Robin L. Gilmore

Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children

OBJECTIVE. Open-label studies indicate that oral dichloroacetate (DCA) may be effective in treating patients with congenital lactic acidosis. We tested this hypothesis by conducting the first double-blind, randomized, control trial of DCA in this disease. METHODS. Forty-three patients who ranged in age from 0.9 to 19 years were enrolled. All patients had persistent or intermittent hyperlactatemia, and most had severe psychomotor delay. Eleven patients had pyruvate dehydrogenase deficiency, 25 patients had 1 or more defects in enzymes of the respiratory chain, and 7 patients had a mutation in mitochondrial DNA. Patients were preconditioned on placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA, at a dose of 12.5 mg/kg every 12 hours. The primary outcome results were (1) a Global Assessment of Treatment Efficacy, which incorporated tests of neuromuscular and behavioral function and quality of life; (2) linear growth; (3) blood lactate concentration in the fasted state and after a carbohydrate meal; (4) frequency and severity of intercurrent illnesses and hospitalizations; and (5) safety, including tests of liver and peripheral nerve function. OUTCOME. There were no significant differences in Global Assessment of Treatment Efficacy scores, linear growth, or the frequency or severity of intercurrent illnesses. DCA significantly decreased the rise in blood lactate caused by carbohydrate feeding. Chronic DCA administration was associated with a fall in plasma clearance of the drug and with a rise in the urinary excretion of the tyrosine catabolite maleylacetone and the heme precursor δ-aminolevulinate. CONCLUSIONS. In this highly heterogeneous population of children with congenital lactic acidosis, oral DCA for 6 months was well tolerated and blunted the postprandial increase in circulating lactate. However, it did not improve neurologic or other measures of clinical outcome.

Effectiveness of vagus nerve stimulation in epilepsy patients A 12-year observation

A retrospective review of the safety, tolerability, and efficacy of vagus nerve stimulation (VNS) in 48 patients with intractable partial epilepsy was performed. Side effects were few and mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment.

NON-LINEARITY IN INVASIVE EEG RECORDINGS FROM PATIENTS WITH TEMPORAL LOBE EPILEPSY

Electrographic recordings from depth and subdural electrodes, performed in two patients with seizures of mesial temporal origin, were analyzed for the presence of non-linearities in the signal. The correlation integral, a measure sensitive to a wide variety of non-linearities, was used for detection. Statistical significance was determined by comparison of the original signal to surrogate datasets. Statistically significant non-linearities were present in signals generated by the epileptogenic hippocampus and interictal spike foci in the temporal neocortex. Less prominent non-linearities were found in EEG signals generated by more normal areas of the brain. These results indicate that techniques developed for the study of non-linear systems can be used to characterize the epileptogenic regions of the brain during the interictal period and can elucidate the dynamical mechanisms of the epileptic transition.

Conduction Aphasia and the Arcuate Fasciculus: A Reexamination of the Wernicke–Geschwind Model ☆

Wernicke, and later Geschwind, posited that the critical lesion in conduction aphasia is in the dominant hemispheres arcuate fasciculus. This white matter pathway was thought to connect the anterior language production areas with the posterior language areas that contain auditory memories of words (a phonological lexicon). Alternatively, conduction aphasia might be induced by cortical dysfunction, which impairs the phonological output lexicon. We observed an epileptic patient who, during cortical stimulation of her posterior superior temporal gyrus, demonstrated frequent phonemic paraphasias, decreased repetition of words, and yet had intact semantic knowledge, a pattern consistent with conduction aphasia. These findings suggest that cortical dysfunction alone may induce conduction aphasia.

Planum temporale asymmetry and language dominance

Language is lateralized to the left hemisphere in most individuals, and leftward asymmetry of the planum temporale has been reported in postmortem and imaging studies. In this study we measured the planum temporale on magnetic resonance imaging (MR) scans of patients (11 right-handers, 1 non-right-hander) who had selective hemispheric anesthesia or Wada testing performed for language lateralization. All subjects who had language lateralized to the left hemisphere (11 right-handers) had a leftward asymmetry of the planum temporale. One subject who had language lateralized to the right hemisphere (non-right-hander) had a strong rightward asymmetry of the planum temporale. These data suggest that planum temporale asymmetries determined by MR are associated with language dominance and may predict language laterality.

Asymmetry of the hippocampus and amygdala in MRI volumetric measurements of normal adults.

Multiple studies have explored the relationship between MRI-based volumetric measurements of the hippocampus and amygdala, the degree of volumetric asymmetry of these structures, and symptom manifestation. However, considerable variability exists with regard to the reported volumetric values of these structures. The present study employed meta-analytic procedures to provide a systematic analysis of the normal population parameters of hippocampal and amygdala volumetric asymmetry as well as the absolute intrahemispheric volumes of these structures in normal adults. A literature review of studies published between 1990 and 2002 resulted in a representative sample of 82 studies (N = 3,564 participants) providing volumetric information of the hippocampus and 51 studies (N = 2,000 participants) providing volumetric information of the amygdala. Results revealed that both the hippocampus and the amygdala are reliably asymmetrical structures in normal adults, with larger right hippocampal (D = 0.21, p.001) and right amygdala (D = 0.09, p.01) volumes. Additional analyses indicated that differences in MRI magnet field strength and slice thickness values might differentially contribute to volumetric asymmetry estimates. These results expand on previous volumetric normative studies and may be relevant to investigators studying the clinical correlates of hippocampal and amygdala volumes.

Chronic Intractable Epilepsy as the Only Symptom of Primary Brain Tumor

We identified 39 patients with chronic epilepsy (seizures ≥2 years) proven to have primary brain tumors. These cases represent ∼12% of the surgery cases for epilepsy in the same period. Mean age of seizure onset was 13.2 years: mean duration before operation was 10.5 years. Thirty‐eight of 39 had normal neurologic examination. Twenty‐six tumors were temporal, 7 were frontal, 4 were parietal, and 2 were occipital. Nine of 26 (34.6%) of the temporal group had contralateral interictal EEG spikes. Pathology was 15 ganglioglioma, 13 low‐grade astrocytoma, 4 oligodendroglioma, 2 low‐grade mixed glioma, 1 pleomorphic xanthoastrocytoma, 2 dysembryoplastic neuroepithelial tumor, and 1 ependymoma. Postoperative seizure frequency (minimum follow‐up 6 months) ranged from 15 to 16 seizure‐free or auras only in patients with temporal tumors and total gross tumor removal (mean follow‐up 28 months) to 0 of 6 seizure‐free in patients with extratemporal tumors who underwent subtotal resections or biopsy.

Experimentally induced disorders of neuronal migration produce an increased propensity for electrographic seizures in rats

Disorders of neuronal migration in humans are associated with intractable epilepsy and some evidence suggests a causal relationship. This study evaluated electroencephalograms (EEG) of rats with experimentally induced disorders of neuronal migration. Fetal Sprague-Dawley rats were exposed to 196 cGy external irradiation on days 16 and 17 of gestation. This produced adult offspring with diffuse cortical dysplasias, agenesis of the corpus callosum, periventricular heterotopias, and dispersion of the pyramidal cell layer of the hippocampus. Epidural electrodes were implanted in four experimental (irradiated on gestational day 17) and four control rats. EEGs were recorded without anesthesia and in the presence of the anesthetic agents ketamine, acepromazine, and xylazine. In the presence of acepromazine, xylazine, or a combination of the two drugs, two of the four experimental rats had prolonged ictal activity on EEG. In one of the rats the ictal activity progressed to electrographic status epilepticus. Ketamine alone did not produce ictal EEG activity. None of the control rats demonstrated ictal activity under any treatment condition. This study demonstrates that disorders of neuronal migration are associated with an increased propensity for seizures in the presence of certain sedating agents.

Electroencephalographic findings in Hashimoto's encephalopathy

Article abstract—Hashimotos encephalopathy (HE) is a steroid-responsive relapsing disorder that frequently presents with seizures and diffuse EEG abnormalities. We report the EEG findings in seven patients with encephalopathy, seizures, or both, associated with elevated antithyroid antibodies. There were several combinations of findings within the same patient and between patients. The EEGs of five patients had generalized slowing or frontal rhythmic slowing; two also had triphasic waves and one had periodic sharp waves. Three had focal left temporal slowing. HE is heterogeneous clinically and electrographically. A high level of suspicion is necessary to establish the diagnosis.

Characterizing nonlinearity in invasive EEG recordings from temporal lobe epilepsy

Abstract Invasive electroencephalographic (EEG) recordings from depth and subdural electrodes, performed in eight patients with temporal lobe epilepsy, are analyzed using a variety of nonlinear techniques. A surrogate data technique is used to find strong evidence for nonlinearities in epileptogenic regions of the brain. Most of these nonlinearities are characterized as “spiking” by a wavelet analysis. A small fraction of the nonlinearities are characterized as “recurrent” by a nonlinear prediction algorithm. Recurrent activity is found to occur in spatio-temporal patterns related to the location of the epileptogenic focus. Residual delay maps, used to characterize “lag-one nonlinearity”, are remarkably stationary for a given electrode, and exhibit striking variations among electrodes. The clinical and theoretical implications of these results are discussed.