Antiepileptics Audit - PDF Free Download

Antiepileptics Audit Dr Kate Marley Dr Lucy Potter Dr Melanie Brooks Dr Averil Fountain CNS Sue Croft External Reviewer: Dr A Nicolson Consultant Neurologist c

CURRENT GUIDANCE

4.1 GENERAL PRINCIPLES Anti-epileptic drugs should be considered in all patients with primary or secondary brain tumours who have a history of one or more seizures. The acute management of seizures includes maintaining the airway, emergency drug treatment and a reassessment of the anti-epileptic drugs prescribed. A prolonged seizure in a patient who is not in the terminal phase requires immediate emergency management, resuscitation and possible admission to hospital.

4.1 GENERAL PRINCIPLES A clear distinction should be made between anti-epileptic drugs for the control of seizures and corticosteroid medication for control of symptoms due to tumour oedema e.g. headaches / vomiting due to raised intracranial pressure or focal neurological signs. Increasing the dose of corticosteroid is not recommended for seizures in the absence of new neurological symptoms / signs or evidence of raised intracranial pressure. However, as seizures may increase cerebral oedema, patients who develop new seizures in spite of anti-epileptic drugs may need optimization of anti-oedema therapies before modifying antiepileptic drugs.

4.1 GENERAL PRINCIPLES In the terminal phase, the aim is to prevent and control seizures with the minimum of disruption for the patient. Midazolam or clonazepam may be given without the need for transfer to hospital. Corticosteroids can be discontinued in the terminal phase unless they are required for control of raised intra-cranial pressure e.g. headaches/vomiting or seizures.

Table 4.1 illustrates the World Health Organisation classification of seizures Table 4.1 International Classification of Seizures [Level 4] 1. Generalised (involving the entire cortex). Tonic-clonic seizures (grand mal). Absence seizures (petit mal). Myoclonic seizures. Atonic seizures. 2. Partial/focal (involves a localised area of brain). Note: May spread to involve the whole c cortex i.e. secondary generalisation. Simple (no effect on conscious level). Complex (interrupt consciousness to varying degree). Secondary generalised tonic-clonic seizures.

Guidelines 4.2.1 Antiepileptic medication The ideal drug for controlling seizures in palliative care patients is not easy to establish due to the variety of metabolic interactions and potential side effects. [Level 4] There are a variety of anti-epileptic drugs available and Table 4.2 gives further details. The choice of drug will depend on the type of seizure. [Level 4]

Clinical assessment should be used to optimise the dose of the anti-epileptic drug with the minimum of side effects. Monotherapy should be used whenever possible. [Level 4] It has been considered appropriate to use only new antiepileptic drugs when the older drugs (e.g. carbamazepine, sodium valproate) have been unsuccessful, or where they are unsuitable due to contraindications or drug interactions. However, lamotrigine or carbamazepine are now considered first line therapy for partial onset epilepsy, and lamotrigine has the advantage of being better tolerated with few drug interactions. [Level 4]

Guidelines Clobazam and clonazepam can be used for myoclonic or generalised tonic-clonic seizures. They will be effective for short-term use but patients may develop tolerance to the anti-epileptic effects of the benzodiazepines. In addition, any benefit may diminish over time although this may not always be relevant in the palliative care setting. Despite the possibility of tolerance with benzodiazepines many patients do get a sustained response to drugs such as Clobazam. [Level 4]

The metabolism of dexamethasone is accelerated by carbamazepine and phenytoin which reduce the steroid effect. The metabolism of phenytoin can be either increased or decreased by dexamethasone so altering the anti-epileptic effect. When using these drug combinations it may be necessary to increase the dose of anti-epileptic and / or corticosteroid. Drug levels are useful for patients on phenytoin. Levels can be used to guide dose titration if seizures are poorly controlled or side effects become apparent. [Level 3]

4.2.2 Management of seizures An acute seizure may settle spontaneously. Intranasal, buccal or subcutaneous midazolam should be available for the control of prolonged or recurrent seizures. Alternatively, lorazepam 2mg-4mg can be given intravenously or subcutaneously. [Level 4] For more information on intranasal midazolam see Figure 4.1. If seizures continue despite above measures, consider transfer to hospital for emergency management. A secure airway should be established, oxygen should be administered, cardio- respiratory function should be assessed and intravenous access should be established. Administer diazepam 10mg-20mg rectally and repeat 15 min later if status continues to threaten. Alternatively, consider giving midazolam 10mg via the buccal route or intravenously.[level 4]

Guidelines Clusters of seizures (i.e. with recovery in between attacks) may respond to oral clobazam. Starting dose is 10mg per day and the usual maintenance dose is 10mg-20mg twice daily. The maximum dose is 30mg twice daily. This drug can be used for a short period if required e.g.. a few days. [Level 4]

4.2.3 Use of anti-epileptics in the terminal phase In the terminal phase convert oral anti-epileptics to a continuous subcutaneous infusion of midazolam 30mg- 60mg/24 hours. Clonazepam is an alternative and will require less volume. [Level 4] If seizures are not controlled with midazolam / clonazepam, consider a change to phenobarbital 200mg-600mg/24h via a continuous subcutaneous infusion. Phenobarbital can be mixed with sodium chloride 0.9% or water, although anecdotal evidence suggests that may get less site reactions with sodium chloride 0.9%. It is generally recommended that a separate syringe driver should be used because of the high c ph of the drug. [Level 4]

4.2.3 Use of anti-epileptics in the terminal phase Discontinue oral corticosteroids unless needed for control of symptoms due to raised intracranial pressure e.g.. headaches, vomiting, seizures. Dexamethasone may be administered by subcutaneous bolus injection (for doses <8mg daily) or by a CSCI. [Level 4]

Standards 1. For all patients with primary or secondary brain tumours, the following information should be documented in the case notes: 14 [Grade D] History of seizures including the frequency and type. Anti-epileptic drug(s) used and the dose(s).

Standards 2. The dose of corticosteroids should not be increased if seizures occur in the absence of new neurological symptoms / signs or evidence of raised intracranial pressure, unless the patient is also taking phenytoin or carbamazepine. [Grade D] 3. All patients with a history of seizures should have access to medication that can be given in the event of an episode of prolonged seizures. [Grade D]

Standards 4. If a patient is in the terminal phase, oral anti-epileptic drugs should be converted to midazolam / clonazepam via a continuous subcutaneous infusion. [(Grade D] 5. If a patient is in the terminal phase and unable to take oral medication, corticosteroids should be discontinued unless they are needed for control of symptoms related to raised intracranial pressure. If they are required, they can be given via the subcutaneous route. [Grade D]

LITERATURE REVIEW

Before we start AED= NOT By definition, all patients with brain tumour associated epilepsy suffer from PARTIAL-ONSET seizures

Anti-epileptic drugs: a guide for the non-neurologist Choice of Anti-epileptic drug (AED) is complex: Age Co-morbidity Other medication Possibility of pregnancy Patient s epilepsy classification When patients are nil by mouth: Try to use iv preparation where possible or NGT Beware Phenytoin suspension 90mg = 100mg tablet Anderson J; Moor C: Clinical Medicine: Vol 10, Number 1, February 2010, pp. 54-58(5)

Anti-epileptic drugs: a guide for the non-neurologist Routine checking of AED levels not needed Consider when: 1 week following change of phenytoin dose Status epilepticus Following emergency initiation of iv phenytoin Beware of enzyme inducing drugs and interactions: May decrease levels of warfarin and digoxin Many antidepressants lower seizure threshold Antipsychotics antagonise many AEDs Erythromycin/clarithromycin may increase levels of some AEDs In the elderly may need to choose drugs with fewer side effects rather than most efficacious Anderson J; Moor C: Clinical Medicine: Vol 10, Number 1, February 2010, pp. 54-58(5)

SANAD Study (Arm A) Aim was to assess efficacy of other drugs for partial onset seizures where carbamazepine would have been considered standard treatment Un-blinded RCT in hospital OPDs in UK Arm A 1721 pts. randomised to carbamazepine, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes: time to treatment failure and time to 12 months remission Results: Lamotrigine sig better than carbamazepine for time to treatment failure outcomes and is a cost-effective alternative for partial onset seizures Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW. SANAD study of effectiveness of valproate, lamotrigine and topiramate for generalised and unclassifiable epilepsy: an un-blinded randomised controlled trial. Lancet 2007; 369: 1016-1026

NICE Guidance Offer carbamazepine or lamotrigine as first-line treatment to children, young people and adults with newly diagnosed focal seizures. [new 2012] Combination therapy (adjunctive or 'add-on' therapy) should only be considered when attempts at monotherapy with AEDs have not resulted in seizure freedom. If an AED has failed because of adverse effects or continued seizures, a second drug should be started (which may be an alternative first-line or second-line drug) and built up to an adequate or maximum tolerated dose and then the first drug should be tapered off slowly National Institute for Health and Clinical Excellence. Clinical guideline 137. NICE, 2012.

NICE Guidance Regular blood test monitoring in adults is not recommended as routine, and should be done only if clinically indicated Indications for monitoring of AED blood levels are: detection of non-adherence to the prescribed medication suspected toxicity adjustment of phenytoin dose management of pharmacokinetic interactions (for example, changes in bioavailability, changes in elimination, and co-medication with interacting drugs) specific clinical conditions, for example, status epilepticus, organ failure and certain situations in pregnancy National Institute for Health and Clinical Excellence. Clinical guideline 137. NICE, 2012.

NICE Guidance: Management of a Seizure in the Community Only prescribe buccal midazolam or rectal diazepam for use in the community for children, young people and adults who have had a previous episode of prolonged or serial convulsive seizures. [new 2012] Administer buccal midazolam as first-line treatment in children, young people and adults with prolonged or repeated seizures in the community. Administer rectal diazepam if preferred or if buccal midazolam is not available. If intravenous access is already established and resuscitation facilities are available, administer intravenous lorazepam National Institute for Health and Clinical Excellence. Clinical guideline 137. NICE, 2012.

SPECIFIC GUIDANCE FOR BRAIN TUMOURS

Seizure Prophylaxis in Brain Metastases Systematic review of studies on patients with brain metastases comparing anticonvulsant prophylaxis versus none Only 1 underpowered RCT Conclusion: there is a lack of clear and robust benefit from the routine prophylactic use of anticonvulsants Mikkelson T et al. The role of prophylactic anticonvulsants in the management of brain metastases: a systematic review and evidence-based clinical practice guideline. Journal of Neuro-Oncology January 2010, Volume 96, Issue 1, pp. 97-102

Cochrane Review of Seizure Prophylaxis in Brain Tumours 5 trials met inclusion criteria Different brain tumours with different seizure risks Phenobarbital, phenytoin and divalproex sodium did not prevent seizures in people with brain tumours who had been seizure-free before participation in the study No studies on the newer AEDs Clinical heterogeneity limits any claim of effectiveness or ineffectiveness of prophylaxis Need to be mindful of the risks of side effects Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR. Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD004424.

SEIZURES IN PALLIATIVE CARE CONTEXT

RAMPART Trial Rapid Anticonvulsant Medication Prior to Arrival Trial Randomized double-blind phase 3 non-inferiority clinical trial IM midazolam vs. IV lorazepam Children and adults requiring treatment for status epilepticus in the pre-hospital setting Given either 10mg IM midazolam followed by IV placebo or IM placebo followed by 4mg IV lorazepam Primary outcome termination of seizures prior to arrival at A&E. Secondary outcomes time from opening box and time from administration of meds to seizure termination Midazolam at least as effective as lorazepam (p<0.001) Silbergleit R, Durkalsk V, Lowenstein D, Conwi R, Pancioli A, Palesch Y, Barsan W, Intramuscular versus Intravenous Therapy for Prehospital Status Epilepticus. NEJM vol 366(7) 2012 591-600

Palliative Care Adult Network Guidelines Useful drugs in syringe driver :- clonazepam 1-4 mg/24h CSCI midazolam 20-100mg/24h CSCI phenobarbital 200-600mg/24h CSCI Avoid using drugs that may increase cerebral irritability such as phenothiazines (e.g.. levomepromazine) if possible. Should not be necessary to replace oral steroids with SC in dying patients who are unconscious or semi-conscious Watson M, Lucas C, Hoy A, Back I, Armstrong P. Palliative Care Adult Network Guidelines 2011

Seizures At End of Life No data regarding the preferred drug. In this Italian paper IM phenobarbital was used in community pts. and IV levetiracetam in hospitalised pts. at end of life [Pace et al 2012] American paper: stop AED if pt. never had a seizure and manage any seizures that occur. Aim to convert to rectal preparation. Data on midazolam not available but they say 5mg/hr [Hendrikus et al 2000] Pace A, Andrea, Villani V, Di Lorenzo C, Guariglia L, Maschio M, Pompili A, Carapella C, Epilepsy in the end-of-life phase in patients with high-grade gliomas. Journal of Neuro-Oncology Online first. Doi: 10.1007/s11060-012-0993-2 Hendrikus GJ, Krouwer MD, Jeanne L, Pallagi MD Graves NM. Management o seizures in Brain Tumor Patients at the End of Life J Pall Med 2000 3(4) 465-475

Status Epilepticus in the Hospice Setting Problems specific to this setting: Cachexic frail patients with difficult iv access Not always appropriate to transfer to hospital Lack of monitoring facilities May need large doses of medications. May get toxicity from the medications Droney J, Hall E. Status Epilepticus in a Hospice Inpatient Setting. J pain sympt management 1 July 2008 (volume 36 issue 1 Pages 97-105)

Status Epilepticus in the Hospice Setting Benzodiazepines helpful as they enter cerebral tissues quickly. Durations of action: Diazepam < 2 hours Midazolam 3-4 hours Clonazepam 24 hours Lorazepam up to 72 hours Clonazepam use may be limited by sorption to driver giving set and precipitation Droney J, Hall E. Status Epilepticus in a Hospice Inpatient Setting. J pain sympt management 1 July 2008 (volume 36 issue 1 Pages 97-105)

Status Epilepticus in the Hospice Setting In refractory cases: Switch to different benzodiazepine May need drugs from 2 classes e.g.. midazolam and phenobarbitone May need to switch from SC to iv route May need to consider moving to acute setting depending on situation Droney J, Hall E. Status Epilepticus in a Hospice Inpatient Setting. J pain sympt management 1 July 2008 (volume 36 issue 1 Pages 97-105)

AUDIT RESULTS

RESULTS PATIENT BASED SURVEY

Title of Professional Completing Survey 1 6 1 Consultant SAS Registrar 22 10 CMT/VTS Doctor CNS 2 Nurse

Setting 26% 43% Community Hospice Hospital 31%

12 ICN 10 8 6 4 2 0 Aintree Halton Isle of Man Liverpool Southport, Formby and West Lancashire c St Helen's andwest Cheshire Knowsley Wirral

35 30 Rescue Medication to Treat Seizures 29 25 20 15 10 5 0 4 3 2 0 0 4 4 3 3 6 1 c

12 Patients who entered the Dying Phase 10 8 6 4 2 0 There was no substitute medication prescribed Midazolam 10mg csci Midazolam 20mg csci Midazolam 30mg csci PRN midazolam subcutaneously Other

Patients Without Brain Tumours Patients With Brain Tumours 30 30 25 25 20 20 15 15 10 5 NO YES 10 5 NO YES 0 Was the seizure type documented in the notes? Was the seizure frequency documented in the notes? 0 Was the seizure type documented in the notes? Was the seizure frequency documented in the notes?

For Patients With Brain Tumours 17 patients had a seizure during the audit period 14 12 10 8 6 Patients who had a seizure 13 7 4 2 0 There was a change in neurology There was evidence of raised intracranial pressure

18 What happened to the steroid dose? 16 14 12 10 8 6 4 2 0 Steroid dose changed Steroid dose Increased Steroid dose decreased

12 11 Anticonvulsant Use 10 9 8 8 6 4 2 1 0 Anticonvulsant dose changed Anticonvulsant dose increased Anticonvulsant dose decreased New anticonvulsant drug added

Steroids in Dying Phase The steroids were stopped 28% 24% 5% 43% The steroids were converted to SUBCUT stat injections no dose change The steroids were converted to SUBCUT stat injections and the dose was decreased The steroids were converted to a csci at the same dose

RESULTS PRACTICE BASED SURVEY

Role of People Completing Survey 9 1 6 8 Consultant SAS doctor Specialty Registrar Clinical Nurse Specialist

12 ICN 10 10 8 6 4 4 3 3 4 2 0 Aintree Wirral Liverpool Halton Warrington

Predominant Setting of Work 8 2 3 11 Community Hospice Hospital Across settings

16 On diagnosis of brain mets I would start an anticonvulsant... 15 14 12 10 8 6 5 4 2 0 0 1 On diagnosis After the first seizure After second seizure After 3rd seizure I would not normally initiate therapy 0

What anticonvulsant medication would you prescribe in epilepsy related to cerebral metastases? 18 16 14 12 10 8 6 4 2 Third line Second line First line 0

12 Confidence in initiating anticonvulsants 11 10 8 6 6 4 3 2 0 1 Very Confident Confident Neither Not confident Not at all confident 0

10 9 Confidence in adjusting anticonvulsant dose 9 9 8 7 6 5 4 3 3 2 1 0 0 Very Confident Confident Neither Not confident Not at all confident 0

12 10 Confidence in adding in another anticonvulsant 10 8 6 4 3 4 4 2 0 0 Very Confident Confident Neither Not confident Not at all confident

12 For patients with pre-existing epilepsy 10 10 8 6 4 2 1 1 4 5 2 5 4 5 8 8 3 3 4 Confidence initiating anticonvulsant therapy Confidence adjusting anticonvulsant dose Confidence adding in another anticonvulsant 0 0 Very Confident Confident Neither Not confident Not at all confident

16 When Phenytoin/Carbamazepine levels checked 14 12 10 8 6 4 2 0 Weekly Fortnightly Monthly On change in dose Steroid dose change Signs or symptoms of toxicity If the renal function changes If the liver function changes I don't routinely check levels

18 From where advice is sought 17 16 14 12 10 8 6 6 4 2 1 2 3 1 1 0 Audit Guidelines Doctor Neurologist Palliative Care Doctor Palliative Care Team Pharmacist Treating Doctor

18 Medications to manage a seizure 16 14 12 10 8 6 4 2 Partial Seizures Generalized Seizures Multiple seizures 0

9 8 Conversion of anticonvulsants in the dying phase 8 7 6 5 4 4 5 3 2 2 1 0 0 Midazolam 10mg csci Midazolam 20mg csci Midazolam 30mg csci Midazolam other dose csci 0 0 0 Midazolam sc prn only Clonazepam csci Stop anticonvulsants only Other (please specify)

12 Steroids in the dying phase 11 10 8 8 7 6 4 3 4 2 0 Stop Steroids Convert steroid dose to syringe driver Convert steroid dose to sc injections Reduce steroids to a daily sc dose Other

UPDATED STANDARDS AND GUIDELINES

4.1 GENERAL PRINCIPLES Anti-epileptic drugs should be considered in all patients with primary or secondary brain tumours who have a history of one or more seizures. Patients with seizures due to brain tumours by definition have partial-onset seizures. The acute management of seizures includes maintaining the airway, emergency drug treatment and a reassessment of the anti-epileptic drugs prescribed. A prolonged seizure in a patient who is not in the terminal phase requires immediate emergency management, resuscitation and possible admission to hospital.

Guidelines Clinical assessment should be used to optimise the dose of the anti-epileptic drug with the minimum of side effects. Monotherapy should be used whenever possible. [Level 4] Lamotrigine or carbamazepine are now considered first line therapy for partial onset epilepsy, and lamotrigine has the advantage of being better tolerated with few drug interactions. This means that Lamotrigine or Carbamazepine will be the first choice foe seizures associated with brain tumours [Level 4]

Guidelines For generalised-onset seizures sodium valproate should be considered as the first line anti-epileptic medication. Routine, regular blood test monitoring of antiepileptic drug levels is not recommended as and should be done only if clinically indicated. Indications for monitoring of AED blood levels are: suspected toxicity Poorly controlled seizures 1 week following adjustment of phenytoin dose management of pharmacokinetic interactions Status epilepticus Organ failure

Guidelines Clobazam and clonazepam can be used as an adjunct for myoclonic or generalised tonic-clonic seizures. They will be effective for short-term use but patients may develop tolerance to the anti-epileptic effects of the benzodiazepines. In addition, any benefit may diminish over time although this may not always be relevant in the palliative care setting. Despite the possibility of tolerance with benzodiazepines many patients do get a sustained response to drugs such as Clobazam. [Level 4]

4.2.3 Use of anti-epileptics in the terminal phase In the terminal phase convert oral anti-epileptics to a continuous subcutaneous infusion of midazolam 20mg- 60mg/24 hours. Clonazepam is an alternative and will require less volume. [Level 4] If seizures are not controlled with midazolam / clonazepam, consider a change to phenobarbital 200mg-600mg/24h via a continuous subcutaneous infusion. Phenobarbital can be mixed with sodium chloride 0.9% or water, although anecdotal evidence suggests that may get less site reactions with sodium chloride 0.9%. It is generally recommended that a separate syringe driver should be used because of the high ph of the drug. [Level 4]

4.2.3 Use of anti-epileptics in the terminal phase For patients with brain tumours: Discontinue oral corticosteroids unless needed for control of symptoms due to raised intracranial pressure e.g. headaches, vomiting, seizures. Dexamethasone may be administered by subcutaneous bolus injection (for doses 8mg daily) or by a CSCI. [Level 4]

Patient has seizure Ensure airway secure and administer oxygen if available Seizure may settle spontaneously If seizure does not settle within 5 minutes give rescue medication e.g. Buccal or IM midazolam 10mg or rectal diazepam 10-20mg or lorazepam 2-4mg iv or sub cut If seizure does not settle after 15mins give another dose of rescue medication. Consider transfer to hospital If patient to stay in hospice or at home consider a syringe driver with midazolam 30mg over 24 hours

Standards 1. For all patients with primary or secondary brain tumours, any history of seizures should be documented in the case notes: [Grade D] 2. For all patients with a history of seizures the following should be documented: Frequency and type of seizure Anti-epileptic drug(s) used and the dose(s) [Grade D].

Standards 3. All patients with a history of seizures should have access to medication that can be given in the event of an episode of prolonged seizures. [Grade D] 4. For patients with brain tumours the dose of corticosteroids should not be increased if seizures occur in the absence of new neurological symptoms / signs or evidence of raised intracranial pressure, unless the patient is also taking phenytoin or carbamazepine. [Grade D]

Standards 5. If a patient is in the terminal phase, oral anti-epileptic drugs should be converted to midazolam or clonazepam via a continuous subcutaneous infusion initially. [Grade D] 6. If a patient is in the terminal phase and unable to take oral medication, corticosteroids should be discontinued unless they are needed for control of symptoms related to raised intracranial pressure. [Grade D]