New valproate regulations, informed choice and seizure risk.

Valproate is the most effective medication for generalised epilepsies, and several specific epilepsy syndromes. For some people, it will be the only medication to establish seizure remission, and withdrawing it carries risks of seizure recurrence and Sudden Unexpected Death in Epilepsy (SUDEP). It is also of proven efficacy for bipolar disorder and migraine prevention. Guidelines based on observational and epidemiological studies stress that maternal valproate related teratogenicity and neurodevelopmental effects are significantly higher than for other antiseizure medications (ASMs). It should, therefore, only be used if other medications are ineffective and after balancing the teratogenicity risk. Regulatory restrictions have changed prescribing practices and reduced valproate use. The number of other medications that must be trialled in the different conditions for which valproate has effectiveness and the consequences of the lack of efficacy of those drugs leading to significant harm including death remains unexplored. Risk minimisation measures (RMMs) for valproate, chiefly Pregnancy Prevention practices (PPP), consider foetal risk and not risk to people living with epilepsy. In the United Kingdom (UK), limitations relating to valproate use in all people < 55 years commenced in January 2024. While the evidence in child-bearing women is not disputed, the data in males are based on animal models, case reports, and one commissioned, unpublished, non-peer reviewed report unavailable to the UK public, stakeholder charities or professionals. Evidence suggests that 30-40% of people switching from valproate have breakthrough seizures. Thus, an estimated 21,000-28000 people in the UK will imminently be exposed to the potential hazards of breakthrough seizures, including death. There is little government investment in monitoring the effects of these changes to valproate prescribing on patient health and quality of life. This review summarises the history of valproate regulation, evidence underpinning it and argues how the latest regulations in the UK do not align with the country's medical regulatory bodies ethical principles nor with the Montgomery principles of informed patient choice and autonomy. It dissects how such regulations infringe Common Law principles, nor give due regard for patient outcomes beyond reproduction. The paper looks to provide recommendations to redress these concerns while appreciating the core need for such governance to emerge in the first place.

New-onset seizures in older people: Clinical features, course and outcomes.

OBJECTIVE: The incidence of epilepsy increases with age. With current demographic trends, this presents a healthcare challenge. We investigated the clinical spectrum of first seizures, evaluated neuroimaging and EEG findings, and determined clinical outcomes, including anti-seizure medication (ASM) response in older people. In addition, we sought to understand the relative effects of age and frailty on ASM response. METHODS: A retrospective single centre cohort study of 207 cases ≥60 years' old, 113 of whom were eventually diagnosed with a first seizure in a specialist epilepsy clinic. RESULTS: 65/113 (57.5%) presented with either focal aware or focal impaired awareness seizures. Stroke was the most common aetiological association (31.9%, 36/113), and odds of seizure recurrence did not significantly differ between aetiologies. 55/86 (64.0%) who started an ASM had no seizure recurrence. 14/48 (29.2%) who underwent EEG had epileptiform abnormalities, however EEG result directly affected management in only 4/48 (8.3%). The most common MRI findings were small vessel disease (37/93, 39.8%), stroke (27/93, 29.0%) and global atrophy (14/93, 15.1%). Increasing age and frailty did not affect the odds of seizure recurrence or of experiencing ASM side effects. Severity of small vessel disease or atrophy did not affect odds of seizure recurrence. CONCLUSION: Our data inform the management of first seizures in older people and provisionally support the use of ASMs in patients with increasing age and frailty, despite concerns over polypharmacy and comorbidity. Our findings should be replicated in larger cohorts.

Epilepsy & gambling: Risk factors for problem gambling behaviors in people with epilepsy.

OBJECTIVE: Problem gambling results from the complex interaction of neurological factors with psychological, demographic, and socioeconomical influences. The vulnerabilities of people with epilepsy to many of these influences may increase their susceptibility to developing problematic gambling behaviors. The aim of this study was to establish the frequency of gambling participation and the clinical correlates of problem gambling behaviors in people with epilepsy. METHODS: Lifestyle questions, including the Lie/Bet screening questionnaire were administered to 250 consecutive attendees at a neurology clinic. Valid data were available for 174 adults with epilepsy and 65 adults with other neurological conditions. RESULTS: With the exception of people with frontal lobe epilepsy (FLE), gambling participation rates in people with epilepsy and those with other neurological conditions were lower than those reported in the general population. While the overall levels of gambling participation were relatively low in this sample, the number of gamblers who responded positively to the lie/bet questionnaire was ten times higher than that seen in the general population, with one in three gamblers in our series reporting signs of escalation. All had epilepsy and were more likely to be taking Levetiracetam or Brivaracetam than the other gamblers in our series. While epilepsy classification was not related to gambling escalation, patients with FLE were overrepresented in this group due to their significantly higher baseline levels of participation in gambling. CONCLUSIONS: People with FLE may have a heightened vulnerability to developing problem gambling behaviors. The role of the neurological consultation in managing these risks is discussed.

Memory complaints in the epilepsy clinic.

Cognitive complaints in people with epilepsy are usually multifactorial in their nature and origin. While antiepileptic medications are an important consideration, we explore other ways in which neurologists can address cognitive problems in this population. It is never too early to ask about cognitive impairment, and the answers can have diagnostic significance. Understanding and accepting that cognitive problems may result, at least in part, from the same pathological process that generates seizures is an important part of the rehabilitation process. Patients referred for neurorehabilitation for cognitive difficulties who have realistic expectations and goals tend to benefit more from the intervention than those expecting a cure. Developing an understanding of this and managing patient expectations should start in the neurology clinic. Although we focus primarily on memory function, the principles we discuss in this paper apply to the broad spectrum of cognitive and neurobehavioral problems that accompany the many diagnoses of epilepsy.

Neuropsychological outcomes following traumatic brain injury.

This review examines the clinical and neuroradiological features of traumatic brain injury that are most frequently associated with persistent cognitive complaints. Neuropsychological outcomes do not depend solely on brain injury severity but result from a complex interplay between premorbid factors, the extent and nature of the underlying structural damage, the person's neuropsychological reserve and the impact of non-neurological factors in the recovery process. Brain injury severity is only one of these factors and has limited prognostic significance with respect to neuropsychological outcome. We examine the preinjury and postinjury factors that interact with the severity of a traumatic brain injury to shape outcome trajectories. We aim to provide a practical base on which to build discussions with the patient and their family about what to expect following injury and also to plan appropriate neurorehabilitation.

The role of obesity in cognitive dysfunction in people with epilepsy.

OBJECTIVE: In the general population, obesity is associated with accelerated age-related cognitive decline. The impact of obesity on cognitive function in neurological populations who already have a heightened risk of cognitive decline is unknown. This study explored the relationship between obesity and cognitive underfunction in people with medically intractable epilepsy. METHODS: Eighty-one consecutive patients admitted for evaluation for medically intractable epilepsy (36 females and 45 males) underwent tests of memory and intellectual function. Optimal level of function was assessed using the National Adult Reading Test - Revised. Measures of underfunction were calculated by subtracting current measures of intellectual ability from the NART IQ. Body mass index (BMI) was used as an index of obesity. RESULTS: Twenty-nine people had a BMI in the healthy range (36%), 31 were overweight (38%), and 21 were obese (26%). The healthy weight, overweight, and obese groups did not differ in age at the time of assessment, age at seizure onset, or optimal level of function (NART IQ). The obese group had a greater degree of suboptimal processing speed and demonstrated a greater degree of underfunction on the Full Scale IQ (FSIQ) measure compared to the healthy weight group. Body mass index accounted for 14% of the variance in underfunction in processing speed and 10% of the variance in underfunction in FSIQ. Controlling for the effects of age, all measures of memory function were significantly correlated with BMI, with poorer scores associated with higher BMIs. SIGNIFICANCE: A small but significant proportion of the variance in memory function and intellectual underfunction in people with epilepsy is explained by BMI. Further work is needed to establish whether a reduction in BMI to within healthy limits is associated with improvements in cognitive function in this group.

Bright light therapy for symptoms of anxiety and depression in focal epilepsy: randomised controlled trial.

BACKGROUND: Bright light therapy is an effective treatment for seasonal affective disorder and non-seasonal depression. Depression and anxiety are common psychiatric comorbidities in epilepsy. AIMS: To examine the efficacy of bright light therapy for symptoms of anxiety and depression in adults with focal epilepsy (trial registration at ClinicalTrials.gov: NCT01028456). METHOD: We recruited 101 adults with medically intractable focal epilepsy. Participants completed the Hospital Anxiety and Depression Scale (HADS) at the beginning (T1) and end of a 12-week baseline period (T2) and again after 12 weeks of daily light therapy (T3), with 51 participants using a high-intensity light box and 50 using a low-intensity one. Seizure diaries were kept throughout the baseline and trial period. RESULTS: A total of 58 patients completed the trial. Anxiety and depression scores were significantly reduced following the light therapy at T3 in both the high- and low-intensity groups. CONCLUSIONS: Light therapy resulted in a significant reduction in symptoms of anxiety and depression but we did not find any differences between high- v. low-intensity treatment. This may, therefore, be an effective treatment for symptoms of low mood in epilepsy at lower intensities than those typically used to treat seasonal affective disorder. Further work is needed to investigate this possibility with an adequate placebo condition.

Bright light therapy as an add on treatment for medically intractable epilepsy.

BACKGROUND: Bright light therapy (BLT) influences the regulation of melatonin and is an established treatment for seasonal affective disorder (SAD). This study was designed to examine the efficacy of BLT for seizure control in adults with focal epilepsy. DESIGN: 101 adults with medically intractable focal epilepsy were recruited to a parallel-design, double-blind, randomized trial of BLT as an add on treatment for epilepsy. METHODS: All patients monitored their seizure frequency at home for a 12-week baseline period (September 2010 to December 2010). 51 of the participants were allocated with a high-intensity (HI) light box emitting 10,000 lx using an automated permuted block randomization grid. 50 were allocated with a cosmetically identical box emitting 2000 lx (low-intensity - LI), a subtherapeutic dose in other patient populations. Both groups were instructed to use their box for 20-30 min, upon waking every day for 12 weeks (January-March 2011). The primary outcome measure for the trial was seizure frequency. RESULTS: 77 participants (39 high-intensity/38 low-intensity) completed the trial and returned adequate data for analyses. Median reduction of seizures during the treatment phase was 1.5 in the LI group and 3 in the HI group (p>0.05). 6 patients (15%) in the high-intensity condition experienced an overall reduction of 50% or more in the frequency of complex partial seizures compared to 9 (24%) patients who used the low intensity light box. Response rates in the HI and LI treatment conditions were not significantly different (p>0.05). Patients with hippocampal sclerosis were more likely to respond to BLT at either intensity than patients with other focal epilepsies (risk ratio=1.7 95% CI lower limit=0.6, upper limit=4.6). CONCLUSIONS: We did not find a significant difference in the responder rates in the low- vs. high-intensity arms of the trial. Some patterns within the data suggest that BLT may warrant further investigation as a treatment for people with hippocampal pathology. Our initial findings suggest that caution should be exercised in using BLT in people with extra temporal focal epilepsy as it may result in an increase in seizures for some.

Socioeconomic status, cognition, and hippocampal sclerosis.

OBJECTIVE: Poorer surgical outcomes in patients with low socioeconomic status have previously been reported, but the mechanisms underlying this pattern are unknown. Lower socioeconomic status may be a proxy marker for the limited economic opportunities associated with compromised cognitive function. The aim of this study was to examine the preoperative neuropsychological characteristics of patients with unilateral hippocampal sclerosis (HS) and their relationship to socioeconomic status. METHODS: Two hundred ninety-two patients with medically intractable temporal lobe epilepsy and unilateral HS completed tests of memory and intellectual function prior to surgery. One hundred thirty-one had right HS (RHS), and 161 had left HS (LHS). The socioeconomic status of each participant was determined via the Index of Multiple Deprivation (IMD) associated with their postcode. RESULTS: The IMD was not associated with age at the time of assessment, age at onset of epilepsy, or duration of active epilepsy. The RHS and LHS groups did not differ on the IMD. The IMD was negatively correlated with all neuropsychological test scores in the LHS group. In the RHS group, the IMD was not significantly correlated with any of the neuropsychological measures. There were no significant correlations in the RHS group. Regression analyses suggested that IMD score explained 3% of variance in the measures of intellect, but 8% of the variance in verbal learning in the LHS group. The IMD explained 1% or less of the variance in neuropsychological scores in the RHS group. Controlling for overall level of intellectual function, the IMD score explained a small but significant proportion of the variance in verbal learning in the LHS group and visual learning for the RHS group. CONCLUSIONS: Our findings suggest that patients living in an area with a high IMD enter surgery with greater focal deficits associated with their epilepsy and more widespread cognitive deficits if they have LHS. Further work is needed to establish the direction of the relationship between low socioeconomic status and the neurocognitive sequelae of epilepsy.

Cognitive consequences of childhood-onset temporal lobe epilepsy across the adult lifespan.

OBJECTIVES: To examine the influence of side of pathology and gender on changes in cognitive function across the adult lifespan in a homogenous sample of patients with mesial temporal lobe epilepsy (MTLE) associated with unilateral hippocampal sclerosis (HS). METHODS: We retrospectively examined the neuropsychological profiles of 382 patients in 3 cohorts: cohort 1 aged 18-30 (n = 171), cohort 2 aged 31-45 (n = 170), and cohort 3 aged 46-65 (n = 41). All participants had medically intractable seizures associated with unilateral HS and an onset of epilepsy in childhood, with an average onset at 7 years. RESULTS: There were no significant differences between the age cohorts on the measures of intellect, language, or memory. Duration of epilepsy (years) was not related to IQ, memory, or language scores in any group. Male subjects performed better than female subjects on verbal IQ, performance IQ, and naming tasks. Verbal learning and recall scores were worse in those with left than right HS. CONCLUSIONS: Our findings suggest that the profile of cognitive deficits associated with MTLE is already established as children with temporal lobe epilepsy enter adulthood. While memory and language skills are maximally affected, intellectual function is also compromised in MTLE. This profile appears to remain stable across the adult lifespan, at least until 60 years of age, despite the intractable nature of the seizures. Side of pathology and gender are significant mediating factors in shaping the profile of cognitive deficits associated with childhood-onset MTLE, with people with left-sided HS and female subjects particularly vulnerable to more widespread cognitive dysfunction.

The long-term retention of pregabalin in a large cohort of patients with epilepsy at a tertiary referral centre.

Pregabalin (PGB) is a new antiepileptic drug (AED) which is a structural, non-functional analogue of gamma-aminobutyric acid. It acts at presynaptic calcium channels to modulate neurotransmitter release in the CNS. While the efficacy and tolerability of PGB have been demonstrated in several randomised controlled trials, few studies have addressed long-term outcome in large groups of patients. A cohort of patients attending a tertiary referral centre for epilepsy was identified as having started taking PGB. Patients' data were obtained through medical records. Of 402 patients included, 42% of patients were still taking PGB at last follow-up. The estimated 2.5-year retention rate was 32%. Males appeared more likely to continue on PGB therapy than females. The common adverse experiences (AEs) leading to withdrawal were CNS-related, psychiatric AEs and weight gain. Published retention rates for levetiracetam appear to be higher, and those for gabapentin lower, than the rates estimated for PGB.

First report of Creutzfeldt-Jakob disease occurring in 2 siblings unexplained by PRNP mutation.

Sibling concurrence of pathologically confirmed prion disease has only been reported in association with pathogenic mutation of the prion protein gene (PRNP). Here, we report 2 siblings with classic neuropathologic features of sporadic Creutzfeldt-Jakob disease unexplained by PRNP mutation or known risk factors for iatrogenic transmission of prion infection. Possible explanations include coincidental occurrence, common exposure to an unidentified environmental source of prions, horizontal transmission of disease, or the presence of unknown shared genetic predisposition.

The socioeconomic, cultural, and emotional implications of starting or withholding treatment in a patient with a first seizure.

The decision to treat or not treat individuals who have suffered a single epileptic seizure is based on clinical factors, which are considered within the individual's social, cultural, and emotional environment. Even if optimally communicated, individuals and their carers will make different decisions about first seizures and their treatment, as they will judge the risks and benefits of treatment (or its deferment) in this wider context. There is a significant body of literature that describes the impact of established epilepsy on aspects of an individual's overall quality of life (QoL), and more recently evidence is emerging about the factors that may be important in 2 years after a single seizure on and off treatment. Little research, however, has considered the importance of nonclinical factors in individual's choices at the time of a first seizure, and in particular in an individual's decision to use or not use treatment. Understanding these issues may improve communication of risks and benefits to individuals, and may offer insight into the mechanisms by which social and socioeconomic disadvantage occur in epilepsy.

Antiepileptic drugs: generic versus branded treatments.

Antiepileptic drugs (AEDs) are relatively cheap but high volumes of prescriptions mean that substantial drug-budget savings may be possible by switching from innovator brands to cheaper generic drugs. Such savings have been achieved in many other treatment areas. However, more caution may be needed in the case of epilepsy because of the narrow therapeutic range of most AEDs; clinical principles of prescribing, which include making only cautious and gradual changes to dosing; the health and socioeconomic impact of breakthrough seizures or toxicity; and the need for long-term consistency of supply. Many physicians and patient groups are insufficiently reassured by current definitions of similarity between generics and innovator brands. Switching to the cheapest generic AED may offer drug-budget savings that outweigh any risk to patient safety. But to date, this cost-benefit analysis has not been done. We propose that all changes to established principles of treating epilepsy are evidence based and that the risks of switching are clearly defined.

Home versus outpatient administration of intravenous steroids for multiple-sclerosis relapses: a randomised controlled trial.

BACKGROUND: Intravenous steroids are routinely used to treat disabling relapses in multiple sclerosis, and can be administered in an outpatient or home setting. We developed a rating scale that allowed us to compare the two strategies formally in a trial setting. METHODS: Patients who had a clinically significant multiple-sclerosis relapse within 4 weeks of onset were randomly assigned administration of a 3-day regimen of intravenous methylprednisolone either in an outpatient clinic (n=69) or at home (n=69). The MS relapse management scale (MSRMS) was developed to measure patients' experiences of relapse management as the primary outcome. Efficacy of the two treatment modalities was compared in terms of traditional measures and economic cost. A cost-minimisation analysis was also done. Analysis was by intention to treat. FINDINGS: Of 149 eligible patients, 138 consented to participate in the trial and were randomly assigned to a treatment group. Coordination of care was significantly better in the home-treatment group (median score 4.5 [IQR 3.0-11.4]) than in the hospital-treatment group (12.1 [3.0-18.6]; p=0.024). The other dimensions of the MSRMS did not differ between groups (p>0.10). Administration of steroids was equally safe and effective in either location, and cost was either the same or cheaper when delivered at home than when delivered in hospital. INTERPRETATION: Treatment of relapses in multiple sclerosis with intravenous steroids can be effectively and safely administered at home, from both patient and economic perspectives. Moreover, the trial indicates the importance of explicit and valid outcome measures of all aspects of service delivery when making decisions about health policy. This finding has implications for complex service delivery care models for long-term diseases.

Cost-effectiveness of carbamazepine in epilepsy.

Carbamazepine is widely recommended as a first-line antiepileptic drug for new-onset partial seizures with or without generalization. Branded carbamazepine remains commonly prescribed. Newer antiepileptic drugs have higher acquisition costs than carbamazepine, but may offer advantages in terms of tolerability and side-effect profile that may offset their additional cost. Furthermore, generic carbamazepine is often cheaper than branded forms, and many argue for a policy of prescribing the cheapest available generic form. This study reviews the scant health economic data concerning the use of carbamazepine to treat epilepsy to establish whether use of this drug is cost effective. Carbamazepine would appear to be a cost-effective treatment for epilepsy in certain contexts, although evidence from a prospective, randomized, controlled trial is awaited and this assertion may not be true for certain patient subgroups, or in developing world health services. Furthermore, at this time there is insufficient evidence to support policies of cheapest generic or brand-only prescribing.