Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease

Study Overview
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Brief Summary
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Levetiracetam (Keppra) is used to treat partial onset seizures. Its biological effects suggest it might also be useful in treating 3 aspects of human motor neuron diseases (MNDs) for which no effective therapy exists: cramps, spasticity, and disease progression.

Detailed Description
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Cramps in MNDs are believed to occur as a result of high-frequency burst firing of alpha motor neurons. Levetiracetam inhibits burst firing in epileptic rat hippocampus. Levetiracetam has never been tested against cramps in humans; however, it has helped another condition believed to result from burst firing of a motor nerve: hemi-facial spasm. The mechanisms underlying spasticity in MNDs likely involve imbalance between excitatory and inhibitory influences on the alpha motor neurons. Levetiracetam may modulate these influences in a number of ways, including reducing the effects of zinc and beta-carbolines in GABA and glycine receptors. Levetiracetam reduces phasic (but not tonic) spasticity in patients with multiple-sclerosis. Levetiracetam may have neuroprotective properties. In a model of cerebral ischemia induced by occlusion of the rat internal carotid artery, pre-treatment with levetiracetam reduced infarct size in a dose-dependent manner. In rats injected with kainic acid to induce calcium overload, oxidative stress and neurotoxicity, pretreatment with levetiracetam offset kainic acid's effects. The mechanisms for these effects may relate to levetiracetam's ability to influence calcium currents, or its ability to increase the release of growth factors from astrocytes, mechanisms that would be relevant in MNDs. Levetiracetam's ability to inhibit histone deacetylase may also help slow MNDs progression. OBJECTIVES: 1. Assess the safety and tolerability of levetiracetam over 9 months in patients with MNDs. 2. Determine whether treatment with levetiracetam is associated with a reduction in cramps, spasticity or motor neuron disease progression. METHODS:Open-label, Phase 2 trial of 20 adult patients with MNDs (ALS, PLS or PMA) at Duke University ALS Clinic. Eligible patients have cramps with average severity 50/100 points, are able to provide informed consent, have normal renal functions and are on a stable riluzole dose. Exclusions include pregnancy, unstable mental illness, dementia, drug abuse or non-compliance. The first 3 months of the study are a baseline period. Over the remaining 9 months, patients take levetiracetam at increasing doses up to 3000mg per day. Outcome measures include adverse events, tolerability,cramp-pain-severity score, cramp-frequency score, modified Ashworth Spasticity Score, Penn Spasm Score, FVC, ALSFRS-R and MMT.

Official Title
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A Pilot Trial of Levetiracetam for Cramps, Spasticity and Neuroprotection in Motor Neuron Disease

Conditions
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Motor Neuron Disease, Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis, Progressive Muscular Atrophy

Intervention / Treatment
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* Biological: Levetiracetam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with MNDs (ALS, PLS or PMA)who have cramps with average severity 50/100 points, are able to provide informed consent, have normal renal function and are on a stable riluzole dose. Exclusion Criteria: Pregnancy; unstable medical illness, dementia; drug abuse or non-compliance

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Levetiracetam|Levetiracetam 1500 mg BID|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability at 9 months of treatment. |  | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cramps scores, spasticity scores, FVC, ALSFRS, MMT |  | 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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motor neuron disease, amyotrophic lateral sclerosis primary lateral, sclerosis; progressive muscular atrophy, cramps, spasticity