Long-Term Effects of Antiseizure Medications.

Most patients with epilepsy will benefit from seizure control with one of an array of chronic antiseizure medications. Knowledge of the potential long-term effects of these medications is critical to prevent adverse consequences on overall health. Antiseizure medications vary in their capacities to affect the brain and peripheral nerves, hormones, bone mineralization, cardiovascular risk, renal health, hepatic, hematological, and dermatological systems. Understanding of pathophysiology and population risk has evolved, although most of the data available are still on older generation antiseizure medications such as phenytoin, carbamazepine, and valproic acid. The enzyme-inducing properties of some antiseizure medications make their effects on cardiovascular risk and bone health detrimental. Few clear guidelines exist for monitoring long-term effects of medication therapy for epilepsy. When selecting an antiseizure medication, consideration should be given to the individual patient's risks of adverse consequences on other organ systems. During monitoring of patients on chronic therapy, screening tools such as metabolic panels and bone density measurements can help stratify risk and guide management.

Paraneoplastic limbic encephalitis following treatment with single-agent pembrolizumab for advanced gastroesophageal adenocarcinoma.

The use of immune checkpoint inhibitors is increasing in clinical practice. While they have provided significant benefit to many patients, a new category of adverse effects, immune-related adverse effects, has emerged with their use. These effects can range from mild to severe and affect nearly every organ system. A man in his 70swith metastatic gastro-oesophageal junction adenocarcinoma who received one cycle of third-line pembrolizumab presented after three episodes of transient left facial paresthesia, the last of which extended to the left extremities and disturbed peripheral vision of the left eye. He was found to have subclinical seizures and cerebrospinal fluid positive for Ma2/Ta paraneoplastic antibodies, consistent with paraneoplastic limbic encephalitis. We describe an unusual presentation of paraneoplastic limbic encephalitis. This case adds to the limited literature describing the association of paraneoplastic limbic encephalitis and treatment with immune checkpoint inhibitors as well as the observed associations with immune-related adverse events and treatment responses.

Impact of carbamazepine on vitamin D levels: A meta-analysis.

PURPOSE: There are longstanding concerns about the impact of enzyme-inducing anti-seizure medications (ASMs) on vitamin D, an important molecule in both bone metabolism and inflammation pathways. The relationship between chronic use of carbamazepine and vitamin D levels has been studied, but no comprehensive review to inform practitioners and policymakers is currently available. We performed a meta-analysis on studies that measured 25-hydroxyvitamin D (25OHD) levels in persons taking carbamazepine to determine whether this drug significantly reduces circulating 25OHD. PRINCIPAL RESULTS: From a literature search of the terms "carbamazepine" and "vitamin D", we identified 12 studies that measured 25OHD levels in persons on carbamazepine monotherapy groups and controls. Persons taking carbamazepine had significantly lower 25OHD levels than persons not taking carbamazepine. The average 25OHD levels of carbamazepine-treated patients across all studies was 21.8 ng/mL (IQR 15.4,26.0) whereas 25OHD levels of control subjects was 28.0 ng/mL (IQR 20.8,30.4). The weighted difference of means was 4.00 ng/mL of 25OHD. Neither age nor sex nor duration of carbamazepine therapy had a significant impact on this finding. The effect was similar irrespective of whether the comparator group consisted of healthy controls or epilepsy patients taking non-inducing medications. MAJOR CONCLUSIONS: Carbamazepine use is associated with a reduction of 25OHD levels. In combination with other literature establishing the problematic metabolic effects of carbamazepine, this meta-analysis provides additional evidence in favor of the use of alternative ASMs as first-line agents. At minimum, vitamin D supplementation should be strongly considered for patients prescribed carbamazepine.

Clinical features and postoperative seizure outcome in patients with drug-resistant gelastic seizures without hypothalamic hamartoma.

OBJECTIVES: The objective of this study was to describe the clinical characteristics and surgical outcome in patients with gelastic seizures without hypothalamic hamartoma. METHODS: We retrospectively reviewed all the video-EEG reports over a 5-year period (2007-2011) for the occurrence of the terms "laugh" or "giggle" in the text body. All the patients with at least one documented gelastic seizure at the epilepsy monitoring unit were studied. In patients who underwent epilepsy surgery, seizure outcomes were analyzed. RESULTS: Sixteen patients (10 females and 6 males) with a mean age of 46.3years were studied. Seven patients had invasive intracranial EEG recordings. Seizure onset zone was in a temporal lobe in four patients and the frontal lobe in one patient. Two patients did not have gelastic seizures during their intracranial EEG monitoring. Nine patients underwent resective epilepsy surgery for their seizures. Six patients (67%) were seizure-free after surgery. CONCLUSION: In adult patients, gelastic seizures can be seen in patients with focal epilepsy without hypothalamic hamartoma. Nonhypothalamic hamartoma gelastic seizures originating from the temporal lobe can be amenable to surgery.

Autoimmune status epilepticus.

OPINION STATEMENT: Autoimmune status epilepticus is a rare condition but one that has been increasingly recognized by neurologists and clinicians in the intensive care unit. As more cases are described in the literature and more antibody tests become commercially available, diagnosis is now feasible; however, early diagnosis remains a challenge. For practical purposes, status epilepticus may be considered as possibly autoimmune if it is refractory to anticonvulsant treatment and there is no other known cause; this may then lead to empiric immunomodulatory therapy. Major factors that raise the index of suspicion are recent cognitive or behavioral alterations, a history of malignancy or tumor, or presence of other neurological features. There is a lack of high level evidence in the literature for treatment of status epilepticus, and almost none for autoimmune encephalitis. Patients with autoimmune status epilepticus may be treated with immunomodulatory therapy, including steroids, intravenous immunoglobulin (IVIG), plasmapheresis (PLEX), and other immunosuppressive agents while maximizing their anticonvulsant therapy. For some patients, resective surgery may be necessary, such as hemispherectomy for Rasmussen's encephalopathy. In the case of status epilepticus due to paraneoplastic autoantibodies, urgent and aggressive testing and treatment of a primary malignancy is needed. Importantly, any suspicion of autoimmune mediated status epilepticus should prompt the transfer of the patient to a specialized center with experience in refractory status epilepticus whenever possible.

Cerebral venous sinus thrombosis secondary to typhoid fever: a case report and brief summary of the literature.

BACKGROUND: There have been few reports of typhoid fever (or salmonellosis) presenting with cerebral venous sinus thrombosis. We present such a case to highlight the importance of recognizing an etiology for cerebral sinus thrombosis and to discuss the role of salmonella in thrombogenesis. PATIENT: A 19-year-old man with a history of migraine presented with headache, nausea, vomiting, and fever, and was found to have a cerebral venous sinus thrombosis on magnetic resonance venography. He later developed profuse watery diarrhea and cultures grew salmonella species, consistent with typhoid fever. RESULTS: Treatment with antibiotics and oral anticoagulation led to resolution of his symptoms within 2 days and recanalization of the thrombosis was proven on magnetic resonance venography 6 months later. CONCLUSIONS: The development of profuse diarrhea after thrombosis suggests a direct thrombogenic effect of salmonella independent of dehydration. Systemic infections should be considered in all patients with thrombosis to identify treatable causes.

Surgical outcome in PET-positive, MRI-negative patients with temporal lobe epilepsy.

PURPOSE: Fluorodeoxyglucose positron emission computed tomography (FDG-PET) hypometabolism is important for surgical planning in patients with temporal lobe epilepsy (TLE), but its significance remains unclear in patients who do not have evidence of mesial temporal sclerosis (MTS) on magnetic resonance imaging (MRI). We examined surgical outcomes in a group of PET-positive, MRI-negative patients and compared them with those of patients with MTS. METHODS: We queried the Thomas Jefferson University Surgical Epilepsy Database for patients who underwent anterior temporal lobectomy (ATL) from 1991 to 2009 and who had unilateral temporal PET hypometabolism without an epileptogenic lesion on MRI (PET+/MRI-). We compared this group to the group of patients who underwent ATL and who had MTS on MRI. Patients with discordant ictal electroencephalography (EEG) were excluded. Surgical outcomes were compared using percentages of Engel class I outcomes at 2 and 5 years as well as Kaplan-Meier survival statistic, with time to seizure recurrence as survival time. A subgroup of PET+/MRI- patients who underwent surgical implantation prior to resection was compared to PET+/MRI- patients who went directly to resection without implantation. KEY FINDINGS: There were 46 PET+/MRI- patients (of whom 36 had 2-year surgical outcome available) and 147 MTS patients. There was no difference between the two groups with regard to history of febrile convulsions, generalized tonic-clonic seizures, interictal spikes, depression, or family history. Mean age at first seizure was higher in PET+/MRI- patients (19 ± 13 vs.14 ± 13 years, Mann-Whitney test, p = 0.008) and disease duration was shorter (14 ± 10 vs. 22 ± 13 years, student's t-test, p = 0.0006). Class I surgical outcomes did not differ significantly between the PET+/MRI- patients and the MTS group (2 and 5 year outcomes were 76% and 75% for the PET+/MRI- group, and 71% and 78% for the MTS group); neither did outcomes of the PET+/MRI- patients who were implanted prior to resection versus those who went directly to surgery (implanted patients had 71% and 67% class I outcomes at 2 and 5 years, whereas. nonimplanted patients had 77% and 78% class I outcomes, p = 0.66 and 0.28). Kaplan-Meier survival statistics for both comparisons were nonsignificant at 5 years. Dentate gyrus and hilar cell counts obtained from pathology for a sample of patients also did not differ between groups. SIGNIFICANCE: PET-positive, MRI-negative TLE patients in our study had excellent surgical outcomes after ATL, very similar to those in patients with MTS, regardless of whether or not they undergo intracranial monitoring. These patients should be considered prime candidates for ATL, and intracranial monitoring is probably unnecessary in the absence of discordant data.

Antiepileptic drugs and markers of vascular risk.

OPINION STATEMENT: The most-used treatments for epilepsy worldwide are older-generation drugs such as phenytoin, carbamazepine, phenobarbital, and valproic acid, which have prominent enzymatic effects. Our sense of comfort with these treatments is starting to fade, however, as more and more potential long-term consequences of these drugs come to light. Epidemiologic studies demonstrate that ischemic disease of the heart and brain is more common among patients with epilepsy. Enzyme-inducing drugs are associated with elevations in a host of surrogate markers of vascular risk, suggesting that they could be responsible for increased rates of cardiovascular and cerebrovascular disease. The enzyme-inhibiting drug valproate may have adverse consequences of its own pertaining to glucose and lipid metabolism. These effects stand in addition to those well established in the literature regarding bone metabolism, hormonal abnormalities, and drug-drug interactions. Because patients with epilepsy require medication for years, and often for life, it is difficult to justify the long-term use of these agents when there are capable alternatives. Many of the adverse effects of the older drugs appear to be rapidly reversible, prompting consideration of whether patients who are currently treated with these agents should be switched to alternative therapies, even in the absence of obvious side effects. Newer medications without effects on hepatic enzymes likely do not have these chronic metabolic consequences, and we recommend their use over older-generation drugs whenever possible.