SV2A Ligands: New Antiepileptic Drug for Modern Neurosurgical Consideration!

Transcription

1 SV2A Ligands: New Antiepileptic Drug for Modern Neurosurgical Consideration Sorayouth Chumnanvej,M.D. Neurosurgeon Ramathibodi Hospital, Mahidol University Professor Carole Longson, Director of the Health Technology Evaluation Centre at NICE said: Seizures can be extremely debilitating as they can interfere with a person's social life, employment and other daily activities. While there are a number of effective anti-epileptic drugs already widely available on the NHS, people can have different responses to them. It's therefore very important for doctors to have a broad range of options so that they can find the right combination for their patients. 1

2 Prophylactic treatment is not a guarantee that seizures will be prevented The benefit of seizure prevention must be weighed against the potential for anticonvulsant drug toxicity. Seizures occur as part of acute illnesses Metabolic disorders --hypoglycemia --hyponatremia Neurosurgical conditions --stroke --subarachnoid hemorrhage --brain tumor --closed head injury --intracranial surgery Risk(%) 6-12 >

3 The prevention and early treatment of seizures is important following neurosurgery, because -seizures can precipitate serious complications secondary intracranial bleeding hypoxia aspiration raised intracranial pressure -seizures can be provoked by Hyponatremia Acidosis Alcohol withdrawal Hypoxemia Sepsis Steroid therapy Postoperative hematoma 3

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5 Levetiracetam is licensed for the combination treatment of partial seizures with or without secondary generalization. It is not recommended for children younger than 16 years. It has no reported drug interactions. 5

6 Overview Introduction Mechanism of action of AED The SV2A Ligands Application & Evidence in Neurosurgery Future Outlook Introduction Epilepsy is a complex phenotype with multiple etiologies. Loscher and Schmidt, 1988: seizures induced by electrical stimulation Bouilleret et al., 1999: seizures induced by chemical treatment 6

7 12/13/11 Introduction Two traditional models employed in routine screening and identification of new AEDs are the maximal electroshock (MES) subcutaneous pentylenetetrazol (PTZ or Metrazol) tests Introduction Pathophysiology of the form of Acquired Epilepsy massive release of the excitatory amino acid neurotransmitter glutamate excessive activation of postsynaptic glutamate receptors The neurons that survive in the penumbra region are the underlying substrates for ischemia-induced epileptogenesis 7

8 Mechanism of action of AED Three major classes of molecular targets are believed to be relevant for limiting seizure activity including: (1) voltage-gated sodium and calcium channels (2) GABA receptors (3) ionotropic glutamate receptors (i.e., NMDA or N- methyl-d-aspartate, AMPA, or a-amino-3-hydroxy-5- methyl-4-isoxazoleproprionic acid) and kainate receptors. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia. 1999;40:

9 Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia. 1999;40: SV2A Ligands synaptic vesicle protein 2 (SV2), was originally identified with a monoclonal antibody generated against cholinergic vesicles from the electric organ of the electric ray Discopyge ommata 9

10 SV2A Ligands Three forms of SV2 are expressed in all brain regions. SV2 is a 12-transmembrane protein incorporated in the membrane of synaptic vesicles, present in the presynaptic terminal. SV2A is the most widely distributed in the brain and also present on many neuroendocrine cells. SV2A Ligands Approximately 12,000 compounds were screened in vitro for SV2A binding affinity, 900 compounds were examined for seizure protection in audiogenic susceptible mice, and 30 compounds were characterized more widely in animal models of seizures and epilepsy. 10

11 Application & Evidence in Neurosurgery The overall postoperative epilepsy incidence is 17% with a wide range from 3 to 92%, during a follow-up period of 5 years Foy PM, Copeland GP, Shaw MDM. The incidence ofpostoperative seizures. Acta Neurochir 1981; 55: North JB, Penhall RK, Hanieh A, Frewin DB, Taylor WB. Phenytoin and postoperative epilepsy: a double blind study. J Neurosurg 1983; 58: Application & Evidence in Neurosurgery 1/5of patients undergoing aneurysm surgery will develop postoperative seizures. Operations for MCA aneurysms are associated with a 38% risk of epilepsy. Operations for Acom A aneurysms have a 21 % risk of epilepsy. Arteriovenous malformations have a 20 % risk of postoperative epilepsy. Cerebral abscess is associated with a 72% incidence of epilepsy. North JB, Penhall RK, Hanieh A, Hann CS, Challen RG, Frewin DB: Postoperative epilepsy: a doubleblind trial of phenytoin after craniotomy. Lancet 1980;1: Legg NJ, Gupta PC, Scott DF. Epilepsy followingcerebral abscess: a clinical and EEG study of 70 patients. Brain 1973; 96:

12 12/13/11 Application & Evidence in Neurosurgery TRAUMATIC BRAIN INJURY Early epilepsy; in post traumatic brain injury, is an indication for anticonvulsants because two thirds of these patients have more than one fit and 10% develop status epilepticus. Three factors increase the risk of late epilepsy (1) Intracranial haematoma (35%); (2) Early epilepsy (25%); (3) Depressed fracture (3-70%). Application & Evidence in Neurosurgery AED Prophylaxis indication in Neurosurgery 1) be at significant risk for seizures, 2) have some expectation that the seizures might cause harm, 3) be at low risk of an adverse drug reaction from the AED. Nathan B.F. Epilepsy Currents, Vol. 9, No. 3 (May/June) 2009 pp

13 An American Academy of Neurology clearly suggests that AED prophylaxis is useful for severe traumatic brain injury but does not recommend it for newly diagnosed brain tumors Chang BS, Lowenstein DH. Practice parameter: antiepileptic drugprophylaxis in severe traumatic brain injury: report of the QualityStandards Subcommittee of the American Academy of Neurology.Neurology 2003;60: Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, ChamberlainMC, Grossman SA, Cairncross JG. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosedbrain tumors: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54: RCT study in Add-on phenytoin of supratentorial neurosurgery did not find AED prophylaxis to be beneficial De Santis A, Villani R, Sinisi M, Stocchetti N, Perucca E. Add-onphenytoin fails to prevent early seizures after surgery for supratentorialbrain tumors: a randomized controlled study. Epilepsia 2002;43: Application & Evidence in Neurosurgery Use Pubmed search since Dec, 2011 for levetiracetam and neurosurgery and refining including Humans, Randomized Controlled Trial, English, and published in the last 10 years, there is only one RCT study Lim DA, Tarapore P, Chang E, Burt M, Chakalian L, Barbaro N, et al. Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study. J Neurooncol 2009 Jul;93(3): Under Pubmed search engine for levetiracetam and seizure prophylaxis since Dec, 2011 with limitation including Humans, Randomized Controlled Trial, English, and published in the last 10 years, there is only one RCT study Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care 2010 Apr;12(2): van Tuijl JH, van Raak EP, de Krom MC, Lodder J, Aldenkamp AP.Early treatment after stroke for the prevention of late epileptic seizures: a report on the problems performing a randomised placebo-controlled double-blind trial aimed at anti-epileptogenesis. Seizure May; 20(4): Epub 2011 Jan

14 Application & Evidence in Neurosurgery The study of levetiracetam add-on for drug-resistant localization related (partial) epilepsy with medication-resistant partial seizures. Chaisewikul R, Privitera MD, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant localization related (partial) epilepsy. Cochrane Database Syst Rev 2001;(1)(1):CD Future Outlook -The newer AED - Promising ideal drug that will be an alternative AEDs for prophylaxis and seizure control 14