A decision tree to determine fitness to drive in epilepsy: Results of a pilot in two Australian states.

OBJECTIVE: Certification by treating physicians of fitness to drive in people with epilepsy creates a conflict of interest that may result in unsafe decisions, damage the doctor-patient relationship, expose the physician to legal liability and prevent optimal treatment. Ideally, the treating physician should provide objective clinical information to the driver licensing authority (DLA), which then determines fitness or otherwise. However, DLAs in Australia do not employ medical staff and the national standards are complex. Fitness is determined by the treating physician, according to published national standards. The purpose of this study was to determine the feasibility of using a decision tree to determine fitness, according to the Australian standards. METHODS: A decision tree was constructed to use clinical data to determine whether a patient met the national standard to drive a private motorcar, failed to meet it or required further assessment. A form was designed to collect the necessary clinical data from the treating physician. A computerized version of the decision tree was then used in a pilot in two Australian states in parallel with the existing certification system. Four hundred thirty-nine drivers with declared epilepsy and their treating physicians were invited to participate when their annual driver licence review was due. RESULTS: Two hundred fifty-three (58%) forms were returned. All patients were considered fit to drive by their physician. Seventy-six percent had not had a seizure for over two years. In 88.1%, there was agreement between the decision tree and treating physician, with 3.6% identified by the decision tree as requiring review. Although considered fit by their physician, 6.3% did not meet the national standard to drive. SIGNIFICANCE: The decision tree model is a practical alternative to fitness certification by treating physicians. This Australian pilot can serve as a model for applying objective standards to driving assessments in other jurisdictions, using local driving standards. It has the potential to improve road safety by avoiding the negative effects of certification by treating physicians and can cope with complex standards. It is now in use in two states of Australia.

Clinicopathological associations in temporal lobe epilepsy patients utilising the current ILAE focal cortical dysplasia classification.

OBJECTIVES: This study utilised the revised 2011 ILAE classification of focal cortical dysplasia (FCD) (Blümcke et al., 2011) to examine pathology in a cohort of children and adults who underwent temporal lobe epilepsy (TLE) surgery, and to describe the electroclinical and imaging features associated with these pathologies. METHODS: The sample population were children (n=26) and adults (n=47) who underwent TLE surgery between 2002 and 2011 at our institutions. Neuropathology and MRI studies were re-reviewed by experts blinded to the original diagnosis. EEG and clinical data including current seizure outcome were determined by patient file review and/or patient contact. Pre-operative data, post-operative outcome and pathological diagnoses were compared. RESULTS: The commonest pathology in the adult cohort was isolated hippocampal sclerosis (HS) (n=24, 51.1%) and in the paediatric cohort, isolated tumour (n=10, 38.5%). Overall, HS with associated FCD (FCD IIIA) was the third most common pathology (n=12, 16.4%). Temporal grey matter signal changes on MRI were associated with FCD IIIA (p=0.035). FCD IIIA had the poorest post-surgical seizure outcome compared to all other pathologies (p=0.026). A history of bilateral convulsive seizures was more common in adults (n=40, p<0.0005), and was associated with failure to achieve postoperative seizure freedom (p=0.045). Postoperatively, paediatric TLE had higher rates of seizure freedom (p=0.005) and more children had ceased medication (p<0.0005). SIGNIFICANCE: FCD IIIA is a comparatively common pathological subtype in TLE, with a poor post-surgical outcome. Pre-operative recognition of FCD IIIA may be feasible through grey matter signal change on MRI. Paediatric patients had a higher rate of seizure freedom than adults. Pre-operative bilateral convulsive seizures were associated with poor outcome after surgery.

Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis.

OBJECTIVE: To describe a distinctive seizure semiology that closely associates with voltage-gated potassium channel (VGKC)-complex/Lgi1 antibodies and commonly precedes the onset of limbic encephalitis (LE). METHODS: Twenty-nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC-complex antibodies was studied. RESULTS: Videos and still images showed a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency. INTERPRETATION: Recognition of FBDS should prompt testing for VGKC-complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment.

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.

Some treatments cause seizure aggravation in idiopathic epilepsies (especially absence epilepsy).

Seizure aggravation by antiepileptic drugs (AEDs) is a rare phenomenon, occurring mostly in generalized epilepsies treated with drugs that are more efficacious against partial seizures. Its frequency is greatly overestimated by doctors and especially by patients. There are many other reasons for seizures to deteriorate but they are often not considered. Seizure aggravation by AEDs is important to recognize but equally important not to overdiagnose. It can largely be prevented by accurate syndromic diagnosis and the treatment of generalized epilepsies with drugs that are effective against primary generalized seizures and avoiding those that are not.

Adjunctive therapy of uncontrolled partial seizures with levetiracetam in Australian patients.

OBJECTIVE: The goal of the work described here was to explore the efficacy, safety, and tolerability of adjunctive therapy with levetiracetam and associated changes in health-related quality of life in Australian patients with uncontrolled partial seizures. METHODS: A phase IV open-label 16-week clinical trial was undertaken. Patients received adjunctive levetiracetam, adjusted according to clinical response to a final daily dose of 1000-3000 mg. Seizure frequency and adverse events were recorded. A quality-of-life questionnaire (QOLIE-10-P) was administered at the start and end of therapy. RESULTS: The intention-to-treat population (N=152) experienced a median reduction in total seizure frequency of 57.7%. The 50% responder rate was 56.6%, and 12.5% of patients were free of seizures throughout the trial. Adverse events were mostly mild or moderate, leading to discontinuation in 9.9%. The most common adverse events were somnolence, fatigue, headache, and dizziness. Behavioral adverse events occurred in approximately one-quarter of patients, including two-thirds of those who withdrew because of adverse events. There was an improvement in the QOLIE-10-P score. CONCLUSION: Levetiracetam is effective and well tolerated when added to existing therapy in patients with uncontrolled partial seizures.

The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy.

The Safety of Keppra as Adjunctive Therapy in Epilepsy (SKATE) study aimed to evaluate the safety and efficacy of levetiracetam (Keppra, LEV) as add-on therapy for refractory partial seizures in clinical practice. This Phase IV, 16-week, open-label study recruited patients > or =16-year old with treatment-resistant partial seizures. LEV (1000 mg/day) was added to a stable concomitant antiepileptic drug regimen. LEV dosage was adjusted based on seizure control and tolerability to a maximum of 3000 mg/day. 1541 patients (intent-to-treat population) were recruited including 1346 (87.3%) who completed the study and 77.0% who declared further continuing on LEV after the trial. Overall, 50.5% of patients reported at least one adverse event that was considered related to LEV treatment. The most frequently reported drug-related adverse events were mild-to-moderate somnolence, fatigue, dizziness and headache. Serious adverse events considered related to LEV occurred in 1.0% of patients. 7.5% of patients reported adverse events as the most important reason for study drug discontinuation. The median reduction from baseline in the frequency of all seizures was 50.2%; 15.8% of patients were seizure free; 50.1% had seizure frequency reduction of > or =50%. At the end of the study, 60.4% of patients were considered by the investigator to show marked or moderate improvement. There was a significant improvement in health-related quality of life as assessed with the QOLIE-10-P (total score increasing from 55.6 to 61.6; p<0.001). This community-based study suggests that LEV is well tolerated and effective as add-on therapy for refractory partial seizures in adults. These data provide supportive evidence for the safety and efficacy of LEV demonstrated in the pivotal Phase III placebo-controlled studies.

Seizure aggravation by antiepileptic drugs.

Seizure aggravation by antiepileptic drugs (AEDs) is an overestimated phenomenon. While it undoubtedly occurs, the quality of evidence in most published reports is poor. Although seizure aggravation can be examined in clinical trials in the same way as seizure improvement, this is rarely done. Before concluding that an increase in seizures after the introduction of a new drug represents pharmacodynamic aggravation, alternative explanations should be explored. These include spontaneous fluctuation of seizure frequency, the presence of known seizure aggravators (such as sleep deprivation, alcohol, and psychotropic medications), progression of epilepsy, the development of drug resistance, and replacement of a partially effective drug with a less effective drug. The risk of incorrectly blaming a drug for a deterioration in seizures can be minimized by establishing baseline seizure frequency over a period long enough to encompass the extremes of seizure fluctuation and by educating the patient that a temporal relationship may not be a causal relationship. When feasible, the patient should continue the drug long enough to establish if the deterioration is transient. If the drug is stopped, rechallenge should be considered. The risk of seizure aggravation can be minimized by accurate diagnosis of the epilepsy syndrome and appropriate choice of AED.

Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials?

OBJECTIVES: To assess clinical trials for evidence that antiepileptic drugs (AED) aggravate partial seizures. To determine if the methodology used to examine drug efficacy can also be used to examine seizure aggravation. BACKGROUND: It is widely accepted that AED aggravate epilepsy in some patients. However, there is little published objective or quantitative evidence. Most reports concern generalized epilepsies. METHODS: Pharmaceutical companies responsible for the development of five of the new AED were asked to provide data concerning seizure increases during randomized placebo-controlled, add-on clinical trials in patients with uncontrolled partial seizures. Seizure frequency in individual patients taking drug or placebo was compared with the baseline pretreatment seizure frequency. The counterpart of the 50% reduction used in efficacy analyses is a 100% increase, because both represent a twofold change. A dose-response relationship was also explored. RESULTS: More than 40% of subjects in clinical trials of tiagabine (TGB), topiramate (TPM), and levetiracetam (LEV) experienced an increase in seizures while taking a placebo. Seizure increases were no more likely to occur when taking any of the three drugs than taking placebo. A doubling or more of seizure frequency was less likely to occur with TPM or LEV than with placebo but more likely with TGB. However, for TGB, this did not reach significance. There was some evidence for a dose-response effect with TGB but a negative effect with TPM (aggravation less likely with increasing dose). Data on gabapentin and lamotrigine were not provided. CONCLUSIONS: Many patients with partial seizures experience an increase in seizures when a new AED is added to their therapy. However, it occurs no more frequently when taking drug than placebo. It probably represents the spontaneous fluctuation of seizure frequency. When a patient who has started a new AED deteriorates, this is not necessarily a drug effect.

Community versus individual benefit.

Australian law embodies a "communitarian" conception of the doctor's responsibility to respect the confidentiality of the doctor-patient relationship. This implies that respect for confidentiality sits alongside two other responsibilities: proper care for the patient's general wellbeing and proper attention to the safety of the community. Most jurisdictions now require drivers to advise their local driver-licensing authority of any permanent or long-term injury or illness that affects their ability to drive safely. Some jurisdictions require doctors to inform the driver-licensing authority about patients whose medical condition may impair their driving to the extent that they are likely to endanger the public. If you can not persuade a patient to inform the driver-licensing authority of the need for an assessment of his or her ability to drive safely, then you should inform the relevant authorities yourself.