Faculty Bibliography

We describe diffuse glioma-like infiltrates in excised tubers in five out of forty Tuberous sclerosis complex (TSC) patients undergoing excision of a tuber at our institution within the last 10 years. All patients presented with refractory seizures. Resection specimens from four patients had the pathognomonic histologic features of neuroglial hamartomas (tubers) and in one case there was cortical microdysgenesis lacking cells typical of TSC. All lesions were associated with an infiltrate of atypical, mostly elongate, glioma-like small cells, which were immunoreactive for GFAP in three, and pS6 (a marker for activity of the mTOR pathway), in two cases. MAP-2 and CD34, were negative and MIB-1 (Ki67) immunostains ranged from <1-21%. Array-based comparative genomic hybridization revealed that these proliferative phenomena were associated with 21 different copy number aberrations in comparison with a tuber without atypical infiltrates. Postoperatively (follow-up period ranging from 8 to 34 months) none of the patients have any evidence of a glioma. We report that tubers resected for treatment of seizures are sometimes associated with glioma-like lesions, which are indistinguishable from infiltrating gliomas by morphology and immunohistochemistry. Genomic analysis with SNP arrays revealed copy number changes which may be associated with the pathogenesis of such infiltrates

Transmeningeal pharmacotherapy has been proposed to treat neurological disorders with localized pathology, such as intractable focal epilepsy. As a step toward understanding the diffusion and intracortical spread of transmeningeally delivered drugs, the present study used histological methods to determine the extent to which a marker compound, N-methyl-D-aspartate (NMDA), can diffuse into the neocortex through the meninges. Rats were implanted with bilateral parietal cortical epidural cups filled with 50 mM NMDA on the right side and artificial cerebrospinal fluid (ACSF) in the contralateral side. After 24 h, the histological effects of these treatments were evaluated using cresyl violet (Nissl) staining. The epidural NMDA exposure caused neuronal loss that in most animals extended from the pial surface through layer V. The area indicated by this neuronal loss was localized to the neocortical region underlying the epidural cup. These results suggest that NMDA-like, water soluble, small molecules can diffuse through the subdural/subarachnoid space into the underlying neocortex and spread in a limited fashion, close to the meningeal penetration site

OBJECTIVE: The mechanism of action of levetiracetam (LEV), an antiepileptic drug, is related to a novel binding site, SV2, but LEV acts on GABA-A receptors. The objective of the study described here was to determine if LEV modulates brain GABA in vivo. METHODS: Concentrations of cerebral GABA and serum LEV were obtained in seven healthy individuals using 1H magnetic resonance spectroscopy at baseline and 3 and 6 hours following oral administration of 1 g of LEV. RESULTS: Brain cerebral GABA acutely concentrations did not change from baseline. CONCLUSION: The results indicate that LEV does not increase human cerebral GABA concentrations acutely in healthy individuals

Antiepileptic drug (AED) delivery directly into the neocortex has recently been shown to be able to both prevent and terminate focal seizures in rats. The present clinical experiment aimed to test the local effects of lidocaine delivered onto the pia mater adjacent to epileptogenic zones in human patients. Administration of lidocaine resulted in a marked diminishment of spike counts on all patients, with a decremental effect of lidocaine on the faster frequency elements of individual spikes and overall testing epochs. The direct cortical application of lidocaine appears to affect local epileptogenic activity in human patients with intractable focal epilepsy

Revered in some cultures but persecuted by most others, epilepsy patients have, throughout history, been linked with the divine, demonic, and supernatural. Clinical observations during the past 150 years support an association between religious experiences during (ictal), after (postictal), and in between (interictal) seizures. In addition, epileptic seizures may increase, alter, or decrease religious experience especially in a small group of patients with temporal lobe epilepsy (TLE). Literature surveys have revealed that between .4% and 3.1% of partial epilepsy patients had ictal religious experiences; higher frequencies are found in systematic questionnaires versus spontaneous patient reports. Religious premonitory symptoms or auras were reported by 3.9% of epilepsy patients. Among patients with ictal religious experiences, there is a predominance of patients with right TLE. Postictal and interictal religious experiences occur most often in TLE patients with bilateral seizure foci. Postictal religious experiences occurred in 1.3% of all epilepsy patients and 2.2% of TLE patients. Many of the epilepsy-related religious conversion experiences occurred postictally. Interictal religiosity is more controversial with less consensus among studies. Patients with postictal psychosis may also experience interictal hyper-religiosity, supporting a 'pathological' increase in interictal religiosity in some patients. Although psychologic and social factors such as stigma may contribute to religious experiences with epilepsy, a neurologic mechanism most likely plays a large role. The limbic system is also often suggested as the critical site of religious experience due to the association with temporal lobe epilepsy and the emotional nature of the experiences. Neocortical areas also may be involved, suggested by the presence of visual and auditory hallucinations, complex ideation during many religious experiences, and the large expanse of temporal neocortex. In contrast to the role of the temporal lobe in evoking religious experiences, alterations in frontal functions may contribute to increased religious interests as a personality trait. The two main forms of religious experience, the ongoing belief pattern and set of convictions (the religion of the everyday man) versus the ecstatic religious experience, may be predominantly localized to the frontal and temporal regions, respectively, of the right hemisphere

OBJECTIVE: Divergent findings among prior studies on correlates of risk for postictal psychosis (PIP) suggest the value of a controlled study involving a relatively large number of patients. METHODS: The study population consisted of a consecutive series of 59 patients with partial epilepsy and a history of PIP, and 94 control patients with partial epilepsy and no history of PIP evaluated as inpatients with video-electroencephalography. The groups did not differ significantly regarding demographic features. Exact tests yielded a subset of variables and a tentative interpretation that were evaluated further utilizing principal components analysis and logistic regression. RESULTS: PIP was associated with extratemporal versus temporal (p = 0.036) or undetermined (p = 0.001) localization of seizure onset, bilateral interictal epileptiform activity (p = 0.017), secondary generalization (p = 0.049), and history of encephalitis (p = 0.018). Interictal slow activity was more frequently absent in control patients (p = 0.045). PIP was associated with family histories of psychiatric disorders (p = 0.007) and epilepsy (p = 0.042), which themselves were significantly intercorrelated (r = 0.225; p = 0.006). Age of onset or duration of epilepsy and lateralized electroencephalographic or magnetic resonance imaging asymmetries did not differ significantly between control and PIP groups. The analysis indicated four underlying domains of risk for PIP: ambiguous/extratemporal localization, family neuropsychiatric history, abnormal interictal electroencephalographic activity, and encephalitis. Each unit increase on a simple additive scale composed of 9 dichotomous independent variables multiplied the odds ratio for PIP by 1.71 (95% confidence interval, 1.36-2.15; p < 0.0001). INTERPRETATION: PIP in partial epilepsy is associated with relatively broadly and bilaterally distributed epileptogenic networks, genetic determinants of psychiatric disorders and seizures, and encephalitis