Rajiv Mohanraj

Predictors of pharmacoresistant epilepsy

Outcome data were analysed from 780 patients newly diagnosed with epilepsy and followed up at a single centre over a 20-year period to investigate which clinical factors predicted pharmacoresistance. Patients were divided at the time of analysis into those whose seizures had been controlled for at least the last 12 months of follow up (n=462) and those whose epilepsy remained refractory (n=318). Numbers of pre-treatment seizures were greater in uncontrolled patients. Those reporting more than 10 seizures prior to initiation of therapy were more than twice as likely to develop refractory epilepsy. Univariate and multivariate logistic regression analyses demonstrated that pharmacoresistance was also associated with family history of epilepsy, previous febrile seizures, traumatic brain injury as the cause of the epilepsy, intermittent recreational drug use, and prior or current psychiatric comorbidity, particularly depression. Factors not predicting poorer outcome included gender, neurological deficit and mental retardation. The most interesting new finding was the correlation between psychiatric comorbidity and lack of response to antiepileptic drug therapy. The deleterious neurobiological processes that underpin depression, anxiety and psychosis may interact with those producing seizures to increase the extent of brain dysfunction and thereby the likelihood of developing pharmacoresistant epilepsy.

Lack of Association between the C3435T Polymorphism in the Human Multidrug Resistance (MDR1) Gene and Response to Antiepileptic Drug Treatment

Summary:  Purpose: P‐glycoprotein (P‐gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P‐gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C‐variant, which is associated with higher expression and increased activity of P‐gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic.

Mortality in epilepsy

All studies report an increased mortality risk for people with epilepsy compared with the general population. Population-based studies have demonstrated that the increased mortality is often related to the cause of the epilepsy. Common etiologies include neoplasia, cerebrovascular disease, and pneumonia. Deaths in selected cohorts, such as sudden unexpected death in epilepsy (SUDEP), status epilepticus (SE), suicides, and accidents are more frequently epilepsy-related. SUDEP is a particular cause for concern in younger people, and whether and when SUDEP should be discussed with patients with epilepsy remain problematic issues. Risk factors for SUDEP include generalized tonic-clonic seizures, increased seizure frequency, concomitant learning disability, and antiepileptic drug polypharmacy. The overall incidence of SE may be increasing, although case fatality rates remain constant. Mortality is frequently secondary to acute symptomatic disorders. Poor compliance with treatment in patients with epilepsy accounts for a small proportion of deaths from SE. The incidence of suicide is increased, particularly for individuals with epilepsy and comorbid psychiatric conditions. Late mortality figures in patients undergoing epilepsy surgery vary and are likely to reflect differences in case selection. Future studies of mortality should be prospective and follow agreed guidelines to better quantify risk and causation in individual populations.

Pharmacological outcomes in newly diagnosed epilepsy.

The response to antiepileptic drugs (AEDs) has been examined in 780 adult and adolescent patients with newly diagnosed epilepsy presenting with a range of seizure types and epilepsy syndromes over a 20-year period. Carbamazepine (CBZ, n=312), sodium valproate (VPA, n=315), and lamotrigine (LTG, n=249) were the most common AEDs prescribed as monotherapy. More patients with localization-related epilepsies became seizure free with LTG (63%) than with CBZ (45%, P=0.006) or VPA (42%, P=0.006). For idiopathic generalized epilepsies a greater proportion of patients achieved control with VPA (68%) than with CBZ (31%) or LTG (45%). In particular, more patients with juvenile myoclonic epilepsy responded to VPA (75%) compared with LTG (39%, P=0.014). Seizure freedom was achieved with modest or moderate daily doses (median CBZ 400mg, VPA 1000 mg, (LTG) 150 mg) of all three AEDs in the majority of patients achieving remission. Time to first seizure did not differ among these three drugs when given as first treatment. Adverse effects leading to withdrawal were more frequent with CBZ (16%) than with VPA (7%, P=0.03) or LTG (7%, P=0.018). In patients failing initial monotherapy, response to a combination of two AEDs (27%) was not different from that with alternative monotherapy (32%). The majority of patients with newly diagnosed epilepsy responding to treatment did so rapidly and completely with moderate doses of AEDs, with no differences in time to first seizure.

Pharmacological outcomes in older people with newly diagnosed epilepsy.

BACKGROUND Old age is the most common time in life to develop epilepsy. Despite this, there are few published data exploring pharmacological outcomes in this population. METHODS We analyzed outcomes in 117 older patients (median age, 73; range, 65-92) for whom localization-related epilepsy was newly diagnosed and treatment begun at a single center over a 20-year period. RESULTS Seventy-three (62%) patients became seizure-free for at least 12 months on their first AED, with 30 (26%) failing to respond and 14 (12%) not tolerating the treatment. Following pharmacological manipulation, 93 (79%) patients attained remission, 87 (93%) on monotherapy and 6 (7%) on duotherapy. No individual AED was more likely to confer seizure freedom than any other. Patients attaining remission were more likely to have had fewer pretreatment seizures (P=0.0078) than those who did not obtain full seizure control. CONCLUSION The prognosis in epilepsy may be better in older than younger people, perhaps reflecting lower lesional epileptogenicity and genetic predisposition.

Outcomes in newly diagnosed localization-related epilepsies

A total of 558 patients with a range of localization-related epilepsy syndromes starting treatment in a single centre were followed over a period of up to 20 years. Overall, 343 (62%) patients became seizure free for 12 months or more (responders), 92% of whom (57% of total population) remained in remission until the end of follow-up. Only 27 (5%) responders relapsed and subsequently developed refractory epilepsy. The remaining 215 (38%) patients never became seizure free for any 12-month period. There were no significant differences in outcome between cryptogenic (56% remission) and symptomatic (57% remission) epilepsies. Patients with underlying cortical atrophy (71% remission; p<0.05) or cerebrovascular disease (70% remission; p<0.01) did better, while those with traumatic brain injury (35% remission; p<0.001) did worse than the remainder of the symptomatic group. Remission rates in patients with cortical dysplasias (60%), hippocampal atrophy (50%) and primary brain tumors (52%) appeared no different from those with other symptomatic epilepsies. Overall, 20-40% patients with each epilepsy syndrome reported no further seizures after starting AED treatment including 21% with hippocampal atrophy and 33% with cortical dysplasia. More than 50% of patients developing localization-related epilepsy during adolescence or in adulthood had a good outcome. Prognosis in those with underlying hippocampal atrophy or cortical dysplasia was not always bad.

Levetiracetam in refractory epilepsy: a prospective observational study

This prospective open-label study used flexible dosing schedules of levetiracetam (LEV) in patients with refractory epilepsy attending a single centre to explore its effectiveness in everyday clinical practice. One hundred and fifty-six patients with uncontrolled localisation-related or idiopathic-generalised epilepsy were prescribed adjunctive LEV following a 3-month baseline. The primary end points were seizure freedom for at least 6 months, > or = 50% reduction (responder) or <50% reduction for 6 months, or discontinuation of LEV due to lack of efficacy, adverse effects or both. Overall, 40 (26%) patients became seizure free on adjunctive LEV, including 8 (40%) with idiopathic-generalised epilepsy. Twenty-five (63%) of the seizure-free patients took 1000 mg LEV per day or less. A further 33 (21%) patients were classified as responders. LEV was withdrawn in 46 (29%) patients (27 adverse effects, 8 lack of efficacy, 11 both). Intolerable sedation, reported by 20 (13%) patients, was the commonest complaint leading to treatment failure. Behavioural side effects led to LEV withdrawal in 7 (5%) patients. LEV is an effective adjunctive treatment for refractory idiopathic and localisation-related epilepsies. Many patients who responded optimally to LEV did so at 1000 mg per day or less.

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.

Five cases of new onset refractory status epilepticus (NORSE) syndrome: Outcomes with early immunotherapy

UNLABELLED Cryptogenic new onset refractory status epilepticus (NORSE) syndrome has been described in both adults and children, and is often associated with poor outcome. A variety of terms have been used in the literature to refer to this syndrome. The condition may be triggered by as yet unidentified infections or an immunological mechanism. We present a series of 5 patients with NORSE syndrome treated at 2 neuroscience centres in the North of England, in whom early use of immunotherapy appears to be associated with good neurological outcomes. METHODS Case note review of the index case and four other patients was undertaken to obtain details of clinical presentation, imaging and CSF findings, infectious/inflammatory tests, management of seizures, immunotherapy and outcome. RESULTS Case 1 was a 26 year old male with a prodrome of headache and vomiting. He developed refractory multifocal and generalised seizures, which required admission to intensive care unit and administration of general anaesthetic. Seizures recurred on withdrawal of barbiturate anaesthetic until day 29. MR imaging, CSF examination and serological tests for viral and autoimmune aetiologies were normal apart from positive anti-TPO antibodies: the patient had previously treated hyperthyroidism. He was initially treated with aciclovir and antibacterials. IV steroids were administered day 12 and IV immunoglobulin day 18. He made a good recovery being discharged home 2 months after admission. Seizures recurred on withdrawal of steroid therapy, and required longer term immunosuppressant treatment with azathioprine. Clinical features and investigations of the four other patients were similar. Two were given early immunotherapy with steroids and intravenous immunoglobulins and survived with few deficits. One patient who was not given immunotherapy died from complications associated with prolonged ICU stay. Outcome was not known for the fourth patient as she was repatriated to her home country in thiopentone coma. CONCLUSION In our experience, early immunotherapy has been associated with good outcomes in NORSE. Multicentre collaboration is required to establish the diagnostic criteria and appropriate management of patients presenting with NORSE.

VGKC complex antibodies in epilepsy: Diagnostic yield and therapeutic implications

PURPOSE In a significant number of patients developing epilepsy in adult life, the aetiology of their seizures remains unclear. Antibodies directed against the voltage gated potassium channel complex (VGKC Ab) have been identified in various cohorts of patients with epilepsy, although the role of these antibodies in epilepsy pathogenesis is not fully known. METHOD We reviewed the notes of 144 patients with unexplained adult onset epilepsy who had been tested for VGKC Abs. We collected data on their clinical syndrome, investigation results and response to treatment. RESULTS We identified 6 (4.2%) patients who had titres of >400 pM. One of the six patients was positive for LGI1 and another for CASPR2 subunit antibodies. All patients were given immunotherapy and experienced improvement in seizure control. No patient had the clinical syndrome of limbic encephalitis. CONCLUSION Patients with otherwise unexplained epilepsy and positive VGKC Abs are a heterogeneous group. In our cohort there was an overall favourable response to immunotherapy but further prospective studies are needed to determine the significance of these antibodies and the optimum treatment regimen for patients.