The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy.

PURPOSE: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. METHODS: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16-36 years; n = 247) and oldest (55-92 years; n = 155) tertiles. We analyzed one-year retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6-month seizure freedom. KEY FINDINGS: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One-year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6-month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 µg/ml). SIGNIFICANCE: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one-year retention is comparable. Some patients may benefit from high serum levels of LTG.

Intracortical electroencephalography in acute brain injury.

OBJECTIVE: Continuous electroencephalography (EEG) is used in patients with neurological injury to detect electrographic seizures and clinically important changes in brain function. Scalp EEG has poor spatial resolution, is often contaminated by artifact, and frequently demonstrates activity that is suspicious for but not diagnostic of ictal activity. We hypothesized that bedside placement of an intracortical multicontact electrode would allow for improved monitoring of cortical potentials in critically ill neurological patients. METHODS: Sixteen individuals with brain injury, requiring invasive neuromonitoring, underwent implantation of an eight-contact minidepth electrode. RESULTS: Intracortical EEG (ICE) was successfully performed and compared with scalp EEG in 14 of these 16 individuals. ICE provided considerable improvement in signal-to-noise ratio compared with surface EEG, demonstrating clinically important findings in 12 of 14 patients (86%) including electrographic seizures (n = 10) and acute changes related to secondary neurological injury (n = 2, 1 ischemia, 1 hemorrhage). In patients with electrographic seizures detected by ICE, scalp EEG demonstrated no concurrent ictal activity in six, nonictal-appearing rhythmic delta in two, and intermittently correlated ictal activity in two. In two patients with secondary neurological complications, ICE demonstrated prominent attenuation 2 to 6 hours before changes in other neuromonitoring modalities and more than 8 hours before the onset of clinical deterioration. INTERPRETATION: ICE can provide high-fidelity intracranial EEG in an intensive care unit setting, can detect ictal discharges not readily apparent on scalp EEG, and can identify early changes in brain activity caused by secondary neurological complications. We predict that ICE will facilitate the development of EEG-based alarm systems and lead to prevention of secondary neuronal injury.

Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs.

Subjective cognitive side effects (CSEs) are common in patients taking antiepileptic drugs (AEDs). The objective of this study was to predict which patients are at risk for CSEs, and compare the CSE profiles of all commonly used AEDs. In this nonrandomized retrospective study, medical records of 1694 adult outpatients with epilepsy seen at our center over a 5-year period who had taken one or more AEDs were examined. Non-AED predictors of CSEs were investigated, and rates of AED-related CSEs were compared in 1189 patients (546 on monotherapy) newly started on an AED at our center. The average rate of AED-related intolerable CSEs (leading to dosage change or discontinuation) was 12.8%. On multivariate analysis, no significant non-AED predictors of CSEs were found. Significantly more intolerable CSEs were attributed to topiramate (21.5% of 130 patients) than to most other AEDs, including carbamazepine (9.9%), gabapentin (7.3%), levetiracetam (10.4%), lamotrigine (8.9%), oxcarbazepine (11.6%), and valproate (8.3%). CSE rates with zonisamide (14.9%) were significantly higher than those for gabapentin and lamotrigine. After exclusion of CSEs during the first 8 weeks of therapy, rates of CSEs were lower, but relative differences remained unchanged. In monotherapy, significantly more intolerable CSEs occurred with topiramate (11.1% of 18 patients) than with carbamazepine or valproate, and both phenytoin and zonisamide were associated with more CSEs than valproate. From this study, it can be concluded that intolerable patient-reported CSEs are most common with topiramate, followed by zonisamide, phenytoin, and oxcarbazepine. They are least likely to be reported with gabapentin, valproate, lamotrigine, carbamazepine, and levetiracetam.

Drug compliance after stroke and myocardial infarction: a comparative study.

BACKGROUND: Stroke and myocardial infarction (MI) are both life-threatening diseases of vascular origin with a tendency to recur. In both conditions, risk of recurrence is reduced through similar drug regimens. AIM: To determine if compliance with prescribed medication after stroke or MI was similar in the two populations. SETTING AND DESIGN: Retrospective data collection and cross-sectional telephonic survey of patients discharged from a single academic medical center. MATERIALS AND METHODS: Adult patients consecutively discharged over a two-year period with a diagnosis of first-ever stroke (ischemic or hemorrhagic) or first-ever MI (ST-elevation) were identified through ICD-9 codes. Clinical details were abstracted from hospital records. Medication compliance was assessed through a structured telephone interview. STATISTICAL ANALYSIS: Bivariate analysis using Chi-square and Fisher exact tests, to determine the prevalence of noncompliance in stroke versus MI patients and differences in baseline characteristics and multivariate analysis with logistic regression to determine independent predictors of noncompliance. RESULTS: Follow-up data was collected for 298 stroke and 275 MI patients. Compliance was lower in stroke patients (68% stroke patients compliant with at least half their discharge prescriptions versus 90% MI patients; P < 0.001). Literacy and post-discharge follow-up were associated with greater compliance (P < 0.05 for both). Compliance was highest with anti-hypertensive drugs (98% after MI, 78% after stroke), followed by anti-platelet agents (94% after MI, 75% after stroke) and anti-lipid agents (70% after MI, 59% after stroke). Patients reported simply not feeling the need, acquiring fresh medical advice or a perceived lack of benefit, as reasons for not complying with their discharge prescriptions. CONCLUSIONS: Although similar drugs are involved, compliance with prescribed regimens is appreciably lower after stroke than after MI. Our findings underscore the need for better patient education regarding secondary prevention after stroke.

Characteristics of acute transverse myelitis at Aga Khan University Hospital, Karachi.

OBJECTIVE: To determine the presenting features and etiological classification of acute transverse myelitis (ATM) at Aga Khan University Hospital, a tertiary care hospital in Pakistan. METHODS: Twenty consecutive patients of ATM (1996-2003) fulfilling a preset criterion were analyzed for demographic features, clinical presentation, laboratory investigations and neuro-imaging. RESULTS: Half of the patients were males and their median age was 29 years (range 6-73 years). Fever, paraparesis, quadri-paresis and bladder dysfunction were the most common presentations. Median score on disability rating scale (DRS) was twelve. Sixty percent of the patients were classified as Idiopathic-ATM while 30% and 10% as Para infectious associated-ATM and Multiple sclerosis associated-ATM respectively. CONCLUSION: Idiopathic acute transverse myelitis is the most common type of ATM in the studied population. Our data suggested that the severity of motor impairment is greater in our population than that reported in western literature which might hint to different genetic or environmental etiological factors involved in the pathogenesis of acute transverse myelitis.

Neuroimaging of tuberculous myelitis: analysis of ten cases and review of literature.

We retrospectively reviewed the clinical and neuroimaging features of 10 patients with tuberculous myelitis. The most common presenting symptoms were fever (70%) and paraplegia (60%). Bladder and bowel symptoms were present in 90% patients. On MRI, the involvement of the cervical/thoracic segment of the spinal cord was most commonly seen (90%). The most consistent finding was hyperintense signals on T2-weighted MRI. T1-weighted images showed isointense (n= 5) and hypointense (n= 4) signals in the spinal cord lesions. Post-contrast enhancement was present in 6 patients, epidural enhancement in 4 patients, and cord swelling in 2 patients. We reviewed more than 250 published cases with the diagnosis of tuberculous myelitis and radiculomyelitis with special attention to MRI findings. It is predominantly a disease of the thoracic spinal cord. Most spinal cord lesions appear as hyperintense on T2 and iso- or hypointense on T1-weighted images. MRI findings in patients with spinal cord tuberculosis have both diagnostic and prognostic significance. Cord atrophy or cavitation and the presence of syrinx on MRI may be associated with poor outcome.

Interrater reliability of ICU EEG research terminology.

BACKGROUND: Standardized research terminology critical to the establishment of a multicenter intensive care unit (ICU) electroencephalogram (EEG) database was originally proposed in 2005 and has been modified many times since. However, interrater agreement (IRA) of the revised terminology has not been investigated. METHODS: After a brief tutorial, investigators of ICU EEG research centers (n = 16) took an 82-question EEG certification test comprising 10-second EEG samples, which assessed the use of main term 1 (pattern location), main term 2 (pattern type), and modifiers from the most recently revised terminology. RESULTS: Kappa values for main terms 1 and 2 were 0.87 and 0.92, respectively. Agreement was 93% for determination of amplitude and 80% for determination of frequency. Kappa values for each of the "plus" modifiers (fast, rhythmic, and sharp/spike activity) were 0.54, 0.62, and 0.16 respectively. CONCLUSIONS: Main terms 1 and 2 have high IRA and are reasonable for use in multicenter research. There is a suggestion that assessment of amplitude has good reliability, while assessment of frequency may have less reliability. The fast and rhythmic "plus" modifiers have moderate IRA, while sharp/spike modifier has only slight IRA implying that further refinement and assessment of terminology modifiers may be necessary.

Comparative effectiveness of 10 antiepileptic drugs in older adults with epilepsy.

OBJECTIVE: To compare the effectiveness of antiepileptic drugs (AEDs) for use in older adults with epilepsy. DESIGN: Retrospective review. SETTING: Columbia Comprehensive Epilepsy Center, New York, New York. PATIENTS: Four hundred seventeen outpatients 55 years and older newly taking any of the 10 most commonly prescribed AEDs between 2000 and 2005. MAIN OUTCOME MEASURE: The percentage of patients who remained taking the AED for 12 or more months (12-month "retention"). We also measured efficacy (12-month seizure freedom) and adverse effects leading to dose change. Retention and seizure-freedom rates were analyzed by pairwise comparisons using chi(2) for the overall group and patients with refractory and nonrefractory disease as well as patients newly taking their first AED. RESULTS: The 10 AEDs newly taken by 10 or more patients were analyzed. There were no significant non-AED predictors of retention. Without controlling for severity, lamotrigine had the highest 12-month retention rate (79%), significantly higher than carbamazepine (48%), gabapentin (59%), oxcarbazepine (24%), phenytoin (59%), and topiramate (56%). The retention rate for levetiracetam (73%) was second highest and significantly higher than carbamazepine and oxcarbazepine. Oxcarbazepine had the lowest retention rate, significantly lower than all other AEDs. Lamotrigine had the highest 12-month seizure-freedom rate (54%), followed by levetiracetam (43%). When stratified into patients with nonrefractory and refractory disease, relative rates of seizure freedom and retention remained comparable with the overall group. Imbalance, drowsiness, and gastrointestinal symptoms were the most common intolerable adverse effects. CONCLUSION: In this study of older adults with epilepsy, lamotrigine was the most effective AED as measured by 12-month retention and seizure freedom, with levetiracetam a close second. Oxcarbazepine was consistently less effective than most other AEDs.

Treatment of status epilepticus.

Status epilepticus (SE) is a neurological emergency that requires prompt diagnosis and treatment, as delay is associated with a higher likelihood of poor response to treatment and worse outcome. Lorazepam has been well established as a first-line therapy. Subsequent steps are less established, and there are many reasonable options, including intravenous fosphenytoin, valproate, midazolam, propofol, and phenobarbital. If intravenous access is not immediately available, rectal diazepam or nasal or buccal midazolam should be given; this can also be used as out-of-hospital treatment to prevent or treat SE. For refractory SE, continuous intravenous midazolam and propofol, separately or in combination, are rapidly effective, with pentobarbital remaining the gold standard for prolonged cases. If a patient does not awaken after treatment, urgent electroencephalogram (EEG) should be obtained to rule out nonconvulsive seizure activity. In refractory SE, continuous EEG monitoring is required to recognize recurrence of seizure activity, as most seizures will be nonconvulsive.

Efficacy of clobazam as add-on therapy for refractory epilepsy: experience at a US epilepsy center.

RATIONALE: Clobazam (CLB) has proven efficacy against multiple seizure types. Although available in many countries, it is not approved by the US Food and Drug Administration. The objective of this study was to evaluate the usage patterns, efficacy, tolerability, and 1-year retention of CLB in patients with refractory epilepsy seen at a tertiary US epilepsy center. METHODS: We retrospectively reviewed the use of CLB, 1 measure of efficacy (6-month seizure freedom), 1-year retention, and tolerability in patients with epilepsy who were prescribed CLB as part of their antiepileptic drug regimen at the Columbia Comprehensive Epilepsy Center over a 5-year period. RESULTS: Two hundred fifty-one patients were prescribed CLB, of which 62 were newly started on CLB at our center during this period (29 male and 33 female subjects; mean age, 43.9 years; range, 8-88 years). Clobazam dose ranged from 5 to 60 mg/d (mean, 23.9 mg/d). The mean number of previous antiepileptic drug trials per patient was 7.7. Of the 62 patients newly started on CLB, 7 patients (11.3%) became seizure-free for at least 6 months after introduction of CLB. Binary logistic regression was unable to identify any significant predictors of seizure freedom or CLB retention. Four patients remained seizure-free on CLB for more than 18 months. The Kaplan-Meier 12-month retention curve (n = 54 eligible patients) showed a 1-year retention rate of 61%. CONCLUSIONS: In this population of patients with highly refractory epilepsy at a US center, 11% of patients became seizure-free for at least 6 months after addition of CLB, and the 1-year retention rate was 61%.

Effect of age and comedication on levetiracetam pharmacokinetics and tolerability.

PURPOSE: To compare pharmacokinetics and tolerability of levetiracetam (LEV) in older versus younger adults. METHODS: As part of the Columbia Antiepileptic Drug Database, we retrospectively studied the pharmacokinetics and tolerability of LEV in patients who had been seen as an outpatient at our center during a 4-year period. We compared apparent clearance (CL) of LEV in the youngest (16-31 years; n=151) and oldest (55-88 years; n=157) quartile of 629 adult outpatients who had taken LEV. We also analyzed the frequency of adverse effects leading to dose change or discontinuation ("intolerability") and specific adverse effects in the younger versus older adults. One-year retention was determined for younger and older adults newly started on LEV at our center. RESULTS: Mean LEV CL differed significantly between older (46.5 ml/h/kg) and younger adults (78.3 ml/h/kg). On average, older patients had a 40% lower LEV CL than younger patients. Comedication with an enzyme-inducing antiepileptic drug (EIAED; mostly carbamazepine) was associated with a 24% higher clearance of LEV compared to those who were not on EIAEDs. This difference was 37% in a subgroup of patients whose LEV CL was compared while they were on and off EIAEDs. Stepwise linear regression identified younger age and comedication with an EIAED as significant predictors of increased LEV CL. A total of 34.3% of the 629 patients (31.7% of younger vs. 40.7% of older patients; p=0.16) reported intolerability to LEV on at least one occasion. This difference in tolerability reached significance in the group of patients newly started on LEV (26.3% vs. 41.0%; p=0.017). Drowsiness and psychiatric/behavioral side effects were the most common adverse effects associated with LEV use in both age groups. One-year retention was 72% in the older group vs. 54% in the younger group (not significant). CONCLUSION: Older adults have lower CL than younger adults and require a mean 40% lower dose of LEV to achieve the same serum level. Comedication with an EIAED increases LEV CL by 24-37%. Younger adults tolerate LEV better than older adults, but 1-year retention was (nonsignificantly) higher in the older group.

Lamotrigine and its applications in the treatment of epilepsy and other neurological and psychiatric disorders.

Lamotrigine is a broad-spectrum antiepileptic drug, initially approved in 1994 for the adjunctive treatment of partial seizures in adults and for the generalized seizures of Lennox-Gastaut syndrome in pediatric (>2 years old) and adult populations. Its role in the treatment of bipolar disorder type I has also been well established. In addition, lamotrigine has been successfully used for the management of other neurological conditions such as migraines and neuropathic pain, and preliminary data show promising results. It has favorable pharmacokinetic properties and is generally well tolerated. The small risk of serious skin rash can be minimized with slow titration of the drug and dose adjustment with concomitant medications. Lamotrigine has demonstrated particular benefit in the treatment of women and elderly patients with epilepsy.

Topiramate for the treatment of epilepsy and other nervous system disorders.

Initially synthesized as an oral hypoglycemic agent, topiramate was approved for use as an anticonvulsant in 1996. Its broad spectrum efficacy in epilepsy, including as monotherapy and in children, is well established. Topiramate has also been used in the management of nonepileptic neurologic and psychiatric conditions, including migraine prophylaxis (with firmly established efficacy), obesity (with some evidence of long-term maintenance of weight loss), substance dependence, bipolar disorder and neuropathic pain, and it has been investigated as a possible neuroprotective agent. Paresthesias and cognitive side effects are the most common troublesome adverse effects. Recent trends towards lower doses may help achieve the best combination of efficacy and tolerability.