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

NCT04759196 | Unknown Phase 4

• 1 other identifier: MP-31-2021-3687
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

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

Keywords

Transient neurological symptoms; Levetiracetam; keppra; Lamotrigine; lamictal

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Between-group difference in the number of TNS reported at 6 month in all participants (all NESIS scores)

  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.

  Through study completion, an average of 3 years

Study Arms (4)

NESIS - Levetiracetam

ACTIVE COMPARATOR

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

NESIS - Topiramate

EXPERIMENTAL

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

Non NESIS - Levetiracetam

ACTIVE COMPARATOR

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

Non-NESIS - Topiramate

EXPERIMENTAL

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

Interventions

Topamax DRUG

TPM : 50 mg BID, with increased of 50 mg by week until efficacy, to a maximum of 100 mg BID.

Also known as: Topiramate, TPM

NESIS - Topiramate; Non-NESIS - Topiramate

Levetiracetam DRUG

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.

Also known as: LEV, Keppra

NESIS - Levetiracetam; Non NESIS - Levetiracetam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Be aged ≥ 18 years
• Chronic subdural hematoma
• Transient neurological symptoms (Sensory, motor, cerebellar or speech symptoms, lasting 6 hours or less)
• Initial negative EEG

You may not qualify if:

• 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

Sponsors & Collaborators

• Université de Sherbrooke: lead

Study Sites (1)

Centre Hospitalier Universitaire de Sherbrooke

Sherbrooke, Quebec, J1H 5N4, Canada

RECRUITING

Related Publications (26)

• Cousseau DH, Echevarria Martin G, Gaspari M, Gonorazky SE. [Chronic and subacute subdural haematoma. An epidemiological study in a captive population]. Rev Neurol. 2001 May 1-15;32(9):821-4. Spanish.

  PMID: 11424031 BACKGROUND

• Toi H, Kinoshita K, Hirai S, Takai H, Hara K, Matsushita N, Matsubara S, Otani M, Muramatsu K, Matsuda S, Fushimi K, Uno M. Present epidemiology of chronic subdural hematoma in Japan: analysis of 63,358 cases recorded in a national administrative database. J Neurosurg. 2018 Jan;128(1):222-228. doi: 10.3171/2016.9.JNS16623. Epub 2017 Feb 3.

  PMID: 28156246 BACKGROUND

• Won SY, Dubinski D, Herrmann E, Cuca C, Strzelczyk A, Seifert V, Konczalla J, Freiman TM. Epileptic Seizures in Patients Following Surgical Treatment of Acute Subdural Hematoma-Incidence, Risk Factors, Patient Outcome, and Development of New Scoring System for Prophylactic Antiepileptic Treatment (GATE-24 score). World Neurosurg. 2017 May;101:416-424. doi: 10.1016/j.wneu.2017.02.024. Epub 2017 Feb 16.

  PMID: 28213197 BACKGROUND

• King MA, Newton MR, Jackson GD, Fitt GJ, Mitchell LA, Silvapulle MJ, Berkovic SF. Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients. Lancet. 1998 Sep 26;352(9133):1007-11. doi: 10.1016/S0140-6736(98)03543-0.

  PMID: 9759742 BACKGROUND

• Levesque M, Iorio-Morin C, Bocti C, Vezina C, Deacon C. Nonepileptic, Stereotypical, and Intermittent Symptoms (NESIS) in Patients With Subdural Hematoma: Proposal for a New Clinical Entity With Therapeutic and Prognostic Implications. Neurosurgery. 2020 Jul 1;87(1):96-103. doi: 10.1093/neuros/nyz355.

  PMID: 31555809 BACKGROUND

• Woitzik J, Hecht N, Pinczolits A, Sandow N, Major S, Winkler MK, Weber-Carstens S, Dohmen C, Graf R, Strong AJ, Dreier JP, Vajkoczy P; COSBID study group. Propagation of cortical spreading depolarization in the human cortex after malignant stroke. Neurology. 2013 Mar 19;80(12):1095-102. doi: 10.1212/WNL.0b013e3182886932. Epub 2013 Feb 27.

  PMID: 23446683 BACKGROUND

• Klass A, Sanchez-Porras R, Santos E. Systematic review of the pharmacological agents that have been tested against spreading depolarizations. J Cereb Blood Flow Metab. 2018 Jul;38(7):1149-1179. doi: 10.1177/0271678X18771440. Epub 2018 Apr 20.

  PMID: 29673289 BACKGROUND

• Harriott AM, Takizawa T, Chung DY, Chen SP. Spreading depression as a preclinical model of migraine. J Headache Pain. 2019 May 2;20(1):45. doi: 10.1186/s10194-019-1001-4.

  PMID: 31046659 BACKGROUND

• Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE. An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action. Epilepsia. 2000;41(S1):3-9.

  PMID: 10768292 BACKGROUND

• Bagnato F, Good J. The Use of Antiepileptics in Migraine Prophylaxis. Headache. 2016 Mar;56(3):603-15. doi: 10.1111/head.12781. Epub 2016 Mar 3.

  PMID: 26935348 BACKGROUND

• Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand. 2008 Nov;118(5):301-5. doi: 10.1111/j.1600-0404.2008.01087.x.

  PMID: 18713156 BACKGROUND

• Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001 Nov-Dec;41(10):968-75. doi: 10.1046/j.1526-4610.2001.01190.x.

  PMID: 11903524 BACKGROUND

• Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, Jacobs D; MIGR-002 Study Group. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004 Feb 25;291(8):965-73. doi: 10.1001/jama.291.8.965.

  PMID: 14982912 BACKGROUND

• Millan-Guerrero RO, Isais-Millan R, Barreto-Vizcaino S, Gutierrez I, Rivera-Castano L, Trujillo-Hernandez B, Baltazar LM. Subcutaneous histamine versus topiramate in migraine prophylaxis: a double-blind study. Eur Neurol. 2008;59(5):237-42. doi: 10.1159/000115637. Epub 2008 Feb 8.

  PMID: 18264012 BACKGROUND

• Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, Neto W, Vijapurkar U, Doyle A, Jacobs D; MIGR-003 Study Group. Topiramate in migraine prophylaxis--results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004 Aug;251(8):943-50. doi: 10.1007/s00415-004-0464-6.

  PMID: 15316798 BACKGROUND

• Mei D, Capuano A, Vollono C, Evangelista M, Ferraro D, Tonali P, Di Trapani G. Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurol Sci. 2004 Dec;25(5):245-50. doi: 10.1007/s10072-004-0350-0.

  PMID: 15624081 BACKGROUND

• Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004 Apr;61(4):490-5. doi: 10.1001/archneur.61.4.490.

  PMID: 15096395 BACKGROUND

• Gupta P, Singh S, Goyal V, Shukla G, Behari M. Low-dose topiramate versus lamotrigine in migraine prophylaxis (the Lotolamp study). Headache. 2007 Mar;47(3):402-12. doi: 10.1111/j.1526-4610.2006.00599.x.

  PMID: 17371357 BACKGROUND

• Beran RG, Spira PJ. Levetiracetam in chronic daily headache: a double-blind, randomised placebo-controlled study. (The Australian KEPPRA Headache Trial [AUS-KHT]). Cephalalgia. 2011 Apr;31(5):530-6. doi: 10.1177/0333102410384886. Epub 2010 Nov 8.

  PMID: 21059626 BACKGROUND

• Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013 Jun 24;2013(6):CD010608. doi: 10.1002/14651858.CD010608.

  PMID: 23797674 BACKGROUND

• Unekawa M, Tomita Y, Toriumi H, Suzuki N. Suppressive effect of chronic peroral topiramate on potassium-induced cortical spreading depression in rats. Cephalalgia. 2012 May;32(7):518-27. doi: 10.1177/0333102412444015. Epub 2012 Apr 20.

  PMID: 22523186 BACKGROUND

• Akerman S, Goadsby PJ. Topiramate inhibits cortical spreading depression in rat and cat: impact in migraine aura. Neuroreport. 2005 Aug 22;16(12):1383-7. doi: 10.1097/01.wnr.0000175250.33159.a9.

  PMID: 16056144 BACKGROUND

• Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006 Apr;59(4):652-61. doi: 10.1002/ana.20778.

  PMID: 16450381 BACKGROUND

• Lin CH, Hsu SP, Cheng TC, Huang CW, Chiang YC, Hsiao IH, Lee MH, Shen ML, Wu DC, Zhou N. Effects of anti-epileptic drugs on spreading depolarization-induced epileptiform activity in mouse hippocampal slices. Sci Rep. 2017 Sep 19;7(1):11884. doi: 10.1038/s41598-017-12346-y.

  PMID: 28928441 BACKGROUND

• Abou-Khalil BW. Update on Antiepileptic Drugs 2019. Continuum (Minneap Minn). 2019 Apr;25(2):508-536. doi: 10.1212/CON.0000000000000715.

  PMID: 30921021 BACKGROUND

• Zhuo C, Jiang R, Li G, Shao M, Chen C, Chen G, Tian H, Li J, Xue R, Jiang D. Efficacy and Tolerability of Second and Third Generation Anti-epileptic Drugs in Refractory Epilepsy: A Network Meta-Analysis. Sci Rep. 2017 May 31;7(1):2535. doi: 10.1038/s41598-017-02525-2.

  PMID: 28566726 BACKGROUND

Related Links

• Topiramate. Drug information.
• Levetiracetam. Drug information.
• Santé canada, registres des produits pharmaceutiques. (Canadian drugs register)
• Side effects classification

MeSH Terms

Conditions

Hematoma, Subdural, Chronic; Epilepsy

Interventions

Topiramate; Levetiracetam

Condition Hierarchy (Ancestors)

Hematoma, Subdural; Intracranial Hemorrhage, Traumatic; Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Vascular Diseases; Cardiovascular Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Hematoma; Hemorrhage; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Christian Iorio-Morin, MD

  Université de Sherbrooke

  PRINCIPAL INVESTIGATOR

Central Study Contacts

suzie adam, MD

CONTACT

5146990518; suzie.adam@usherbrooke.ca

Mathieu Lévesque, MD

CONTACT

Levesque@neurorivesud.ca

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: CARE PROVIDER, OUTCOMES ASSESSOR
• Masking Details: The participant will not know the medication they are taking. When accepting to participate, they are going to have the full list of possible side effects, without knowing which one are link to which medication. The doctors in charge of administering the questionnaires will be blind. The person in charge of analyzing the results will also be blind.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: October 27, 2020
• First Posted: February 18, 2021
• Study Start: March 1, 2021
• Primary Completion: September 1, 2024
• Study Completion: December 1, 2024
• Last Updated: April 30, 2021

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)