Lamotrigine, levetiracetam effective first-line treatments in post-stroke epilepsy

 What is your confidence level that your stroke hospital will have protocols ready for treating your post stroke seizures? I have none. 

Your risk of post-stroke seizure is highest in the first 30 days following a stroke. Approximately 5 percent of people will have a seizure within a few weeks after having a stroke, according to the National Stroke Association.

Be careful out there. Some research points to a 10-40% epilepsy incidence rate for survivors. What is your doctor doing to ensure you don't get epilepsy? YOUR DOCTOR'S RESPONSIBILITY!

Lamotrigine, levetiracetam effective first-line treatments in post-stroke epilepsy

 

By Joe Gramigna, MA

Source/Disclosures

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Researchers observed differences in survival between antiseizure medications in post-stroke epilepsy, with lamotrigine and levetiracetam appearing to be reasonable first-line treatment options, according to a study in JAMA Neurology.

“The association of post-stroke epilepsy (PSE) with mortality varies between studies, but the hazard ratio (HR) of death seems increased on a population level,” David Larsson, MD, of the department of neurology at Sahlgrenska University Hospital in Sweden, and colleagues wrote. “The reason for the increased mortality with PSE is unknown. Potential explanations include detrimental effects from antiseizure medications (ASMs), especially enzyme inducers, which could increase cardiovascular risk and interact with drugs used for secondary stroke prevention.”

However, the researchers noted a lack of population-based real-world data on links between ASMs and mortality among patients with PSE. To address this research gap, analyzed individual-level data from linked registers on all adults in Sweden with acute stroke between July 1, 2005, and Dec. 31, 2010, and subsequent epilepsy onset prior to Dec. 31, 2014. They included 2,577 patients (54% men; median age, 78 years) who received continuous ASM monotherapy. They used Cox proportional hazards regression with carbamazepine as the reference to analyze all-cause death, which served as the primary outcome. Further, they used Fine-Gray competing risk regression models to examine cardiovascular death based on ICD-10 criteria.

Results showed lamotrigine, levetiracetam, valproic acid, phenytoin and oxcarbazepine had adjusted HRs of all-cause death compared with carbamazepine of 0.72 (95% CI, 0.6-0.86), 0.96 (95% CI, 0.8-1.15), 1.4 (95% CI, 1.23-1.59), 1.16 (95% CI, 0.88-1.51) and 1.16 (95% CI, 0.81-1.66), respectively. Larsson and colleagues noted adjusted HRs for cardiovascular death compared with carbamazepine of 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.4 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine.

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“Patients treated with lamotrigine had significantly lower mortality than those treated with carbamazepine, whereas patients prescribed valproic acid had an increased risk of both cardiovascular and all-cause death,” the researchers wrote. “Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine. Altogether, our findings suggest an association between ASM selection and mortality among patients with a history of cerebrovascular disease.”

Post-Stroke Epilepsy Treatment May Influence Mortality

Does your doctor already have a protocol to prevent post stroke epilepsy and seizures? 

Your risk of post-stroke seizure is highest in the first 30 days following a stroke. Approximately 5 percent of people will have a seizure within a few weeks after having a stroke, according to the National Stroke Association.

Be careful out there. Some research points to a 10-40% epilepsy incidence rate for survivors. What is your doctor doing to ensure you don't get epilepsy?

 

Post-Stroke Epilepsy Treatment May Influence Mortality

All-cause death lowest in people taking lamotrigine

by Judy George, Senior Staff Writer, MedPage Today December 13, 2021

All-cause mortality was significantly lower in people with post-stroke epilepsy treated with continuous lamotrigine (Lamictal) monotherapy compared with people who received carbamazepine (Tegretol), registry data in Sweden showed.

The opposite applied to people prescribed valproic acid (Depakene), who had a higher risk of cardiovascular and all-cause death compared with those treated with carbamazepine or lamotrigine, reported David Larsson, MD, of Sahlgrenska University in Gothenburg, and co-authors in JAMA Neurology.

"Our findings raise the possibility that specific anti-seizure medications influence the risk of cardiovascular and all-cause death, although our study design does not allow causal inference," Larsson and colleagues wrote. "Altered vascular risk is suspected to be the main reason behind our findings."

"Currently, treatment recommendations for post-stroke epilepsy are based primarily on trials conducted in older adults with epilepsy of various causes," they added. "The evidence supporting the use of specific anti-seizure medications is limited, but experts have suggested lamotrigine and levetiracetam [Keppra] as valid treatment options. Nonetheless, carbamazepine and valproic acid are commonly used among elderly patients with new-onset epilepsy."

In October 2020, the FDA added a warning about arrhythmia risk to lamotrigine's prescribing information and medication guides based on in vitro studies. In February 2021, an ad hoc task force of the International League Against Epilepsy and the American Epilepsy Society released an advisory statement about the FDA label change.

The Larsson study provides "another piece of evidence that drugs that interfere with hepatic enzyme induction may have significant negative cardiovascular consequences," said Jacqueline French, MD, of the NYU Comprehensive Epilepsy Center in New York City, who wasn't involved with the research. A recent cohort study of people in England also found an increase in poor cardiovascular outcomes associated with enzyme-inducing anti-seizure medicines, she noted.

"In regards to the recent FDA warning regarding lamotrigine, these findings suggest that switching patients with cardiovascular disease off lamotrigine to other anti-seizure medications, depending on selection and circumstances, might actually worsen outcomes," French told MedPage Today.

In their analysis, Larsson and colleagues looked at linked registry data on all adults in Sweden with acute stroke from July 2005 through December 2010, with subsequent epilepsy onset before Dec. 31, 2014. The primary outcome was all-cause death, using carbamazepine as the reference. Cardiovascular death was also assessed.

Overall, 2,577 patients receiving continuous anti-seizure drug monotherapy were eligible for the study. A total of 1,199 patients received carbamazepine, 477 received valproic acid, 354 received levetiracetam, 320 received lamotrigine, 73 received phenytoin (Dilantin), and 46 received oxcarbazepine (Trileptal).

Median age of patients was 78, and 54% were men. Most participants (84%) had acute ischemic stroke, while 16% had intracerebral hemorrhage. Median follow-up was 2.2 years, and event-free patients had a median observation time of 4.3 years.

Compared with carbamazepine, the adjusted HR for all-cause mortality was 0.72 (95% CI 0.60-0.86) for lamotrigine, 0.96 (95% CI 0.80-1.15) for levetiracetam, 1.40 (95% CI 1.23-1.59) for valproic acid, 1.16 (95% CI 0.88-1.51) for phenytoin, and 1.16 (95% CI 0.81-1.66) for oxcarbazepine.

The adjusted HR of cardiovascular death compared with carbamazepine was 0.76 (95% CI 0.61-0.95) for lamotrigine, 0.77 (95% CI 0.60-0.99) for levetiracetam, 1.40 (95% CI 1.19-1.64) for valproic acid, 1.02 (95% CI 0.71-1.47) for phenytoin, and 0.71 (95% CI 0.42-1.18) for oxcarbazepine. Levetiracetam showed a reduced risk of cardiovascular death over carbamazepine, but no significant difference in overall mortality, Larsson and co-authors pointed out.

Lamotrigine had the highest 3-year survival rate (0.62), followed by levetiracetam (0.55), oxcarbazepine (0.54), carbamazepine (0.53), valproic acid (0.34), and phenytoin (0.32).

Enzyme-inducing epilepsy drugs like carbamazepine and phenytoin enhance the metabolism of many secondary stroke prevention drugs, including anticoagulants, calcium channel blockers, and statins, Larsson and colleagues observed. Anti-seizure medications also have been linked directly to markers of vascular disease.

"For instance, carbamazepine and phenytoin have been associated with lipid abnormalities and increased levels of C-reactive protein, whereas valproic acid has been linked to weight gain, metabolic syndrome, and related endocrine abnormalities," they wrote. "Carbamazepine, phenytoin, and valproic acid, but not lamotrigine, have also been associated with increased carotid intima-media thickness (a surrogate marker for stroke and myocardial infarction)."

Sensitivity analyses adjusted for the year of treatment start suggested differences were not explained by improved stroke care over time, the researchers noted.

The study has several limitations, Larsson and colleagues acknowledged. It did not include information about all factors influencing anti-seizure drug selection and some confounding likely occurred. The findings are based only on patients using a single anti-epilepsy agent and do not extend to patients requiring drug changes for seizure control.

Last Updated December 14, 2021

• Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

Disclosures

This study was funded by grants from the Swedish state under the ALF agreement, and grants from the Swedish Society of Medicine, the Swedish Society of Medical Research, the Linnea and Josef Carlsson Foundation, the Göteborg Medical Society, and the Magnus Bergvall Foundation.

Larsson had no disclosures. Co-authors reported relationships with Janssen Cilag, Eisai, GW, UCB Pharma, AstraZeneca, SK Life Science, and Bial outside the submitted work.

French receives NYU salary support for consulting work or attending scientific advisory boards on behalf of the Epilepsy Study Consortium for Adamas, Aeonian/Aeovian, Anavex, Arkin Holdings, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Baergic Bio, Biogen, BioXcel Therapeutics, Cavion, Cerebral Therapeutics, Cerevel, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epiminder, Equilibre Biopharmaceuticals, Fortress Biotech, Greenwich Biosciences, GW Pharma, Janssen Pharmaceutica, Knopp Biosciences, Lundbeck, Marinus, Mend Neuroscience, Merck, NeuCyte, Inc., Neurocrine, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Praxis, Redpin, Sage, SK Life Sciences, Sofinnova, Stoke, Supernus, Synergia Medical, Takeda, UCB Inc., West Therapeutic Development, Xenon, Xeris, Zogenix, and Zynerba. She also has received research support from other groups.

Primary Source

JAMA Neurology

Source Reference: Larsson D, et al "Association between antiseizure drug monotherapy and mortality for patients with poststroke epilepsy" JAMA Neurol 2021; DOI: 10.1001/jamaneurol.2021.4584.

 

Lamotrigine Treatment for Post-Stroke Pathological Laughing and Crying

Well at least this one is only 11 years old, still incompent but not mind-boggling.
http://journals.lww.com/clinicalneuropharm/Abstract/2003/09000/Lamotrigine_Treatment_for_Post_Stroke_Pathological.6.aspx

Ramasubbu, Rajamannar

Abstract

Pathologic laughing and crying (PLC) is a common distressing and socially disabling condition in stroke patients. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), have been increasingly recognized as the treatment of choice for pathologic crying (PC). However, little is known about etiologies and other treatment options for various clinical manifestations of PLC. This case report illustrates the beneficial effect of lamotrigine, a novel antiepileptic drug with antidepressant and mood-stabilizing properties in post-stroke PLC. A 60-year-old woman developed PLC after an ischemic stroke affecting the left frontal and temporal lobes. She was treated with lamotrigine initially at the dose of 50 mg a day, which was gradually increased to 100 mg a day over a 4-week period. There was a significant and rapid recovery in both laughing and crying components of PCL with lamotrigine treatment. The symptoms of pathologic laughing have shown a better response to lamotrigine than PC. Controlled investigations are needed to evaluate the beneficial as well as the differential effects of lamotrigine on PLC.

The syndrome of pathologic laughing and crying (PLC) involves uncontrollable motor expression of emotion in the absence of corresponding feelings of sadness or happiness. PLC is often precipitated by nonspecific stimuli. 1 Emotional lability is a second type of pathologic affect that represents a rapid fluctuation in emotional expression that is out of proportion to an appropriate stimulus or situation and is accompanied by an alteration in mood states. 1 The validity of the existence of these two types has not been substantiated because of a great deal of overlap in the phenomenology between PLC and emotional lability. 2 In this context, a commonly used instrument, namely the pathologic laughing and crying scale (PLCS), has included items to measure both the intensity of pathologic laughing (PL) and pathological crying (PC) and also the severity of emotional lability. 3 The other terms used in the literature to describe the pathologic affect of laughing and crying include emotionalism, 4 emotional incontinence, 5 and pseudobulbar affect. 6

PLC is a common emotional consequence of stroke. Approximately 15% to 20% of patients may experience this condition during the first year after stroke. 7 Pathologic crying is the most common manifestation in stroke patients. However, some patients may have episodes of laughing without episodes of crying and some display both laughing and crying. Brain stem lesions and right frontal damage are frequently associated with PLC. 7 Double-blind placebo-controlled studies documented the efficacy of both tricyclics (nortriptyline, amitriptyline) and selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, sertraline) in PLC. 3,8–11 However, since the controlled treatment studies to date focused largely on patients with PC and only a few patients with PL were in the cohort, our understanding of the efficacy of antidepressants in PL is limited. Furthermore, anecdotal reports described a rapid transition of PC to PL during treatment with SSRIs 12 and a slow transformation of PC to PL as a natural course of PLC in some patients. 13,14

L-dopa was reported to be effective in patients with PL in an open trial. 15 However, taking into account the depressogenic side effect of l-dopa 16 and the frequent co-occurrence of depression with PLC in stroke patients, 7 l-dopa may not be a suitable agent for post-stroke patients with PLC and depression. This report describes a case of post-stroke PLC that markedly improved with lamotrigine, a novel antiepileptic drug with antidepressant and mood stabilizing properties.

Cerebroprotective Effect of Lamotrigine After Focal Ischemia in Rats

It has only been 19 f*cking years. Has anyone followed this up with human trials?
This just completely and totally proves that stroke has no strategic plan with the existing medical team. They all need to be fired and we need to start over with stroke-addled survivors. We can't do any worse than supposedly healthy brain normal people.
https://stroke.ahajournals.org/content/26/1/117.full

1. Stuart E. Smith, MSc, PhD;
2. Brian S. Meldrum, MB, BChir, PhD

+ Author Affiliations

1. From the Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, UK.

1. Correspondence to B.S. Meldrum, Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, SE5 8AF, UK.

 

Next Section

Abstract

Background and Purpose Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. We describe the cerebroprotective effect of lamotrigine (as the isethionate salt) after middle cerebral artery occlusion in rats.

Methods Neurological deficit and infarct volume (visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride) 24 hours after permanent left middle cerebral artery occlusion were studied in Fischer rats (n=8 per group per dose).

Results Lamotrigine at 20 mg/kg IV over 10 minutes administered immediately after middle cerebral artery occlusion reduced total infarct volume by 31% and cortical infarct volume by 52%. Lamotrigine at 8 mg/kg IV over 10 minutes reduced cortical infarct volume by 38%. Lamotrigine at 50 mg/kg IV for 10 minutes was not cerebroprotective and induced a decrease of 29±15 mm Hg in mean arterial blood pressure (P<.05, n=8). The optimum dose of lamotrigine (20 mg/kg IV over 10 minutes) when administered with a 1-hour delay after middle cerebral artery occlusion reduced cortical infarct volume by 41%. Lamotrigine (20 mg/kg IV over 10 minutes) with a 2-hour delay after middle cerebral artery occlusion was ineffective. Neurological deficits after 24 hours were improved after immediate treatment with lamotrigine at 20 mg/kg IV over 10 minutes.

Conclusions The cerebroprotective effect of lamotrigine in rats is limited to a narrow dose range between 8 and 20 mg/kg. Lamotrigine or analogous compounds may be useful when given shortly after the onset of stroke.

Differential Inhibition by Riluzole, Lamotrigine, and Phenytoin of Sodium and Calcium Currents in Cortical Neurons: Implications for Neuroprotective Strategies

So where are the therapy protocols for this? Its only been known since 1997.

Complete failure on our stroke associations part. How can they look survivors in the eye? Somebody needs to be fired.

Rodent research was done in 1990.

Differential Inhibition by Riluzole, Lamotrigine, and Phenytoin of Sodium and Calcium Currents in Cortical Neurons: Implications for Neuroprotective Strategies

Abstract

Among the several classes of drugs currently studied as neuroprotective agents, glutamate release blockers have been indicated as being rather effective. In particular, lamotrigine and riluzole have shown promise in the treatment of either acutely developing cellular damages (stroke, posttraumatic lesions) or slowly progressing neurodegenerative diseases as amyotrophic lateral sclerosis. These drugs are supposed to interfere with the release of endogenous glutamatein situ,yet the mechanisms underlying this effect are not fully defined. One possibility is that lamotrigine and riluzole act by inhibiting voltage-dependent inward conductances active in the soma and/or in the axon terminal region. Therefore, we have investigated the effects of lamotrigine and riluzole on the voltage-gated sodium and calcium currents of acutely isolated neurons from the adult rat neocortex. In addition, since phenytoin is a well-known blocker of the sodium channel, we have compared lamotrigine and riluzole responses with the peak current inhibition produced by phenytoin in the same cells. Lamotrigine produced a large reduction of the high-voltage-activated calcium currents and a smaller, use-dependent inhibition of the sodium conductance. Riluzole inhibited significantly the sodium current at surprisingly low concentrations (nanomolar range) and by up to 80% at saturating doses (1–10 μM). Furthermore, riluzole inhibited both high- and low-voltage-activated calcium currents in neocortical neurons isolated from adult and young animals. By contrast, phenytoin caused only a slight reduction of high-voltage-activated calcium currents even at supratherapeutic doses (by &lt12% at 10 μM). Taken together, the different pharmacological profiles of the tested agents might indicate that glutamate release blockers do not represent a homogenous class of drugs. Conversely, our findings could support their selective utilization in different disease status.