Thomas RH

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Newcastle University E-Prints

Clinical Medicine 24 (2024) 100040 Contents lists available at ScienceDirect Clinical Medicine journal homepage: https://www.sciencedirect.com/journal/clinical-medicine Practical approach to anti seizure medications, an update Rhys H Thomas Royal Victoria Infirmary, Newcastle-Upon-Tyne, United Kingdom and Translational and Clinical Research Institute, Henry Wellcome Building, Framlington Place, Newcastle-Upon-Tyne, United Kingdom  e  s  f  ‘  i  s  n  a  a  s  t  a  t  m  j e  a  E  a  h  aA t  a  W  m  d  m  ‘  l  c  s  m  f  v  m  a  s e  d  a  n  A  a  s  p  u  i  d  a i  e  p t  I  s  e  l  t w  e  s  iT  s  n  b  s  fi  t  t  a  ah1(Seizures are unpleasant, may cause injury and contribute to soci-tal impairments such as cessation of driving privileges. Critically eveneizures that stop by themselves, and are not unduly prolonged, may beatal. 1 All adults who have a first seizure should be referred to their localFirst Seizure Service’ where someone with expertise will identify if theres a seizure mimic present, such as reflex vasovagal syncope, dissociativeeizures and rarely cardiogenic syncope. Following a second seizure, orow the first – if there is a strong indicator of seizure recurrence, suchs a major scan abnormality – anti-seizure medications (ASM) are initi-ted. 2 Safety advice and avoidance of lifestyle factors known to triggereizures are important, but for the majority of people with epilepsy,he mainstay of their treatment is medication. Anti-seizure medicationsre the preferred term to reinforce an important point – these medica-ions reduce the likelihood of seizures occurring, but they are not diseaseodifying (not ‘anti-epilepsy drugs’) and there is more complexity thanust grand mal seizures (not ‘anti-convulsants’). 3 The Getting it Right First Time report for Neurology (2021) identifiedpilepsy as the second most common neurological reason for admission,fter headache, with 83/100,000 in 2018. 4 Whilst only 4% of people inngland are admitted to hospitals with no neurological presence, 28% ofdmissions (66,781 emergency admissions/year) are to district generalospitals with a visiting neurologist only and so it is important that allcute medics are familiar with manipulating ASMs. nti seizure medication choice The dogma is that identifying the seizure type(s) and putting this inhe context of the age of onset, EEG and MRI findings, co-morbidities,llows for an epilepsy classification that then facilitates ASM choice.hilst this is undoubtedly correct this is much less important for acuteedics, as the vast majority of people that they see and almost all ofe novo epilepsy in adults will be of focal onset. This presents with twoain seizure types – major convulsive seizures, now technically calledfocal to bilateral tonic-clonic seizures’ and smaller ‘focal seizures withoss of awareness’. The latter seizure type has been known as petit mal,omplex partial seizures and focal dyscognitive seizures and patientstill commonly call them absences. Furthermore, the two most com-only started ASMs for focal onset seizures are very reasonable choicesor the other type of epilepsy, idiopathic generalised. This pragmaticiew is further strengthened by the fact that the ‘odd one out’ of theajor ASMs, sodium valproate (meaning it is primarily used for seizuresE-mail address: rhys.thomas@ncl.ac.uk ttps://doi.org/10.1016/j.clinme.2024.100040 470-2118/© 2024 The Author. Published by Elsevier Ltd on behalf of Royal College http://creativecommons.org/licenses/by-nc-nd/4.0/ ) ssociated with idiopathic generalised epilepsy, rather than focal onseteizure) is increasingly hard to prescribe safely (see valproate below). Adherence matters – the most common reason someone withpilepsy will attend with breakthrough seizures will be accidental oreliberate under-dosing. This may because we have not recommended sufficient dose (answer; increase dose as per Table 1 ) or they haveot absorbed, vomited their last dose, or there is an adherence issue.cute medics have a critical role to play in identifying medication non-dherence, it is only the initial blood tests that can be used to identifyub-optimal ASM levels, as all subsequent bloods will represent the su-ervised treatment as an inpatient. All ASMs can be assayed by the DTMnit at Chalfont, 5 but pragmatically it is unusual for someone to be tak-ng some of their ASMs religiously and others haphazardly and so it isefensible if you choose to only assay the ASMs that you have readyccess to (likely to be the five drugs in Table 1 , plus phenobarbital). Identifying adherence is crucial as the episodic seizures seen withndifferently taking ASMs are a very good mimic of a drug-resistantpilepsy and so medication doses may be increased unnecessarily, oreople might be swapped on to other, often inferior ASMs. The route of medication is important to know; Table 1 identifieshat lamotrigine and carbamazepine lack an intravenous formulation.t is vitally important that people with epilepsy do not miss doses ando options here include i) a nasogastric tube; ii) a short-term levetirac-tam or benzodiazepine bridge. This latter strategy utilises the fact thatevetiracetam, lorazepam, diazepam, and clonazepam are available in-ravenously and are rapidly therapeutic. 6 There are five ASMs that all acute medics should know, and knowell ( Table 1 ). Lamotrigine has high-quality pragmatic randomised trialvidence from the UK to support its role as the first choice for focal on-et epilepsy; this is based on comparison with levetiracetam and zon-samide, where it had good efficacy, tolerability and was inexpensive. 7 here is a lag of weeks before it becomes therapeutic as it is startedlowly (typically starting at 25 mg od and going up by 25 mg a fort-ight). This strategy is important to combat skin reactions which cane mild to severe when escalated quickly. If seizure control is neededooner, consider co-prescribing clobazam (perhaps 10 mg bd) for therst 6 weeks until lamotrigine is close to therapeutic. The slow escala-ion helps with avoiding initiation side effects, but may also contributeo under-dosing. Lamotrigine trough levels are helpful as a guide; thesere best before the next dose is due, or at least 6 h or more post dose so ‘near trough’ late in the afternoon is convenient.  of Physicians. This is an open access article under the CC BY-NC-ND license R.H. Thomas Clinical Medicine 24 (2024) 100040Table 1 Commonly prescribed ASMs that all acute medics should be confident with. Ranges BNF (2023). 14 Generic Trade Formulations Smallest tablet Titration dose Maximum dose lamotrigine Lamictal Tablet, dispersible 25 mg (2 mg dispersible) 50–100 mg bd 250 mg bd levetiracetam Keppra Tablet, liquid, granules, IV 250 mg As per effect - 750 mg bd 1,500 mg bd carbamazepine Tegretol Tablet, liquid, PR 100 mg 400–600 mg bd 1,000 mg bd (rarely tolerated) phenytoin Epanutin Capsules, tablet, liquid, IV 25 mg capsules 100–250 mg bd (200–500 mg od) As per blood levels valproate Epilim Tablet, liquid, granules, IV 200 mg standard (100 mg crushable) 500–1,000 mg bd 1,250 mg bd  c  e  s  u  i  n  m  a  mw  e  o  e  l  p b  c  tH  e m  n  m  h  w  fi  a p  v  f  c  b  c  i  m  c  p  m  t  a  pN c  q  a  m  s  c  h  p  c  z  a  w  a  w  t  t  c  m  pD B  PR                1    11   1  1  1  1   Levetiracetam is a widely adopted anti-seizure medicine with indi-ations for children and adults, for urgent seizure control (such as statuspilepticus) as well as long-term prophylaxis. It is renally excreted ando doses need to be adjusted with significant renal disease, but is muchsed partly because it has an absence of clinically meaningful drug-drugnteractions. Of less importance to acute medics, but commonly seen ineurology clinics, it has no mood stabilising properties and is the ASMost commonly stopped for mood aggravation; irritability and anxietyggravation is common, psychosis is rare. 8 Some neurologists recom-end supplementary vitamin B6 to mitigate against this side effect 9 hilst others swap to a mechanistically similar medication, brivarac-tam, which can be done immediately overnight with a conversion ratiof approximately 15:1 (so levetiracetam 1,500 mg bd becomes brivarac-tam 100 mg). 10 There is little concerning pregnancy safety data foramotrigine or levetiracetam and so these are our preferred choices ifregnancy is possible. Carbamazepine is a legacy drug meaning that it is much less likely toe initiated now, and in many ways has been superseded by mechanisti-ally similar medications such as oxcarbazepine, elsicarbazepine. Long-erm use of this liver metabolised drug can contribute to osteoporosis. 11 igher doses or moderate doses in vulnerable individuals, such as thelderly, commonly cause ataxia. Phenytoin is a medication best retained for emergency use to ter-inate prolonged seizures, or for expert use only for patients in whomothing else has worked. There is a dual concern that the long-term so-atic side effects (many of which are cosmetic such as hirsutism, gumypertrophy but others are more cryptic such as osteoporosis), may out-eigh the seizure-control benefit. Alongside this is that phenytoin is dif-cult to prescribe reliably in the long-term with drug-drug interactionsnd complex zero-order pharmacokinetics. Sodium valproate is a drug in the headlines because it is a recognisedhysical and cognitive teratogen. Concordantly there is a pregnancy pre-ention programme with a standardised process of annual consentingor all people taking valproate who may become pregnant. 12 In mostircumstances it would be unwise for a non-specialist to start valproate,ut were you to do so, be aware that you need to do a pregnancy test,omplete a shared-care document for the GP and give the patient med-cation until their GP can take over this role. The committee for hu-an medicines (CHM) reviewed data regarding safety of valproate forhildren born to fathers taking the medication; now for all new val-roate prescriptions in men and boys under 55 years, patients need for-al counselling and documentation. 13 Irrespective of this controversyhere are a plethora of reasons why long-term valproate use may be bestvoided, primarily the weight gain can be egregious and contribute toremature metabolic syndrome. ewer anti seizure medications Proportionally fewer people are taking newer ASMs, however be-ause these are more likely to be prescribed to people with more fre-uent seizures and or more complex needs, they may be disproportion-tely represented in emergency admissions. All people taking a neweredication should have seen a neurologist recently and almost certainlyhould have access to an epilepsy specialist nurse, either of whom, whenontacted could provide advice and support. Some of the newer drugsave longer half-lives than previously available medications which helps2revent breakthrough seizures due to adherence issues. For exampleannabidiol (56–61 h), cenobamate (50–60 h), perampanel (70–110 h),onisamide (50–68), and in contrast levetiracetam is 6–8 h. 15 A practicaldvantage of this is that if a patient presents with side effects in keepingith drug toxicity from one of these medications, it may be safe to omit dose and then amend the regular regimen, whereupon previously thisas not an option. Cenobamate is increasingly used because it appearso be more likely to control seizures in people with multi-drug refrac-ory epilepsy, however with this benefit comes a cost, there are a host oflinically meaningful and theoretical drug-drug interactions, includingonoclonals and some anaesthetic agents, so care must be taken whenrescribing for anyone of cenobamate. 16 eclaration of competing interest R Thomas has received honoraria from Arvelle/Angelini, Bial,iocodex, Eisai, Jazz, LivaNova, Neuraxpharm, Sanofi, Takeda, UCBharma/Zogenix and UNEEG. eferences 1. https://sudep.org/ (last accessed 17-Mar-24). 2. Epilepsies in children, young people and adults (2022) NICE guideline NG217 https://www.nice.org.uk/guidance/ng217 (last accessed 17-Mar-24). 3. Perucca E, French JA, Aljandeel G, et al . Which terms should be used to describe med-ications used in the treatment of seizure disorders? An ILAE position paper. Epilepsia .2024;65(3):533–541 . 4. The Getting it Right First Time report for Neurology (2021) https://gettingitrightfirsttime.co.uk/medical_specialties/neurology/ (last accessed 17-Mar-24). 5. Epilepsy society – contact our therapeutic drug monitoring unit https://epilepsysociety.org.uk/what- we- do/medical- services/therapeutic- drug- monitoring/ contact- our- therapeutic- drug- monitoring (last accessed 17-Mar-24). 6. Bank AM, Lee JW, Krause P, Berkowitz AL. What to do when patients with epilepsycannot take their usual oral medications. Pract Neurol . 2017;17(1):66–70. doi: 10.1136/practneurol- 2016- 001437 . 7. Marson A, Burnside G, Appleton R, et al . The SANAD II study of the effectivenessand cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diag-nosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomisedcontrolled trial. Lancet . 2021;397(10282):1363–1374. doi: 10.1016/S0140-6736(21)00247-6 . 8. Chen B, Choi H, Hirsch LJ, et al . Psychiatric and behavioral side effects of antiepilepticdrugs in adults with epilepsy. Epilepsy Behav . 2017;76:24–31. doi: 10.1016/j.yebeh.2017.08.039 . 9. Besag FMC, Vasey MJ, Sen A. Current evidence for adjunct pyridoxine (vitamin B6) forthe treatment of behavioral adverse effects associated with levetiracetam: a systematicreview. Epilepsy Behav . 2023;140:109065. doi: 10.1016/j.yebeh.2022.109065 . 0. Watkins LV, Dunstall H, Musicha C, et al . Rapid switching from levetiracetam tobrivaracetam in pharmaco-resistant epilepsy in people with and without intellec-tual disabilities: a naturalistic case control study. J Neurol . 2023;270(12):5889–5902.doi: 10.1007/s00415- 023- 11959- w . 1. Antiepileptics: adverse effects on bone (2009) https://www.gov.uk/drug-safety- update/antiepileptics- adverse- effects- on- bone# :∼:text=Data%20suggests%20that% 20long%2Dterm,%2C%20osteoporosis%2C%20and%20increased%20fractures (last accessed 17-Mar-24). 2. Valproate use by women and girls MHRA https://www.gov.uk/guidance/valproate- use- by- women- and- girls# full- publication- update- history (last accessed17-Mar-24). 3. MHRA update on new study on risk in children born to men taking val-proate https://www.gov.uk/government/news/mhra- update- on- new- study- on- risk- in- children- born- to- men- taking- valproate (last accessed 17-Mar-24). 4. Joint Formulary Committee British National Formulary London: BMJ and Pharma-ceutical 2023. 5. Hakami T. Neuropharmacology of antiseizure drugs. Neuropsychopharmacol Rep .2021;41(3):336–351. doi: 10.1002/npr2.12196 . 6. Roberti R, De Caro C, Iannone LF, Zaccara G, Lattanzi S, Russo E. Pharmacologyof cenobamate: mechanism of action, pharmacokinetics, drug-drug interactions andtolerability. CNS Drugs . 2021;35(6):609–618 . 

Practical approach to anti seizure medications, an update

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Practical approach to anti seizure medications, an update

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