings from free-moving animals indicate that the MCC becomes activated by exposure of the animal to food stimuli, and that the activation parallels the presence of a food-arousal state. Food-arousal is characterized by enhanced strength and increased frequency of biting responses. Both these effects can result from activity of the MCC. Thus, in this system, modulatory synaptic actions function to provide the substrate for a type behavioral modulation.

Trisomy 5 mosaicism detected prenatally with an affected liveborn.

This paper reports a case of chromosomal mosaicism for trisomy 5 recovered from amniotic fluid cells and from skin fibroblasts of a liveborn dysmorphic male. Routine amniocentesis was performed at 16 weeks' gestation because of parental concern. Trisomy 5 cells were measured from 25 per cent of amniocytes from two culture vessels. No further invasive testing was performed until 32 weeks' gestation, at which time ultrasound examination showed a fetus with intrauterine growth retardation. Fetal blood sampling was then performed, with only karyotypically normal cells recovered. At birth, the child was found to have multiple dysmorphic features and congenital anomalies, including an eventration of the diaphragm and ventricular septal defect, both of which required surgical correction. Chromosomal analysis of cord blood lymphocytes indicated 46,XY; however, 20 per cent of the cultured fibroblasts obtained from the chest skin at the incision site for diaphragmatic repair had a 47,XY, +5 karyotype. Trisomy 5 mosaicism may be another example of tissue-limited mosaicism. Fetal blood sampling can then be falsely reassuring. Furthermore, because some cell lines rarely appear in lymphocyte populations, cytogenetic analysis of multiple tissues is warranted as part of the evaluation of individuals with developmental delay and dysmorphic features.

Hyperfractionated radiotherapy for children with brainstem gliomas: a pilot study using 7,200 cGy.

Brainstem gliomas, constituting approximately 10% of all childhood central nervous system tumors, remain the most resistant of all brain tumors to therapy. A subgroup of high-risk patients with tumors that diffusely involve the brainstem or that microscopically demonstrate foci of anaplasia on biopsy specimens rarely survive after treatment. Conventional doses of radiotherapy result in temporary clinical improvement in the majority of these high-risk patients; however, few if any remain alive 18 months after treatment. Hyperfractionated radiotherapy, with delivery of larger numbers of smaller fractions of radiotherapy, is a possible way to increase tumor control without increasing neurological toxicity. In 1985, a multiinstitutional phase I/phase II trial, using 100 cGy of radiation therapy twice daily to a total dose of 7,200 cGy, was undertaken for patients with high-risk brainstem gliomas. At the time of writing, 24 (69%) had developed progressive disease and 11 remained in continuous progression-free remission. Actuarial progression-free survival at 20 months is approximately 30%. Twenty-three of 31 evaluable patients had an objective radiographic response to therapy. In comparison to both historical control patients and patients treated in a previous trial using 6,480 cGy of hyperfractionated radiation therapy, there was a statistically significant improvement in progression-free survival rate for patients treated with 7,200 cGy of hyperfractionated radiation therapy (p less than 0.01). To date no patient has died as a result of treatment. Six patients developed transient neurological deterioration or cystic intralesional changes, as demonstrated on magnetic resonance imaging, within 6 weeks of the completion of radiotherapy. Postmortem examination performed in 7 patients did not disclose significant radiation necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)