Evidence Based Guidelines Management of Epilepsy in Adults

Evidence Based Guidelines
Management of Epilepsy
in Adults
Evidence Based Guidelines recommended for use in
The Royal Melbourne Hospital
July 2002
Review Date: July 2004
Department of Neurology & Clinical Epidemiology and Health Service
Evaluation Unit
Supported by funding from the Department of Human Services
1
Table of Contents
Introduction......................................................................................................................................................3
Multi-disciplinary Review Group ................................................................................................................3
Other Contributors .......................................................................................................................................3
Document Preparation..................................................................................................................................3
Intent of the guidelines.................................................................................................................................3
Process of Guidelines Development ............................................................................................................4
Levels of Evidence for Evaluating the Clinical Research data....................................................................4
Emergency Department management of First Seizure in adults – 1 Page Flow-Chart ..................................5
Emergency Department management of Status Epilepticus in adults – 1 Page Flow-Chart ..........................6
1. FIRST SEIZURE – click for evidence review.........................................................................................7
1.a Emergency department management of first seizure in adults ............................................................7
Table 1. Recommendations: Emergency Department management of first seizure ..............................7
1.b Decision to start an Antiepileptic Drug................................................................................................8
Table 2: Information to discuss with patient prior to commencing AED...............................................8
Table 3. Recommendations. Decision to start AED following first seizure ..........................................8
Table 4. Choice of antiepileptic drug for seizure type............................................................................9
2. ESTABLISHED EPILEPSY....................................................................................................................9
2.a Ongoing management of patients with Epilepsy .................................................................................9
Table 5: Recommendations: Ongoing management of patients with epilepsy......................................9
2.b Therapeutic dose & haematological monitoring for adverse effects - click for evidence review .......9
Table 6: Recommendations: Therapeutic dose & haematological monitoring for adverse effects ......10
2.c Treatment of refractory epilepsy........................................................................................................10
Table 7: Recommendations: Treatment of refractory epilepsy.............................................................10
3. STATUS EPILEPTICUS - click for evidence review ...........................................................................11
Table 8: Recommendations: Management of Convulsive Status Epilepticus .....................................11
4. VIDEO EEG MONITORING - click for evidence review....................................................................12
Table 9: Recommendation: Indications for Video EEG monitoring ...................................................12
5. SURGERY - click for evidence review .................................................................................................12
Table 10: Recommendations: Surgery for epilepsy.............................................................................12
6. WOMEN WITH EPILEPSY- click for evidence review.......................................................................13
Table 11: Recommendations. Management of women with epilepsy .................................................13
7. DRIVING GUIDELINES ......................................................................................................................14
Table 12. Recommendations: Driving guidelines................................................................................14
Appendix 1: International Classification of Epileptic Seizures (abbreviated)..............................................15
Appendix 2: Guidelines for fitness to drive following an epileptic seizure...................................................16
For non-commercial drivers.......................................................................................................................16
For Commercial licences ...........................................................................................................................16
Appendix 3: Emergency Department Discharge Pack - First Seizure ..........................................................17
Appendix 4: Letter to General Practitioner following a presumed seizure – First Seizure ..........................18
Appendix 5: Emergency Department Discharge Pack – Established Epilepsy ............................................19
Appendix 6: Letter to General Practitioner following a presumed seizure – Established Epilepsy .............20
References ......................................................................................................................................................21
2
Introduction
Multi-disciplinary Review Group
The guidelines were developed by Christine Kilpatrick, Donald Campbell, and Adrian Lowe. The
following multi-disciplinary group reviewed and contributed to the guidelines.
A/Prof Christine Kilpatrick
Dr Alastair Meyer
A/Prof David Russell
A/Prof Donald Campbell
Mr Andrew Van Slobbe
A/Prof David Taylor
Dr Cassandra Szoeke
Dr Kasha Singh
Dr Isabella Taylor
Dr Anita Vinton
Dr Mark Parsons
Dr Mark Hew
Dr Helmut Butzkueven
Dr Peter Greenberg
Dr Karen Honson
Dr Ian Fraser
Dr Heather Smith
Mr Adrian Lowe
Deputy Director
Acting Director, Emergency
Medicine
Director
Unit Head
Nurse Unit Manager
Director of Emergency
Medicine Research
Epilepsy Registrar
Stroke Registrar
Neurology Registrar
Neurology Registrar
Neurologist
Senior Medical Registrar
Neurologist
Director of Evidence Based
Medicine
Neuroscience Pharmacist
Director of Physician Training
Medical Education Officer
Epilepsy Project Officer
Department of Neurology
Emergency Department
Department of General Medicine
Clinical Epidemiology
Ward 4 South
Emergency Department
Department of Neurology
Department of Neurology
Department of Neurology
Department of Neurology
Department of Neurology
Department of General Medicine
Department of Neurology
Department of General Medicine
Department of Pharmacy
Department of Nephrology
Medical Administration
Department of Neurology
Other Contributors
Internal review of the guidelines was performed by A/Prof Terry O’Brien and Dr Zelko Matkovic, who are
both epileptologists and work at The Royal Melbourne Hospital. Dr Raymond Martyres reviewed the
guidelines from the perspective of a General Practitioner.
Document Preparation
This document was prepared by Adrian Lowe, and reviewed by all members of the multi-disciplinary
reference group.
Intent of the guidelines
This document provides current evidence-based guidance about critical decisions in the management of
adult patients with epilepsy and a first seizure attending Royal Melbourne Hospital.
•
•
•
These guidelines are not a prescriptive standard of medical care. Standards of medical care are
determined on the basis of all clinical data available for an individual patient.
This is a guide to evidence-based practice. Adherence to these guidelines will not ensure a successful
outcome in every case. The guidelines may not include all proper methods of care or exclude other
acceptable methods of care aimed at achieving the same results.
The ultimate choice about clinical procedures and/or treatments are made by the patient (and/or carer)
following recommendations from the treating medical practitioner based on the range of options
available.
3
Process of Guidelines Development
The development of these guidelines has been based on existing international and national guidelines for
12
3-13
the overall management of epilepsy and specific aspects of epilepsy . Further systematic searching of
the literature has been undertaken to supplement the information presented in existing guidelines. Key
articles referenced by existing guidelines were retrieved, and search strategies were devised around the
Medical Subject Headings (MeSH) and key words that described these core papers. The reference list of
each article retrieved was reviewed for articles relevant to the topic under review. These articles were
obtained, checked, and summarised if appropriate. If the article was appropriate, but did not appear in the
results from the original search strategy, the articles MESH headings were examined to determine why it
was not identified previously, and the search strategy modified accordingly to determine if other articles
had also been missed for the same reason. As such, a cascade approach was adopted.
Individual searches were conducted on various topics (see
http://www.mh.org.au/clinicalepidemiology/epreview.pdf) for full details of each search strategy’s results).
The search strategy aimed to find the highest level of evidence possible for a particular question. If a high
level of evidence was located, then the search ceased. If not, the search continued for lower levels of
evidence. To view the evidence review on a particular topic, click on the heading of the topic in this
document. This will open the evidence review document used to from this document.
Two general search limits were applied to all strategies. Due to time and budget limitations, only articles
in English were retrieved. As these guidelines are directed only at treatment of adult patients at Royal
Melbourne Hospital, articles that only studied children were excluded, unless no other studies existed.
The guidelines were developed through weekly focus group meetings conducted at The Royal Melbourne
Hospital between Christine Kilpatrick, Donald Campbell, and Adrian Lowe. Please send any comments or
recommendations concerning these guidelines please e-mail [email protected]
.
Levels of Evidence for Evaluating the Clinical Research data
The National Health and Medical Research Council’s (NH&MRC’s) levels of evidence when evaluating
clinic research data have been used.
77el Type of Evidence
Level
I
II
III – 1
III – 2
III – 3
IV
Type of Evidence.
Evidence obtained from a systematic review of all relevant randomised controlled trials
Evidence obtained from at least one properly designed randomised controlled trial
Evidence obtained from well-designed controlled studies without randomisation
Evidence obtained from well-designed cohort or case-control analytic studies preferably
from more than one centre or research group
Evidence obtained from multiple time series with or without the intervention. Dramatic
results in uncontrolled experiments (such as the results of the introduction of penicillin
treatment in the 1940s) are examples of this type of evidence
Opinions of respected authorities, based on clinical experience, descriptive studies
and/or reports of expert committees
4
Emergency Department management of First Seizure in adults
– 1 Page Flow-Chart
Confirm diagnosis and type of seizure
Initial treatment to stop seizure activity if patient
in Status or has multiple seizures. See Emergency
Department Status Protocol
If epileptic seizure not suspected refer if
appropriate to General Medical Registrar
Evaluate potential causes of Seizure
Consider: Infection, provoked seizure (medication, alcohol, drug use or sleep
deprivation), metabolic disturbance & non-epileptic seizure
CT brain & contrast, ECG, FBE, U&E, LFT in Emergency Department
Order outpatient EEG
Abnormal test results
If appropriate treat underlying cause.
(eg CT lesion/tumour)
Normal test results
AED usually not commenced if single seizure and investigations normal
Consider commencement of AED medication
If definite Seizure &
CT reveals an epileptogenic lesion
or history of recent previous seizure
Discuss with Neurology registrar
Admit or Discharge?
Admit if:
Multiple Seizures or Status
Prolonged post ictal confusion, or focal neurological deficit
Investigations reveal underlying condition that requires treatment
Discharge if:
Patient has normal test results, and has fully recovered.
Actions on Discharge
Confirm EEG ordered
Make appointment for First Seizure Clinic
Give safety advice (no driving or operating heavy machinery, swimming alone,
heights, or baths)
Give patient discharge pack (see appendix 3 & 4)
5
Emergency Department management of Status Epilepticus in adults
– 1 Page Flow-Chart
1. Secure airway
2. Commence oxygen
3. Assessment of cardiac and respiratory function
4. IV access
5. Draw blood for FBC, U&E, LFTs, Ca, Glucose,
clotting, AED levels and storage for later analysis
IMMEDIATE ACTIONS
IV Diazepam (0.15mg/kg at 5mg/min). Repeat if
status epilepticus continues
Establish aetiology.
50ml 50% glucose IV if suggestion of hypoglycaemia;
250mg thiamine IV if suggestion of alcohol abuse or
impaired nutritional status
IV Phenytoin (18mg/kg at 50mg/min)
FOLLOWED BY
Resume or commence oral AED when patient is able
IF STATUS / SEIZURES
CONTINUE
Transfer to ICU
Call Neurology registrar for all cases of status
epilepticus
6
1.
FIRST SEIZURE – click for evidence review
1.a
Emergency department management of first seizure in adults
Seizures and seizure like events may be induced by a myriad of conditions. The role of the Emergency
Department assessment of patients presenting with a seizure is to confirm that the patient is in no
immediate danger, establish a probable cause for the seizure, and to refer the patient to appropriate followup services.
Table 1. Recommendations: Emergency Department management of first seizure
1 3 14-19
Perform physical and neurologic examination, and take medical history that includes:
- Provoking factors (sleep deprivation, medication, alcohol or drugs)
- Type of seizure
- Details of previous seizures
Brain CT scan with contrast. This will help determine if there is an underlying cause for the
20-22 23-33
seizure and assist making a differential diagnosis
.
20-22 34-39
Perform EEG within 48 hours of seizure if possible. If not, as soon as available
MRI brain scan will be ordered through First Seizure clinic, if indicated
1 14 16 18
Consider differential diagnosis. Common conditions that should be considered are
1.
Syncope
2.
Migraine
3.
TIA
4.
Psychogenic seizures
5.
Metabolic disturbances (eg. Na, Mg)
An attempt to determine the seizure type, as per the International Classification of Seizures
1 14 18 40
(See appendix 1), should be made
Discuss with Neurology registrar, including need for Anti-epileptic drug (AED) treatment if:
- Multiple seizures
- History of recent previous seizures
- CT brain scan reveals an epileptogenic lesion
See table 4 choice of AED drug
14
The decision to admit or discharge the patient should be made on the following grounds
Discharge if
Admit if
- patient fully recovered
- Prolonged postictal state
- brain CT satisfactory and
- Multiple seizures or status epilepticus
- laboratory tests satisfactory
- Focal signs on examination
- Investigations reveal underlying
condition that requires treatment
If a patient is deemed appropriate for discharge, and an epileptic seizure is suspected, the
14
following actions should be taken:
1. Make appointment for First Seizure Clinic, and an outpatient EEG, or organise
follow up as a private patient
2. Give advice that due to the risk of further seizures, patients should
a. Not drive any form of motor vehicle (see appendix 2 for guidelines)
b. Not swim alone
c. Have a shower instead of a bath. Turn on the cold tap first. Lower the
temperature on the hot water service.
d. Avoid heights
e. Avoid dangerous machinery
3. Give patient a copy of the First Seizure Discharge Pack (see appendix 3 & 4). Fill
in details of the patient’s follow up appointments
If the patient has an established diagnosis of epilepsy, give them the Established Epilepsy
Discharge Pack (see appendix 5 & 6). Refer the patient to their GP, or to their specialist or
the Epilepsy Clinic at the Royal Melbourne Hospital.
Evidence
grade
IV
III-2
III-2
IV
IV
IV
IV
IV
IV
IV
7
1.b
Decision to start an Antiepileptic Drug
There are a number of antiepileptic medications available. The possibility of commencing medication
should be raised with the patient following a seizure. It is ultimately the patient’s decision as to whether or
not to start this medication. The following information should be discussed with patients prior to deciding
to take AED medication.
Table 2: Information to discuss with patient prior to commencing AED
20-22 34-39 41-53
The overall risk of a second seizure over a 3-year period is 40 - 50%
The risk of further seizures is highest in the first months following a seizure, and drops
20-22 34-39 41-53
quickly following this period
An epileptic discharge on an EEG test increases the risk of recurrence, to approximately
20 21 34-39
80%
20An epileptogenic lesion on CT scan increases the risk of recurrence to approximately 80%
Evidence
grade
III-2
III-2
III-2
III-2
22
39 51-53
AED medication lowers risk of a further seizure to 20 - 25%
All AED medication can cause adverse reactions (such as somnolence and rash). If these do
54-69
occur, most effects are reversible simply by discontinuing the medication
Very rarely, a patient may have severe or even fatal adverse reaction to AED. This will
70
normally occur in the first 6 months of treatment
AEDs can cause reproductive difficulties and possibly have some teratogenic effects in some
6 11 72-74
women, and reduce the effectiveness of oral contraception
Staff should consider discussing the risk of Sudden Unexplained Death in Epilepsy (SUDEP)
with the patient. SUDEP is a rare event (0.5 to 2 per 1,000 patient years) where a patient
75-78
with epilepsy dies for no known reason. The causes of SUDEP are uncertain
Patients should consider the benefit of this reduced risk of seizures, but also the lifestyle and
67
safety issues of taking AED
II
I
Table 3. Recommendations. Decision to start AED following first seizure
Evidence
grade
IV
1
Use of an AED following a single seizure is generally not recommended, if tests are normal
III-3
III-3
IV
IV
67
If epileptic discharge is detected on EEG, or neuroimaging reveals an epileptogenic lesion,
or the patient has had one or more seizures in the recent past, then commencing an AED is
1 67
recommended
If the patient elects to begin AED therapy, they should be warned that the AED may have
adverse effects, and to seek medical attention for symptoms including rash, bruising or
somnolence with vomiting especially if they occur in the first weeks of treatment. If a rash
1 67
develops the drug should be ceased
IV
IV
8
Table 4. Choice of antiepileptic drug for seizure type
2
Recommendations made by Therapeutic Guidelines
Seizure Type
Partial Seizures (simple or complex)
Tonic-clonic seizures
- generalised
- secondarily generalised
- undetermined if generalised or partial
Absence seizures
Myoclonic seizures
Anti-epileptic drug
Carbamazepine
Sodium valproate
Carbamazepine
Carbamazepine, Sodium valproate
Ethosuximide (absence only)
Sodium valproate (absence and tonic-clonic)
Sodium valproate
For additional information on the use of AEDs, please refer to the ‘Clinician’s Health Channel’ and
(http://www.clinicians.vic.gov.au/eleclib.htm) and click on the Neurology section of the ‘Therapeutic
Guidelines’.
2. ESTABLISHED EPILEPSY
2.a
Ongoing management of patients with Epilepsy
Epilepsy is a chronic condition, with potentially complex management issues. Communication between
hospital staff and the patient’s General Practitioner (GP) is essential to maintain a continuum of care for the
patient. Unfortunately, patients with epilepsy often report feeling that care for their condition is not being
shared properly between hospital staff and their GP.
Table 5: Recommendations: Ongoing management of patients with epilepsy
Staff from the First Seizure Clinic and Epilepsy Clinic should correspond with the patient’s
GP concerning the diagnosis and management of the patient’s epilepsy
Patients with epilepsy should be encouraged to visit their GP every 3 months, to review their
condition
GPs should be encouraged to refer patients with refractory epilepsy, or who require
medication regime alterations, to the Epilepsy Clinic
Staff should encourage patients to gain a greater understanding of their epilepsy. Patient
information on various topics concerning epilepsy has been produced by the Epilepsy
Foundation of Victoria, which can be contacted with the following details:
Epilepsy Foundation of Victoria’s: http://www.epinet.org.au/, or by calling 1300 852 853
Evidence
grade
IV
IV
IV
IV
2.b
Therapeutic dose & haematological monitoring for adverse effects - click for
evidence review
All AEDs may cause adverse effects, with the majority being dose related. The effectiveness of AED
medication is determined by the free plasma concentration of the active anti-epileptic drug. Routine
plasma AED concentration measures total not free drug. This needs to be taken into consideration when
interpreting levels. Each AED has a recommended dosage regime, and plasma concentration of the active
drug (see http://www.amh.hcn.net.au/).
There is no evidence that routine AED level monitoring increases seizure control, when compared to
clinical management of dosage level based on seizure frequency and signs of toxicity. However, there are
instances where AED level monitoring is appropriate (see table 6).
9
Due to the potential for serious adverse effects, haematological monitoring for liver function and blood cell
count has been proposed. There is however, no evidence that such monitoring reduces the risk of such
events, due to the enormous sample sizes required to form a definitive answer to this question.
Table 6: Recommendations: Therapeutic dose & haematological monitoring for
adverse effects
79-87
Routine AED plasma level monitoring should not be undertaken
84
Measurement of plasma AED levels should be taken only for one of the following purposes
Evidence
grade
III-2
IV
88 89
1. Establishing compliance
2. Establishing ‘baseline’ effective concentrations
3. Evaluating potential cause for lack of efficacy
4. Evaluation potential cause for toxicity
5. Evaluating potential cause for loss of efficacy
6. Judging ‘room to move’ or when to change AEDs
7. Patients who are pregnant
There is no conclusive evidence to support or refute the use of haematological monitoring
90 91
for serious adverse effects
Many however, recommend FBE, U&E and LFT be performed on initiation of AED therapy
92-95
and every 6 months thereafter
2.c
III-2
IV
Treatment of refractory epilepsy
In approximately 30% of patients, the initial AED will not prevent all seizures. The patient has a number
of options in this situation.
Table 7: Recommendations: Treatment of refractory epilepsy
Patients with refractory epilepsy should be referred to the epilepsy clinic
If seizures continue following initiation of AED medication at an appropriate dose, the
patient should be presented with the following options
54 56-59 64 96
1. If reasonable response to initial AED, add another AED
2. If limited response to initial AED, replace with another AED
2 97
Evidence
grade
IV
I
IV
10
3. STATUS EPILEPTICUS - click for evidence review
Status epilepticus is defined as epileptic activity lasting longer than 30 minutes. Generalised convulsive
status epilepticus is a medical emergency, and is associated with high levels of morbidity and mortality.
Frequent recurrence seizures should also be treated in this manner.
Table 8: Recommendations: Management of Convulsive Status Epilepticus
Immediate measures: Secure airway; commence oxygen; assessment of cardiac and
respiratory function; IV access; draw blood for FBC, U&E, LFTs, Ca, Glucose, clotting,
1 15 98
AED levels and storage for later analysis
99 100
IV Diazepam (0.15mg/kg at 5mg/min). Repeat if status epilepticus/seizures continue
Establish aetiology. Give 50ml 50% glucose IV if any suggestion of hypoglycaemia; IV
15 98
thiamine 250mg if any suggestion of alcohol abuse or impaired nutritional status
100
Followed by: IV Phenytoin (18mg/kg at 50mg/min).
When the patient is able, long term oral AED medication should be initiated as indicated by
2
seizure type
101
If status continues or seizures recur: Transfer the patient to ICU
The Neurology registrar should be informed of all cases of status epilepticus
Evidence
grade
IV
II
IV
II
IV
III - 3
IV
11
4.
VIDEO EEG MONITORING - click for evidence review
Video EEG monitoring involves the simultaneous recording of a patient’s EEG pattern and a video
recording of the patient’s behaviour. Epileptic seizures are defined by abnormal electrical patterns in the
brain. An interictal EEG is conducted between seizures, and aims to detect epileptiform activity not
associated with a seizure. However, not all patients with epilepsy will have epileptiform EEG activity
between seizures. The aim of video-EEG is to record a patient’s EEG activity whilst having a seizure, and
correlate this with their behaviour. To do this, patients are recorded for extended periods of time. Due to
the time and the intensive nature of Video EEG, indications for its use are limited.
Table 9: Recommendation: Indications for Video EEG monitoring
4 7 102-106
Indications for Video-EEG monitoring
1. Diagnosis of non-epileptic attacks
Evidence
grade
IV
2. Classification of seizure types (eg complex partial and atypical absence seizure),
particularly where seizures are refractory to AED therapy
3. Localisation of epileptogenic region in preparation for epilepsy surgery
5.
SURGERY - click for evidence review
Surgery can be performed in some patients to remove the region of the brain responsible for the epileptic
activity. However, only a small group of patients are suitable for this form of therapy. Patients with
Temporal Lobe Epilepsy caused by hippocampal sclerosis are the most common surgical candidates. Such
patients normally undergo a temporal lobectomy. Surgery for epilepsy is invasive, and is associated with
some risk of adverse effects.
Table 10: Recommendations: Surgery for epilepsy
Patients who have intractable epilepsy, despite appropriate use of AEDs, should be referred
14
for surgical evaluation
Approximately 63% of patients with temporal lobe epilepsy who undergo surgery will be
seizure free at twelve months following the operation, compared to only 8% of patients
107
treated medically
70-80% of patients with well lateralised temporal lobe seizure focus due to hippocampal
sclerosis, have an excellent outcome. AED medication should be continued following
108
surgery
Approximately 5% of patients will have a major complication associated with surgery for
epilepsy (such as infarct, infection, and decline in memory), while approximately 10% will
108
have minor and resolvable complications
Evidence
grade
IV
II
III - 1
III - 2
12
6.
WOMEN WITH EPILEPSY- click for evidence review
Women with epilepsy face a number of potential problems, particularly concerning child-bearing. These
problems include decreased effectiveness of oral contraception whilst taking AED medications, increased
risk of adverse outcomes associated with pregnancy and other health related issues.
Table 11: Recommendations. Management of women with epilepsy
Contraception. Due to their liver enzyme inducing properties, the following AEDs are
associated with decreased effectiveness of oral contraception: carbamazepine, phenytoin,
phenobarbitone, primidone, and possibly topiramate. A high dose contraceptive
formulations may provide some protection, but women should be warned that there is still an
109-120
increased risk of conception whilst taking these AEDs
Referral for women considering pregnancy. Any woman with epilepsy who is
considering a pregnancy should be referred to a Neurologist/Epileptologist or a physician
with particular knowledge of this topic
Pre-pregnancy. To reduce risk of neural tube defects in the foetus, all women of child121-124
bearing age on an AED should take a folate supplement (5mg/day).
However, women should also be warned that folate supplementation may be associated with
125 126
an increased incidence of multiple births
Risk of seizures during pregnancy. Women should be warned that there maybe an
increased risk of seizures during pregnancy, although the majority of patients remain
127-138
stable
AED treatment practice during pregnancy. Women with epilepsy should be treated with
the lowest effective dose of AED. Where possible, monotherapy should be used. The need
for AED medication should be re-evaluated prior to a woman becoming pregnant, to ensure
73 139
the medication is truly needed
AED serum monitoring during pregnancy. The pharmacokinetics of AEDs change during
pregnancy, resulting in reduced serum levels. Serum AED levels may need to be monitored
more closely during pregnancy and post partum. Ideally, the free level of the AED should be
10 72 73 139 140
measured, due to decreased protein binding during pregnancy
Risk of foetal malformation. Women on AEDs should be warned that the risk of major
malformations in their foetus is twice to three times that of the general population, and is
probably between 4-9%. This risk increases with the number of AEDs used, and higher
11 72 73 139 140
doses of AEDs during the pregnancy
At birth. Vitamin K supplement should be administered, to reduce the risks of cerebral
haemorrhage in the neonate, due to the inhibitory actions of AEDs on vitamin K
141-145
production.
Following birth. Close attention should be paid to the mother following delivery. AED
10 72 73 139
levels can rise rapidly, as the pharmacokinetics of the AEDs return to normal state
Evidence
grade
IV
IV
IV
III-2
IV
IV
III-2
III-2
IV
140
Breast-feeding. All AEDs are excreted in breast milk. The rates of transfer vary between
AEDs. If it is decided to breast feed, attention should be paid to ensure that the infant is not
sedated by the AEDs. Breast-feeding is contraindicated if the patient is taking
146 147
benzodiazepines or barbiturates
Other health issues. AEDs may be associated with dyslipidemia and accelerated
11
osteoporosis
IV
III-3
13
7.
DRIVING GUIDELINES
The effect of having an epileptic seizure whilst driving a car, or other vehicle, can be devastating for both
the patient and the public. To balance the needs of the individual and the public, and maintain fairness and
a uniform approach, guidelines have been produced by Austroads and National Road Transport
Commission (NRTC). These should be used to assess a patient’s fitness to drive. The Medical Advisory
Board of VicRoads may be contacted to clarify recommendations for specific patients.
Table 12. Recommendations: Driving guidelines
What to tell the patient: Advice must be given to patients concerning their fitness to drive
12
following a seizure. The guidelines formulated by Austroads (non-commercial licences) &
13
NRTC (commercial licences) should be utilised (see appendix 2)
Where to go if the guidelines are unclear: If the Austroads or NRTC guidelines are
unclear on their recommendations for a particular patient’s circumstances, or there is some
dispute over the recommended seizure free time, the Medical Advisory Board from
VicRoads should be contacted (Medical Review, VicRoads Registration and Licensing, PO
Box 2504, Kew 3101)
Evidence
grade
IV
IV
14
Graphic
Appendix 1: International Classification of Epileptic Seizures (abbreviated)
I Partial (arising from a focal or local cortical lesion, most commonly
the temporal lobe)
A Simple partial
(no loss of consciousness)
B Complex partial
(loss of consciousness; may start with loss of awareness or may follow a simple partial seizure; may be with or
without automatisms, e.g. lipsmacking, rubbing hands, walking, running with no recollection)
C Partial evolving to secondarily generalised seizure with tonic, tonic-clonic or clonic features
II Generalised (with bilateral discharges involving subcortical structures -convulsive or nonconvulsive; EEG shows bilateral discharges; consciousness is lost at the onset except in myoclonus;
motor features bilateral)
A Absence
(previously called ‘petit mal’; last seconds; +/- minor automatisms)
B Myoclonic
(may be simple or multiple jerks, often upper limbs)
C, D, E Tonic, Tonic-clonic or Clonic
(previously called ‘grand mal’)
F Atonic
(a form of ‘drop attack’; sudden loss of posture of head, limbs or body)
III Unclassified (usually used when an adequate description is not available, e.g. often in seizures
from sleep)
Adapted from Commission of Classification and Terminology of the International League against Epilepsy.
148
Epilepsia 1981; 22:489-501.
15
Appendix 2: Guidelines for fitness to drive following an epileptic seizure
For non-commercial drivers
Excerpt from Austroads (2001). Assessing fitness to drive: Guidelines and standards for health
12
professionals in Australia. Austroads: Sydney. pp 27-29 . Also located at
http://www.austroads.com.au/austroads/Others/ftd2001(sec).pdf. Please see this document for a discussion
of the principles behind these recommendations. The Medical Advisory Board of VicRoads may be
contacted to clarify recommendations for specific patients.
MEDICAL STANDARDS – EPILEPSY (recommended seizure-free periods)
Condition
Drivers of cars and light trucks, motorcycle riders
Chronic Epilepsy
Generally 2 years. A shorter period only on
(history of previously uncontrolled
recommendation of an experienced consultant where
seizures)
there is clear evidence of seizure control (eg. following
adjustment and stabilisation of anti-epileptic drug
treatment)
Isolated Seizure
3-6 months. Consultant opinion recommended
Recently Diagnosed Epilepsy
3-6 months. Consultant opinion recommended
Recurrent Seizure in a Person Previously 3 months from last seizure, if fulfilling all other
Seizure Free due to Identifiable
criteria as set out in these guidelines. Provocation may
Provocation
include illness, drug interaction, sleep deprivation
Recurrent Seizure on Withdrawal of
1 month after resuming previously effective
Medication on Medical Advice
medication or 2 years if refusing to resume medication
Seizure Causing Accident
Minimum of 1 year. Consultant opinion essential
Seizures only in Sleep
12 months from the last seizure whilst awake
Surgery for Epilepsy
12 months
Withdrawal of Anti-Epileptic Drug
The full period of withdrawal and at least 3 months
Therapy where there is significant risk of thereafter. Consultant opinion is recommended to
recurrent seizure
determine if there is a significant level of risk or
otherwise.
For Commercial licences
Excerpt from National Road Transport Commission (1994). Medical Guidelines for Commercial Vehicle
13
Drivers . NRTC. Located at http://www.nrtc.gov.au/publications/med-e.asp?lo=public. Please see this
document for a discussion of the principles behind these recommendations.
Criteria
The criteria are NOT met:
∙ if epilepsy is confirmed.
A conditional licence may be considered:
∙ if the person has - a past history of febrile convulsions; or
- a past history of epilepsy with seizure free period of 5 years whilst not on any
anticonvulsant medication; or
- had a past single seizure, or cluster of seizures, due to exceptional and nonrepeatable circumstances; or
∙ if the person has epilepsy which is so well controlled as to reduce the risk of a convulsion to that of
any member of the general population, noting the inherent features of the individual’s job.
16
Appendix 3: Emergency Department Discharge Pack First Seizure
Appointments
You have experienced what is suspected to be a seizure. To investigate the cause of this seizure the
following appointments have been made for you.
First Seizure Clinic appointment:
Date:
____________________
Location:
Royal Melbourne Hospital,
1st Floor Main Block, Ambulatory Care Centre
Contact Number:
9342 7393
EEG appointment
Date:
Location:
Contact Number:
____________________
Royal Melbourne Hospital,
4th Floor, Ward 4 North, Main Block.
9342 7583
Safety information
As you have had one seizure, there is a risk you may have another, particularly in the next few months. To
avoid injuring yourself, and others, please observe these safety precautions.
• Do not drive a motor vehicle or operate dangerous machinery until advised otherwise by a doctor.
• Have a shower instead of a bath. Run the cold water first, then the hot. Lower the temperature setting
on your hot water service.
• Do not go swimming alone.
• Avoid heights (eg. walking on roofs).
• Please consider and avoid any other activities that could cause serious harm to yourself or others in the
event of another seizure. Discuss with your doctor if you are uncertain.
• Avoid consuming excess alcohol, sleep deprivation and flashing lights. These may trigger seizures in
some people.
In the event of another seizure, an observer should
• Clear the area around the person so that they do not injure themselves.
• Do not place anything in the person’s mouth, or try to restrain them.
• If possible, place a pillow or soft item under their head.
• When the seizure finishes, place the person into the recovery position, lying them on their side.
• Arrange for the patient to return to hospital as soon as possible. If needed call an ambulance on 000,
and say “epileptic seizure”
If you need further information about seizures or epilepsy
If you wish to talk to a doctor at the Royal Melbourne Hospital, please ring the
• Royal Melbourne Hospital Switch:
9342-7000 or
• Neurology Department:
9342 7722 and ask to speak to the Neurology or
Epilepsy registrar
Alternatively, you can contact your local General Practitioner (GP).
Also, if you would like to talk to someone about your experience, you can contact the Epilepsy Foundation
of Victoria. The contact details for the Epilepsy Foundation of Victoria’s are as follows:
http://www.epinet.org.au/, or by calling 1300 852 853
17
Appendix 4: Letter to General Practitioner following a presumed seizure –
First Seizure
Dear Dr _____________________________
Your patient, __________________________(patient name), attended the emergency department at the
Royal Melbourne Hospital following a presumed first seizure. Whilst in the emergency department they
received a CT brain scan. This scan revealed
Insert Details
An outpatient EEG appointment has been made for __________________(insert date), and an appointment
has been made for the First Seizure Clinic for __________________(insert date). The doctor at the First
Seizure Clinic will write to you to inform you of the results of these further investigations.
Your patient has been discharged, but due to the risk of further seizures, I have warned him/her of a
number of safety issues. Specifically, the patient should not drive or operate heavy machinery, should
avoid heights, have a shower instead of a bath, and avoid any other situations where a seizure may cause
themselves or others harm.
I have prescribed the following medication
Medication
Indication
Dose
Plan
Royal Melbourne Hospital contact details
If you wish to talk to a doctor at the Royal Melbourne Hospital with regards to this patient, please ring the
• Royal Melbourne Hospital Switch:
9342-7000 or
• Neurology Department:
9342 7722 and ask to speak to the Neurology or
Epilepsy registrar
(Insert any other comments)
Yours sincerely,
Insert ED doctor’s name.
18
Appendix 5: Emergency Department Discharge Pack –
Established Epilepsy
Safety information
You have experienced what is suspected to be another epileptic seizure. As you will be aware, you have
previously been diagnosed with epilepsy. To avoid injuring yourself, and others, please observe these
safety precautions.
•
•
•
•
•
•
Do not drive a motor vehicle or operate dangerous machinery until advised otherwise by a doctor.
Have a shower instead of a bath. Run the cold water first, then the hot. Lower the temperature setting
on your hot water service.
Do not go swimming alone.
Avoid heights (eg. walking on roofs).
Please consider and avoid any other activities that could cause serious harm to yourself or others in the
event of another seizure. Discuss with your doctor if you are uncertain.
Avoid consuming excess alcohol, sleep deprivation and flashing lights. These may trigger seizures in
some people.
In the event of another seizure, an observer should
• Clear the area around the person so that they do not injure themselves.
• Do not place anything in the person’s mouth, or try to restrain them.
• If possible, place a pillow or soft item under their head.
• When the seizure finishes, place the person into the recovery position, lying them on their side.
• If needed, take the patient to hospital, or call an ambulance on 000, and say “epileptic seizure”.
If you need further information about seizures or epilepsy
If you wish to talk to a doctor at the Royal Melbourne Hospital, please ring the
• Royal Melbourne Hospital Switch:
9342-7000 or
• Neurology Department:
9342 7722 and ask to speak to the Neurology or
Epilepsy registrar
Alternatively, you can contact your local General Practitioner (GP).
Also, if you would like to talk to someone about your experience, you can contact the Epilepsy Foundation
of Victoria. The contact details for the Epilepsy Foundation of Victoria’s are as follows:
http://www.epinet.org.au/, or by calling 1300 852 853
19
Appendix 6: Letter to General Practitioner following a presumed seizure
– Established Epilepsy
Dear Dr _____________________________
Your patient, __________________________(patient name), attended the emergency department at the
Royal Melbourne Hospital following a presumed seizure. As you will be aware, this patient has been
diagnosed with epilepsy.
Your patient has been discharged, but due to the risk of further seizures, I have warned him/her of a
number of safety issues. Specifically, the patient should not drive or operate heavy machinery, should
avoid heights, have a shower instead of a bath, and avoid any other situations where a seizure may cause
themselves or others harm.
This patient is on the following medications.
Medication
Indication
Dose
Plan
Follow up arrangements
I have made the following follow up arrangements for this patient.
❐ Referred to General Practitioner or current specialist.
❐ Referred to Royal Melbourne Hospital Epilepsy Clinic.
Royal Melbourne Hospital contact details
If you wish to talk to a doctor at the Royal Melbourne Hospital with regards to this patient, please ring the
• Royal Melbourne Hospital Switch:
9342-7000 or
• Neurology Department:
9342 7722 and ask to speak to the Neurology or
Epilepsy registrar
• Pathology Results:
9342 8000
(Insert any other comments)
Yours sincerely,
Insert ED doctor’s name.
20
References
1. SIGN. Diagnosis and management of epilepsy in adults: A national clinical guideline. Edinburgh: Scottish Intercollegiate
Guideline Network, 1997.
2. Anonymous. Epilepsy. Therapeutic Guidelines: Neurology. 2 ed. Melbourne: Therapeutic Guidelines Limited, 2002: .
3. AHRQ. Management of newly diagnosed patients with epilepsy: a systematic review of the literature: AHRQ, 2001.
4. anonymous. Surgery for Epilepsy. NIH Consensus Statement: NIH, 1990.
5. anonymous. Guidelines for therapeutic monitoring on antiepileptic drugs. Commission on Antiepileptic Drugs,
International League Against Epilepsy. Epilepsia 1993; 34(4): 585-7.
6. anonymous. Guidelines for the care of women of childbearing age with epilepsy. Commission on Genetics, Pregnancy,
and the Child, International League Against Epilepsy. Epilepsia 1993; 34(4): 588-9.
7. anonymous. Guideline twelve: guidelines for long-term monitoring for epilepsy. American Electroencephalographic
Society. Journal of Clinical Neurophysiology 1994; 11(1): 88-110.
8. International-League-Against-Epilepsy. Recommendations for neuroimaging of patients with epilepsy. Commission on
Neuroimaging of the International League Against Epilepsy. Epilepsia 1997; 38(11): 1255-6.
9. anonymous. Guidelines for neuroimaging evaluation of patients with uncontrolled epilepsy considered for surgery.
Commission on Neuroimaging of the International League Against Epilepsy. Epilepsia 1998; 39(12): 1375-6.
10. anonymous. Consensus statements: medical management of epilepsy. Neurology 1998; 51(5 Suppl 4): S39-43.
11. Morrell MJ. Guidelines for the care of women with epilepsy. Neurology 1998; 51(5 Suppl 4): S21-7.
12. Austroads. Assessing fitness to drive: Guidelines and standards for health professionals in Australia. Sydney: Austroads,
2001: 27-29.
13. NRTC. Epilepsy. Medical Guidelines for Commercial Vehicle Drivers. Melbourne: NRTC, 2001: .
14. Pellegrino TR. An emergency department approach to first-time seizures. Emergency Medicine Clinics of North America
1994; 12(4): 925-39.
15. Willmore LJ. Epilepsy emergencies: the first seizure and status epilepticus. Neurology 1998; 51(5 Suppl 4): S34-8.
16. anonymous. Clinical policy for the initial approach to patients presenting with a chief complaint of seizure who are not in
status epilepticus. American College of Emergency Physicians. Annals of Emergency Medicine 1997; 29(5): 706-24.
17. Bradford JC, Kyriakedes CG. Evaluation of the patient with seizures: an evidence based approach. Emergency Medicine
Clinics of North America 1999; 17(1): 203-20.
18. Holmes GL. How to evaluate the patient after a first seizure. Postgraduate Medicine 1988; 83(2): 199-209.
19. McLachlan RS. Managing the first seizure. Canadian Family Physician 1993; 39: 885-8.
20. Hopkins A, Garman A, Clarke C. The first seizure in adult life. Value of clinical features, electroencephalography, and
computerised tomographic scanning in prediction of seizure recurrence. Lancet 1988; 1(8588): 721-6.
21. Annegers JF, Shirts SB, Hauser WA, Kurland LT. Risk of recurrence after an initial unprovoked seizure. Epilepsia 1986;
27(1): 43-50.
22. Hui AC, Tang A, Wong KS, Mok V, Kay R. Recurrence after a first untreated seizure in the Hong Kong Chinese
population. Epilepsia 2001; 42(1): 94-7.
23. Schoenenberger RA, Heim SM. Indication for computed tomography of the brain in patients with first uncomplicated
generalised seizure. BMJ 1994; 309(6960): 986-9.
24. Reinus WR, Wippold FJ, 2nd, Erickson KK. Seizure patient selection for emergency computed tomography. Annals of
Emergency Medicine 1993; 22(8): 1298-303.
25. Forsgren L, Fagerlund M, Zetterlund B. Electroencephalographic and neuroradiological findings in adults with newly
diagnosed unprovoked seizures. European Neurology 1991; 31(2): 61-7.
26. Eisner RF, Turnbull TL, Howes DS, Gold IW. Efficacy of a "standard" seizure workup in the emergency department.
Annals of Emergency Medicine 1986; 15(1): 33-9.
27. Henneman PL, DeRoos F, Lewis RJ. Determining the need for admission in patients with new-onset seizures. Annals of
Emergency Medicine 1994; 24(6): 1108-14.
28. Sempere AP, Villaverde FJ, Martinez-Menendez B, Cabeza C, Pena P, Tejerina JA. First seizure in adults: a prospective
study from the emergency department. Acta Neurologica Scandinavica 1992; 86(2): 134-8.
29. Russo LS, Goldstein KH. The diagnostic assessment of single seizures. Is cranial computed tomography necessary?
Archives of Neurology 1983; 40(12): 744-6.
30. Ramirez-Lassepas M, Cipolle RJ, Morillo LR, Gumnit RJ. Value of computed tomographic scan in the evaluation of
adult patients after their first seizure. Annals of Neurology 1984; 15(6): 536-43.
31. Scollo-Lavizzari G, Eichhorn K, Wuthrich R. Computerized transverse axial tomography (CTAT) in the diagnosis of
epilepsy. European Neurology 1977; 15(1): 5-8.
32. McGahan JP, Dublin AB, Hill RP. The evaluation of seizure disorders by computerized tomography. Journal of
Neurosurgery 1979; 50(3): 328-32.
33. Young AC, Costanzi JB, Mohr PD, Forbes WS. Is routine computerised axial tomography in epilepsy worth while?
Lancet 1982; 2(8313): 1446-7.
34. Hauser WA, Rich SS, Annegers JF, Anderson VE. Seizure recurrence after a 1st unprovoked seizure: an extended followup. Neurology 1990; 40(8): 1163-70.
35. Lindsten H, Stenlund H, Forsgren L. Seizure recurrence in adults after a newly diagnosed unprovoked epileptic seizure.
Acta Neurologica Scandinavica 2001; 104(4): 202-7.
21
36. Cleland PG, Mosquera I, Steward WP, Foster JB. Prognosis of isolated seizures in adult life. British Medical Journal
Clinical Research Ed. 1981; 283(6303): 1364.
37. Thomas M. The single seizure - its study and management. JAMA 1959; 169: 457-733.
38. van Donselaar CA, Geerts AT, Schimsheimer RJ. Idiopathic first seizure in adult life: who should be treated? BMJ 1991;
302(6777): 620-3.
39. Das CP, Sawhney IM, Lal V, Prabhakar S. Risk of recurrence of seizures following single unprovoked idiopathic seizure.
Neurology India 2000; 48(4): 357-60.
40. anonymous. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the
Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1981; 22(4):
489-501.
41. Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review.
Neurology 1991; 41(7): 965-72.
42. Elwes RD, Chesterman P, Reynolds EH. Prognosis after a first untreated tonic-clonic seizure. Lancet 1985; 2(8458): 7523.
43. Hyllested K. Prognosis in epilepsy of late onset. Neurology 1963; 13: 641-644.
44. Saunders M, Marshall C. Isolated seizures: an EEG and clinical assessment. Epilepsia 1975; 16(5): 731-3.
45. Johnson LC, DeBolt WL, Long MT, Ross JJ, Sassin JF, Arthur RJ, et al. Diagnostic factors in adult males following
initial seizures. A three-year follow-up. Archives of Neurology 1972; 27(3): 193-7.
46. Luhdorf K, Jensen LK, Plesner AM. Epilepsy in the elderly: prognosis. Acta Neurologica Scandinavica 1986; 74(5): 40915.
47. Hart YM, Sander JW, Johnson AL, Shorvon SD. National General Practice Study of Epilepsy: recurrence after a first
seizure. Lancet 1990; 336(8726): 1271-4.
48. Gupta SK, Satishchandra P, Venkatesh A, Subbakrishna DK. Prognosis of single unprovoked seizure. Journal of the
Association of Physicians of India 1993; 41(11): 709-10.
49. Bora I, Seckin B, Zarifoglu M, Turan F, Sadikoglu S, Ogul E. Risk of recurrence after first unprovoked tonic-clonic
seizure in adults. Journal of Neurology 1995; 242(3): 157-63.
50. Hauser WA, Rich SS, Lee JR, Annegers JF, Anderson VE. Risk of recurrent seizures after two unprovoked seizures. New
England Journal of Medicine 1998; 338(7): 429-34.
51. Musicco M, Beghi E, Solari A, Viani F. Treatment of first tonic-clonic seizure does not improve the prognosis of
epilepsy. First Seizure Trial Group (FIRST Group). Neurology 1997; 49(4): 991-8.
52. Gilad R, Lampl Y, Gabbay U, Eshel Y, Sarova-Pinhas I. Early treatment of a single generalized tonic-clonic seizure to
prevent recurrence. Archives of Neurology 1996; 53(11): 1149-52.
53. Chandra B. First seizure in adults: to treat or not to treat. Clinical Neurology & Neurosurgery 1992; 94 Suppl: S61-3.
54. Chaisewikul R, Privitera MD, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant localization related
(partial) epilepsy. Cochrane Database Syst Rev 2001; 1: .
55. Chaisewikul R, Baillie N, Marson AG. Calcium antagonists as an add-on therapy for drug-resistant epilepsy (Cochrane
Review). Cochrane Database Syst Rev 2001; 4: .
56. Chadwick DW, Marson AG. Zonisamide for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000; 2: .
57. Jette NJ, Marson AG, Kadir ZA, Hutton JL. Topiramate for drug-resistant partial epilepsy. Cochrane Database Syst Rev
2000; 2: .
58. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. Gabapentin add-on for drug-resistant partial epilepsy. Cochrane
Database Syst Rev 2000; 3: .
59. Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst
Rev 2000; 3: .
60. Harden CL. Therapeutic safety monitoring: what to look for and when to look for it. Epilepsia 2000; 41 Suppl 8: S37-44.
61. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39(1): 517.
62. Greenwood RS. Adverse effects of antiepileptic drugs. Epilepsia 2000; 41 Suppl 2: S42-52.
63. French JA, Gidal BE. Antiepileptic drug interactions. Epilepsia 2000; 41 Suppl 8: S30-6.
64. Marson AG, Kadir ZA, Hutton JL, Chadwick DW. The new antiepileptic drugs: a systematic review of their efficacy and
tolerability. Epilepsia 1997; 38(8): 859-80.
65. Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Drug Safety 2000; 23(1): 35-56.
66. Vermeulen J, Aldenkamp AP. Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of
research. Epilepsy Research 1995; 22(2): 65-95.
67. Perucca E, Beghi E, Dulac O, Shorvon S, Tomson T. Assessing risk to benefit ratio in antiepileptic drug therapy.
Epilepsy Research 2000; 41(2): 107-39.
68. Schmidt D, Kramer G. The new anticonvulsant drugs. Implications for avoidance of adverse effects. Drug Safety 1994;
11(6): 422-31.
69. Wallace SJ. Newer antiepileptic drugs: advantages and disadvantages. Brain & Development 2001; 23(5): 277-83.
70. Arroyo S, de la Morena A. Life-threatening adverse events of antiepileptic drugs. Epilepsy Research 2001; 47(1-2): 15574.
71. Schlienger RG, Shear NH. Antiepileptic drug hypersensitivity syndrome. Epilepsia 1998; 39(Suppl 7): S3-7.
72. Yerby MS. The use of anticonvulsants during pregnancy. Seminars in Perinatology 2001; 25(3): 153-8.
73. Pschirrer ER, Monga M. Seizure disorders in pregnancy. Obstetrics & Gynecology Clinics of North America 2001;
28(3): 601-11.
22
74. Delgado-Escueta AV, Janz D. Consensus guidelines: preconception counseling, management, and care of the pregnant
woman with epilepsy. Neurology 1992; 42(4 Suppl 5): 149-60.
75. Walczak TS, Leppik IE, D'Amelio M, Rarick J, So E, Ahman P, et al. Incidence and risk factors in sudden unexpected
death in epilepsy: a prospective cohort study. Neurology 2001; 56(4): 519-25.
76. Nilsson L, Bergman U, Diwan V, Farahmand BY, Persson PG, Tomson T. Antiepileptic drug therapy and its
management in sudden unexpected death in epilepsy: a case-control study. Epilepsia 2001; 42(5): 667-73.
77. Opeskin K, Harvey AS, Cordner SM, Berkovic SF. Sudden unexpected death in epilepsy in Victoria. J Clin Neurosci
2000; 7(1): 34-7.
78. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a
case-control study. Lancet 1999; 353(9156): 888-93.
79. Jannuzzi G, Cian P, Fattore C, Gatti G, Bartoli A, Monaco F, et al. A multicenter randomized controlled trial on the
clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study
Group in Epilepsy. [see comments]. Epilepsia 2000; 41(2): 222-30.
80. Woo E, Chan YM, Yu YL, Chan YW, Huang CY. If a well-stabilized epileptic patient has a subtherapeutic antiepileptic
drug level, should the dose be increased? A randomized prospective study. Epilepsia 1988; 29(2): 129-39.
81. Froscher W, Eichelbaum M, Gugler R, Hildenbrand G, Penin H. A prospective randomised trial on the effect of
monitoring plasma anticonvulsant levels in epilepsy. Journal of Neurology 1981; 224(3): 193-201.
82. Wing DS, Duff HJ. The impact of a therapeutic drug monitoring program for phenytoin. Therapeutic Drug Monitoring
1989; 11(1): 32-7.
83. Sherwin AL, Robb JP, Lechter M. Improved control of epilepsy by monitoring plasma ethosuximide. Archives of
Neurology 1973; 28(3): 178-81.
84. Eadie MJ. Plasma antiepileptic drug monitoring in a neurological practice: a 25-year experience. Therapeutic Drug
Monitoring 1994; 16(5): 458-68.
85. Jackson M, Dawson P, McCrea W. The hazards of prescribing from serum levels. Seizure 1994; 3(3): 225-33.
86. McKee PJ, Percy-Robb I, Brodie MJ. Therapeutic drug monitoring improves seizure control and reduces anticonvulsant
side-effects in patients with refractory epilepsy. Seizure 1992; 1(4): 275-9.
87. Beardsley RS, Freeman JM, Appel FA. Anticonvulsant serum levels are useful only if the physician appropriately uses
them: an assessment of the impact of providing serum level data to physicians. Epilepsia 1983; 24(3): 330-5.
88. Glauser TA, Pippenger CE. Controversies in blood-level monitoring: reexamining its role in the treatment of epilepsy.
Epilepsia 2000; 41 Suppl 8: S6-15.
89. Tomson T, Johannessen SI. Therapeutic monitoring of the new antiepileptic drugs. European Journal of Clinical
Pharmacology 2000; 55(10): 697-705.
90. Mattson r, Cramer j, Collins j, al. e. Connective tissue changes, hypersensitivity rash and blood laboratory test changes
associated with antiepileptic drug therapy (absract). Annals of Neurology 1986; 20: 119-120.
91. Camfield C, Camfield P, Smith E, Tibbles JA. Asymptomatic children with epilepsy: little benefit from screening for
anticonvulsant-induced liver, blood, or renal damage. Neurology 1986; 36(6): 838-41.
92. Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs.
Neurology 1991; 41(7): 961-4.
93. Camfield P, Camfield C, Dooley J, Farrell K, Humphreys P, Langevin P. Routine screening of blood and urine for severe
reactions to anticonvulsant drugs in asymptomatic patients is of doubtful value. CMAJ 1989; 140(11): 1303-5.
94. Green SH. Sodium valproate and routine liver function tests. Archives of Disease in Childhood 1984; 59(9): 813-4.
95. De Vries S. Haematological aspects during treatment with anticonvulsant drugs. Epilepsia 1965; 6: 1-15.
96. Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev
2000; 3: .
97. Brodie MJ. Management strategies for refractory localization-related seizures. Epilepsia 2001; 42 Suppl 3: 27-30.
98. Treatment of convulsive status epilepticus. Recommendations of the Epilepsy Foundation of America's Working Group
on Status Epilepticus. Jama 1993; 270(7): 854-9.
99. Alldredge BK, Gelb AM, Isaacs SM, Corry MD, Allen F, Ulrich S, et al. A comparison of lorazepam, diazepam, and
placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001; 345(9): 631-7.
100. Treiman DM, Meyers PD, Walton NY, Collins JF, Colling C, Rowan AJ, et al. A comparison of four treatments for
generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med
1998; 339(12): 792-8.
101. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treatment of refractory status epilepticus with pentobarbital, propofol,
or midazolam: a systematic review. Epilepsia 2002; 43(2): 146-53.
102. Lagerlund TD, Cascino GD, Cicora KM, Sharbrough FW. Long-term electroencephalographic monitoring for diagnosis
and management of seizures. Mayo Clinic Proceedings 1996; 71(10): 1000-6.
103. Thompson JL, Ebersole JS. Long-term inpatient audiovisual scalp EEG monitoring. Journal of Clinical
Neurophysiology 1999; 16(2): 91-9.
104. Erlichman M. Electroencephalographic (EEG) video monitoring. Health Technology Assessment Reports 1990; (4): 114.
105. anonymous. Assessment: intensive EEG/video monitoring for epilepsy. Report of the American Academy of Neurology,
Therapeutics and Technology Assessment Subcommittee. [erratum appears in Neurology 1989 Nov;39(11):1437.].
Neurology 1989; 39(8): 1101-2.
106. Quesney LF, Gloor P. Localization of epileptic foci. Electroencephalogr Clin Neurophysiol Suppl 1985; 37: 165-200.
107. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N
Engl J Med 2001; 345(5): 311-8.
23
108. McIntosh AM, Wilson SJ, Berkovic SF. Seizure outcome after temporal lobectomy: current research practice and
findings. Epilepsia 2001; 42(10): 1288-307.
109. Fattore C, Cipolla G, Gatti G, Limido GL, Sturm Y, Bernasconi C, et al. Induction of ethinylestradiol and levonorgestrel
metabolism by oxcarbazepine in healthy women. Epilepsia 1999; 40(6): 783-7.
110. Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ. Gabapentin does not interact with a contraceptive regimen of
norethindrone acetate and ethinyl estradiol. Neurology 1998; 50(4): 1146-8.
111. Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral
contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38(3): 317-23.
112. Bartoli A, Nocentini G, Ronchetti S, Moraca R, Riccardi C. A double-blind, placebo-controlled study on the effect of
vigabatrin on in vivo parameters of hepatic microsomal enzyme induction and on the kinetics of steroid oral
contraceptives in healthy female volunteers. Molecular & Cellular Biochemistry 1997; 167(1-2): 135-44.
113. Saano V, Glue P, Banfield CR, Reidenberg P, Colucci RD, Meehan JW, et al. Effects of felbamate on the
pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 1995; 58(5): 523-31.
114. Klosterskov Jensen P, Saano V, Haring P, Svenstrup B, Menge GP. Possible interaction between oxcarbazepine and an
oral contraceptive. Epilepsia 1992; 33 Suppl 1(6): S13-22.
115. Holdich T, Whiteman P, Orme M, Back D, Ward S. Effect of Lamotrigine on the pharmocology of the combined oral
contraceptive pill. Epilepsia 1991; 32(suppl 1): 96.
116. Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with
combined oral contraceptive steroids. British Journal of Clinical Pharmacology 1990; 30(6): 892-6.
117. Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant
treatment. Contraception 1986; 33(6): 559-65.
118. Crawford P, Chadwick D, Cleland P, Tjia J, Cowie A, Back DJ, et al. The lack of effect of sodium valproate on the
pharmacokinetics of oral contraceptive steroids. Contraception 1986; 33(1): 23-9.
119. Back DJ, Bates M, Bowden A, Breckenridge AM, Hall MJ, Jones H, et al. The interaction of phenobarbital and other
anticonvulsants with oral contraceptive steroid therapy. Contraception 1980; 22(5): 495-503.
120. Coulam CB, Annegers JF. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979; 20(5): 519-25.
121. Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for
preventing neural tube defects. Cochrane Database Syst Rev 2002; 2: .
122. Lewis DP, Van Dyke DC, Stumbo PJ, Berg MJ. Drug and environmental factors associated with adverse pregnancy
outcomes. Part II: Improvement with folic acid. Ann Pharmacother 1998; 32(9): 947-61.
123. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth
defects. N Engl J Med 2000; 343(22): 1608-14.
124. Dansky LV, Andermann E, Rosenblatt D, Sherwin AL, Andermann F. Anticonvulsants, folate levels, and pregnancy
outcome: a prospective study. Annals of Neurology 1987; 21(2): 176-82.
125. Lumley J, Watson L, Watson M, Bower C. Modelling the potential impact of population-wide periconceptional
folate/multivitamin supplementation on multiple births. Bjog 2001; 108(9): 937-42.
126. Parazzini F, Chatenoud L, Bettoni G, Tozzi L, Turco S, Surace M, et al. Selected food intake and risk of multiple
pregnancies. Human Reproduction 2001; 16(2): 370-3.
127. Tomson T, Lindbom U, Ekqvist B, Sundqvist A. Epilepsy and pregnancy: a prospective study of seizure control in
relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia 1994; 35(1): 122-30.
128. Tanganelli P, Regesta G. Epilepsy, pregnancy, and major birth anomalies: an Italian prospective, controlled study.
Neurology 1992; 42(4 Suppl 5): 89-93.
129. Lander CM, Eadie MJ. Plasma antiepileptic drug concentrations during pregnancy. Epilepsia 1991; 32(2): 257-66.
130. Wilhelm J, Morris D, Hotham N. Epilepsy and pregnancy--a review of 98 pregnancies. Australian & New Zealand
Journal of Obstetrics & Gynaecology 1990; 30(4): 290-5.
131. Bag S, Behari M, Ahuja GK, Karmarkar MG. Pregnancy and epilepsy. Journal of Neurology 1989; 236(5): 311-3.
132. Gjerde IO, Strandjord RE, Ulstein M. The course of epilepsy during pregnancy: a study of 78 cases. Acta Neurologica
Scandinavica 1988; 78(3): 198-205.
133. Schmidt D, Canger R, Avanzini G, Battino D, Cusi C, Beck-Mannagetta G, et al. Change of seizure frequency in
pregnant epileptic women. Journal of Neurology, Neurosurgery & Psychiatry 1983; 46(8): 751-5.
134. Canger R, Avanzinin G, Battino D, Bossi L, Franceschetti S, Spina S. Modifications of seizure frequency in pregnant
patients with epilepsy: a prospective study. In: Janz Dea, editor. Epilepsy, pregnancy, and the child. New York: Raven
Press, 1982: 33-38.
135. Schmidt D, Beck-Mannagetta G, Janz D, Koch S. The effect of pregnancy on the course of epilepsy: A prospective
study. In: Janz Dea, editor. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982: 39-49.
136. Bardy AH. Seizure frequency in epileptic women during pregnancy and puerperium: results of the prospective Helsinki
Study. In: Janz Dea, editor. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982: 27-31.
137. Remillard G, Dansky L, Andermann E, Andermann F. Seizure frequency during pregnancy and the puerperium. In: Janz
Dea, editor. Epilepsy, pregnancy, and the child. New York: Raven Press, 1982: 15-26.
138. Schmidt D. The effect of pregnancy on the natural history of epilepsy: Review of the literature. In: Janz Dea, editor.
Epilepsy, pregnancy, and the child. New York: Raven Press, 1982: 3-14.
139. O'Brien TJ, Vajda FJ. Contemporary management of epilepsy in pregnancy. Australian & New Zealand Journal of
Obstetrics & Gynaecology 2000; 40(4): 413-5.
140. Eller DP, Patterson CA, Webb GW. Maternal and fetal implications of anticonvulsive therapy during pregnancy.
Obstetrics & Gynecology Clinics of North America 1997; 24(3): 523-34.
24
141. Hey E. Effect of maternal anticonvulsant treatment on neonatal blood coagulation. Archives of Disease in Childhood:
Fetal & Neonatal Edition 1999; 81(3): F208-10.
142. Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Motohara K, Monnens L. Supplementation of vitamin K in
pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency. American Journal of
Obstetrics & Gynecology 1993; 168(3 Pt 1): 884-8.
143. Cornelissen M, Steegers-Theunissen R, Kollee L, Eskes T, Vogels-Mentink G, Motohara K, et al. Increased incidence
of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. American Journal of Obstetrics &
Gynecology 1993; 168(3 Pt 1): 923-8.
144. Deblay MF, Vert P, Andre M, Marchal F. Transplacental vitamin K prevents haemorrhagic disease of infant of epileptic
mother. Lancet 1982; 1247: 1247.
145. Mountain KR, Hirsh J, Gallus AS. Neonatal coagulation defect due to anticonvulsant drug treatment in pregnancy.
Lancet 1970; 1(7641): 265-8.
146. Chaudron LH, Jefferson JW. Mood stabilizers during breastfeeding: a review. Journal of Clinical Psychiatry 2000;
61(2): 79-90.
147. Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Safety 2000; 22(6): 425-40.
148. Commission of Classification and Terminology of the International League against Epilepsy. Epilepsia 1981; 22: 489501.
25