Generating Evidence on NonEpileptic, Stereotypical and Intermittent Symptoms (NESIS) in Chronic Subdural Hematomas

Study Overview
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Brief Summary
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Some patients with chronic subdural hematomas and transient neurological symptoms do not respond to standard antiepileptic drugs. The investigators think that some of them could have cortical depression rather than epileptic discharges. After an intensive literature review, the investigators found out that some antiepileptic dugs (Lamotrigine, Topiramate) were found to be efficient to treat cortical depression in other conditions (migraine, subarachnoid hemorrhage). In contrast, some other drugs (Levetiracetam) were not proved to be efficient. Knowing that, the investigators want to compare the efficacy of Topiramate against Levetiracetam in two different groups, the NESIS group (based on a NESIS score of 4 or more - increased risk of cortical depression) versus a non-NESIS group (score of 3 or less - increased risk of epileptic discharges).

Detailed Description
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Patients presenting with transient neurological symptoms in the context of subdural hemorrhage may present a diagnostic challenge. Many of these patients end up with a probable diagnosis of epilepsy (or acute symptomatic seizures), despite a negative electroencephalogram. The investigators believe that the origin of these transient neurologic symptoms in a significant subpopulation of these patients may in fact be cortical depolarization, rather than epileptiform activity. Very specific characteristics have already been identified that differentiate these patients from those who ultimately have epilepsy. The NESIS entity (nonepileptic, stereotypical, and intermittent symptoms) has been proposed to represent this group of patients. A NESIS score was then designed to help distinguish patients with epileptiform activity (confirmed by EEG) from those likely to have cortical depolarization. In other diseases presenting cortical depolarizations, certain antiepileptic treatments (including Topiramate) have already been recognized as effective. The investigators therefore want to perform a prospective, multicenter, randomized-controlled study (Topiramate group and Levetiracetam group) to determine whether a significant difference in the response to treatment exists between Topiramate and Levetiracetam in the NESIS group compared to the non-NESIS group. In addition, in a few eligible patients, the investigators will implant an electrocorticography electrode to demonstrate the existence of cortical depolarizations.

Official Title
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Generating Evidence on NonEpileptic, Stereotypical and Intermittent Symptoms (NESIS) in Chronic Subdural Hematomas

Conditions
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Chronic Subdural Hematoma, Epilepsy; Seizure, Cortical Depression; Cortical Depolarization, Nonepileptic, Stereotypical and Intermittent Symptoms, NESIS

Intervention / Treatment
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* Drug: Topamax
* Drug: Levetiracetam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be aged ≥ 18 years Chronic subdural hematoma Transient neurological symptoms (Sensory, motor, cerebellar or speech symptoms, lasting 6 hours or less) Initial negative EEG Exclusion Criteria: Contraindications to Levetiracetam Psychiatric history (major depression, psychosis, risk of suicide) History of hypersensitivity to LEV (anaphylaxis, angioedema, skin reaction) Contraindications to Topiramate History of hypersensitivity to TPM Glaucoma Past of nephrolithiasis Known epilepsy or past seizure before the current subdural hemorrhage Actual taking of an antiepileptic drug Intracranial pathology not caused by subdural hematoma (intra-parenchymal hemorrhage, neoplasia) Pregnancy or planning to Inability to carry out the necessary follow-ups for the study Refusal of the attending physician

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients with chronic subdural hematomas, transient neurological symptoms with negative EEG will be divided in two groups based on their NESIS scores (up to 3 (increased risk of epileptic seizures) and 4 or more (increased risk of cortical depression)). Those two groups are going to receive both Levetiracetam or Lamotrigine.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NESIS - Levetiracetam<br>Participant with a score NESIS of 4 or more (increased risk of having cortical depression). Levetiracetam is an anti-epileptic drug known to be inefficient in other condition with cortical depression. It will be use as an active comparator. | Drug: Levetiracetam<br>* LEV : 500 mg BID, with increase of 1000 mg die divided in two doses each week until efficacy, to a maximum of 1500 mg BID.<br>* Other names: Keppra;|
| Experimental: NESIS - Topiramate<br>Participant with a score NESIS of 4 or more (increased risk of having cortical depression). Topiramate is an anti-epileptic drug known to be efficient in other condition with cortical depression. The investigators want to test his efficacy in chronic subdural hematoma with probable cortical depression. | Drug: Topamax<br>* TPM : 50 mg BID, with increased of 50 mg by week until efficacy, to a maximum of 100 mg BID.<br>* Other names: TPM;|
| Active Comparator: Non NESIS - Levetiracetam<br>Participant with a score NESIS of 3 or less (increased risk of having epileptic discharges). Levetiracetam is an anti-epileptic drug known to be inefficient in other condition with cortical depression. It will be use as an active comparator. Levetiracetam should be as efficient as Topiramate in a group a participant with epileptic discharges. | Drug: Levetiracetam<br>* LEV : 500 mg BID, with increase of 1000 mg die divided in two doses each week until efficacy, to a maximum of 1500 mg BID.<br>* Other names: Keppra;|
| Experimental: Non-NESIS - Topiramate<br>Participant with a score NESIS of 3 or less (increased risk of having epileptic discharges). Topiramate is an anti-epileptic drug known to be efficient in other condition with cortical depression. The investigators want to test his efficacy in chronic subdural hematoma with probable cortical depression. Topiramate should be as efficient as Levetiracetam in a group a participant with epileptic discharges. | Drug: Topamax<br>* TPM : 50 mg BID, with increased of 50 mg by week until efficacy, to a maximum of 100 mg BID.<br>* Other names: TPM;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference in the number of TNS reported at 6 month in participants with a positive Nonepileptic, Stereotyped, Intermittent Symptoms (NESIS) score (4 and more) | The aim of this study is to demonstrate the efficacy of Topiramate in the treatment of patients with transient neurological symptoms in the context of chronic subdural hemorrhage with a positive NESIS score (4 and more), in whom usual epilepsy treatment appears to be less effective. To do this, the effect of Topiramate (shown to be effective in cortical depressions) will be compared with that of Levetiracetam (which has not been shown to be effective in cortical depressions). This is going to be done by a questionnaire that will assess the resolution of symptoms or not, or the percentage of diminution. | Through study completion, an average of 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference in the number of TNS reported at 6 month in all participants (all NESIS scores) | If the investigators manage to demonstrate a significant difference between the response to TPM and LEV in the NESIS group compared to the non-NESIS group with our questionnaire, the evidence concerning the existence of a different process at the origin of the NESIS group will then be more numerous. As demonstrated in studies on rats, cortical spreading depolarization respond well to TPM and not to LEV. Cortical depolarizations will then be the main hypothesis of the reason why some responds better to TPM than LEV in our study. | Through study completion, an average of 3 years | 
| Incidence of cortical spreading depression on electrocorticography in the first postoperative week of patients with preoperative TNS. | The investigators think that cortical depression rather then epileptic discharges could be involved in some patients with transient neurological symptoms in context of subdural hematomas. Some participant could need decompression surgery for their subdural hematoma. The investigators will offer the insertion of electrocorticography electrods while this surgery. The aim of this intervention will be to prove cortical depression in some subjects by using electrocorticography that will be read by a neurologist specialized in epilepsy. | Through study completion, an average of 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transient neurological symptoms, Levetiracetam; keppra, Lamotrigine; lamictal