Would people living with epilepsy benefit from palliative care?

Palliative care (PC) is an approach to the care of persons living with serious illness and their families that focuses on improving quality of life and reducing suffering by addressing complex medical symptoms, psychosocial needs, spiritual well-being, and advance care planning. While PC has traditionally been associated with hospice care for persons with cancer, there is now recognition that PC is relevant to many noncancer diagnoses, including neurologic illness, and at multiple points along the illness journey, not just end of life. Despite the recent growth of the field of neuropalliative care there has been scant attention paid to the relevance of PC principles in epilepsy or the potential for PC approaches to improve outcomes for persons living with epilepsy and their families. We believe this has been a significant oversight and that PC may provide a useful framework for addressing the many sources of suffering facing persons living with epilepsy, for engaging patients and families in challenging conversations, and to focus efforts to improve models of care for this population. In this manuscript we review areas of significant unmet needs where a PC approach may improve patient and family-centered outcomes, including complex symptom management, goals of care, advance care planning, psychosocial support for patient and family and spiritual well-being. When relevant we highlight areas where epilepsy patients may have unique PC needs compared to other patient populations and conclude with suggestions for future research, clinical, and educational efforts.

Continuing Burden of Refractory Epilepsy.

Epilepsy is one of the most common neurological diseases, and uncontrolled seizures remain a significant problem for one-third of patients with epilepsy on drug therapy. Ongoing seizures affect the morbidity and mortality of patients with epilepsy. Premature death is up to 3 times higher in those with epilepsy than in the general population. Quality of life is affected by refractory epilepsy with physical, social, and psychological consequences. Patients may be stigmatized by society, institutions, and their own shame surrounding seizures. Questions remain on how to treat refractory epilepsy, also called drug-resistant, pharmacoresistant, or intractable epilepsy. Cenobamate, a novel antiseizure medication, may provide additional benefit for refractory epilepsy treatment.

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

PURPOSE: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE. METHODS: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process. RESULTS: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study). CONCLUSIONS: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

Survey highlights the need to expand offerings of introductory pharmacy practice experiences in psychiatry and neurology: Benefits and example experiences.

INTRODUCTION: Introductory pharmacy practice experiences (IPPEs) are 1 requirement schools and colleges of pharmacy must fulfill to meet accreditation standards. The purpose of this manuscript is to report existing IPPEs in psychiatry and neurology across the United States. METHODS: Two separate electronic surveys were administered to individual College of Psychiatric and Neurologic Pharmacists members with board certification in psychiatric pharmacy with an academic affiliation and academic institutions in the 2014-15 academic year to assess the neuropsychiatric curriculum in pharmacy programs. Results focusing on IPPEs were summarized using descriptive statistics. RESULTS: Academic institutional data reveal only 37.3% offered IPPEs in psychiatry, and 6.7% offered neurology. The number of available IPPEs is low even if a program offered an available rotation. The majority of College of Psychiatric and Neurologic Pharmacists member respondents (69.9%) did not offer IPPEs in psychiatry in the 2014-15 academic year, and none offered an IPPE in neurology. More than half of individual respondents feel their institution should increase IPPEs in psychiatry and neurology in order to enhance their curriculum. DISCUSSION: To expand IPPE availability, pharmacy programs should increase early exposure of pharmacy students to patients with psychiatric and neurologic conditions. Longitudinal experiences may allow students to engage in hands-on experiences, which may impact future career aspirations and reduce stigma. Current example IPPEs at the authors' institutions are included to stimulate discussion and action among readers on how IPPEs in these practice areas may be developed. Implementation of IPPEs in psychiatry and neurology is needed for students to gain experience working with these patients.

Association of metabolic syndrome and change in Unified Parkinson's Disease Rating Scale scores.

OBJECTIVE: To explore the association between metabolic syndrome and the Unified Parkinson's Disease Rating Scale (UPDRS) scores and, secondarily, the Symbol Digit Modalities Test (SDMT). METHODS: This is a secondary analysis of data from 1,022 of 1,741 participants of the National Institute of Neurological Disorders and Stroke Exploratory Clinical Trials in Parkinson Disease Long-Term Study 1, a randomized, placebo-controlled trial of creatine. Participants were categorized as having or not having metabolic syndrome on the basis of modified criteria from the National Cholesterol Education Program Adult Treatment Panel III. Those who had the same metabolic syndrome status at consecutive annual visits were included. The change in UPDRS and SDMT scores from randomization to 3 years was compared in participants with and without metabolic syndrome. RESULTS: Participants with metabolic syndrome (n = 396) compared to those without (n = 626) were older (mean [SD] 63.9 [8.1] vs 59.9 [9.4] years; p < 0.0001), were more likely to be male (75.3% vs 57.0%; p < 0.0001), and had a higher mean uric acid level (men 5.7 [1.3] vs 5.3 [1.1] mg/dL, women 4.9 [1.3] vs 3.9 [0.9] mg/dL, p < 0.0001). Participants with metabolic syndrome experienced an additional 0.6- (0.2) unit annual increase in total UPDRS (p = 0.02) and 0.5- (0.2) unit increase in motor UPDRS (p = 0.01) scores compared with participants without metabolic syndrome. There was no difference in the change in SDMT scores. CONCLUSIONS: Persons with Parkinson disease meeting modified criteria for metabolic syndrome experienced a greater increase in total UPDRS scores over time, mainly as a result of increases in motor scores, compared to those who did not. Further studies are needed to confirm this finding. CLINICALTRIALSGOV IDENTIFIER: NCT00449865.

Autonomic and electrocardiographic findings in Parkinson's disease.

Parkinson disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and signs. Many reports suggest that diminished heart rate variability occurs early, even prior to the cardinal signs of PD. In a longitudinal study of PD, we evaluated whether heart rate variability (HRV) obtained using a 10-second ECG tracing, and the electrocardiographic QT-interval would be associated with PD severity and progression. Subjects were derived from a longitudinal study of 1741 individuals with early, stable PD. The severity of PD was measured using the global statistical test (GST). In a subset, the heart rate corrected QT-interval (QTcB) was calculated for each electrocardiogram (ECG). The HRV was measured for each ECG and then transformed to fit a normal distribution. The baseline analysis included 653 subjects, with 256 completing the 5-year follow up study. There was an association (P<0.05) between QTcB and PD severity in individuals that were taking QT-interval affecting drugs. A longer QT-interval at baseline was associated with more advanced PD at 5years (P<0.05), and greater disease progression over 5years (P<0.05). There was an association between diminished HRV and an orthostatic decrease in standing blood pressure at baseline in individuals with PD (P<0.05). HRV was not associated with PD severity or progression. In conclusion, we were able to detect measurable associations between the QTcB interval and PD severity, PD severity 5years later, and the change in disease over time. However, routine ECG tracings appear inadequate for the evaluation of autonomic function in PD.

Epilepsy during pregnancy: focus on management strategies.

In the US, more than one million women with epilepsy are of childbearing age and have over 20,000 babies each year. Patients with epilepsy who become pregnant are at risk of complications, including changes in seizure frequency, maternal morbidity and mortality, and congenital anomalies due to antiepileptic drug exposure. Appropriate management of epilepsy during pregnancy may involve frequent monitoring of antiepileptic drug serum concentrations, potential preconception switching of antiepileptic medications, making dose adjustments, minimizing peak drug concentration with more frequent dosing, and avoiding potentially teratogenic medications. Ideally, preconception planning will be done to minimize risks to both the mother and fetus during pregnancy. It is important to recognize benefits and risks of current and emerging therapies, especially with revised pregnancy labeling in prescription drug product information. This review will outline risks for epilepsy during pregnancy, review various recommendations from leading organizations, and provide an evidence-based approach for managing patients with epilepsy before, during, and after pregnancy.

Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation.

Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy, affecting approximately one in five pregnant women in Western countries. Many report moderate or severe symptoms and negative impact on sleep. There is very little information in the medical literature for practitioners on the management of this condition during pregnancy. Accordingly, a task force was chosen by the International RLS Study Group (IRLSSG) to develop guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation. A committee of nine experts in RLS/WED and/or obstetrics developed a set of 12 consensus questions, conducted a literature search, and extensively discussed potential guidelines. Recommendations were approved by the IRLSSG executive committee, reviewed by IRLSSG membership, and approved by the WED Foundation Medical Advisory Board. These guidelines address diagnosis, differential diagnosis, clinical course, and severity assessment of RLS/WED during pregnancy and lactation. Nonpharmacologic approaches, including reassurance, exercise and avoidance of exacerbating factors, are outlined. A rationale for iron supplementation is presented. Medications for RLS/WED are risk/benefit rated for use during pregnancy and lactation. A few are rated "may be considered" when RLS/WED is refractory to more conservative approaches. An algorithm summarizes the recommendations. These guidelines are intended to improve clinical practice and promote further research.

Clinical overview of dalfampridine: an agent with a novel mechanism of action to help with gait disturbances.

BACKGROUND: Medication used to treat multiple sclerosis (MS) can be categorized as disease-modifying therapies, symptomatic therapies, or treatment of acute exacerbations. Dalfampridine is the first symptomatic therapy approved by the Food and Drug Administration to improve walking in patients with MS. OBJECTIVE: This article reviews the pharmacology, pharmacodynamic properties, and pharmacokinetic properties of dalfampridine, as well as its clinical efficacy, safety profile, pharmacoeconomic considerations, and place in therapy. METHODS: Three PubMed searches were conducted for original articles published in English between 1966 and August 2012 with human study participants. Articles concerning the pharmacology, pharmacokinetic properties, pharmacodynamic properties, efficacy, and safety profile of dalfampridine were evaluated. RESULTS: Dalfampridine theoretically works to improve conduction and enhance walking by inhibiting potassium channels in the axonal membrane and by prolonging action potentials in demyelinated neurons. The efficacy of dalfampridine has been reported in 2 Phase III clinical trials in patients with MS. When comparing dalfampridine 10 mg twice daily with placebo, these studies found a statistically significant improvement in walking (42.9% vs 9.3% and 35% vs 8%; P < 0.001). However, clinical trials and postmarketing surveillance have shown an increased risk of seizures with dalfampridine use that appears to be dose related [corrected]. CONCLUSIONS: Dalfampridine has a unique mechanism of action, leading to its approval as the first symptomatic therapy for MS to improve walking speed. The increased risk of seizures can be a safety concern and will require health care providers to be diligent in monitoring patients and to ensure adequate patient education [corrected]. The addition of dalfampridine as symptomatic therapy for MS may lead to additional novel products in the future.

Probable levetiracetam-associated depression in the elderly: two case reports.

BACKGROUND: Compared with traditional antiepileptic drugs, levetiracetam has a unique mechanism of action and unique properties, including predominant renal excretion and lack of drug-drug interactions. In the elderly, depression associated with levetiracetam has not been reported. CASE SUMMARIES: A 73-year-old black man (height, 172.7 cm; weight, 92.7 kg; body mass index [BMI], 31 kg/m(2)) with stage 4 kidney disease was taking levetiracetam 500 mg BID for partial complex seizures. After 5 months of taking medication, new-onset depression, evidenced by depressed mood, weight loss, fatigue, and appearing withdrawn, was noted in this patient. Levetiracetam was discontinued by order of the patient's primary care physician. At a follow-up appointment 4 weeks later, the depressive symptoms had nearly resolved. The patient's Naranjo Adverse Drug Reaction Probability Scale score was 6, indicating levetiracetam to be a probable cause of depression in this patient. In a second case, a 92-year-old white woman (height, 154.9 cm; weight, 54.5 kg; BMI, 22.7 kg/m(2)) with existing chronic kidney disease and new-onset partial seizure, likely due to a meningioma, was initiated on levetiracetam 500 mg once daily. Depressive symptoms (eg, anhedonia, hypersomnolence, decreased appetite) were noted within 5 weeks. Cessation led to improvement in mood and cognition within 8 days. Based on this patient's Naranjo Adverse Drug Reaction Probability Scale score of 6, levetiracetam was a probable cause of depression in this patient. CONCLUSIONS: Levetiracetam was a probable cause of depression in these 2 elderly patients. Cautious use and additional monitoring may be necessary when prescribing levetiracetam to elderly patients, especially when prescribing to those with a history of renal impairment.

Challenges of treatment adherence in older patients with Parkinson's disease.

Patient adherence to a medication regimen is critical to treatment outcome, quality of life and future healthcare costs. For elderly patients with Parkinson's disease, obstacles to adherence can be particularly complex. Beyond age-related and economic factors, elderly patients with Parkinson's disease often require complicated dosing or titration schedules and have multiple co-morbidities that necessitate administration of therapies from multiple drug classes. In addition, neuropsychiatric disturbances and cognitive impairment, which are often part of the disease process, can affect adherence, as can variable responses to anti-parkinsonian agents as the disease progresses. Several recent studies in patients with Parkinson's disease point to the need for establishing good adherence patterns early and maintaining these throughout the course of treatment. To achieve optimal adherence in elderly patients with Parkinson's disease, a combination of pharmacological and non-pharmacological approaches appears to be the best strategy for success. Examples include a strong provider-patient relationship, educational intervention by phone or face-to-face contact, simplified dosing and administration schedules, management and understanding of medication adverse events, and the use of adherence aids such as pill boxes and hour-by-hour organizational charts. Research into new avenues that include improved drug monitoring, pharmacogenetics and neuroprotective regimens may give rise to better adherence in elderly patients with Parkinson's disease in the future.

Elucidating the mechanism of action and potential interactions of MAO-B inhibitors.

A critical enzyme in neurotransmitter metabolism is monoamine oxidase (MAO). MAO occurs in two isoforms, MAO-A and MAO-B. MAO inhibitors are classified as selective for a particular subtype of MAO or nonselective and can be reversible or irreversible. Nonselective MAO inhibitors originally were studied as antidepressants. Newer MAO-B selective irreversible inhibitors are indicated for use in treatment of Parkinson's disease. MAO-B inhibitors offer modest antiparkinsonian effects, as they do not inhibit brain MAO-A effectively at the dose used in treating Parkinson's disease. In this article, the mechanism of action of MAO-B inhibitors, their potential neuroprotective effects, interactions such as the cheese reaction, and serotonin syndrome are discussed.

Optimal frequency for measuring health care resource utilization in Parkinson's disease using participant recall: the FS-TOO resource utilization substudy.

OBJECTIVE: The aim of this substudy was to determine the agreement between 2 approaches for measuring health care resource utilization (eg, number of hospital visits, number of primary care physician visits) in trial participants with Parkinson's disease (PD). METHODS: A substudy of the 1-year multicenter futility trial of GPI-1,485 and coenzyme Q(10) (FS-TOO) was performed to assess health care resource utilization agreement by measuring participant utilization recall after 12 months versus measuring participant utilization recall at regular 3-month intervals. Trial participants were selected from patients in the National Institutes of Health-sponsored FS-TOO multicenter study. Persons aged >or=30 years with confirmed PD diagnosis within the previous 5 years were eligible for inclusion in the substudy. Participants were also required to have at least 2 of 3 cardinal manifestations of PD (tremor, rigidity, and bradykinesia). Participants were excluded from the study if they had presence of atypical Parkinson's syndromes due to drugs, metabolic identified neurogenetic disorders, encephalitis, or other degenerative diseases. Agreement was determined using Lin's concordance and Cohen's kappa statistics. RESULTS: Between March and July of 2004, a total of 424 potential subjects were identified and evaluated for trial eligibility. Of these, 213 subjects (139 men, 74 women; mean [SD] age, 61.5 [10.3] years) met entry criteria and were included in the study. Trial participants were randomized equally to 1 of 3 groups. The 3 groups had similar baseline characteristics in terms of demographic data (age, race, sex, employment status, and annual income), total Unified Parkinson Disease Rating Scale (UPDRS) score, and UPDRS subscores. In this substudy, 141 participants had a true baseline visit, indicating a clinical baseline date, and 182 participants completed the Baseline Resource Utilization Form within 3 months of the true baseline visit. The comparison of concordance between the summed information over 3-month recalls and the 12-month recall from baseline was derived from these 182 participants. The level of agreement between the 2 approaches was high, ranging from 64.4% to 95.1%. Where disagreement was identified, the more frequent measurement approach (every 3 months) led to higher estimates, ranging from 20.4% to 77.4%. CONCLUSION: The results of this trial indicate internal consistency with the self-reported measures of health care resource utilization, suggesting that these simple measures might provide reliable information about units of health care resource utilization in the context of clinical trials for PD.

Restless legs syndrome induced by escitalopram: case report and review of the literature.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by distressing sensations deep inside the limbs, typically occurring at bedtime or rest. These paresthesias involve an irresistible urge to move the limb, which provides temporary relief but at the expense of sleep and quality of life. The pathophysiology of RLS has been related to dopaminergic pathway dysfunction, thereby aligning it closely with depression from both pathophysiologic and treatment perspectives. Certain antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), may induce or exacerbate RLS. We describe the case of a 34-year-old woman with no history of RLS who came to the emergency department with acute decompensated heart failure. After 7 days of hospitalization, she was waitlisted to receive a heart transplant. Her mood became depressed, and she requested a psychiatric consultation; escitalopram 10 mg at bedtime was started. Within 2 days of starting therapy, she developed very severe (determined by a score based on an RLS symptom rating scale) RLS symptoms, warranting the discontinuation of escitalopram. Within 2 days of stopping therapy, her RLS symptoms improved considerably (rated as mild). One week later, the patient was rechallenged with a lower dose of escitalopram, and her very severe RLS symptoms reappeared. Within 2 days of stopping escitalopram, her RLS symptoms again improved, with complete resolution 1 week later. Using the Naranjo adverse drug reaction probability scale, which assesses the probability of a drug causing an adverse event, the patient's score was 9, indicating a definite adverse drug reaction. Although published case reports have linked fluoxetine, sertraline, citalopram, paroxetine, and mirtazapine to RLS, this is the first report, to our knowledge, of escitalopram as a cause of RLS. Based on this case and additional data published with other SSRIs and SNRIs, we believe that escitalopram should be added to the list of agents that can induce RLS.

Intractable epistaxis associated with topiramate administration.

OBJECTIVE: To report a case of a patient who experienced serious, intractable epistaxis warranting emergency department (ED) visits and hospital admission after initiation of topiramate therapy. CASE SUMMARY: A 61-year-old woman with significant cardiovascular disease was started on topiramate 25 mg daily for lower extremity neuropathy. After 7 days of treatment, she began to experience severe, intractable epistaxis that lasted 8 days, warranting an ED visit. The epistaxis resolved 1 week after topiramate discontinuation. Topiramate was restarted 3 months later, and the patient again developed intractable epistaxis. After 2 days of epistaxis, she returned to the ED with significant anginal pain and was admitted to the hospital, where she received 2 units of packed red blood cells. One week after stopping topiramate, the epistaxis stopped. At the time of writing, she had exhibited no epistaxis for 6 months. According to the Naranjo probability scale, topiramate was the probable cause of epistaxis. DISCUSSION: Topiramate is a neuromodulatory compound approved for management of migraines, as well as partial and generalized tonic-clonic seizures. Over the past decade, its use has expanded to include many other neuropathic conditions. Currently, epistaxis has been reported in only 1-4% of patients receiving topiramate in clinical trials; however, these data were derived from a young study population. Like topiramate, calcium-channel blockers (CCBs) modulate voltage-gated L type calcium ion channels. These specific channels are located on vascular smooth muscle and non-contractile tissues such as platelets. Due to their possible antiplatelet effects, CCBs have been associated with an increased risk of hemorrhage, epistaxis, and prolonged bleeding time. The same may hold true for topiramate. CONCLUSIONS: Topiramate, particularly in combination with antiplatelet medications, may be associated with severe, intractable epistaxis. Intractable epistaxis should be added to the list of potentially serious adverse reactions that are monitored when topiramate is administered.