Marco Mula

The global burden and stigma of epilepsy

Epilepsy is one of the most prevalent neurological conditions and it knows no age, racial, social class, geographic, or national boundaries. The impact of epilepsy rests not only on the individual patient, but also on the family and indirectly on the community. The burden of epilepsy may be due to the physical hazards of epilepsy resulting from the unpredictability of seizures; the social exclusion as a result of negative attitudes of others toward people with epilepsy; and the stigma, as children with epilepsy may be banned from school, adults may be barred from marriage, and employment is often denied, even when seizures would not render the work unsuitable or unsafe. Furthermore, epilepsy is a disorder associated with significant psychological consequences, with increased levels of anxiety, depression, and poor self-esteem compared with people without this condition. Here we discuss some of the aspects of the global burden of epilepsy.

Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan

Epilepsy is a common neurological disorder that is complicated by psychiatric, cognitive, and social comorbidities that have become a major target of concern and investigation in view of their adverse effect on the course and quality of life. In this report we define the specific psychiatric, cognitive, and social comorbidities of paediatric and adult epilepsy, their epidemiology, and real life effects; examine the relation between epilepsy syndromes and the risk of neurobehavioural comorbidities; address the lifespan effect of epilepsy on brain neurodevelopment and brain ageing and the risk of neurobehavioural comorbidities; consider the overarching effect of broader brain disorders on both epilepsy and neurobehavioural comorbidities; examine directions of causality and the contribution of selected epilepsy-related characteristics; and outline clinic-friendly screening approaches for these problems and recommended pharmacological, behavioural, and educational interventions.

Negative Effects of Antiepileptic Drugs on Mood in Patients with Epilepsy

With the introduction of several new antiepileptic drugs into clinical practice, renewed attention has been focussed on treatment-emergent adverse effects, including mood disorders. There are several possible causes of psychiatric disorders in patients with epilepsy, including antiepileptic drugs, and it is often difficult to determine whether psychopathological manifestations, especially depressive symptoms, are due to drug therapy or to multiple other factors. Assessment of the negative effects of antiepileptic drugs on mood should always consider all potential factors. Case series, audits and open observational studies can identify psychopathological features, case-control studies are useful for identifying the endophenotypes of patients at risk of adverse effects on mood, and controlled clinical trials give good estimates of incidence of such effects, adjusted for the spontaneous occurrence of symptoms.The barbiturates, vigabatrin and topiramate show greater associations with the occurrence of depressive symptoms than other antiepileptic drugs, presenting in up to 10% of all patients, but even more so in susceptible patients. Data on zonisamide are scarce but it seems that mood disorders may occur in approximately 7% of patients who are receiving high dosages of this drug. In most cases, the use of monotherapy, with slow titration schedules, can significantly reduce the incidence of mood disorders. Tiagabine, levetiracetam and felbamate present an intermediate risk, with prevalence of depression of about 4% or lower. Phenytoin, ethosuximide, carbamazepine, oxcarbazepine, gabapentin, sodium valproate, pregabalin and lamotrigine are all associated with low risks for depression (<1%), and several of these antiepileptic drugs seem to have a positive effect on mood. Antiepileptic drugs can negatively affect mood and behaviour by different mechanisms: potentiation of GABA neurotransmission, folate deficiency, pharmacodynamic interactions with other antiepileptic drugs in polytherapy regimens, forced normalisation.Individuals with a personal or family history of depression should be carefully followed after initiation of therapy with a new antiepileptic drug, especially if structural brain abnormalities such as hippocampal sclerosis are present.

International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy

In order to address the major impact on quality of life and epilepsy management caused by associated neuropsychiatric conditions, an international consensus group of epileptologists met with the aim of developing clear evidence‐based and practice‐based statements to provide guidance on the management of these conditions. Using a Delphi process, this group prioritized a list of key management areas. These included: depression, anxiety, psychotic disorders, nonepileptic seizures, cognitive dysfunction, antiepileptic drug (AED)–related neurobehavioral disorders, suicidality, disorders in children and adolescents, disorders in children with intellectual disability, and epilepsy surgery. Clinical practice statements were developed for each area and consensus reached among members of the group. The assessment and management of these conditions needs to combine knowledge of psychiatric disorders, knowledge of the impact of epilepsy and its treatment on psychopathology, and an ability to deliver care within epilepsy services. The aim of these statements is to provide guidance on quality care for people with epilepsy that have a range of neuropsychiatric disorders.

Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors.

Cognitive dysfunction is frequently observed in patients with epilepsy and represents an important challenge in the management of patients with this disorder. In this respect, the relative contribution of antiepileptic drugs (AEDs) is of relevance. The fact that a considerable number of patients require AED therapy for many years, or perhaps even a lifetime, emphasizes the need to focus on the long-term adverse effects of these drugs on cognition.The most prevalent of the CNS adverse effects observed during AED therapy are sedation, somnolence, distractibility, insomnia and dizziness. Sedation, in particular, is associated with most of the commonly used AED therapies. Nevertheless, cognitive function in individuals with epilepsy may also be influenced by several factors, of which AEDs constitute only one of many putative causes.In general terms, most studies agree that some differences exist among the older AEDs with regard to the effects on cognition, and some newer generation molecules may have a better cognitive profile than older AEDs. The mechanisms of action are an obvious determinant; however, there is still a lack of evidence for differentiation between available drugs with regard to cognitive effects. Some authors have suggested that there may be different cognitive effects associated with individual drugs; however, the question as to whether there are more specific deficits related to the action of individual drugs remains unsolved.There seems to be agreement that polytherapy and high-dose treatment can produce cognitive adverse effects and when high dosages or adjunctive polytherapy is needed, the balance between benefits and disadvantages may be negatively biased against drug treatment. Thus, drug treatment requires careful balancing in the attempt to reach maximal seizure control while avoiding neurotoxic adverse effects.Finally, the mood status of the patient and clinical relevance of the information obtained by neuropsychological testing represent important variables that need to be taken into account when discussing cognitive adverse effects of AEDs.

Antiepileptic drugs and psychopathology of epilepsy: an update

Anti-epileptic drugs (AEDs) continue to be the mainstay of epilepsy treatment, but the benefits of seizure control need to be weighed carefully against possible adverse effects, which can include behavioral problems and psychiatric disorders. In this paper, the associations between AEDs and psychosis, depression and behavioral changes are reviewed. The concept of forced normalization and its clinical counterpart, alternative psychosis, are also discussed. Depression seems to be linked with AEDs potentiating GABAergic neurotransmission in patients with limbic system abnormalities such as hippocampal sclerosis. Psychoses have been described as associated with several of the new AEDs, and they are often seen in a setting in which previously refractory patients suddenly become seizure-free. In general terms, the use of AEDs in monotherapy, adopting slow titration schedules and low doses when possible, can significantly reduce the occurrence of behavioral adverse effects. A previous history of psychiatric disorder or a familial predisposition are important risk factors and should be always considered when choosing the appropriate AED.

Neuroanatomic correlates of psychogenic nonepileptic seizures: A cortical thickness and VBM study

Purpose:  Psychogenic nonepileptic seizures (PNES) are among the most common clinical manifestations of conversion disorder and consist of paroxysmal behavior that resembles epileptic seizures. Preliminary data from functional neuroimaging studies gave plausible evidence that limbic circuits and sensorimotor cortex might be engaged in conversion disorder. Nonetheless, no advanced magnetic resonance imaging (MRI) studies have focused on patients with PNES.

Clinical and psychopathological definition of the interictal dysphoric disorder of epilepsy.

Purpose: Different authors suggested the occurrence of a pleomorphic affective syndrome in patients with epilepsy named interictal dysphoric disorder (IDD). We sought to investigate whether IDD occurs only in patients with epilepsy and to validate IDD features against DSM‐IV criteria.

Topiramate and word-finding difficulties in patients with epilepsy.

Objective: To evaluate the prevalence of word-finding difficulties as a treatment-emergent adverse event in patients with epilepsy taking topiramate and to identify a clinical phenotype at risk. Methods: The authors investigated the relationship of word-finding difficulties to topiramate titration schedule, seizure frequency and pattern, and EEG and neuroradiologic findings in 431 consecutively and prospectively collected patients taking topiramate. Results: Thirty-one patients (7.2%) developed word-finding difficulties. Presence of simple partial seizures (OR = 6.7 p = 0.007) and a left temporal EEG epileptic focus (OR = 5.2 p = 0.021) were significantly associated with word-finding difficulties. Conclusions: The presence of word-finding difficulties seems to be a titration schedule independent phenomenon that occurs in a subgroup of patients with a specific biologic vulnerability.

Suicidality in People Taking Antiepileptic Drugs: What is the Evidence?

Suicide is an important cause of premature death. In the general population, most people who commit suicide have a psychiatric problem at the time. People with epilepsy are thought to be at increased risk from suicide and suicidality (suicidal ideation or behaviour). Standardized mortality ratios estimated for suicide in people with epilepsy are usually between 3 and 5. Risk factors for suicide in people with epilepsy have been suggested, including early age of onset of seizures, temporal lobe epilepsy, severe seizures and recent control of seizures. Psychiatric co-morbidity also seems to be an important factor in people with epilepsy who commit suicide.In recent years, suicidality has been recognized as a complication of several groups of drugs and, most recently, antiepileptic drugs (AEDs) have been implicated. The US FDA performed a meta-analysis of 199 placebo-controlled studies of 11 AEDs used for seizure control, psychiatric or ‘other’ indications. There were four completed suicides in those taking AEDs and none in those taking placebo. The odds ratio for suicidal behaviour or ideation was 1.8 (95% CI 1.24, 2.66), suggesting that people taking AEDs are more at risk than those taking placebo. The odds ratio was significantly raised for people taking AEDs for epilepsy, but not for the other indications.AEDs may affect mood by means of several mechanisms. In people with epilepsy, however, the concept of forced normalization (or alternative psychosis) may also play a part. In this situation, control of seizures (by AEDs or epilepsy surgery) may alternate with psychotic features or, less commonly, depression, although this is not fully understood.The risk of suicidal ideation and behaviour as adverse effects of AED treatment, although increased, seems low. As a result of the FDA’s alert clinicians are supposed to inform patients and their families of this increased risk but it is important to place it in a proper perspective. Some people with epilepsy are more likely to develop psychiatric adverse effects with any AEDs, and these people should be followed closely whenever a new AED is introduced. Nonetheless, in people with epilepsy the risk of suicidality associated with AEDs needs to be balanced against the risk of not treating the seizures. In fact, the risk of stopping AEDs or refusing to start AEDs for the control of a seizure disorder may be significantly worse and may result in serious harm, including death of the patient