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.

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.

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.

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.

Familial adult myoclonic epilepsy: recognition of mild phenotypes and refinement of the 2q locus.

BACKGROUND: Familial adult myoclonic epilepsy (FAME) is an autosomal dominant syndrome characterized by a core triad of cortical tremor, multifocal myoclonus, and generalized tonic-clonic seizures. OBJECTIVES: To expand the phenotypic spectrum of FAME, to highlight diagnostic pointers to this underrecognized disorder, and to refine the FAME2 genetic locus. DESIGN: Observational family study. SETTING: The study was coordinated in a tertiary academic hospital, with data acquired in diverse primary, secondary, and tertiary care settings. PARTICIPANTS: Consenting members of a single large family. RESULTS: A 6-generation FAME kindred of European descent was ascertained in New Zealand and Australia. Affected family members (N = 55) had fine hand tremor, with onset typically in adolescence (median age, 15 years; age range, 4-60 years). Proximal myoclonus was present in 44 of 55 (80%), arising later than hand tremor (median age, 17 years; age range, 5-60 years). Generalized tonic-clonic seizures occurred in 8 of 55 (15%), with a median age at onset of 43.5 years (age range, 18-76 years). Neurophysiological testing confirmed features of cortical reflex myoclonus. Genetic mapping narrows the FAME2 (OMIM 607876) locus on chromosome 2 to a 13.3-megabase interval, harboring 99 known protein-coding genes. CONCLUSIONS: The most common FAME phenotype in this large family is mild postural hand tremor resembling essential tremor, combined with subtle proximal myoclonus. Generalized tonic-clonic seizures are uncommon and occur around sleep onset following severe generalized myoclonus.

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.

Treatment of refractory anterior knee pain using botulinum toxin type A (Dysport) injection to the distal vastus lateralis muscle: a randomised placebo controlled crossover trial.

OBJECTIVES: This randomised controlled crossover trial examined the efficacy of botulinum toxin type A (BoNT-A) injection, plus an exercise programme, to remediate chronic anterior knee pain (AKP) associated with quadriceps muscle imbalance. METHODS: 24 individuals with refractory AKP received either BoNT-A (500 U Dysport) or the same volume saline injection to the vastus lateralis (VL) muscle and performed home exercises focusing on re-training the vastus medialis (VM) muscle. All subjects were offered open-label injection at 12 weeks. Knee-related disability (anterior knee pain scale; AKPS) and activity-induced pain (10 cm visual analogue scale) at 12 weeks were the primary outcomes. Peak isometric extensor force was recorded and normalised VL:VM ratios were derived from simultaneous surface electromyography. Self-reported pain and disability measures were collected at six time points to a mean of 20±8 months. RESULTS: 14 subjects received BoNT-A and 10 placebo injection. Improvement at 12 weeks was significantly greater for BoNT-A compared with placebo-injected subjects for the AKPS (p<0.03), pain on kneeling (p<0.004), squatting (p<0.02) and level walking (p<0.04). At week 12, five placebo subjects crossed over to open-label injection. At 24 weeks, 16 of 19 BoNT-A-injected and two of the remaining five placebo-injected subjects were either satisfied or very satisfied with treatment outcomes. Improvements were maintained in 11 of 14 BoNT-A-injected and two of five placebo subjects available at longer-term follow-up. CONCLUSION: BoNT-A injection produced a greater reduction in pain and disability than placebo injection in carefully selected patients with chronic AKP related to quadriceps muscle imbalance.

Driving to distraction--certification of fitness to drive with epilepsy.

Assessment of medical fitness to drive can be a sensitive and difficult task, particularly when it involves a condition such as epilepsy, where impairment is intermittent. The patient, their doctor and the driver licensing authority (DLA) each have responsibilities, both to the patient and to the wider community of road users. DLAs in Australia have shifted most of the responsibility for determining fitness to drive to the treating doctor. This creates a conflict of interest and may lead to unsafe decisions, damage to the doctor-patient relationship, interference with medical management and legal vulnerability for the doctor. Australian neurologists have argued for a system in which the treating doctor provides objective information about the patient's condition, rather than an opinion on fitness to drive, and the DLA uses that information to determine fitness. This must be supported by an expert review process. Although drivers are legally obliged to notify the DLA when they become unfit, most people are unaware of this law. However, passing this responsibility to doctors in the form of mandatory reporting is counterproductive to road safety.

Prolonged vastus lateralis denervation after botulinum toxin type A injection.

Intramuscular injection of botulinum toxin (BoNT) produces reversible blockade of neuromuscular transmission. In animal experimental models, recovery begins within four weeks and is usually complete by twelve weeks. We present evidence of prolonged denervation following BoNT injection of the vastus lateralis (VL) muscle to correct quadriceps muscle imbalance in patients with chronic anterior knee pain. Needle electromyography data were obtained from 10 subjects who had received a single BoNT treatment 5 to 19 months earlier as part of a clinical trial. Insertional and spontaneous activity, recruitment, and motor unit action potentials were examined. Clear differences between the injected and non-injected VL muscles, which correlated with the time since injection, were identified in all subjects. All 10 subjects studied with needle EMG showed evidence of persisting denervation in the BoNT-A injected VL muscle beyond the period of neuromotor recovery expected from animal experimental studies.

The role of botulinum toxin injections in the management of muscle overactivity of the lower limb.

Muscle overactivity is common in patients with adult onset central nervous system damage. It can produce significant disablement in conjunction with other impairments such as adaptive soft tissue shortening and loss of muscle strength. Muscle overactivity is not evenly distributed throughout the body; across joints there is frequently imbalance between agonist and antagonist, producing abnormal joint postures and movement patterns. Due to the asymmetric nature of the abnormal activity across joints, in general we recommend local treatment targeting the more overactive of the two agonists, rather than systemic treatment. Considerable experience with the use of botulinum toxin, both serotypes A and B, in the treatment of muscle overactivity has been accumulated in the last two decades through pragmatic clinical practice and open label studies, supported by an increasing number of randomized controlled trials. In most cases, it is important to use botulinum toxin injection for treatment of muscle overactivity in the setting of wider rehabilitation goals and interventions. Focal and partial blocks with botulinum toxin should be used as a component of a general neurorehabilitation programme rather than as an alternative to other treatments. We review the evidence supporting the use of botulinum toxin to treat muscle overactivity in the lower limb, present practical guidelines on when and how to use botulinum toxin and provide direction for future research.

Laryngeal dystonia causing upper airway obstruction in progressive supranuclear palsy.

A 58-year-old man with progressive supranuclear palsy (PSP) developed two episodes of respiratory failure associated with laryngeal spasm. It was revealed he had adductor laryngeal breathing dystonia, a relatively unrecognized complication of PSP.

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.

Incidence of ankle contracture after moderate to severe acquired brain injury.

OBJECTIVE: To examine an adult population undergoing rehabilitation after brain injury to determine the incidence of ankle contracture and factors contributing to the development of this deformity. DESIGN: Descriptive study SETTING: Specialist inpatient neurosurgical rehabilitation unit in Australia. PARTICIPANTS: Patients (N=105) admitted with a new diagnosis of moderate to severe brain injury over a 12-month period. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Maximal ankle dorsiflexion range and the presence of abnormal muscle tone affecting the lower limb(s) were evaluated at weekly intervals. Ankle contracture was defined as maximal passive range of less than 0 degrees dorsiflexion with the knee in extension. Patients were grouped into 3 muscle tone categories: normal, predominantly spastic, or predominantly dystonic. Age, sex, mechanism and severity of brain injury, time to onset of ankle contracture, total length of hospital stay, and discharge mobility status data were also recorded. RESULTS: Muscle tone was designated as normal in 68 (64.7%), as spastic in 14 (13.3%), and as dystonic in 23 (21.9%) patients. The incidence of ankle contracture was 16.2% (17/105 cases). Ankle deformity correlated closely with muscle tone category. Of 23 cases with dystonic muscle overactivity, 17 developed contracture at some point between 1 and 16 weeks after brain injury, although no subject with normal tone or spasticity developed the deformity. There was a weak association between the severity of brain injury and development of ankle contracture. CONCLUSIONS: The incidence of ankle contracture was much lower than previously reported. Dystonic overactivity of the plantarflexor and invertor muscles is a major predisposing factor to ankle contracture.

Diabetic amyotrophy progressing to severe quadriparesis.

Diabetic amyotrophy is a distinctive form of diabetic neuropathy usually characterized by the abrupt onset of pain and asymmetric proximal leg weakness and wasting. Involvement of the upper limbs is unusual, and prognosis is said to be good. We describe two patients, each with type II diabetes mellitus, who presented with diabetic amyotrophy progressing to severe quadriparesis. One patient remains severely disabled. The clinical spectrum of diabetic amyotrophy includes progression to severe quadriparesis.

The general practice management of epilepsy in Perth, Western Australia.

Ninety randomly selected general practitioners from the Perth metropolitan area completed a self-administered postal questionnaire aiming to examine the extent of their involvement with epilepsy and how closely their management mirrored best practice guidelines. GPs saw a median of 6 patients with epilepsy, mainly adults. They perceived complementary roles for GPs and neurologists: the GP providing ongoing support and education, monitoring treatment and making dosage adjustments; with the neurologist largely making the formal diagnosis and other management decisions. Only 42% regarded their knowledge of epilepsy as adequate for their practice. About half advised patients on the existence of the Epilepsy Association. Some respondents overestimated the usefulness of EEG. Plasma antiepileptic drug (AED) measurements were overvalued, with 69% of respondents performing plasma levels without regard to symptoms, and 20% would alter AED doses solely on the basis of plasma levels. GPs may tolerate very frequent seizures before referring their patients for more specialised evaluation.