Patients undergo video-EEG monitoring to determine seizure type and focus localization. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are used to study cerebral metabolism, blood flow, binding of neurtransmitter receptors, and structure. Antiepileptic drug blood levels are obtained. Studies are performed in collaboration with NIMH and the NIH Clinical Center PET Department. We perform PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (11C-DASB), for serotonin transporter activity estimation, and PET with FCWAY for 5HT1A receptor visualization. We perform structural MRI for partial volume correction of PET data. We perform PET with fluorodeoxyglucose in order to study the relation cerebral glucose metabolism to depression in epilepsy, and characterize the degree of hippocampal dysfunction. We expect to find reduced 5HT1A receptor binding and reduced transport after partial volume correction, whether or not hypometabolism or hippocampal structural changes are present. We plan to study four subject groups: healthy controls;TLE patients with depression;TLE patients without depression;generalized epilepsy patients without depression. Inclusion of patients with generalized epilepsy will help us to isolate any effect of the seizure disorder itself, in the absence of a temporal lobe focus or depression, on serotonergic neurotransmission in people with epilepsy. We are not planning to study patients with generalized epilepsy and depression, as the incidence of the latter is expected to be lower in this epilepsy syndrome. The diagnosis of depression will be based on the Research Version of the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) including the detailed assessment of the course of both epilepsy and depressive symptoms, as well as the family history of medical and psychiatric conditions, as well as the BDI. This study will test the following hypotheses: 1: 5HTT concentration, as measured by 11C-DASB specific binding, is significantly reduced in TLE patients compared to normal controls in mesial temporal structures, thalamus, striatum and raphe;this is not an artifact of brain atrophy. 2: Reduction of 18F-FCWAY and 11C-DASB specific binding will be greater in TLE patients with concurrent depression (or history of major depressive disorder) than in patients without concomitant depression (or history of depressive disorders). 3: Reductions of 18F-FCWAY specific binding will be greater than 11C-DASB in cortical ROIs, suggesting that reduced post-synaptic, rather than pre-synaptic, serotonergic function plays a greater role for development of depression. The laboratory of Dr David Goldman performed genotyping for the 5HT transporter gene some of our previous patients. There were strong trends for subjects with the SS or SL allele to have a higher BDI, and also to have mesial temporal sclerosis on MRI scan. At present the data are too limited to draw strong conclusions, but provide additional support for the role of serotonergic mechanisms in the etiology of depression in epilepsy, and possibly in the development of MTS. We are planning a a randomized blinded cross-over design of SGS-742 versus placebo in up to 12 patients age 12 years and older with SSADH deficiency. The study will be carried out in collaboration with Dr Philip Pearl of CNMC, and Dr Mike Gibson of Children's Hospital Pittsburgh. SGS-742 is a GABABR antagonist that has demonstrated good safety and tolerability in clinical trials of cognitive impairment. In a phase II double-blind, placebo-controlled study in 110 patients with mild cognitive impairment, oral administration of SGS-742 (600 mg t.i.d. for 8 weeks) significantly improved attention, reaction time, visual information processing, and working memory. Additionally, pre-treatment with SGS-742 antagonized GHB-induced effects on behavior and motor function in baboons. Since GHB has agonist GABAB effects, this effect of SGS-742 may also be contributory in SSADH deficient patients who have markedly elevated levels of both GABA and GHB. Our study will use neurological and neuropsychiatric evaluations, TMS and PET/MRI as biomarkers. We predict that patients will show: 1) improvement in the areas of attention, reaction time, visual information handling, and working memory, and 2) improvement in baseline abnormalities in cortical silent period and long-interval intracortical inhibition as measured by TMS. The trial will be carried out in collaboration with DR Philip Pearl of CNMC, who will ascertain and screen patients, drawing from the database maintained at Childrens Hospital, and Dr K Michael Gibson of the University of Pittsburgh. Screening may be performed at the NIH Clinical Center or at CNMC Washington DC. The study itself, including TMS, imaging, and clinical aspects, will be performed at the NIH Clinical Center. Additional parallel studies in the SSADH Aldh5a1-/- mouse model will be carried out by Dr Gibson. Previous work by Dr Gibson has shown improvement in baseline abnormalities in GABAB receptor (GABABR) binding, electrophysiology and structure in Aldh5a1-/- mice following application of SGS-742. SGS-742 led to a dose-dependent improvement in ECoG tracings, and significantly reduced spike-wave discharge (SWD) duration. The GABABR is the pharmacological target of SGS-742. Alterations of GABABR structure/function have been documented in, both prior to, and after, the onset of lethal status epilepticus (Wu et al 2006;Buzzi et al 2006). The inclusion criteria will be persistent -hydroxybutyric aciduria, documented succinic semialdehyde dehydrogenase enzyme deficiency and/or molecular analysis showing a mutation in the Aldh5a1gene, and parents or guardians available as contact persons. Patients already receiving drugs with GABAergic effects will not be included. At baseline, neurological examination, neuropsychological evaluation, TMS, and FMZ-PET with co-registered MRI will be performed. Patients will be are randomized into a six month trial of treatment versus placebo. Following a two-month washout period, patients will enter the other treatment arm. Patients and examining physicians will be blinded as to the treatment arm in which the patient is enrolled. At 2 months and 6 months of treatment, and at the start of the second six-month arm, patients receive repeat neurological and neuropsychological evaluations, and repeat TMS. PET will be done at the conclusion of each six month treatment phase. Studying a new treatment option in a yet untreatable disorder indicates that this research study has enormous potential benefit to SSADH-deficient patients and may provide a model for approaches to similar disorders. Evidence of SGS-742 efficacy in human or murine Aldh5a1 deficiency will provide insight into underlying pathophysiology and further rationale for expanded clinical intervention. This study has more general relevance for epilepsy. The neuropsychological and psychiatric symptoms of people with SSADH deficiency mirror in more severe form cognitive and behavioral co-morbidities of patients with other epilepsy syndromes. Studying GABAergic neurotransmission in this syndrome may provide more generalizable data. Moreover, we will be able to test the effect of modulatory intervention on clinical, neurophysiologic, and imaging parameters.
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| Weidner, Lora D; Kannan, Pavitra; Mitsios, Nicholas et al. (2018) The expression of inflammatory markers and their potential influence on efflux transporters in drug-resistant mesial temporal lobe epilepsy tissue. Epilepsia 59:1507-1517 |
| Ferastraoaru, Victor; Goldenholz, Daniel M; Chiang, Sharon et al. (2018) Characteristics of large patient-reported outcomes: Where can one million seizures get us? Epilepsia Open 3:364-373 |
| Hodges, Sarah; Goldenholz, Daniel M; Sato, Susumu et al. (2018) Postoperative EEG association with seizure recurrence: Analysis of the NIH epilepsy surgery database. Epilepsia Open 3:109-112 |
| Holtkamp, Martin; Theodore, William H (2018) Generic antiepileptic drugs-Safe or harmful in patients with epilepsy? Epilepsia 59:1273-1281 |
| Goldenholz, Daniel M; Rakesh, Kshitiz; Kapur, Kush et al. (2018) Different as night and day: Patterns of isolated seizures, clusters, and status epilepticus. Epilepsia 59:e73-e77 |
| Goldenholz, Daniel M; Goldenholz, Shira R; Krishnamurthy, Kaarkuzhali B et al. (2018) Using mobile location data in biomedical research while preserving privacy. J Am Med Inform Assoc : |
| Goldenholz, Daniel M; Strashny, Alex; Cook, Mark et al. (2017) A multi-dataset time-reversal approach to clinical trial placebo response and the relationship to natural variability in epilepsy. Seizure 53:31-36 |
| Austermuehle, Alison; Cocjin, John; Reynolds, Richard et al. (2017) Language functional MRI and direct cortical stimulation in epilepsy preoperative planning. Ann Neurol 81:526-537 |
| Koepp, Matthias J; Årstad, Eric; Bankstahl, Jens P et al. (2017) Neuroinflammation imaging markers for epileptogenesis. Epilepsia 58 Suppl 3:11-19 |
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