Faculty Bibliography

We report a patient with a seronegative autoimmune panencephalitis, adding a subtype to the emerging spectrum of seronegative autoimmune encephalitis, and we review the sparse literature on isolated psychiatric presentations of autoimmune encephalitis. (A PubMed search for "seronegative autoimmune encephalitis," "nonvasculitic autoimmune inflammatory meningoencephalitis," and related terms revealed <25 cases.) A 15-year-old girl developed an acute-onset isolated psychosis with prominent negative symptoms and intermittent encephalopathy. Despite clinical worsening, her brain magnetic resonance imaging (MRI) scans remained normal for 7 years. Serology was negative for voltage-gated potassium channel (VGKC)-complex, N-methyl-D-aspartate receptor (NMDAR), and glutamic acid decarboxylase (GAD) autoantibodies. We excluded genetic, metabolic, paraneoplastic, degenerative, and infectious etiologies. The patient's symptoms remitted fully with immune therapy, but recurred in association with widespread bihemispheric brain lesions. Brain biopsy revealed mild nonvasculitic inflammation and prominent vascular hyalinization. Immune therapy with plasma exchanges cleared the MRI abnormalities but, 10 years after onset, the patient still suffers neuropsychiatric sequelae. We conclude that autoimmune panencephalitis seronegative for VGKC-complex, NMDAR, and GAD autoantibodies is a subtype of autoimmune encephalitis that can present with pure neuropsychiatric features and a normal brain MRI. Immunologic mechanisms may account for psychiatric symptoms in a subset of patients now diagnosed with classical psychotic disorders. Delay in starting immune therapy can lead to permanent neuropsychiatric sequelae. We propose a standardized classification system for the autoimmune encephalitides, integrating earlier pathology-oriented terms with more recently defined serologic and clinical phenotypes.

Vigabatrin (VGB) has been shown to be particularly effective in the treatment of infantile spasms for those with tuberous sclerosis complex (TSC). However, many patients with TSC continue to have treatment-resistant seizures. For many patients with TSC, partial-onset seizures are prominent. Therefore, we examined the efficacy and tolerability of VGB for treatment of refractory partial-onset seizures. We performed a retrospective cohort study on 49 TSC patients with treatment-resistant seen at our center from 1997 to 2010, examined seizure outcomes, and reported adverse effects. We found that 13 (24.5%) patients became seizure-free or experienced a >90% decrease in seizure episode frequency with the addition of VGB to their regimens. Only one patient stopped VGB use because of excess sedation. The remaining 21 patients discontinued VGB use because of lack of efficacy. We conclude that VGB may be a safe and effective treatment in TSC patients with refractory partial-onset seizures.

BACKGROUND AND PURPOSE:There are few articles characterizing cerebellar lesions in patients with TSC and no published series documenting longitudinal evaluation of these lesions, to our knowledge. Recent suggestion of a correlation between autism and cerebellar lesions in patients with TSC heightens the importance of understanding these lesions. Our purpose was to characterize cerebellar lesions in a cohort of young patients with TSC with specific interest in assessing longitudinal changes.MATERIALS AND METHODS:We retrospectively reviewed MR images from 145 pediatric and young adult patients with tuberous sclerosis (mean age, 7.6 years). A number of imaging characteristics of cerebellar tubers were recorded, and patients were evaluated for SGAs. Patients with follow-up scans >3 months from the original scan were further analyzed for longitudinal tuber characterization.RESULTS:There were 24.1% of patients with focal cerebellar lesions; 52.4% of patients with cerebellar lesions demonstrated change in imaging characteristics during longitudinal analysis. Fifty-one percent of the lesions were enhanced after gadolinium administration. Twenty percent of the patients with cerebellar lesions had pathologically confirmed SGAs compared with the incidence of 11% in the 145 patients with TSC reviewed.CONCLUSIONS:In our large cohort of young patients with TSC, cerebellar tubers were common and 52% of patients had tubers that changed with time. A higher percentage of patients with cerebellar lesions developed SGAs than patients with TSC without cerebellar lesions. Because this is the first reported longitudinal study of cerebellar lesions in TSC, further investigation may provide additional insight into TSC pathology and associated clinical manifestations, such as autism, developmental delay, and seizures.

Object Tuberous sclerosis complex (TSC) brain pathology is characterized on MRI by cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas. Seizures, the prominent feature of TSC, are frequently intractable to medical therapy and, in many patients, resection of tubers results in seizure control. However, in approximately 40% of patients, resection of tubers does not control seizures. This fact, as well as evidence from invasive electrophysiological recordings and experimental animal models, suggests that in patients with TSC, there may be extratuberal epileptogenic brain that does not display any apparent abnormality on conventional MRI. The authors hypothesized that high field strength MRI might uncover lesions not seen on conventional MRI in these patients. Methods Institutional review board approval was obtained to scan 4 patients with TSC (ages 18-26 years) in a 7-T MR unit. Optimized 7-T sequences, including T1- and T2-weighted, FLAIR, SPACE FLAIR, T2*, and MPRAGE studies, were performed. Imaging studies were compared with identical sequences performed using a conventional 1.5-T MR scanner. Results In all 4 patients, there was improved visualization of the findings demonstrated on conventional imaging. Importantly, new lesions were detected in all 4 patients, which were not well visualized with conventional MRI. Newly detected lesions included microtubers, radial glial signal abnormalities, subependymal nodules arising from the caudate nucleus, and caudate nucleus lesions. Conclusions High field strength MRI detects previously uncharacterized lesions in patients with TSC and allows better detection and delineation of subtle abnormalities. In addition, the data demonstrate a compelling relationship between intraventricular lesions and the caudate nucleus. These data support previous electrophysiological and animal-model findings that demonstrate neurological pathology beyond the conventionally detected lesions in TSC.

Epilepsy is characterized by recurrent spontaneous seizures due to hyperexcitability and hypersynchrony of brain neurons. Current theories of pathophysiology stress neuronal dysfunction and damage, and aberrant connections as relevant factors. Most antiepileptic drugs target neuronal mechanisms. However, nearly one-third of patients have seizures that are refractory to available medications; a deeper understanding of mechanisms may be required to conceive more effective therapies. Recent studies point to a significant contribution by non-neuronal cells, the glia - especially astrocytes and microglia - in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability and inflammation in epilepsy.

OBJECTIVE: To measure the volume of basal forebrain septal nuclei in patients with temporal lobe epilepsy (TLE) as compared to patients with extratemporal epilepsy and controls. In animal models of TLE, septal lesions facilitate epileptogenesis, while septal stimulation is antiepileptic. METHOD: Subjects were recruited from 2 sites and consisted of patients with pharmacoresistant focal epilepsy (20 with TLE and mesial temporal sclerosis [MTS], 24 with TLE without MTS, 23 with extratemporal epilepsy) and 114 controls. Septal volume was measured using high-resolution MRI in association with newly developed probabilistic septal nuclei maps. Septal volume was compared between subject groups while controlling for relevant factors. RESULTS: Patients with TLE without MTS had significantly larger septal nuclei than patients with extratemporal epilepsy and controls. This was not true for patients with MTS. These results are interpreted with reference to prior studies demonstrating expansion of the septo-hippocampal cholinergic system in animal models of TLE and human TLE surgical specimens. CONCLUSION: Septal nuclei are enlarged in patients with TLE without MTS. Further investigation of septal nuclei and antiepileptic septo-hippocampal neurocircuitry could be relevant to development of new therapeutic interventions such as septal stimulation for refractory TLE.

Hemispheric asymmetry represents a cardinal feature of cerebral organization, but the nature of structural and functional differences between the hemispheres is far from fully understood. Using Magnetic Resonance Imaging morphometry, we identified several volumetric differences between the two hemispheres of the human brain. Heteromodal inferoparietal and lateral prefrontal cortices are more extensive in the right than left hemisphere, as is visual cortex. Heteromodal mesial and orbital prefrontal and cingulate cortices are more extensive in the left than right hemisphere, as are somatosensory, parts of motor, and auditory cortices. Thus, heteromodal association cortices are more extensively represented on the lateral aspect of the right than in the left hemisphere, and modality-specific cortices are more extensively represented on the lateral aspect of the left than in the right hemisphere. On the mesial aspect heteromodal association cortices are more extensively represented in the left than right hemisphere

BACKGROUND AND PURPOSE: Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS: A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS: PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient's seizure focus as identified by ictal and interictal 18F-fluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS: PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci. J Neuroimaging 2011;XX:1-3

The current study examined whether mood-congruent biases in emotion processing extend to epilepsy patients with depressive symptoms and the potentially moderating effects of age of seizure onset on these biases. In addition, we examined associations between depression (Beck Depression Inventory - 2nd Edition; BDI-II) and quality of life (Quality of Life in Epilepsy - 10-item questionnaire; QOLIE-10). Data from 101 epilepsy patients were analyzed, including 61 females and 40 males. Measures included the Comprehensive Affect Testing System - Abbreviated (CATS-A), from which indices of mood-congruent bias were derived. A significant interaction between BDI-II raw scores and age of seizure onset was found for mood-congruent bias scores in the facial affect modality (beta=-0.24, p<.03). Beck Depression Inventory - 2nd Edition raw scores were significantly and positively correlated with quality of life (QOLIE-10; r=.69, p<.01). Results of the current study show that epilepsy patients with an early age of seizure onset may be most at risk for mood-congruent biases when experiencing depressive symptoms and that such symptoms have real-world implications for quality of life for persons living with epilepsy.

Despite decades of cognitive, neuropsychological and neuroimaging studies, it is unclear if letters are identified before word-form encoding during reading, or if letters and their combinations are encoded simultaneously and interactively. Here using functional magnetic resonance imaging, we show that a 'letter-form' area (responding more to consonant strings than false fonts) can be distinguished from an immediately anterior 'visual word-form area' in ventral occipito-temporal cortex (responding more to words than consonant strings). Letter-selective magnetoencephalographic responses begin in the letter-form area approximately 60 ms earlier than word-selective responses in the word-form area. Local field potentials confirm the latency and location of letter-selective responses. This area shows increased high-gamma power for approximately 400 ms, and strong phase-locking with more anterior areas supporting lexico-semantic processing. These findings suggest that during reading, visual stimuli are first encoded as letters before their combinations are encoded as words. Activity then rapidly spreads anteriorly, and the entire network is engaged in sustained integrative processing.