Cognitive function and the longitudinal hippocampal axis in mesial temporal sclerosis.

OBJECTIVE: The relationship of preoperative memory deficits in patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) to the distribution of neuronal loss is uncertain. Building on the material specificity theory, we tested the hypothesis that visual memory deficits are associated with posterior hippocampal atrophy, whereas verbal memory deficits are associated with anterior hippocampal atrophy. METHODS: We studied 22 adults with mTLE and HS, calculating hippocampal head, body, and tail volumes, correcting for estimated total intracranial volume, using automated segmentation. Preoperative memory ability was evaluated with the Wechsler Memory Scale (WMS-II: logical memory, verbal paired associates, family pictures, and faces subtests). We correlated memory ability with hippocampal division volumes using SPSS 26.1 (repeated measures ANOVAs, one-way ANOVAs, Pearson r correlations) for statistical analysis. RESULTS: We found a significant main effect of hippocampal subdivision, reporting volumetric differences between the head, body, and tail. Pairwise comparisons reported that the hippocampal head had significantly greater volume than both the body and tail (p < 0.001). For both left and right focus groups, the ipsilateral hippocampi were significantly smaller than the contralateral. Linear regression reported a left hippocampal model (head, body, and tail volumes) predicted performance on logical memory with the left hippocampal tail volume being the strongest predictor. A right hippocampal model (head, body, and tail volumes) predicted memory ability for family pictures and verbal paired associates at a trend level. CONCLUSIONS: Ipsilateral hippocampal head and tail seem more vulnerable to injury than the body in both the left and right mTLE. Our study suggests there may be functional differences along the hippocampal longitudinal axis, particularly for the left hippocampal tail with verbal memory. Our findings are consistent with material-specific right-left differences in memory processing.

HIV and new onset seizures: slipping through the cracks in HIV care and treatment.

OBJECTIVES: The aim of the study was to describe patient characteristics and outcomes among HIV-positive adults presenting to a Zambian tertiary care hospital with new-onset seizures. METHODS: From July 2011 to June 2013, adults with seizures and a known or probable diagnosis of HIV infection were screened for a cohort study. Demographic and clinical data were obtained, including information on engagement in HIV services and in-patient mortality. Analyses were conducted to identify characteristics associated with poor engagement in care and death. RESULTS: A total of 320 of 351 screened adults were HIV-positive, with 268 of 320 experiencing new-onset seizures. Of these, 114 of 268 (42.5%) were female, and their mean age was 36.8 years. Seventy-nine of the 268 patients (29.5%) were diagnosed with HIV infection during the index illness. Among those who were aware of their HIV-positive status, 59 of 156 (37.8%) had disengaged from care. Significant functional impairment (Karnofsky score < 50) was evident in 44.0% of patients. Cerebrospinal fluid was not obtained in 108 of 268 (40.3%). In-patient mortality outcomes were available for 214 patients, and 47 of these 214 (22.0%) died during hospitalization. Patients with significant functional impairment were more likely to undergo lumbar puncture (P = 0.046). Women and the functionally impaired were more likely to die (P = 0.04 and < 0.001, respectively). CONCLUSIONS: Despite the availability of care, less than half of HIV-infected people with new-onset seizures were actively engaged in care and in-patient mortality rates were high. In the absence of clinical contraindication, lumbar puncture should be performed to diagnose treatable conditions and reduce morbidity and mortality. Continued efforts are needed to expand community-based testing and improve HIV care retention rates. Qualitative studies are needed to elucidate factors contributing to lumbar puncture usage in this population.

Isolated seizures in rats do not cause neuronal injury.

BACKGROUND: Previous studies have shown that status epilepticus can lead to neuronal injury. However, the effect of a small number of isolated seizures is uncertain. METHODS: We used structural MRI and neuropathology to study the effects of isolated seizures induced by kainic acid (KA), (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazole-4-yl)propanoic acid (ATPA), and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate in rats. A group of animals received normal saline. After seizure induction, animals were followed for 12 weeks. RESULTS: ATPA and KA led to small but significant increases in ADC. There were no changes in T2 signal intensity or hippocampal volume. Blinded pathological examination showed no differences between animals receiving saline or glutamatergic agents. CONCLUSION: Our study suggests that isolated seizures cause minimal neuronal injury in rats.

Arterial spin labeling demonstrates that focal amygdalar glutamatergic agonist infusion leads to rapid diffuse cerebral activation.

OBJECTIVES: To investigate acute effects of intra-amygdalar excitatory amino acid administration on blood flow, relaxation time and apparent diffusion coefficient in rat brain. MATERIALS AND METHODS: Several days after MR-compatible cannula placement in right basolateral amygdala, anesthetized rats were imaged at 7 T. Relative cerebral blood flow (CBF) was measured before and 60 min after infusion of 10 nmol KA, cAMPA, ATPA, or normal saline using arterial spin labeling. Quantitative T(2) and diffusion-weighted images were acquired. rCBF, T(2) and ADC values were evaluated in bilateral basolateral amygdala, hippocampus, basal ganglia, frontal and parietal regions. RESULTS: KA led to the highest, and ATPA lowest bilateral rCBF increases. Time courses varied among drugs. T(2) for KA and AMPA was higher while ADC was lower for KA. CONCLUSIONS: Intra-amygdalar injection of GluR agonists evoked bilateral seizure activity and increased rCBF, greater for KA and AMPA than selective ATPA GluR5 activation.

Limitations to plasticity of language network reorganization in localization related epilepsy.

Neural networks for processing language often are reorganized in patients with epilepsy. However, the extent and location of within and between hemisphere re-organization are not established. We studied 45 patients, all with a left hemisphere seizure focus (mean age 22.8, seizure onset 13.3), and 19 normal controls (mean age 24.8) with an fMRI word definition language paradigm to assess the location of language processing regions. Individual patient SPM maps were compared to the normal group in a voxel-wise comparison; a voxel was considered to be significant if its z-value exceeded mid R:2mid R:. Subsequently, we used principal component analysis with hierarchical clustering of variance patterns from individual difference maps to identify four patient sub-groups. One did not differ from normal controls; one had increased left temporal activation on the margin of regions activated in controls; two others had recruitment in right inferior frontal gyrus, middle frontal gyrus and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Our study used novel data driven methods to find evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains.

Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men.

Succinic semialdehyde dehydrogenase (SSADH) deficiency, a disorder of GABA degradation with subsequent elevations in brain GABA and GHB, is a neurometabolic disorder with intellectual disability, epilepsy, hypotonia, ataxia, sleep disorders, and psychiatric disturbances. Neuroimaging reveals increased T2-weighted MRI signal usually affecting the globus pallidus, cerebellar dentate nucleus, and subthalamic nucleus, and often cerebral and cerebellar atrophy. EEG abnormalities are usually generalized spike-wave, consistent with a predilection for generalized epilepsy. The murine phenotype is characterized by failure-to-thrive, progressive ataxia, and a transition from generalized absence to tonic-clonic to ultimately fatal convulsive status epilepticus. Binding and electrophysiological studies demonstrate use-dependent downregulation of GABA(A) and (B) receptors in the mutant mouse. Translational human studies similarly reveal downregulation of GABAergic activity in patients, utilizing flumazenil-PET and transcranial magnetic stimulation for GABA(A) and (B) activity, respectively. Sleep studies reveal decreased stage REM with prolonged REM latencies and diminished percentage of stage REM. An ad libitum ketogenic diet was reported as effective in the mouse model, with unclear applicability to the human condition. Acute application of SGS-742, a GABA(B) antagonist, leads to improvement in epileptiform activity on electrocorticography. Promising mouse data using compounds available for clinical use, including taurine and SGS-742, form the framework for human trials.

Towards a non-invasive interictal application of hypothermia for treating seizures: a feasibility and pilot study.

OBJECTIVES: To evaluate the feasibility and safety of head-neck cooling in conscious normal volunteers (10) and patients with medically refractory epilepsy (5) without causing shivering. PATIENTS AND METHODS: We used a non-invasive head-neck cooling system (CoolSystems Inc., Lincoln, CA, USA). The tympanic temperature (TT) and intestinal temperature (IT) were measured as two measurements of 'core temperature' (CT), and multi-site external temperatures, several physiologic variables and EEG were monitored. Seizure counts over 4-week precooling, treatment and follow-up phases were compared. RESULTS: All 15 participants completed all the cooling sessions without significant complaints. At the end of 60 min of cooling, scalp temperature fell on average by 12.2 degrees C (P < 0.001), TT by 1.67 degrees C (P < 0.001), and IT by 0.12 degrees C (P = NS). Average weekly seizure frequency decreased from 2.7 to 1.7 events per patient per week (MANOVA: P < 0.05). CONCLUSIONS: Non-invasive head-neck cooling is safe and well-tolerated. Initial pilot data in patients suggest that additional therapeutic studies are warranted.

Brain stimulation for epilepsy.

Brain stimulation has been receiving increasing attention as an alternative therapy for epilepsy that cannot be treated by either antiepileptic medication or surgical resection of the epileptogenic focus. The stimulation methods include transcranial magnetic stimulation (TMS) or electrical stimulation by implanted devices of the vagus nerve (VNS), deep brain structures (DBS) (thalamic or hippocampal), cerebellar or cortical areas. TMS is the simplest and least invasive approach. However, the most common epileptogenic areas (mesial temporal structures) probably lie too deep beneath the surface of the skull for effective TMS. The efficacy of VNS in reducing the frequency or severity of seizures is quite variable and depends on many factors which are currently investigated. VNS is well-tolerated and approved in many countries. DBS is much more invasive than either TMS or VNS. Currently, a number of targets for DBS are investigated including caudate, centromedian or anterior thalamic nuclei, and subthalamic nucleus. Direct stimulation of the epileptic cortical focus is another approach to the neuromodulation in epilepsy. Finally, another line of research investigates the usefulness of implantable seizure detection devices. The current chapter presents the most important evidence on the above methods. Furthermore, other important issues are reviewed such as the selection criteria of patients for brain stimulation and the potential role of brain stimulation in the treatment of depression in epileptic patients.

Rational use of antiepileptic drug levels.

Antiepileptic drug (AED) levels are obtained frequently in clinical practice, but their complex relation to seizures or drug toxicity often makes interpretation of the results difficult. Research studies have not always taken into account clinical, as well as pharmacokinetic and pharmacodynamic, factors which may influence the drug level-effect relationship. AED levels should be drawn at an appropriate time in relation to drug ingestion and clinical symptoms. Systematic investigations in selected patients, during which several levels are obtained, may be more rewarding than routine measurements in a large clinic population.

Cortical excitability during prolonged antiepileptic drug treatment and drug withdrawal.

OBJECTIVE: Previous reports characterized the effects of administration of single oral doses of antiepileptic drugs (AED) on cortical excitability. However, AED effects on cortical excitability, and their relationship to plasma blood levels, during chronic drug administration at therapeutic doses are not known. The objective of the study was to determine whether plasma blood levels during chronic administration at therapeutic doses would accurately predict changes in corticomotor excitability. METHODS: We used transcranial magnetic stimulation (TMS) to measure cortical excitability during 5 weeks administration of carbamazepine (CBZ) and lamotrigine (LTG), and subsequent AED withdrawal in 20 healthy volunteers. Data were analyzed using ANOVA(RM) and regression analysis. RESULTS: Resting motor thresholds (r-MT) increased with increasing total and free CBZ and LTG levels during drug administration, but not drug withdrawal. After acute AED withdrawal, r-MT elevation persisted in most individuals with CBZ despite undetectable plasma levels, compared to a rapid normalization with LTG. In contrast, acute drug withdrawal resulted in a transient decrease in r-MT in 3/10 individuals with CBZ and 2/10 with LTG. CONCLUSIONS: Plasma levels provide information on motor cortical function during active treatment phases but not during AED withdrawal. SIGNIFICANCE: The transient decrease in r-MT associated with acute AED withdrawal could represent a physiological substrate contributing to AED withdrawal seizures.

Nonsedative regimens in the treatment of epilepsy.

Trends in the diagnosis of epilepsy have continued to focus on the fundamental cause of the seizures, as well as the seizure type. It is the latter that determines symptomatic therapy. New drugs have improved the lives of many epileptic patients, and emphasis on nonsedative medications, both new and old, is now possible and desirable in most patients. Finally, new and better drugs are needed for the many severely affected epileptic patients who are not helped by the currently available antiepileptic drugs.

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.

Effect of phenytoin on human cerebral glucose metabolism.

We used serial positron emission tomography scans with [18F]2-deoxyglucose to study the effect of phenytoin on human cerebral glucose metabolism in 10 patients with seizure disorders. Local CMRglu for each patient was measured in 10 regions of interest. EEGs were performed during each procedure to match scans for state of consciousness and exclude data from scans with ictal activity. Serial scans without a drug change were performed in six control patients. Metabolic rates were significantly lower in two cortical regions while patients were taking phenytoin. No significant changes on repeat scan were seen in the control population. Measured across all regions of interest, metabolic rates were 13% higher when patients were off phenytoin (p less than 0.02).

Phenytoin: the pseudosteady-state phenomenon.

After reaching an apparent steady state, plasma phenytoin (PHT) levels may then undergo inexplicable changes, a phenomenon called " pseudosteady state". We evaluated 13 pseudosteady -state periods in 10 inpatients with complex partial seizures. Eleven of the periods occurred after a change in PHT dosage and two after drug withdrawal. The pseudosteady -state period began 2 to 12 days (means = 5.7 days) after dosage change and lasted 5 to 10 days (means = 6.3 days), during which plasma PHT levels were stable (+/- 5%). Plasma PHT levels thereafter fluctuated spontaneously by greater than 25% for 5 to 22 days (means = 10.8 days). A final steady-state level was reached 13 to 31 days (means = 21.4 days) after the first dosage change. Falling plasma PHT levels increased seizure frequency in two patients, and a level of 52 micrograms/ml led to medication toxicity in another.

Meningeal carcinomatosis.

We reviewed 33 cases of meningeal carcinomatosis seen at the Mount Sinai Hospital, New York, from 1970 through 1979. The major sources of meningeal disease were carcinoma of the breast (21 cases), carcinoma of the lung (five), and malignant melanoma (five). Seventy-eight percent of the patients had widespread metastases at the time of neurologic diagnosis. A combination of radiotherapy and intrathecal administration of methotrexate was the most successful treatment, and 14 of 22 treated patients showed at least symptomatic improvement; however, mean survival in the most improved group was still less than six months.

Complex partial seizures. Correlation of clinical and metabolic features.

We compared metabolic patterns on 18F-2-deoxyglucose positron emission tomography (PET) with closed circuit television and simultaneous electroencephalographic ictal recordings of complex partial seizures in 48 patients. Closed circuit television and electroencephalographic data and PET scans were scored by "blinded" raters. Of the 48 patients, 26 had unilateral temporal; three, frontal; ten, ipsilateral frontotemporal; one, frontoparietal; and five, temporoparietal hypometabolism; and three had widespread hypometabolism affecting frontal, temporal, and parietal lobes. patients with frontal hypometabolism alone had shorter ictal and postictal durations, but involvement of multiple regions was associated with prolonged seizures. Auras were more likely to be present in patients with temporal hypometabolism alone, but an initial motionless stare did not distinguish this group. However, other metabolic patterns did not predict specific ictal clinical features. Vocalizations (formed or unformed) were not more closely associated with frontal involvement. When hypometabolism is multilobar, it may be difficult to use PET to distinguish between complex partial seizures of frontal and temporal origin.

The dynamics of metabolic change following seizures as measured by positron emission tomography with fludeoxyglucose F 18.

OBJECTIVE: To examine the time course of alterations in glucose metabolism in relation to the interval from the last seizure, focus laterality, seizure frequency, and seizure type. DESIGN: Metabolic study with the use of positron emission tomography with fludeoxyglucose F 18. Blinded scan evaluation with use of a standard template. Multivariate regression analysis of positron emission tomographic data. SETTING: National Institutes of Health Clinical Center, Bethesda, Md. PATIENTS: Thirty-two adults with intractable partial epilepsy and lateralized seizure onset documented by video-electroencephalographic monitoring. MAIN OUTCOME MEASURE: Normalized metabolic rate for glucose ipsilateral and contralateral to the epileptic focus. RESULTS: The most dramatic changes occurred in inferior temporal regions; the midtemporal region was affected as well. Effects lasting 48 hours were found after both simple and complex partial seizures. The time course was different for the two types of seizures. The inferior temporal metabolic rate ipsilateral to the focus increased compared with the interictal rate during the 24-hour period following simple partial seizures; a nadir occurred in the second 24 hours. The rate then rose to an intermediate level after 48 hours. The relative to an intermediate level after 48 hours. The relative regional increase in ipsilateral metabolism following complex partial seizures persisted for 48 hours before falling. CONCLUSION: The brain may take longer than 24 hours after a partial seizure to return to its baseline state.

Familial spastic paraplegia, mental retardation, and precocious puberty.

Two brothers had progressive spastic paraplegia and precocious puberty develop due to Leydig's cell hyperplasia when they were 2 years old. Both later had moderate mental retardation. Family members displayed brisk lower-extremity reflexes and dysarthria in a pedigree that suggested autosomal dominant inheritance with variable expression. Precocious puberty has been associated with other neurologic syndromes. Its occurrence in two brothers with spastic paraplegia has not, to our knowledge, been previously reported.

Benzodiazepine withdrawal delirium with catatonic features. Occurrence in patients with partial seizure disorders.

We report the cases of 3 patients with medically intractable seizures in whom withdrawal of treatment with a long-acting benzodiazepine (clorazepate dipotassium, 2 patients; clonazepam, 1 patient) was followed by delirium with catatoniclike features. While an increase in seizure frequency occurred during withdrawal and prior to the onset of behavioral changes, electroencephalograms did not show epileptiform activity during the delirium. We compared these 3 patients with 10 others with intractable seizures in whom antiepileptic therapy was withdrawn without subsequent behavior changes. High-dose benzodiazepine therapy and a history of viral encephalitis may be risk factors for withdrawal delirium.

Cerebral metabolism and depression in patients with complex partial seizures.

Twenty-three patients with complex partial seizures were evaluated with 18F-2-deoxyglucose positron emission tomography and with the Beck Depression Inventory. Five of 10 patients with left and zero of eight with right temporal electroencephalographic foci had depressive symptoms; one of five patients with poorly localized electroencephalographic foci also scored in the depressed range. Temporal, frontal, caudate, and thalamic normalized glucose metabolic rates among five patients with depressive symptoms and well-localized left temporal epileptogenic regions were compared with five patients without depressive symptoms but with similar electroencephalographic characteristics. Multifactorial analysis of variance yielded a significant nonlateralized mood by region interaction. Of nine individual regions compared, only inferior frontal cortex showed a significant difference in normalized regional metabolic rate between depressed and nondepressed patients. Metabolism in this region also distinguished patients with depressive symptoms from normal control subjects. Depressive symptoms in patients with complex partial seizures are associated with a bilateral reduction in inferior frontal glucose metabolism, compared with patients without depressive symptoms and normal control subjects. The frontal lobe hypometabolism observed in patients with depressions associated with epilepsy, Parkinson's disease, and primary affective disorder suggests that similar frontal lobe metabolic disturbances could underlie these conditions.