Long-term outcome of status epilepticus-related to systemic lupus erythematosus: An observational study and a systematic review.

OBJECTIVES: Status epilepticus-related to systemic lupus erythematosus (SE-SLE) is in general attributed to fulminate neuropsychiatric lupus disease activity, yet the long-term outcome of SE-SLE is not well recognized. This is an observational study of 40 SE-SLE patients pooled from 8 cases at a single tertiary care hospital, and 32 SE-SLE patients identified on a systematic review, with focus on electro-clinical characteristics, imaging studies and the underlying etiology of SE-SLE in correlation with long-term outcome. RESULTS: Clinical phenotypes of SE-SLE were heterogeneous, ranging from patients with aura continua to patients in coma. Convulsive SE-SLE occurred among patients with heightened global lupus disease activity and increased cortical and subcortical brain lesion burden localized mostly in the frontal and temporal regions. There were no specific neuroimaging or laboratory abnormalities that allowed early SE-SLE diagnosis where a cluster of cases were of unclear etiology (17.5%). Most SE-SLE cases evolved to refractory SE-SLE with resistance to multiple anti-seizure medications and intravenous anesthetics requiring aggressive immune therapy that led to resolution of SE-SLE active phase. Seizure freedom occurred in 60.0% of patients and the median time to cessation of SE-SLE seizure activity after aggressive therapy was 14 days. Poor long-term outcomes were apparent in SE-SLE patients with one-year mortality (12.5%), recurrent SE-SLE (25.0%), subsequent epilepsy (37.5.1%), poor functional outcome (55.0%) and cognitive impairment (47.5%). A prolonged time to cessation of SE-SLE seizure activity was associated with unfavorable long-term outcome. CONCLUSIONS: Diagnostic accuracy of SE-SLE requires better understanding of the etio-pathogenesis and the spectrum of clinical presentations of SE-SLE. Prompt initiation of immune therapy improve SE-SLE outcome, yet optimal therapeutic strategies remain to be determined. Identifying novel biomarkers that distinguish between different forms of SE-SLE and target cellular inflammatory response will help with specific SE-SLE treatment guidelines and prevent poor outcome.

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Regulating drivers with epilepsy in Maryland: Results of the application of a United States consensus guideline.

OBJECTIVE: Driving regulations for people with seizures vary widely throughout the United States and the world. Maryland updated their guidelines in 2003 to reflect those of a U.S. consensus guideline requiring a minimum 3-month seizure-free period as well as an individual risk assessment by a Medical Advisory Board (MAB). This retrospective study provides the first analysis of outcomes after the implementation of the consensus guidelines and an assessment of their predictive validity through longitudinal outcome data. METHODS: MAB reviews and licensing records for Maryland driver applicants with seizures between 2004 and 2005 were reviewed, during which 254 first-time applicants were processed. The initial licensing decisions were assessed and the subsequent seizure recurrence and crash rates over the following 7 years were evaluated. RESULTS: The MAB approved driving for 74.8% of initial applicants; most had been seizure-free for over 6 months. Approved drivers had a longer median seizure-free period (563 days) compared to those who were denied (104.5 days, p < 0.01), and 22.7% of approved drivers had seizures recur during monitoring over the next year, although none resulted in crashes or deaths. Of applicants initially denied (n = 50), 89.3% were eventually licensed. Treating physicians recommended driving for 84.4% of applicants rejected by the MAB. SIGNIFICANCE: Maryland's individualized system for assessing driving applicants with seizures resulted in a dynamic process of approvals and denials based on favorable and unfavorable risk factors and lengths of seizure freedom. Seizure recurrences were comparable to internationally accepted rates. Over the course of monitoring, most applicants were eventually licensed. Treating physicians recommended that nearly all their patient applicants be permitted to drive, which raises safety concerns for the 10 states that rely solely on physician recommendations. Further assessment is needed of the risk factors deemed favorable and unfavorable by the U.S. consensus guidelines.

Which patients with epilepsy are at risk for psychogenic nonepileptic seizures (PNES)? A multicenter case-control study.

OBJECTIVE: We sought to examine the clinical and electrographic differences between patients with combined epileptic (ES) and psychogenic nonepileptic seizures (PNES) and age- and gender-matched patients with ES-only and PNES-only. METHODS: Data from 138 patients (105 women [77%]), including 46 with PNES/ES (39±12years), 46 with PNES-only (39±11years), and 46 with ES-only (39±11years), were compared using logistic regression analysis after adjusting for clustering effect. RESULTS: In the cohort with PNES/ES, ES antedated PNES in 28 patients (70%) and occurred simultaneously in 11 (27.5%), while PNES were the initial presentation in only 1 case (2.5%); disease duration was undetermined in 6. Compared with those with ES-only, patients with PNES/ES had higher depression and anxiety scores, shorter-duration electrographic seizures, less ES absence/staring semiology (all p≤0.01), and more ES arising in the right hemisphere, both in isolation and in combination with contralateral brain regions (61% vs. 41%; p=0.024, adjusted for anxiety and depression) and tended to have less ES arising in the left temporal lobe (13% vs. 28%; p=0.054). Compared with those with PNES-only, patients with PNES/ES tended to show fewer right-hemibody PNES events (7% vs. 23%; p=0.054) and more myoclonic semiology (10% vs. 2%; p=0.073). CONCLUSIONS: Right-hemispheric electrographic seizures may be more common among patients with ES who develop comorbid PNES, in agreement with prior neurobiological studies on functional neurological disorders.

Counseling Epilepsy Patients on Driving and Employment.

People with epilepsy identify driving and employment among their major concerns. People with controlled seizures may be permitted to drive in every state in the United States, but people with uncontrolled seizures are restricted from licensure. Unemployment and underemployment for people with epilepsy are serious problems that depend on the frequency and type of seizure disorder and associated medical and psychological problems. Most jobs, with reasonable accommodation by employers, are suitable for people with epilepsy. Federal protections through the Americans with Disabilities Act confer civil rights protection by law on people with disabilities such as epilepsy.

Providing Quality Epilepsy Care for Veterans.

Quality epilepsy care depends on balancing seizure control with medication adverse effects and on understanding a patient's medical history and anxieties related to the illness.

Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard.

OBJECTIVE: To test the current U.S. Food and Drug Administration (FDA) bioequivalence standard in a comparison of generic and brand-name drug pharmacokinetic (PK) performance in "generic-brittle" patients with epilepsy under clinical use conditions. METHODS: This randomized, double-blind, multiple-dose, steady-state, fully replicated bioequivalence study compared generic lamotrigine to brand-name Lamictal in "generic-brittle" patients with epilepsy (n = 34) who were already taking lamotrigine. Patients were repeatedly switched between masked Lamictal and generic lamotrigine. Intensive PK blood sampling at the end of each 2-week treatment period yielded two 12-h PK profiles for brand-name and generic forms for each patient. Steady-state area under the curve (AUC), peak plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) data were subjected to conventional average bioequivalence (ABE) analysis, reference-scaled ABE analysis, and within-subject variability (WSV) comparisons. In addition, generic-versus-brand comparisons in individual patients were performed. Secondary clinical outcomes included seizure frequency and adverse events. RESULTS: Generic demonstrated bioequivalence to brand. The 90% confidence intervals of the mean for steady-state AUC, Cmax , and Cmin for generic-versus-brand were 97.2-101.6%, 98.8-104.5%, and 93.4-101.0%, respectively. The WSV of generic and brand were also similar. Individual patient PK ratios for generic-versus-brand were similar but not identical, in part because brand-versus-brand profiles were not identical, even though subjects were rechallenged with the same product. Few subjects had seizure exacerbations or tolerability issues with product switching. One subject, however, reported 267 focal motor seizures, primarily on generic, although his brand and generic PK profiles were practically identical. SIGNIFICANCE: Some neurologists question whether bioequivalence in healthy volunteers ensures therapeutic equivalence of brand and generic antiepileptic drugs in patients with epilepsy, who may be at increased risk for problems with brand-to-generic switching. Bioequivalence results in "generic-brittle" patients with epilepsy under clinical conditions support the soundness of the FDA bioequivalence standards. Adverse events on generic were not related to the small, allowable PK differences between generic and brand.

Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To provide evidence-based recommendations for treatment of adults with an unprovoked first seizure. METHODS: We defined relevant questions and systematically reviewed published studies according to the American Academy of Neurology's classification of evidence criteria; we based recommendations on evidence level. RESULTS AND RECOMMENDATIONS: Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first 2 years (21%-45%) (Level A), and clinical variables associated with increased risk may include a prior brain insult (Level A), an EEG with epileptiform abnormalities (Level A), a significant brain-imaging abnormality (Level B), and a nocturnal seizure (Level B). Immediate antiepileptic drug (AED) therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first 2 years (Level B) but may not improve quality of life (Level C). Over a longer term (>3 years), immediate AED treatment is unlikely to improve prognosis as measured by sustained seizure remission (Level B). Patients should be advised that risk of AED adverse events (AEs) may range from 7% to 31% (Level B) and that these AEs are likely predominantly mild and reversible. Clinicians' recommendations whether to initiate immediate AED treatment after a first seizure should be based on individualized assessments that weigh the risk of recurrence against the AEs of AED therapy, consider educated patient preferences, and advise that immediate treatment will not improve the long-term prognosis for seizure remission but will reduce seizure risk over the subsequent 2 years.

Neurologic manifestations of sarcoidosis.

Neurologic manifestations occur in more than 5% of sarcoidosis patients and may be the presenting feature. Neurosarcoidosis can manifest in a myriad of ways including: cranial neuropathy, aseptic meningitis, mass lesions, encephalopathy, vasculopathy, seizures, hypothalamic-pituitary disorders, hydrocephalus, myelopathy, peripheral neuropathy, and myopathy. Because its etiology is unknown, its neurological manifestations are so diverse, and its diagnosis cannot be readily confirmed by laboratory tests, neurosarcoidosis poses many clinical problems. The diagnosis of neurosarcoidosis is usually based on the identification of characteristic neurologic findings in an individual with proven systemic sarcoidosis as established by clinical, imaging, or histologic findings. Although corticosteroids are regarded as the foundation of treatment, they are not always successful and have serious side-effects. Moreover, some patients with neurosarcoidosis are refractory to conventional therapy, and approximately 5-10% die. Optimal management of patients with neurosarcoidosis benefits from an understanding of the broad clinical spectrum of neurosarcoidosis, appreciation of the ways to best confirm a diagnosis, and awareness of the full range of treatment options, including the use of alternative therapies such as immunotherapy.

Nonconvulsive status epilepticus: value of a benzodiazepine trial for predicting outcomes.

OBJECTIVES: Managing nonconvulsive status epilepticus (NCSE) poses many challenges that would benefit from additional early measures to predict patient outcomes. Here, we evaluate clinical and electroencephalographic responses to an acute antiepileptic drug trial as an added measure for predicting outcomes in patients presenting with suspected NCSE. METHODS: We analyzed all patients referred to our Neurology Service with suspected NCSE assessed by a standard acute intravenous (IV) benzodiazepine (BDZ) protocol. We correlated patients' clinical and electrographic (EEG) responses to the BDZ trial with their subsequent outcomes, including survival, recovery of consciousness, and functional status at hospital discharge. RESULTS: From 1990 to 2001, we identified 62 patients with NCSE who were initially evaluated with an acute IV BDZ protocol trial. A favorable clinical response with improvement in consciousness was observed in 22 patients (35%), whereas 40 (65%) were clinical nonresponders. All of the positive clinical responders (100%) survived, recovered consciousness, and exhibited good functional outcomes. In contrast, outcomes were significantly poorer (P<0.001) for the clinical nonresponders; only 14 (35%) recovered consciousness and 22 (55%) survived, with 59% of those survivors demonstrating poor functional outcomes. EEG improvement with BDZs also predicted better outcome, but it was less robust than the clinical response, with better subsequent recovery of consciousness (P<0.05), but not functional outcome or survival. CONCLUSIONS: This study demonstrates that a clinical and, to a lesser degree, EEG response to an acute trial of IV BDZs are predictive of subsequent outcome in patients with suspected NCSE, and warrant further consideration and investigation for assessing and managing patients.

Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial.

PURPOSE: To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy. METHODS: Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure. RESULTS: At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047). CONCLUSION: This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

Management issues for women with epilepsy-Focus on pregnancy (an evidence-based review): I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including the risk of pregnancy complications or other medical problems during pregnancy, change in seizure frequency, the risk of status epilepticus, and the rate of remaining seizure-free during pregnancy. The committee evaluated the available evidence according to a structured literature review and classification of relevant articles. For WWE who are taking antiepileptic drugs (AEDs), there is probably no substantially increased risk (>2 times expected) of cesarean delivery or late pregnancy bleeding, and probably no moderately increased risk (>1.5 times expected) of premature contractions or premature labor and delivery. There is possibly a substantially increased risk of premature contractions and premature labor and delivery during pregnancy for WWE who smoke. WWE should be counseled that seizure freedom for at least 9 months prior to pregnancy is probably associated with a high likelihood (84-92%) of remaining seizure-free during pregnancy. WWE who smoke should be counseled that they possibly have a substantially increased risk of premature contractions and premature labor and delivery.