First seizure from sleep: Clinical features and prognosis.

OBJECTIVES: Patients with a first-ever unprovoked seizure commonly have subsequent seizures and identifying predictors of recurrence has important management implications. Both prior brain insult and epileptiform abnormalities on electroencephalography (EEG) are established predictors of seizure recurrence. Some studies suggest that a first-ever seizure from sleep has a higher likelihood of recurrence. However, with relatively small numbers and inconsistent definitions, more data are required. METHODS: Prospective cohort study of adults with first-ever unprovoked seizure seen by a hospital-based first seizure service between 2000 and 2015. Clinical features and outcomes of first-ever seizure from sleep and while awake were compared. RESULTS: First-ever unprovoked seizure occurred during sleep in 298 of 1312 patients (23%), in whom the 1-year cumulative risk of recurrence was 56.9% (95% confidence interval [CI] 51.3-62.6) compared to 44.2% (95% CI 41.1-47.3, p < .0001) for patients with first-ever seizure while awake. First-ever seizure from sleep was an independent predictor of seizure recurrence, with a hazard ratio [HR] of 1.44 (95% CI 1.23-1.69), similar to epileptiform abnormalities on EEG (HR 1.48, 95% CI 1.24-1.76) and remote symptomatic etiology (HR 1.47, 95% CI 1.27-1.71). HR for recurrence in patients without either epileptiform abnormalities or remote symptomatic etiology was 1.97 (95% CI 1.60-2.44) for a sleep seizure compared to an awake seizure. For first seizure from sleep, 76% of second seizures also arose from sleep (p < .0001), with 65% of third seizures (p < .0001) also from sleep. Seizures from sleep were less likely to be associated with injury other than orolingual trauma, both with the presenting seizure (9.4% vs 30.6%, p < .0001) and first recurrence (7.5% vs 16.3%, p = .001). SIGNIFICANCE: First-ever unprovoked seizures from sleep are more likely to recur, independent of other risk factors, with recurrences also usually from sleep, and with a lower risk of seizure-related injury. These findings may inform treatment decisions and counseling after first-ever seizure.

Mortality after a first-ever unprovoked seizure.

OBJECTIVE: Although increased mortality associated with epilepsy is well understood, data in patients after their first-ever seizure are limited. We aimed to assess mortality after a first-ever unprovoked seizure and identify causes of death (CODs) and risk factors. METHODS: A prospective cohort study was undertaken of patients with first-ever unprovoked seizure between 1999 and 2015 in Western Australia. Two age-, gender-, and calendar year-matched local controls were obtained for each patient. Mortality data, including COD, based on International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes, were obtained. Final analysis was performed in January 2022. RESULTS: One thousand two hundred seventy-eight patients with a first-ever unprovoked seizure were compared to 2556 controls. Mean follow-up was 7.3 years (range = .1-20). Overall hazard ratio (HR) for death after a first unprovoked seizure compared to controls was 3.06 (95% confidence interval [CI] = 2.48-3.79), with HRs of 3.30 (95% CI = 2.26-4.82) for those without seizure recurrence and 3.21 (95% CI = 2.47-4.16) after a second seizure. Mortality was also increased in patients with normal imaging and no identified cause (HR = 2.50, 95% CI = 1.82-3.42). Multivariate predictors of mortality were increasing age, remote symptomatic causes, first seizure presentation with seizure cluster or status epilepticus, neurological disability, and antidepressant use at time of first seizure. Seizure recurrence did not influence mortality rate. The commonest CODs were neurological, most relating to the underlying cause of seizures rather than being seizure-related. Substance overdoses and suicide were more frequent CODs in patients compared to controls and were commoner than seizure-related deaths. SIGNIFICANCE: Mortality is increased two- to threefold after a first-ever unprovoked seizure, independent of seizure recurrence, and is not only attributable to the underlying neurological etiology. The greater likelihood of deaths related to substance overdose and suicide highlights the importance of assessing psychiatric comorbidity and substance use in patients with first-ever unprovoked seizure.

Amphetamine-associated seizures: clinical features and prognosis.

Forty-four patients presenting with first-ever seizure within 24 h of illicit use of amphetamine or related analogs (amphetamine-associated seizures, AAS) were identified over 8 years. Patients with AAS were compared to control groups of other first-ever seizure patients (provoked n = 126 and unprovoked n = 401). Cumulative probability of recurrence was calculated using Kaplan-Meier analysis. Seizure recurrence and development of epilepsy were less likely in patients with AAS compared to provoked or unprovoked controls. Forty percent of patients with AAS had clinical risk factors for epilepsy, epileptiform abnormalities on electroencephalography (EEG), or an epileptogenic lesion on neuroimaging. Sleep deprivation was more frequently present in those with AAS. AAS likely relate to an intrinsic proconvulsant effect of these drugs combined with patient susceptibility and environmental factors.

Baclofen Neurotoxicity: A Metabolic Encephalopathy Susceptible to Exacerbation by Benzodiazepine Therapy.

PURPOSE: Baclofen has been reported to cause both a metabolic encephalopathy and nonconvulsive status epilepticus. Baclofen is typically used in the management of muscle spasticity but is being increasingly used to manage alcohol withdrawal and opiate dependency. Given the increasing use of baclofen we describe the clinical and electrographical features of baclofen neurotoxicity seen at our institution. METHODS: The clinical and EEG features of patients with an encephalopathy in the setting of baclofen therapy were analyzed. Patients were identified via our hospital EEG database. RESULTS: Fourteen patients were identified having presented with an acute confusional state without identifiable cause other than baclofen use. Five patients took a deliberate overdose, three of whom were baclofen naive, two patients presented after medication prescription error, and seven patients were on stable doses (30-140 mg daily). All patients presented with an encephalopathy, one patient was reported to have clinical seizures, and seven had multifocal myoclonus. EEGs were abnormal in all patients and showed moderate to severe generalized slowing. Generalized triphasic waves occurring at 1 to 2 Hz, sometimes with an anterior to posterior phase lag, were present in 10 patients (71%), and intermittent generalized suppression of the background was seen in three patients. Three patients received small doses of intravenous benzodiazepines, resulting in a marked depression of consciousness and respiration. All patients recovered within 48 hours of baclofen discontinuation. CONCLUSIONS: Baclofen toxicity can produce an acute encephalopathy even at modest doses, with the EEG showing generalized slowing and triphasic waves consistent with a toxic encephalopathy. Management consists of supportive care and cessation of baclofen. Patients with baclofen neurotoxicity exhibit a marked vulnerability to the depressant effects of benzodiazepines.

Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus?

Metabolic encephalopathy and Non-Convulsive Status Epilepticus (NCSE) have been reported with cephalosporin use, particularly cefepime. We aimed to analyze the clinical and EEG findings in patients with cephalosporin-related neurotoxicity (CRN) at our hospital identified via the hospital EEG database, and to critically review CRN case reports in the literature. A Medline search was performed to identify CRN cases where a representative sample of EEG was provided. EEGs were analyzed using published criteria differentiating NCSE from triphasic waves (TW). Eleven patients at our hospital were identified with CRN (9 cefepime, 2 ceftriaxone): all had an encephalopathy with decreased consciousness and/or confusion. One patient had clinical seizures and 6 had multifocal myoclonus. All patients had abnormal EEGs, all with moderate to severe generalized slowing and 10 also with TW. Recovery was related to cephalosporin withdrawal rather than antiepileptic therapy. Analysis of 37 EEG samples of CRN patients reported in the literature as NCSE (30) or TW (7) revealed that most did not meet criteria for NCSE, with 33 showing TW, 1 showing generalised epileptiform discharges and 3 being uninterpretable. CRN usually produces a toxic encephalopathy rather than NCSE, and is commonly associated with triphasic waves on EEG. In most patients anti-epileptic and/or sedative drugs do not hasten clinical improvement.

Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy.

PURPOSE: Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). METHOD: In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. RESULTS: While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p=0.09), LICF was reduced compared to controls (controls: 141±17% of baseline; untreated patients: 107±12%, p=0.2; treated patients: 79±10%, p=0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56±4% of baseline vs. 26±6% in controls, p=0.004) and normalised with treatment (37±12%, p=0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120±10% of baseline, p=0.017), but not in treated patients. CONCLUSION: Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.

Clinical, magnetic resonance imaging, and electroencephalographic findings in paraneoplastic limbic encephalitis.

OBJECTIVE: To analyze clinical presentation of and paraclinical test abnormalities in patients with paraneoplastic limbic encephalitis (PLE). PATIENTS AND METHODS: We retrospectively reviewed 24 patients seen at the Mayo Clinic in Rochester, Minn, between 1985 and 2002 in whom PLE was suspected. Patients were identified on the basis of clinical history and presence of cancer. Data were reviewed from magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), and paraneoplastic serologic studies. RESULTS: Common manifestations were cognitive dysfunction (92%), seizures (58%), and psychiatric symptoms (50%); 13 patients had small cell lung carcinoma; 11 had other malignancies. Paraneoplastic neuronal autoantibodies were found in 14 (64%) of 22 patients tested. Electroencephalography showed focal or generalized slowing and/or epileptiform activity, maximal in the temporal regions, in all 22 patients tested. Magnetic resonance imaging revealed increased T2 signal involving one or both temporal lobes in 15 (83%) of 18 patients. Cerebrospinal fluid test results were abnormal in 18 (78%) of 23 patients tested. Clinical or radiographic evidence of extralimbic involvement was documented in 12 (55%) of 22 patients. No abnormality on EEG, MRI, or CSF analysis correlated with a specific cancer type or with a specific paraneoplastic autoantibody. CONCLUSIONS: In patients with suspected PLE, EEG is invaluable for confirming cerebral dysfunction. Magnetic resonance imaging can show unequivocal involvement of temporolimbic structures and helps exclude other diagnoses. When EEG and cranial MRI are both normal, PLE is unlikely. Comprehensive testing for paraneoplastic neuronal nuclear, cytoplasmic, and ion channel autoantibodies is an important part of the evaluation, but negative results do not rule out PLE.

Ictal single-photon emission computed tomography imaging in extra temporal lobe epilepsy using statistical parametric mapping.

PURPOSE: To examine the application of statistical parametric mapping (SPM) to analyze ictal single-photon emission computed tomography (SPECT) scans in surgical candidates with extratemporal lobe epilepsy. METHODS: The authors selected patients who underwent successful ictal SPECT acquisition in the process of surgical treatment of intractable partial epilepsy. Thirteen patients were identified who met inclusion criteria for confident seizure localization from either intracranial electroencephalogram recordings or epilepsy surgery outcome. In these cases, ictal scans were registered to an in-house-developed normal SPECT atlas composed of 14 spatially normalized brains of normal subjects. SPM96 was used to test on a voxel-by-voxel basis for statistically significant increases in blood flow associated with each patient's ictal scan. The results were then mapped back onto the patient's magnetic resonance image (MRI) for final interpretation. Statistical parametric mapping (SPM) analysis of ictal SPECT scans was compared to both conventional visual interpretation and the analysis of subtraction ictal SPECT co-registered to MRI (SISCOM). RESULTS: Ten of 13 patient scans showed localizing focal ictal increases in regional cerebral blood flow, all of which were concordant with ultimate epilepsy localization. Of the 3 cases not localized with SPM, 1 was localized by conventional visual interpretation and another, not localized by visual interpretation, was correctly localized with SISCOM. Two cases not localized by SISCOM were localized by both visual and SPM analysis. CONCLUSIONS: This work provides supportive evidence for proof of principle that SPM can be used to provide objective, accurate analysis of ictal SPECT scans in patients with extratemporal lobe epilepsy.

Progress in clinical neurosciences: Status epilepticus: a critical review of management options.

Although generalized tonic-clonic status epilepticus (SE) is frequently seen, an evidence-based approach to management is limited by a lack of randomized clinical studies. Clinical practice, therefore, relies on a combination of expert recommendations, local hospital guidelines and dogma based on individual preference and past successes. This review explores selected and controversial aspects of SE in adults and provides a critical appraisal of currently recommended management strategies.

First seizure presentation: do multiple seizures within 24 hours predict recurrence?

We compared clinical features and prognosis of 72 adults with a first-ever seizure presentation comprising multiple discrete seizures within 24 hours to 425 patients presenting with a single seizure. Those presenting with multiple seizures were no more likely to have seizure recurrence, irrespective of etiology or treatment. Hence, a presentation with multiple seizures within 24 hours should be regarded as a single event, in keeping with the International League Against Epilepsy recommendations.

Ictal SPECT analysis in epilepsy: subtraction and statistical parametric mapping techniques.

Seizures are associated with an increase in regional cerebral blood flow (rCBF). In partial seizures the increased blood flow closely corresponds with the site of seizure origin. Using tracers that accumulate and remain "fixed" in different areas of the brain proportional to rCBF at the time of injection, ictal SPECT is now an important tool for localization of seizures in a presurgical evaluation. However, the best methods for interpretation of partial seizure-induced changes in rCBF remain unclear. Numerous computer-aided tools have been used to increase objectivity and accuracy of ictal SPECT analysis. This review examines the uses of ictal-interictal subtraction methods and statistical parametric mapping (SPM) to enhance interpretation and utility of ictal SPECT. The review covers the evolution of advanced ictal SPECT imaging analysis techniques and the authors' clinical experience with the use of subtraction and SPM methods. The authors discuss the impact of ictal SPECT subtraction or difference imaging methods and the initial evidence for proof-of-principle that SPM can be used to provide objective, accurate analysis of ictal SPECT scans in patients with temporal and extratemporal lobe epilepsy. The limitations of both methodologies are discussed, and suggestions for further study of validation, improvement, and routine clinical implementation of advanced analysis methods are provided.