John Paul Leach

The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial

BACKGROUND Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0.78 [95% CI 0.63-0.97]), gabapentin (0.65 [0.52-0.80]), and topiramate (0.64 [0.52-0.79]), and had a non-significant advantage compared with oxcarbazepine (1.15 [0.86-1.54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0.75 [0.63-0.90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0.91 [0.77-1.09]), topiramate (0.86 [0.72-1.03]), and oxcarbazepine (0.92 [0.73-1.18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (-8 to 7) and 5 (-3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial.

BACKGROUND Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Improvement in adult-onset Rasmussen’s encephalitis with long-term immunomodulatory therapy

Objective: To study the immediate and chronic effects of high-dose, long-term human IV immunoglobulin (hIVIg) therapy in two patients with advanced adult-onset Rasmussen’s encephalitis (RE). Background: Despite advances in our understanding of the autoimmune pathogenesis of RE, medical options for chronic treatment are limited. Methods: In an open-label treatment trial, treatment started with monthly cycles of high-dose hIVIg (0.4 g/kg/d for 5 days) followed by maintenance therapy (0.4 g/kg 1 day each month) after the patients’ conditions began to improve. Outcome measures included clinical, psychological, functional, and laboratory assessments before and at relevant intervals throughout 1 year of treatment. Results: In both patients, unrelenting pretreatment deterioration halted, and after this they displayed striking improvements in seizure control, hemiparesis, and cognition that produced useful recovery of function. Improvements were delayed until after 2 to 4 monthly cycles of high-dose hIVIg and continued when patients switched to maintenance treatment. Their recoveries were accompanied by increased cerebral perfusion on interictal SPECT and suppression of inflammatory markers in CSF. Conclusions: hIVIg can be a useful, possibly disease-modifying, long-term therapy for adult-onset RE that should be considered before radical surgery is performed. Because improvements can be delayed, we propose guidelines for intensive and prolonged trials of immunomodulatory therapy in adults with this syndrome.

Epilepsy in the UK: Misdiagnosis, mistreatment, and undertreatment?: The Wrexham area epilepsy project

OBJECTIVE To assess the diagnostic and therapeutic difficulties in patients with epilepsy who had never come into contact with specialist services. METHODS Assessment was offered to 676 patients diagnosed as having epilepsy and receiving anti-epileptic drug therapy (AED), who had no previous contact with the local epilepsy services. Two hundred and seventy-five patients gave consent and attended for reassessment. We identified the proportion of patients (a) who had previously seen a neurologist, (b) in whom the diagnosis of epilepsy was not secure, (c) in whom planned AED withdrawal could be considered (d) in whom seizure control could be improved. RESULTS 53/275 (19.3%) of those attending for review had previously been seen by a neurologist. 87/275 (31.6%) patients ultimately received continued specialist care. Diagnostic doubt was expressed in 3/53 (5.6%) and 42/222 (18.9%) of patients diagnosed by neurologist and non-specialist, respectively. Of 133/219 (60.7%) of patients whose epilepsy was in remission, only 6 elected to withdraw or change medication. Of 18 patients with diagnostic doubt who accepted follow-up, 12 successfully stopped treatment. 17/55 (30.9%) patients with active epilepsy (10 partial, 7 generalised) achieved at least a 1 year remission consequent upon treatment in this clinic. In 15 cases this was a first ever remission. CONCLUSION Approximately 55% of the population of adults receiving treatment for epilepsy have never received specialist advice. Reassessment of these patients uncovers diagnostic uncertainty, failure to classify (leading to sub-optimal therapy) and lack of information and advice about all aspects of epilepsy care. The development of integrated services for people with epilepsy (PWE) must take account of this hidden need. The new General Medical Services contract for general practitioners will bring this need to our attention, and our experience will help predict the measures required to deal with the under-treatent and mistreatment of this group. The majority of PWE, not currently receiving shared care, merit reassessment and approximately one-third will require continued specialist care. Existing services do not have the capacity to process a marked increase in rate of referral. This project informs prioritisation of referrals and service reorganisation.

Alcohol and drugs in epilepsy: Pathophysiology, presentation, possibilities, and prevention

The potentially serious outcomes from ingestion of and dependence on toxins make this an important topic for epileptologists. We must be aware of the potential for harm from compounds that may be freely available, yet patients may try to conceal their use. Problematic compounds may cause seizures either acutely or on withdrawal: Their use may reduce effectiveness of antiepileptic drugs, or may simply promote and enhance chaotic lifestyles. Any or all of these factors may worsen seizure control or even directly cause seizures. This article highlights the pathophysiology behind provoked seizures, provides clues to diagnosis, and then outlines the steps that clinicians should take to reduce the deleterious effects of toxic compounds.

Polypharmacy with Anticonvulsants

SummaryFor almost 20 years, anticonvulsant monotherapy has been regarded as the ideal method of management of epilepsy. This line of thought, while true, has mutated into a general view of polypharmacy with anticonvulsants as a sign of therapeutic failure. However, even when the ‘right’ drug is given at the ‘right’ dose, studies have shown that in around 30% of patients, epilepsy will not fully respond to anticonvulsant monotherapy. For these patients, polypharmacy with anticonvulsants is an inevitability.There are good reasons why the established anticonvulsants should not be particularly well tolerated in combination. However, anticonvulsant polypharmacy has become so ‘undesirable’ that there has been a failure to search for firm treatment strategies for refractory epilepsy. Nevertheless, there are strong arguments to suggest that the newer anticonvulsants will prove to be better tolerated in combination than their established counterparts, particularly in view of their paucity of drug interactions, more predictable pharmacokinetics and narrower spectrum of action.This review calls for the development of a rational plan for the treatment of refractory epilepsy. Proper double-blind trials should be carried out to compare the efficacy and tolerability of anticonvulsant drug combinations. This is a huge task that could be rationalised by concentrating on combinations that have been reported to have particular benefit, or those with neurochemical properties that suggest an additive or even synergistic effect.

Future Prospects for the Drug Treatment of Epilepsy

Great progress has been made in the last 150 years in the pharmacological management of epilepsy, and, despite the increasing number of technological advances available, antiepileptic drugs (AEDs) remain the mainstay of treatment for the vast majority of patients with epilepsy.This review looks at possible avenues of development in the drug treatment of epilepsy. The strengths and weaknesses of those AEDs which are currently licensed are examined, and ways in which their use may be improved are discussed (e.g. rational combinations, use of new formulations). Potentially new targets that may allow the development of effective treatments are highlighted (neuroimmunological manipulation, decreasing inherent drug resistance mechanisms, and modification of adenosine neurotransmission), and a summary of the most promising AEDs currently in development is provided [e.g. carabersat, ganaxolone, harkoseride, MDL 27192, safinamide (NW 1015), pregabalin, retigabine, talampanel, valrocemide, losigamone and BIA 2093]

Neurological presentation of Fabry's disease in a 52 year old man

Fabrys disease is an X linked inborn error of metabolism due to deficient activity of the lysosomal enzyme α galactosidase A. Previously unrecognised Fabrys disease presenting in a 52 year old man being investigated for progressive dysarthria and ataxia is discussed. Brain magnetic resonance imaging suggested the presence of small vessel disease but skin biopsy (done to exclude cerebral autosomal dominant arteriopathy with subcortical infarcts and leucencephalopathy) showed typical changes of Fabrys disease. This diagnosis was confirmed by subsequent enzyme assays. The authors contend that Fabrys disease should be excluded, at least on clinical grounds, in patients with otherwise unexplained cerebrovascular disease.

REVIEW Antiepileptic drugs: safety in numbers?

Epilepsy is a common neurological condition, with a lifetime prevalence of between 2% 1, 2 and 5%3 of the general population, and a point prevalence of between 4 and 80 per 1000 4. So common is it among all races that epilepsy may be viewed, not as a rare curse on the individual, but as an all-too frequent price that man and other vertebrates pay for maintaining a plastic and adaptable central nervous system. Within the first few years of the next century, some estimates suggest that there will have been 11 new antiepileptic drugs (AEDs) licensed for use as either add-on or monotherapy since the late 1980s 5. Despite these recentwelcome additions to the ranks of available anticonvulsants 6 epilepsy remains both stigmatizing and debilitatingfor many of those with the disorder 7. Are there grounds for optimism about the possibility of treating refractory epilepsy? Previous studies have shown that around one-third of patients will remain refractory to anticonvulsant monotherapy with the established drugs 7, 8. Given this, the new drugs have, with justification, generated a great deal of interest, but despite their use most clinicians would admit that a significant number of patients with epilepsy have seizures that remain unsatisfactorily controlled9. The challenge for epileptologistsover the coming decades is to further reduce the size of this population with refractory disease. The new generation of AEDs are undoubtedly an advance in the treatment of epilepsy (given their advantages of increased tolerability 6, 10 and a decreased tendency to cause pharmacokinetic interactions 11), but it could be argued that a continued search for more new anticonvulsants is an inefficient way of helping our patients. Perhaps it would be more fruitful to look for better ways of using the drugs already at our disposal. For many different conditions in many different specialties, the use of drug combinations is the rule rather than the exception. Admittedly, anticonvulsants are potentially neurotoxic 8, can result in severe systemic reactions4, and have the tendency to sustain multiple pharmacodynamic and pharmacokinetic interactions12. The same, however, is true of antiparkinsonian drugs13, and monotherapy would never be advocated asthe ideal management strategy for the treatment of Parkinson’s disease 13. In fact here the opposite philosophy applies, where a rational combination of compounds is used at an early stage in an attempt to delay symptomatic progression 13. Since the 1970s, in contrast, anticonvulsant monotherapy has long been regarded as the ideal management strategy. A series of studies by Shorvon and Reynolds14–16 argued against AED polypharmacy on thebasis of its strong association with adverse events, they felt, with little evidence of an increase in efficacy. While it seems axiomatic that newly diagnosed epilepsy should be treated with a single drug, the didacticism in favour of monotherapy fails to recognize the realities of everyday practice. One survey has shown17 that even when under review by specialist epilepsy services, almost half the patients required (or, at least, were receiving) long-term treatment with anticonvulsant polypharmacy. At present, even taking into account those compounds currently undergoing phase three testing, it seems unlikely that any of the new AEDs will, by themselves, prove to be the ‘magic bullet’ for epilepsy. In a medical climate so keen on evidence guiding our medical management, it therefore falls to us as epilepsy specialists to formulate a rational strategy for its treatment. Sadly, though, it seems pre-

New variant Creutzfeldt–Jakob disease presenting as localization-related epilepsy

A 20-year-old man with a 6-year history of infrequent nocturnal focal motor seizures with secondary generalization attended an epilepsy clinic. During the seizures, the patient was stiff and rigid, exhibiting left-side convulsive movements. After each episode he had a short-lived left hemiparesis with associated intense vasomotor disturbance. There was no tongue biting or incontinence, but in the morning the patient would complain of being stiff and sore. These seizures had occurred once every 2 to 4 months. He had never had any daytime episodes, although there was a history of occasional daytime jerking of the limbs. Otherwise the patient had been fit and well. Clinical examination was normal, and it was believed that these seizures originated from the right hemisphere. Brain EEG and CT were unremarkable at the time. Three months later, the patient’s condition had deteriorated dramatically. His affect seemed inappropriate, and he had marked ataxia, as well as …