Epilepsy presentation

guidelines for starting antiepileptics

1. Dr. Nishtha jain Senior Resident, Department of Neurology, GMC, Kota. Guidelines for starting antileptics

2. It is a tenet in medical practice that treatment be initiated only when the potential for benefit from the treatment exceeds the potential for harm . In the treatment of epilepsy, this is important to bear in mind because AED treatments all offer obvious potential benefits but they also carry risk.

3. The treating physician must consider all of these when determining the best fit for a particular patient . The ultimate goal is freedom from seizures as well as from side effects .

4. The first principle of prescribing an antiepileptic drug (AED) is to select the most efficacious AED for the seizure type or epilepsy syndrome present. The second principle of prescribing an AED is to consider the side effect profile of each drug and the patient’s unique characteristics, eg , depression, migraine, pain, obesity, woman of childbearing potential, older adult.

5. Studies indicate that, at the time of diagnosis, classification of partial or generalized seizures can only be made about half of the time . If a clear diagnosis cannot be made, it is wise to choose a broad-spectrum antiepileptic drug . The choice of initial therapy can be crucial because many patients will remain on the initial therapy long term . The first antiepileptic drug should be one that is expected to be well tolerated and reasonably safe.

6. When using drugs in polytherapy , pharmacokinetic interactions must be considered and doses should be altered as appropriate. Drugs such as levetiracetam , gabapentin , pregabalin , and valproate have a low risk of hypersensitivity and may be good choices in patients with a history of rash or hypersensitivity to antiepileptic drugs or other agents

7. It is preferable to avoid enzyme-inducing antiepileptic drugs ( eg , phenytoin , carbamazepine , phenobarbital , and primidone ) in patients with chronic medical conditions other than epilepsy since two-thirds of drugs will undergo increased clearance as a result of enzyme induction. Older patients tend to have lower thresholds for developing side effects .

8. The third principle of selecting an AED for a patient is to consider convenience and dosing. Drugs dosed twice per day or less lead to better compliance than drugs dosed more frequently. The fourth principle of prescribing an AED is to select the lowest-cost AED.

9. Risk of Seizure Recurrence Adults presenting with an unprovoked first seizure should be informed that the chance for a recurrent seizure is greatest within the first two years after a first seizure (21 percent to 45 percent) ( Level A). Clinical factors associated with an increased risk for seizure recurrence include a prior brain insult such as a stroke or trauma ( Level A) and an EEG with epileptiform abnormalities (Level A). Clinical factors associated with an increased risk for seizure recurrence include a significant brain-imaging abnormality ( Level B ) and a nocturnal seizure (Level B).

10. Immediate AED therapy, as compared with delay of treatment pending a second seizure, is likely to reduce the risk for a seizure recurrence in the two years subsequent to a first seizure ( Level B). Immediate AED therapy, as compared with delay of treatment pending a second seizure, may not improve quality of life (QOL) ( Level C). Immediate AED treatment is unlikely to improve the prognosis for sustained seizure remission ( Level B).

11. Patients with newly diagnosed epilepsy who require treatment can be initiated on standard AEDs such as carbamazepine , phenytoin , valproic acid, phenobarbital , or on the new AEDs lamotrigine , gabapentin , oxcarbazepine , or topiramate . Choice of AED will depend on individual patient characteristics (Level A).

12. First unprovoked seizure in a child The majority of children who experience a first unprovoked seizure will have few or no recurrences. Treatment with AED after a first seizure as opposed to after a second seizure has not been shown to improve prognosis for long-term seizure remission (Class II evidence).

13. There is a relative paucity of data from studies involving only children after a first seizure. AED therapy in children who have epilepsy (at least two seizures) has potential serious pharmacologic and psychosocial side effects (Class I evidence).

14. Recommendations Treatment with AED is not indicated for the prevention of the development of epilepsy (Level B). Treatment with AED may be considered in circumstances where the benefits of reducing the risk of a second seizure outweigh the risks of pharmacologic and psychosocial side effects (Level B).

15. 2012 NICE GUIDELINES

16. How to use AEDs when treating epilepsy The AED treatment strategy should be individualised according to the seizure type, epilepsy syndrome, co-medication and co-morbidity, the child, young person or adult's lifestyle, and the preferences of the person and their family and/or carers as appropriate. Treat with a single AED ( monotherapy ) wherever possible .

17. If an AED has failed because of adverse effects or continued seizures, a second drug should be started and built up to an adequate or maximum tolerated dose and then the first drug should be tapered off slowly. If the second drug is unhelpful, either the first or second drug may be tapered, depending on relative efficacy, side effects and how well the drugs are tolerated before starting another drug.

18. It is recommended that combination therapy (adjunctive or 'add-on' therapy) should only be considered when attempts at monotherapy have not resulted in seizure freedom. If trials of combination therapy do not bring about worthwhile benefits, treatment should revert to the regimen ( monotherapy or combination therapy) that has proved most acceptable to the child, young person or adult, in terms of providing the best balance between effectiveness in reducing seizure frequency and tolerability of side effects.

19. Treatment with AED therapy is generally recommended after a second epileptic seizure. When possible, choose which AED to offer on the basis of the presenting epilepsy syndrome. If the epilepsy syndrome is not clear at presentation, base the decision on the presenting seizure type(s).

20. AED therapy should be considered and discussed with children, young people and adults and their family and/or carers as appropriate after a first unprovoked seizure if: the child, young person or adult has a neurological deficit the EEG shows unequivocal epileptic activity the child, young person or adult and/or their family and/or carers consider the risk of having a further seizure unacceptable brain imaging shows a structural abnormality.

21. Pharmacological treatment of focal seizures Offer carbamazepine or lamotrigine as first-line treatment to children, young people and adults with newly diagnosed focal seizures. Offer levetiracetam , oxcarbazepine or sodium valproate if carbamazepine and lamotrigine are unsuitable or not tolerated. Offer carbamazepine , clobazam , gabapentin , lamotrigine , levetiracetam , oxcarbazepine , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with focal seizures if first-line treatments are ineffective or not tolerated.

22. Other AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide , phenobarbital , phenytoin , pregabalin , tiagabine , vigabatrin and zonisamide . Carefully consider the risk–benefit ratio when using vigabatrin because of the risk of an irreversible effect on visual fields.

23. Pharmacological treatment of newly diagnosed generalised tonic– clonic (GTC) seizures Offer sodium valproate as first-line treatment to children, young people and adults with newly diagnosed GTC seizures. Be aware of teratogenic risks of sodium valproate . Offer lamotrigine if sodium valproate is unsuitable. If the person has myoclonic seizures or is suspected of having juvenile myoclonic epilepsy (JME), be aware that lamotrigine may exacerbate myoclonic seizures.

24. Consider carbamazepine and oxcarbazepine but be aware of the risk of exacerbating myoclonic or absence seizures. Offer clobazam , lamotrigine , levetiracetam , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with GTC seizures if first-line treatments are ineffective or not tolerated.

25. If there are absence or myoclonic seizures, or if JME is suspected, do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

26. Pharmacological treatment of absence seizures Offer ethosuximide or sodium valproate as first-line treatment to children, young people and adults with absence seizures. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable. Offer lamotrigine if ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated.

27. If two first-line AEDs are ineffective in children, young people and adults with absence seizures, consider a combination of two of these three AEDs as adjunctive treatment: ethosuximide , lamotrigine or sodium valproate . If adjunctive treatment is ineffective or not tolerated consider clobazam, clonazepam, levetiracetam, topiramate or zonisamide.

28. Do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

29. Pharmacological treatment of myoclonic seizures Offer sodium valproate as first-line treatment to children, young people and adults with newly diagnosed myoclonic seizures, unless it is unsuitable. Consider levetiracetam or topiramate if sodium valproate is unsuitable or not tolerated. Be aware that topiramate has a less favourable side-effect profile than levetiracetam and sodium valproate .

30. Offer levetiracetam , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with myoclonic seizures if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated consider clobazam, clonazepam, piracetam or zonisamide.

31. Do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

32. Pharmacological treatment of tonic or atonic seizures Offer sodium valproate as first-line treatment to children, young people and adults with tonic or atonic seizures. Offer lamotrigine as adjunctive treatment to children, young people and adults with tonic or atonic seizures if first-line treatment with sodium valproate is ineffective or not tolerated.

33. Other AEDs that may be considered by the tertiary epilepsy specialist are rufinamide and topiramate . Do not offer carbamazepine , gabapentin , oxcarbazepine , pregabalin , tiagabine or vigabatrin .

34. Pharmacological treatment of infantile spasms Offer a steroid ( prednisolone or tetracosactide ) or vigabatrin as first-line treatment to infants with infantile spasms that are not due to tuberous sclerosis. Offer vigabatrin as first-line treatment to infants with infantile spasms due to tuberous sclerosis. If vigabatrin is ineffective, offer a steroid ( prednisolone or tetracosactide ).

35. Pharmacological treatment of Dravet syndrome Consider sodium valproate or topiramate as first-line treatment in children with Dravet syndrome. If first-line treatments in children, young people and adults with Dravet syndrome are ineffective or not tolerated, and consider clobazam or stiripentol as adjunctive treatment. Do not offer carbamazepine , gabapentin , lamotrigine , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

36. Pharmacological treatment of Lennox– Gastaut syndrome Offer sodium valproate as first-line treatment to children with Lennox– Gastaut syndrome. Offer lamotrigine as adjunctive treatment to children, young people and adults with Lennox– Gastaut syndrome if first-line treatment with sodium valproate is ineffective or not tolerated. Other AEDs that may be considered are rufinamide and topiramate .

37. Do not offer carbamazepine , gabapentin , oxcarbazepine , pregabalin , tiagabine or vigabatrin . Only offer felbamate in centres providing tertiary epilepsy specialist care and when treatment with all of the AEDs has proved ineffective or not tolerated.

38. Pharmacological treatment of benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome or late-onset childhood occipital epilepsy ( Gastaut type)

39. Offer carbamazepine or lamotrigine as first-line treatment to children and young people with these syndromes. Offer levetiracetam , oxcarbazepine or sodium valproate if carbamazepine and lamotrigine are unsuitable or not tolerated. Be aware that carbamazepine and oxcarbazepine may exacerbate or unmask continuous spike and wave during slow sleep, which may occur in some children with benign epilepsy with centrotemporal spikes.

40. Offer carbamazepine , clobazam , gabapentin , lamotrigine , levetiracetam , oxcarbazepine , sodium valproate or topiramate as adjunctive treatment. Other AEDs that may be considered by the tertiary epilepsy specialist are eslicarbazepine acetate, lacosamide , phenobarbital , phenytoin , pregabalin , tiagabine , Vigabatrin and zonisamide .

41. Pharmacological treatment of idiopathic generalised epilepsy (IGE) Offer sodium valproate as first-line treatment to children, young people and adults with newly diagnosed IGE, particularly if there is a photoparoxysmal response on EEG. Offer lamotrigine if sodium valproate is unsuitable or not tolerated. Consider topiramate but be aware that it has a less favourable side-effect profile than sodium valproate and lamotrigine .

42. Offer lamotrigine , levetiracetam , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with IGE if first-line treatments are ineffective or not tolerated. If adjunctive treatment is ineffective or not tolerated consider clobazam , clonazepam or zonisamide . Do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

43. Pharmacological treatment of juvenile myoclonic epilepsy (JME) Offer sodium valproate as first-line treatment to children, young people and adults with newly diagnosed JME, unless it is unsuitable. Consider lamotrigine , levetiracetam or topiramate if sodium valproate is unsuitable or not tolerated. Offer lamotrigine , levetiracetam , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with JME if first-line treatments are ineffective or not tolerated.

44. If adjunctive treatment is ineffective or not tolerated consider clobazam , clonazepam or zonisamide . Do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

45. Pharmacological treatment of epilepsy with generalised tonic– clonic (GTC) seizures only Offer lamotrigine or sodium valproate as first-line treatment to children, young people and adults with epilepsy with GTC seizures only. Offer clobazam , lamotrigine , levetiracetam , sodium valproate or topiramate as adjunctive treatment to children, young people and adults with epilepsy with GTC seizures only, if first-line treatments are ineffective or not tolerated.

46. Pharmacological treatment of childhood absence epilepsy, juvenile absence epilepsy or other absence epilepsy syndromes

47. Offer ethosuximide or sodium valproate as first-line treatment to children, young people and adults with absence syndromes. If there is a high risk of GTC seizures, offer sodium valproate first, unless it is unsuitable. Offer lamotrigine if ethosuximide and sodium valproate are unsuitable, ineffective or not tolerated.

48. If two first-line AEDs are ineffective in children, young people and adults with absence epilepsy syndromes, consider a combination of two of these three AEDs as adjunctive treatment: ethosuximide , lamotrigine or sodium valproate . If adjunctive treatment is ineffective or not tolerated consider clobazam, clonazepam, levetiracetam, topiramate or zonisamide. Do not offer carbamazepine , gabapentin , oxcarbazepine , phenytoin , pregabalin , tiagabine or vigabatrin .

49. For management of epilepsy in india Guidelines of INDIAN EPILEPSY SOCIETY

50. First unprovoked seizure Epilepsy should not be diagnosed after a single seizure. The average risk of developing a second seizure following a single unprovoked seizure is about 35- 40%. The risk of a third seizure following two unprovoked seizures is much higher. Generally the first seizure is not treated. The individual and family are explained about the possible risk of recurrence and need for follow up.

51. Circumstances in which first seizure is treated Prolonged focal seizure First seizure presenting as status epilepticus presence of neurological deficit, hemiparesis , mental retardation, cerebral palsy etc. Family history of seizures among parents, siblings or children. EEG abnormality Abnormality on brain imaging (CT, MRI) High risk jobs (Professional or other activities that may endanger life during a seizure) The individual and family do not accept the expected risk of recurrence

52. Principles of antiepileptic treatment The decision to start AED treatment should be made after discussion of the risks and benefits of treatment and taking into account the person’s seizure type, prognosis, lifestyle and socioeconomic circumstances. Treatment should be started with a single conventional antiepileptic drug (AED monotherapy ). Start with a low dose and gradually increase the dose until seizures are controlled or side-effects occur.

53. If the initial treatment is ineffective or poorly tolerated, then monotherapy using another AED can be tried. The dose of the second drug is slowly increased until adequate or maximum-tolerated dose is reached. The first drug is then tapered off slowly. If the second drug is also unhelpful, the drug with lesser efficacy or tolerability should be taken off.

54. Combination therapy ( polytherapy or adjunctive or ‘add-on’ therapy) can be considered when two attempts at monotherapy with AEDs have not resulted in seizure freedom. The formulation or brand of AED should preferably not be changed (variations in bioavailability or different pharmacokinetic profiles may increase the potential for reduced effect or excessive side effects). Modified release formulations offer ease of administration due to less frequent dosing and better compliance.

55. The following tests may be carried out as necessary: Complete blood count, liver enzymes and renal functions before starting AED. Serum calcium, alkaline phosphatase and other tests of bone metabolism every year for adults taking enzyme-inducing drug.

56. Newer AEDs The newer AEDs ( Gabapentin , Lamotrigine , Levetiracetam , Tiagabine , Topiramate , Vigabatrin and Zonisamide ) are recommended for the management of epilepsy in people who have not benefited from treatment with the conventional AEDs or for whom the older AEDs are unsuitable because of intolerable adverse events. The new AEDS are almost as effective as the conventional drugs but do add significantly to the cost.

57. The newer AEDS can also be used when: There are contraindications to the first line drugs due to coexisting illnesses. The first line drugs interact with other drugs the person is taking (notably oral contraceptives, anticoagulants, anti- retrovirals or immunosuppressants ).

58. Management of provoked seizures Provoked seizures occur within 7 days of brain insult. Can be broadly divided into two groups: Structural: stroke, infections, injury Metabolic/toxic

59. Head injury Severe TBI (GCS < 8/15) and penetrating injuries are associated with high incidence of seizure occurrence. Risk factors for seizures in TBI include penetrating injuries, depressed skull fractures, presence of contusions on brain imaging, post traumatic amnesia.

60. PHT prophylaxis should be given in cases of severe traumatic injury to reduce occurrence of early post traumatic seizure. It should be given intravenously as loading dose. Continuation of AEDs after 7 days of acute insult has no additional benefit.

61. AEDs have no role in preventing late seizures after TBI. In mild head injury there is no role of prophylactic AEDs. If patient develops seizures after two weeks of TBI, then treatment is done as in patient of symptomatic epilepsy.

62. Stroke Stroke significantly increases the risk of seizures. Cortical and haemorrhagic lesions have higher incidence of seizure occurrence. Routine treatment of all stroke patients with AEDs is not recommended.

63. When the treatment is to be done the following factors need to considered: Neurological recovery- PB is not recommended in this context Bone health- PHT and PB can lead to osteoporosis Interaction of AEDs with aspirin, warfarin , statins - PHT, PB, CBZ can have interactions because of their ezyme inducing effects .

64. Lamotrigine and gabapentin have been recommended as first line agents in management of post stroke seizures due to above mentioned causes. CVT has high incidence of seizures. AEDs are recommended for one year after the initial acute episode.

65. Brain tumuors Patients with brain tumours are sometimes given prophylatic AEDs but there is no convincing evidence available.

66. Neurocysticercosis Common cause of provoked seizure in india . Patients with single enhancing lesion on imaging should be treated with AEDs for 6 months. If the lesion disappears on repeat scan after 3-6 months, AEDs should be tapered off in 8-12 weeks slowly. If the single lesion becomes larger or multiple lesions are present or patient is having reccurent seizures AEDs should be continued.

67. Alcohol related seizures Can be due to alcohol intoxication or alcohol withdrawal. EEG/CT/MRI are indicated after first alcohol related seizure. AEDs should be continued for 6-12 months and then tapered off in 8-12 weeks.

68. Avoid using VPA, PB and benzodiazipines as they may precipitate liver failure. GBP, LEV, CBZ, OXC are recommended for seizure prophylaxis. For management of status epilepticus - glucose and benzodiazipines are used .

69. Renal failure Seizures may occur in one third of patients with renal failure and uremic encephalopathy. LTG, PHT, VPA, PB are safe in renal failure.

70. Epilepsy in children Certain situations peculiar to children include:

71. Febrile seizures Occur during fever in the age of 6 months to 5 years without any intracranial infection. Single febrile seizure occur in 3-5% of children. Reccurent febrile seizures occur in one third of children. Reccurrence is higher if it occurs within first year of life.

72. Complex febrile seizures comprise only 15% of FS, are characterised by partial onset, duration > than 15 min, or multiple episodes in the same illness and have poorer outcome as compared to simple FS. Rectal diazepam or buccal midazolam for acute termination of seizures lasting more than 2 minutes.

73. Continuous prophylaxis is not recommended routinely but may be considered in cases where febrile seizures occur beyond 6 yrs of age. Oral clobazam 0.75mg/kg for 2-3 days in two divided doses is most effective drug in preventing reccurrence .

74. Epilepsy in elderly The choice of AEDs in elderly depends on many factors including changes in liver, kidney, GI system and brain itself. Bioavailability of the drug is also altered. The dose required is generally lower than in adults. PHT, VPA, CBZ can be used for generalised and partial seizures in adults.

75. Most of the newer AEDs can be safely used in elderly.

76. Women issues and epilepsy WWE have higher than expected rates of menstrual disorders and infertility. Enzyme-inducing AEDs interact with hormonal contraceptives, potentially limiting options for birth control. Exposure to AEDs during pregnancy increases the risk of congenital malformations and cognitive impairments in children born to WWE. Chronic AED use increases the risk of vitamin D deficiency, decreased bone quality and density, and fractures. These concerns heighten the need to taper AEDs when appropriate and to manage WWE on the simplest AED regimen that will maintain seizure freedom.

77. Referrences Epilepsies: diagnosis and management. Clinical guidelines. 11 jan . 2012. Guidelines for management of epilepsy in india : indian epilepsy society. 2008 Evidence-based guideline: Management of an unprovoked first seizure in adults. Neurology 2015 Practice Parameter update: Management issues for women with epilepsy. Neurology 2009