Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population.

Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

Psychogenic non-epileptic seizure in patients with intellectual disability with special focus on choice of therapeutic intervention.

PURPOSE: There have been a number of studies exploring treatments for psychogenic non-epileptic seizure (PNES) but largely neglecting the sizable subgroup of patients with intellectual disability (ID). In the present study, we attempted to demonstrate effects and preferred modes of therapeutic intervention in PNES patients with ID being treated at a Japanese municipal center with a short referral chain. METHODS: We examined 46 PNES patients with ID (ID group) and 106 PNES patients without ID (non-ID group) retrospectively in case charts. In addition to examining basic demographic and clinical data, effects of different therapeutic intervention were examined as a function of decrease or disappearance of PNES attacks in the ID group. RESULTS: Age at the first visit as well as PNES onset was younger in the ID than in the non-ID group (t=2.651, p=0.009; t=3.528, p=0.001, respectively). PNES-free ratio at the last visit tended to be higher in the non-ID group (chi square=3.455; p=0.063). Psychosis was more often encountered in the ID group (chi square=13.443; p=0.001). Although cognitive therapy and pharmaco-therapeutic approaches were quite similarly distributed in both groups, environmental adjustment was often introduced in the ID group (44%) as compared to the non-ID group (15%) (chi square=14.299; p=0.001). Brief weekly visit service is also more often utilized by the patients with ID (54%) than by those without ID (35%) (chi square=5.021, p=0.025). CONCLUSIONS: Optimal treatment approaches in this sizable patient subgroup should be the subject of future prospective studies.

PNES around the world: Where we are now and how we can close the diagnosis and treatment gaps-an ILAE PNES Task Force report.

An international consensus clinical practice statement issued in 2011 ranked psychogenic nonepileptic seizures (PNES) among the top three neuropsychiatric problems. An ILAE PNES Task Force was founded and initially charged with summarizing the current state of the art in terms of diagnosis and treatment, resulting in two publications. The first described different levels of diagnostic certainty. The second summarized current knowledge of management approaches. The present paper summarizes an international workshop of the ILAE PNES Task Force that focused on the current understanding and management of PNES around the world. We initially provide a knowledge update about the etiology, epidemiology, and prognosis of PNES-in adults and in special patient groups, such as children, older adults, and those with intellectual disability. We then explore clinical management pathways and obstacles to optimal care for this disorder around the world by focusing on a number of countries with different cultural backgrounds and at very different stages of social and economic development (United Kingdom, U.S.A., Zambia, Georgia, China, and Japan). Although evidence-based methods for the diagnosis and treatment of PNES have now been described, and much is known about the biopsychosocial underpinnings of this disorder, this paper describes gaps in care (not only in less developed countries) that result in patients with PNES not having adequate access to healthcare provisions. A range of challenges requiring solutions tailored to different healthcare systems emerges. Continued attention to PNES by the ILAE and other national and international neurologic, psychiatric, and health organizations, along with ongoing international collaboration, should ensure that patients with PNES do not lose out as healthcare services evolve around the world.

Delusional experience awareness gap between patients and treating doctors - Self-reported EPDS questionnaire.

OBJECTIVES: Although early and rapid recognition of a psychotic trend in patients with epilepsy certainly pay dividends, there is no handy assessment instrument for screening because of multiple intrinsic difficulties such as lack of a standard screener as well as a reliability gap for screeners between help-seeking and general populations. On the other hand, the predominance of positive symptoms at the initial stage of psychosis is a promising aspect of this specific group. The following specific questions were examined. Is there a measurable difference between the assessment of the treating doctor and the real feelings of the patient? How well does the attained score correspond to the clinical diagnosis? METHODS: The self-reported Emotions with Persecutory Delusions Scale (EPDS) questionnaire, previously validated in a general population, was used as the assessment tool for psychotic trend in 79 outpatients with epilepsy. Independent from scoring by the patients, the treating doctors also expressed their impressions about the same patients using the same scoring tool. RESULTS: Stepwise multiple regression analysis of the EPDS scores of both doctors and patients revealed that a clinical diagnosis of psychosis was the only independent variable significantly related to EPDS score. Also, there was a significant difference between the EPDS scores of the patients and those of the doctors, in favor of the former. SIGNIFICANCE: Clinical diagnosis of psychosis proved to be the most powerful determinant of EPDS score independent from other clinical factors. The awareness gap between doctors and patients based on EPDS score revealed that treating doctors often clearly underestimate the psychotic trend of their patients. Our findings suggest that such simple tests as EPDS, with a narrow focus on attenuated delusional symptoms, may help screen for an early psychotic episode in patients with epilepsy that may otherwise not be diagnosed by their physicians.

[Therapeutic strategy for mental symptoms in people with epilepsy].

Epilepsy has an association with nearly all types of psychiatric problems and psychiatric symptoms are common clinical manifestations seen in epilepsy patients. For example, interictal depression in individuals with epilepsy is more prevalent than in the general population or among patients with other chronic disorders. The high frequency of depression and clinical impact of psychosis in epilepsy have been well documented in recent studies, indicating the importance of diagnosing and treating psychiatric implications in affected patients. This article reviews various psychiatric symptoms such as postictal psychosis, interictal psychosis, depression, psychogenic non-epileptic seizure(PNES), and cognitive dysfunction encountered in patients with epilepsy.

Anger is a distinctive feature of epilepsy patients with depression.

Controversy exists regarding the similarity between depression as seen in patients with epilepsy and in those with idiopathic major depression. The objective of this study was to examine whether anger is a distinctive feature of depression in epilepsy. Participants included 487 adult patients with epilepsy (study group) and 85 patients with idiopathic major depression according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria, and without other neurological complications (control group). All participants completed the Inventory of Depressive Symptomatology Self-Report (IDS-SR) and the Buss-Perry Aggression Questionnaire (BAQ). The IDS-SR is a self-report questionnaire that measures depression severity and assesses all symptoms of depression as defined by the DSM-IV. The BAQ is a self-rating scale designed for assessing aggression. After examining potential confounding factors (i.e., demographic and clinical variables) using a multivariate linear regression model, BAQ scores were compared between the study (n = 85) and control groups (n = 54) for patients with moderate or severe depression using established cut-off points (IDS-SR score > 25). BAQ scores were significantly higher in the study group (P = 0.009). Among the BAQ subscales, only anger showed a statistically significant difference (P = 0.013). Although a significant correlation was revealed between the IDS-SR and BAQ scores in the study group, no such correlation was found in the control group. Thus, anger might be a constituent component of depression among epilepsy patients, but not among idiopathic major depression patients.

Basic treatment principles for psychotic disorders in patients with epilepsy.

In patients with epilepsy, coexisting psychoses, either interictal (IIP) or postictal (PIP), are associated with serious disturbance in psychosocial function and well-being, and often require the care of a specialist. Unfortunately, evidence-based treatment systems for psychosis in patients with epilepsy have not yet been established. This article aims to propose concise and practical treatment procedures for IIP and PIP based on currently available data and international consensus statements, and primarily targeting nonpsychiatrist epileptologists who are often the first to be involved in the management of these complex patients. Accurate and early diagnosis of IIP and PIP and their staging in terms of acuity and severity form the essential first step in management. It is important to suspect the presence of psychosis whenever patients manifest unusual behavior. Knowledge of psychopathology and both individual and epilepsy-related vulnerabilities relevant to IIP and PIP facilitate early diagnosis. Treatment for IIP involves (1) obtaining consent to psychiatric treatment from the patient, whenever possible, (2) optimization of antiepileptic drugs, and (3) initiation of antipsychotic pharmacotherapy in line with symptom severity and severity of behavioral and functional disturbance. Basic psychosocial interventions will help reinforce adherence to treatment and should be made available. Due consideration must be given to patients' ability to provide informed consent to treatment in the short term, with the issue being revisited regularly over time. Given the often prolonged and recurrent nature of IIP, treatment frequently needs to be long-term. Treatment of PIP consists of two aspects, that is, acute protective measures and preventive procedures in repetitive episodes. Protective measures prioritize the management of risk in the early stages, and may involve sedation with or without the use of antipsychotic drugs, and the judicious application of local mental health legislation if appropriate. As for preventative procedures, optimizing seizure control by adjusting antiepileptic drugs or by surgical treatment is necessary.

[How to cope with psychiatric illness in patients with epilepsy].

Almost every kind of psychiatric problems are associated with epilepsy such as psychotic states, manic as well as depressive states and anxiety attacks. Overall, the prevalence of psychiatric comorbidities in patients with epilepsy amounts to as high as 20-30% of all cases. Acute and chronic interictal psychoses, as well as postictal psychosis (or more precisely periictal psychosis), comprise 95% of psychosis in patients with epilepsy. Prevalence of depressive states in patients with yet active epilepsy ranges from 20-55%. Prevalence in patients with controlled epilepsy ranges from 3-9%. Depressive states comprise 50-80% of psychiatric co-morbidities in patients with epilepsy. Several studies reported that PNES amounted to as high as 30% among patients considered as candidates for epilepsy surgery due to intractable epilepsy. It is of clinical use that PNES is divided into 3 groups: The first group belongs to PNES without either intellectual disability nor epilepsy; The second group suffers from intellectual disability in addition to PNES; The third group shows both epileptic seizure and PNES. These groups need to be differently treated. After temporal lobectomy for controlling pharmacoresistant TLE, severe but transient depression possibly leading to suicide can appear, especially within the first few months after surgery.

Psychotic illness in patients with epilepsy.

Apart from the rather rare ictal psychotic events, such as non-convulsive status epilepticus, modern epileptic psychoses have been categorized into three main types; chronic and acute interictal psychoses (IIPs) and postictal psychosis (PIP). Together, they comprise 95% of psychoses in patients with epilepsy (PWE). Four major questions, that is, "Is psychosis in PWE a direct consequence of epilepsy or schizophrenia induced by epilepsy?", "Is psychosis in PWE homogeneous or heterogeneous?", "Does psychosis in PWE have symptomatological differences from schizophrenia and related disorders?", "Is psychosis in PWE uniquely associated with temporal lobe epilepsy (TLE)?" are tried to be answered in this review with relevant case presentations. In the final section, we propose a tentative classification of psychotic illness in PWE, with special attention to those who have undergone epilepsy surgery. Psychotic disorders in PWE are often overlooked, mistreated, and consequently lingering on needlessly. While early diagnosis is unanimously supported as a first step to avoid this delay, necessity of switching from antiepileptic drugs with supposedly adverse psychotopic effects. to others is more controversial. To elucidate the riddle of alternative psychosis, we need badly further reliable data.

Screening for major depressive episodes in Japanese patients with epilepsy: validation and translation of the Japanese version of Neurological Disorders Depression Inventory for Epilepsy (NDDI-E).

We validated and translated into Japanese the English version of the screening instrument Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to identify major depressive episodes in patients with epilepsy. A total of 159 Japanese subjects with epilepsy underwent a psychiatric structured interview with the Japanese version of the Mini International Neuropsychiatric Interview (M.I.N.I.-J) followed by completion of the Japanese version of NDDI-E (NDDI-E-J). Twelve participants met the M.I.N.I.-J criteria of current major depressive episode. Participants had no difficulties completing the NDDI-E-J. Its Cronbach's alpha coefficient was 0.83 and a cut-off score greater than 16 provided a sensitivity of 0.92, a specificity of 0.89, and a negative predictive value of 0.99. The NDDI-E-J appears to be useful for primary care clinicians to screen for major depressive episodes in epilepsy patients. Routine use of this brief and self-administered instrument in busy clinical settings will likely improve management of depression in Japanese individuals with epilepsy.

Lack of data on depression-like states and antidepressant pharmacotherapy in patients with epilepsy: randomised controlled trials are badly needed.

The prevalence of depression in patients with epilepsy (PWE) is high. To elucidate the nature of depression in PWE, a comparison was made between PWE and patients with idiopathic depression (PWID), applying 3 test batteries: Beck Depression Inventory II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D) and Buss-Perry Aggression Questionnaire (BAQ). The former 2 rating scales were developed to measure depressive symptoms, while the latter was designed to detect anger and aggressive states. As a result, the group of patients with PWE showed significantly higher BAQ scores in comparison to those with PWID. Further, the BAQ and BDI scores were closely related within a group of PWE, while BAQ and BDI scores were not correlated with each other within a group of PWID. With regard to pharmaceutical therapy, the safety of antidepressants, especially SSRIs, is well established. However, there has been only one randomized controlled trial (RCT) thus far, which failed to show a significant difference in efficacy between placebo and various antidepressants. In contrast, there are two RCTs regarding the efficacy of LTG. The clinical profile of the depressiolytic effects of LTG in PWE may be different from that of antidepressants in patients with idiopathic depression, in that BAQ is more sensitive measure than BDI or CES-D. It is now widely recognized that the failure to treat depression in PWE can result in serious consequences. However, even a fundamental question, such as whether antidepressants are as effective in this population as in PWID, remains to be answered.

Impact of antiepileptic drugs on genesis of psychosis.

Opinions regarding the impact of antiepileptic drugs (AEDs) on the genesis of psychotic symptoms are varied. To re-examine this issue, the records of adult patients with partial epilepsy and newly added AEDs were retrospectively surveyed. The types of newly added AEDs and clinical characteristics were compared between 38 patients with active psychosis and 212 without psychotic history during a follow-up period of 3 to 6 months after initiation of AED administration. Using multivariate logistic regression analysis, the significance of possible predictive variables for development of psychosis was evaluated, which demonstrated that use of zonisamide (ZNS) and phenytoin (PHT), presence of complex partial seizures (CPS), and low intelligence level were significantly correlated with psychosis. We concluded that ZNS and PHT are possible risk factors for development of psychosis along with clinical variables, including the presence of CPS and low intelligence level.

SPECT findings during postictal psychoses: predominance of relative increase of perfusion in right temporal lobe.

To identify brain regions activated during episodes of postictal psychoses (PIP), we investigated single-photon emission computed tomography (SPECT) data obtained from five patients treated at our institutions and also reviewed four previous studies. Therefore, SPECT findings in a total of 19 cases were analyzed, including 16 patients with temporal lobe epilepsy (TLE). During nonpsychotic states, the laterality of epileptic foci was judged as left-sided in nine episodes, right-sided in six episodes, and nonlateralized in four episodes. In PIP states, 88% of the patients showed a relative increase of right temporal perfusion (increased right temporal or decreased left temporal perfusion). Regardless of whether right- or left-sided pathology was suspected during a nonpsychotic state, SPECT findings obtained during PIP episodes revealed a trend of right-sided temporal predominance.

Lamotrigine improves aggression in patients with temporal lobe epilepsy.

Aggression in patients with temporal lobe epilepsy (TLE) may have phenomenological and neurobiological heterogeneity. In the present study, we targeted patients with TLE who showed aggression and evaluated the effects of lamotrigine on this symptom using the Buss-Perry Aggression Questionnaire (BAQ), which is based on a four-factor model that includes Physical Aggression, Verbal Aggression, Anger, and Hostility. As compared with the healthy control subjects (n=115), patients with TLE (n=21) had significantly higher BAQ Total, Physical Aggression, Anger, and Hostility scores. Ten weeks after initiation of lamotrigine, the BAQ Total and Anger scores of the patients with TLE were significantly improved. However, the patients with TLE in this study did not exhibit depressive symptoms. Our results suggest that lamotrigine mitigates aggression, especially anger, which represents the emotional factor of aggression in the BAQ.

[Therapeutic strategy for mental symptoms and behavioral problems in people with epilepsy].

Biological and psycho-sociological perspectives are crucial to the complete understanding of the influence of epilepsy on human behavior. In epilepsy, mental dysfunctions caused by direct damage to the brain can be classified into 3 components on the basis of the causative factor: underlying disorder, epilepsy itself, and antiepileptic drugs. Here, we emphasize that for people with epilepsy, the first step of any effective therapeutic approach to psychiatric symptoms is a comprehensive holistic survey of their life to identify the most imminent problem hindering their goodness of life.

Violence and postictal psychosis: a comparison of postictal psychosis, interictal psychosis, and postictal confusion.

The belief that epilepsy is linked with violent behavior acquired a highly stigmatizing value in the late 19th century on the basis of degenerative theory. This widespread medical view lost general acceptance among experts in the 1990s after several large-scale studies showed that aggressive phenomena can arise during epileptic seizures, but are extremely rare. The concept of postictal psychosis (PIP) shed a new light on this old dispute. With this concept, the significance of the chronological relationship between seizures and violent behaviors in patients with epilepsy is newly stressed, which made a simple "yes" or "no" answer to the question implausible. In this review, we discuss violent behaviors at five chronological points relative to seizures and demonstrate representative cases. As shown in our previous study, well-directed violent attacks occurred during 22.8% of the PIP episodes, 4.8% of the IIP episodes, and 0.7% of the postictal confusions. Compared with the other two situations, proneness to violence stood out in the PIP episodes. Suicidal attempts showed a similar trend. Purposeful, organized violence as a direct manifestation of seizures or ictal automatism is highly exceptional. Violent acts could occur in postictal confusion as an expression of unconscious, vigorous resistance against efforts of surrounding people to prevent the affected individual from roaming or fumbling about. In contrast, some PIP episodes can be highly alarming, especially if a violent act has been previously committed in preceding episodes. Violent acts by patients with epilepsy should be treated differently according to the various pathophysiological backgrounds from which the violence arises.

Interictal psychoses in comparison with schizophrenia--a prospective study.

PURPOSE: To prospectively investigate the incidence of interictal psychoses of epilepsy patients, and make a comparison between those with interictal psychoses and patients with schizophrenia in respect to their responses to antipsychotic drugs, as well as psychotic states. METHODS: We undertook a two-part prospective investigation. In Part I, the psychotic episodes of 619 epilepsy patients were investigated, while 182 patients with psychotic syndromes were followed in Part II, of whom 59 were diagnosed with schizophrenia and 13 with epilepsy with interictal psychoses. The Positive and Negative Syndrome Scale was used for efficacy assessment. RESULTS: The average annual incidence of interictal psychosis was 0.42% during the 56-month study period. A significant difference was found between patients with schizophrenia and epilepsy patients with interictal psychoses in respect to results on the negative subscale of the PANSS at the initial examination (mean scores of 18.1 and 13.2, respectively, p = 0.004). The response rates one year later for these groups were 27.1% and 53.8%, respectively, which showed a trend of better response to the antipsychotic medication by the epilepsy group (p = 0.098). Initial and maximum doses of antipsychotic drugs used for epilepsy patients with interictal psychoses were significantly lower than those used for patients with schizophrenia (p = 0.008 and p = 0.006, respectively). CONCLUSIONS: Schizophrenia and epileptic psychosis showed different symptom profiles. On average, epilepsy patients with interictal psychoses achieved higher remission rates with lower doses of antipsychotic drugs as compared to patients with schizophrenia in the present 1-year follow-up study.

Postictal autoscopy in a patient with partial epilepsy.

Autoscopy is an experience of seeing oneself in external space, viewed from within one's own physical body. It is a complex psycho-sensorial hallucinatory perception of one's own body image projected into external visual space, with epilepsy one of the common disorders reported to be associated with the experience. A survey of the literature revealed that there are few case reports of postictal autoscopic phenomena. Herein, we report a case of a patient with partial epilepsy who has experienced postictal autoscopy for nearly 30 years. Although the neurological mechanisms that cause autoscopic phenomena are not fully understood, wish-fulfilling fantasies released as a result of a shaken integrity regarding personal bodily image may contribute to the shaping of the symptoms, at least in the case of postictal autoscopy.

A prospective study of postictal psychoses with emphasis on the periictal type.

PURPOSE: To assess prospectively episodes of postictal psychosis. METHODS: We followed 108 consecutive patients with temporal lobe epilepsy, who were divided into three groups: those without psychotic episodes (n=87, N group), those with interictal psychosis (n=13, IIP group), and those with postictal psychosis (n=8, PIP group). The first episode of postictal psychosis, which was defined as a psychotic episode that occurred within 1 week after the end or within 3 days before the beginning of seizure clusters, was assessed with the Brief Psychiatric Rating Scale (BPRS) and Social Dysfunction and Aggression Scale (SDAS) during the observation period. RESULTS: The duration of illness was significantly different between the N and PIP groups (p=0.004) and between the N and IIP groups (p=0.039). The average initial BPRS score (obtained 3.0 days after the end of the seizure cluster) was 19.7, and then decreased to 5.8 after 1 week, and finally normalized at 1.5 after 1 month. A statistically significant decrease in BPRS scores was found between the initial assessment and those obtained after 1 week (p=0.011). Those who had psychotic episodes without a lucid interval tended to have episodes more often than monthly, and experienced additional seizure recurrence even during the psychotic episodes. Two patients exhibited a frank manic phase, and three patients showed excessively aggressive behavior, as determined by the SDAS. CONCLUSIONS: Postictal psychosis should be subdivided into the nuclear type, with an established clinical picture as an indirect aftereffect of seizure activity, and the atypical periictal type, which is a direct manifestation of limbic discharge.