Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.

PURPOSE: Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy. METHODS: As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs. RESULTS: Psychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P<0.001, OR=6.87). Levetiracetam was also significantly (P<0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P<0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P<0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients. CONCLUSIONS: Psychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.

Drug-resistant epilepsy in adults: Outcome trajectories after failure of two medications.

OBJECTIVE: To examine the seizure trajectories of adults with epilepsy developing drug-resistant epilepsy (DRE) and to identify the predictors of seizure trajectory outcome. METHODS: Adult patients failing two antiepileptic drugs (AEDs) due to inefficacy and starting their third AED at a tertiary epilepsy center were followed for seizure trajectory outcome during medical management. Seizure trajectories were categorized into one of four patterns: (1) course with constant seizures; (2) fluctuating course; (3) delayed attainment of seizure freedom (seizure freedom delayed for >12 months after start of the study, but patient stayed in seizure freedom); and (4) early attainment of seizure freedom (within 12 months of starting study). Multiple ordinal logistic regression models were used to estimate the association between trajectory categories and clinical factors. RESULTS: Four hundred three adult patients met the eligibility criteria. Of these, 212 (53%) never achieved a seizure-free period of a year or more. The trajectories of 63 patients (16%) had a complex fluctuating trajectory, 62 (15%) had delayed onset of seizure freedom, and 66 (16%) had an early seizure freedom. Independent predictors associated with more favorable outcome trajectories were epilepsy type and length of follow-up. Specifically, compared to patients with focal epilepsy of temporal lobe, patients with focal epilepsy of occipital lobe (OR 3.80, 95% confidence interval [CI] 1.00-14.51, p = 0.04), generalized genetic (OR 3.23, 95% CI 1.88-5.57, p < 0.0001), unclear epilepsy type (OR 3.82, 95% CI 1.53-9.52, p < 0.005), and both focal and generalized epilepsy(OR 11.73, 95% CI 1.69-81.34, p = 0.01) were significantly more likely to experience a better trajectory pattern. SIGNIFICANCE: Examination of patterns of seizure trajectory of patients with incident DRE showed that 31% were in continuous seizure freedom at the end of the observation period.

Cross-sensitivity of patient-perceived adverse cognitive effects with antiepileptic drug use.

OBJECTIVE: The extent to which adverse cognitive effects (ACEs) to a specific antiepileptic drug (AED) affect the chance of developing ACEs to other AEDs (i.e., cross-sensitivity) is unknown. We investigated the rates of cross-sensitivity of ACEs among AEDs and examined the association between clinical characteristics and occurrence of having ACEs to multiple AEDs in adults with epilepsy. METHODS: The rates of cross-sensitivity of intolerable ACEs (IACEs; i.e., ACEs leading to dosage reduction or discontinuation) and the non-AED predictors of IACEs were investigated in 2269 patients who had taken at least two AEDs at a single center. We accounted for AED load and looked for specific cross-sensitivities between AEDs as well as cross-sensitivity based on the AED mechanism of action. RESULTS: Among the 2269 patients, the highest rates of IACEs were seen with TPM (26.3%), ZNS (9.8%), PHT (8.8%), and VPA (8.5%). Intolerable ACEs to two or more AEDs occurred in 100 patients (4.4%). History of psychiatric condition(s) and absence seizure type were independent predictors of IACEs to two or more AEDs. High rates of cross-sensitivity of IACEs were seen between phenytoin (PHT) and lamotrigine (LTG), valproate (VPA) and phenytoin, and valproate and zonisamide (ZNS). For example, of patients who had IACEs to VPA and were also prescribed ZNS, 46.2% had IACEs to ZNS (abbreviated as VPA→ZNS: 46.2%); of patients who had IACEs to ZNS and were also prescribed VPA, 37.5% had IACEs to VPA (abbreviated as ZNS→VPA: 37.5%). Other results are as follows: LTG→PHT: 28.6%, PHT→LTG: 20.0%, PHT→VPA: 42.9%, and VPA→PHT: 27.3%. No specific cross-sensitivities were found among AEDs sharing a similar mechanism of action. SIGNIFICANCE: The probability of ACE intolerability to an AED can increase if a patient developed ACE intolerability to another AED. The cross-sensitivity rates for ACE intolerability between LTG and PHT, PHT and VPA, and VPA and ZNS were found to be particularly high. The cross-sensitivity rates provided here may be clinically useful for predicting ACE intolerability in patients taking certain AEDs and for AED selection in individual patients.

'You learn to smile with your eyes', exploring the impact of enhanced personal protective equipment on primary care dental practitioners in the UK: An interpretative phenomenological study.

OBJECTIVE: The aim of the study was to explore how dental practitioners in primary care settings perceive the impact of enhanced personal protective equipment (PPE) upon patient communication and wider clinical practice. METHODS: This study utilized a qualitative approach, rooted in critical realism. An interpretative phenomenological analysis (IPA) methodology was adopted as the study method. In accordance with IPA, in-depth semi-structured interviews were conducted. Eight dental practitioners were recruited, with data analysis conducted according to the principles of IPA. RESULTS: Three themes were synthesized (related to communication and clinical practice): (1) Impaired communication and relationship building; (2) Physical impacts and required adjustments when wearing enhanced-PPE; and (3) Psychological stress of implementing enhanced-PPE. Theme one reflects changes to the dynamic of communication between patients and colleagues brought about by enhanced-PPE. Theme two describes the physical and psychological strains of providing care in enhanced-PPE and the ways through which practitioners tried to overcome these challenges. Theme three explores how the roll-out and guidance related to the use of enhanced-PPE affected clinical practice. CONCLUSIONS: Dental Practitioners described several barriers to communication as well as physical and mental stressors caused by enhanced-PPE, all of which were perceived to impact upon the quality of care provided to patients. Further research is required to develop effective interventions to mitigate the impact of enhanced-PPE upon clinical practice and to explore the long-term impact of enhanced-PPE on clinical practice, post-COVID.

Dental management of a patient with systemic mastocytosis.

Mastocytosis is a term encompassing a group of clinical disorders characterised by clonal proliferation of abnormal mast cells (MCs) in organ systems of the body. Mastocytosis can be systemic (with or without skin involvement) or cutaneous, and can affect organs including bone marrow, liver, spleen, lymph nodes and mucosal surfaces. Patients with systemic mastocytosis (SM) are susceptible to triggers that could cause activation of abnormal MCs, resulting in multiorgan dysfunction and life-threatening anaphylactic reactions. Mastocytosis has a number of ramifications for the dental management of a patient with the condition. Patients are at increased risk of complications due to a number of risk factors for MC activation present within the dental context, including stress, certain prescribed drugs, oral hygiene products and dental materials. This report presents the oral management of an adult with SM, discussing the implications of the condition within the context of the limited existing literature on the subject.

Cross-sensitivity of psychiatric and behavioral side effects with antiepileptic drug use.

PURPOSE: To determine rates of cross-sensitivity of intolerable psychiatric and behavioral side effects (IPBSEs) among commonly used antiepileptic drugs (AEDs) in adult patients with epilepsy. METHODS: IPBSE was defined as a psychiatric or behavioral side effect attributed to AED use that led to a decrease in dose or cessation of an AED. Cross-sensitivity was calculated and was defined as the likelihood of developing IPBSE to a specific AED given IPBSE to another AED. Our sample consisted of 2312 adult patients that were prescribed 2 or more AEDs. Non-AED confounders and were controlled for in all analyses. RESULTS: Among the 2312 patients, 20.2% of patients who had taken at least 2 AEDs had IPBSE(s) attributed to at least one AED; 3.5% had IPBSE to two or more AEDs. History of treated depression and psychosis were found to be significant predictors (p < 0.001) of developing IPBSE and were controlled for in all AED-specific analyses. Cross-sensitivity was seen between LEV and ZNS (p < 0.001). There was a significant increase in odds of experiencing IPBSE to LEV (41.5%; OR = 2.7; p < 0.001) or ZNS (22.1%; OR = 3.5; p < 0.001) given a patient had IPBSE to another AED compared to having no IPBSE to other AEDs (20.5% and 7.5%, respectively). CONCLUSION: History of depression and psychosis increased risk of developing IPBSE to AEDs. The probability of experiencing IPBSE increased for a patient taking LEV or ZNS if the patient experienced IPBSE to another AED. Our results may be clinically useful for predicting IPBSE associated with certain AEDs.

Comparative efficacy of unique antiepileptic drug regimens in focal epilepsy: An exploratory study.

OBJECTIVE: To compare efficacy of unique antiepileptic drug (AED) polytherapy regimens among patients with focal epilepsy. METHODS: From a longitudinal study of AED treatment, we identified patients with active focal epilepsy who had attempted at least two unique AED regimens (mono-, duo-, or tri-therapy). Efficacy was defined as the presence of at least one six-month period of continuous seizure freedom during exposure to a regimen. To control for individual variations in response and epilepsy severity, we used within-patient comparison approaches, in which we: 1) compared head-to-head unique regimens tried within the same patients; 2) compared one regimen versus aggregate of other regimens attempted in that patient; and 3) compared aggregated monotherapy versus polytherapy regimens. RESULTS: 757 patients met our criteria and had collectively attempted 170 unique regimens. In the head-to-head analysis, lamotrigine monotherapy was more effective than phenytoin monotherapy. Two regimens were more effective than the aggregate of other regimens attempted: levetiracetam/lamotrigine duotherapy and lamotrigine monotherapy. Two other regimens exhibited slightly better efficacy but did not reach statistical significance: clobazam/levetiracetam/lamotrigine and levetriacetam/oxcarbazepine. Patients who previously attempted at least four regimens had slightly better outcomes on polytherapy than monotherapy, though this was not significant. SIGNIFICANCE: We identified two unique regimens more likely to be associated with ≥6 months of seizure freedom: levetiracetam/lamotrigine duotherapy and lamotrigine monotherapy. Polytherapy may be an effective alternative to monotherapy for patients with focal epilepsy and persistent seizures.

Prevalence and risk factors of seizure clusters in adult patients with epilepsy.

PURPOSE: In the current study, we explored the prevalence of physician-confirmed seizure clusters. We also investigated potential clinical factors associated with the occurrence of seizure clusters overall and by epilepsy type. METHODS: We reviewed medical records of 4116 adult (≥16years old) outpatients with epilepsy at our centers for documentation of seizure clusters. Variables including patient demographics, epilepsy details, medical and psychiatric history, AED history, and epilepsy risk factors were then tested against history of seizure clusters. Patients were then divided into focal epilepsy, idiopathic generalized epilepsy (IGE), or symptomatic generalized epilepsy (SGE), and the same analysis was run. RESULTS: Overall, seizure clusters were independently associated with earlier age of seizure onset, symptomatic generalized epilepsy (SGE), central nervous system (CNS) infection, cortical dysplasia, status epilepticus, absence of 1-year seizure freedom, and having failed 2 or more AEDs (P<0.0026). Patients with SGE (27.1%) were more likely to develop seizure clusters than patients with focal epilepsy (16.3%) and IGE (7.4%; all P<0.001). Analysis by epilepsy type showed that absence of 1-year seizure freedom since starting treatment at one of our centers was associated with seizure clustering in patients across all 3 epilepsy types. In patients with SGE, clusters were associated with perinatal/congenital brain injury. In patients with focal epilepsy, clusters were associated with younger age of seizure onset, complex partial seizures, cortical dysplasia, status epilepticus, CNS infection, and having failed 2 or more AEDs. In patients with IGE, clusters were associated with presence of an aura. Only 43.5% of patients with seizure clusters were prescribed rescue medications. CONCLUSION: Patients with intractable epilepsy are at a higher risk of developing seizure clusters. Factors such as having SGE, CNS infection, cortical dysplasia, status epilepticus or an early seizure onset, can also independently increase one's chance of having seizure clusters.

Rates and predictors of patient-reported cognitive side effects of antiepileptic drugs: An extended follow-up.

PURPOSE: Impact of adverse effects of antiepileptic medications (AEDs) such as cognitive side effects (CSEs) on quality of life can be significant. Here we provide an extended follow-up to our earlier study to investigate the predictors of cognitive side effects (CSEs) and relative frequency of CSEs among all commonly used AEDs. METHODS: In this retrospective study, medical records of 2860 adult outpatients with epilepsy seen at our center over a 12-year period who had taken one or more AEDs were examined. RESULTS: Of 2860 patients, 15% had intolerable CSEs attributed to at least one AED. On multiple logistic regression analysis, independent predictors of intolerable CSEs were lack of intellectual disability and polytherapy. In polytherapy, we found that intolerable CSEs were most commonly seen with topiramate (22.8% of 281 patients), significantly more than with almost all other AEDs. This was true in monotherapy as well, with significantly more intolerable CSEs occurring with topiramate (18.5% of 54 patients) than with gabapentin, carbamazepine, lamotrigine, and levetiracetam. AEDs with consistently low rates of ICSEs included gabapentin, pregabalin, lamotrigine, levetiracetam and carbamazepine. CONCLUSION: These data can help facilitate selection of AEDs.