Minimal diagnostic and therapeutic standards by EpiStop EpiStop

EpiStop Minimal Diagnostic and Therapeutic Standards in Patients with Epilepsy

This collection of epilepsy care standards (“epi – standards”) continues the series of previous publications, the content of which was the result of panel discussions held by leading Czech and Slovak epileptologists and other experts. The original “epi – standards” editorial board: MUDr. Milan Brázdil, Ph.D.; MUDr. Jindřiška Burešová; MUDr. Jiří Dolanský †; MUDr. Vladimír Donáth, Ph.D.; MUDr. Jan Hadač; Doc. MUDr. Miluše Havlová, CSc.; MUDr. Markéta Jirásková; Doc. MUDr. Jiří Hovorka, CSc.; MUDr. Marie Kolínová; Doc. MUDr. Vladimír Komárek; MUDr. Marián Kuchár, Ph.D.; MUDr. Petr Marusič; Prof. MUDr. Soňa Nevšímalová, DrSc.; Doc. MUDr. Boţena Piťhová, CSc.; Prof. MUDr. Ivan Rektor, CSc.; MUDr. Zdena Salcmanová, CSc.; MUDr. Pavel Sýkora, Ph.D.; Doc. MUDr. Radomír Šlapal, CSc.; Doc. MUDr. Milada Švejdová, CSc. †; MUDr. Jana Zárubová; MUDr.Boris Ţivný. This revised edition of "epi – standards" reflects the progress in epileptology since the publication of the first edition in 1997.

Minimal diagnostic and therapeutic standards in patients with epilepsy EpiStop 2010 All rights reserved. No part of this publication is to be reproduced, stored or modified without previous consent from the owner of the copyright. Copyright © EpiStop www.epistop.cz ISBN 78-80-903979-4-1

The EpiStop working group is honoured to dedicate these epi – standards to the memory of MUDr. Jiří Dolanský, head physician emeritus.

MAIN AUTHORS AND EDITORS Project coordinator: Doc. MUDr. Petr MARUSIČ, Ph.D. Centre for Epilepsies, Department of Neurology, 2nd Faculty of Medicine, Charles University, University Hospital Motol, Prague Prof. MUDr. Milan BRÁZDIL, Ph.D. Centre for Epilepsies, 1st Department of Neurology, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno. MUDr. Jan HADAČ. Ph.D. Centre for Epileptology and Epilepsy Surgery, Department of Paediatric Neurology, Postgraduate Medical School, Thomayer's Teaching Hospital, Prague Doc. MUDr. Jiří HOVORKA, CSc. Centre for Neuropsychiatry and Epileptology, Department of Neurology, Na Františku Hospital, Prague Prof. MUDr. Vladimír KOMÁREK, CSc. Epilepsy Centre, Department of Paediatric Neurology, 2nd Faculty of Medicine, University Hospital Motol, Prague MUDr. Evţen NEŠPOR Department of Neurology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague Mgr. Eva TEYSSLEROVÁ Centre for Epileptology and Epilepsy Surgery, Department of Neurology, Postgraduate Medical School, Thomayer's University Hospital, Prague MUDr. Zdeněk VOJTĚCH Centre for epilepsies, Department of Neurology, Na Homolce Hospital, Prague MUDr. Jana ZÁRUBOVÁ Centre for Epileptology and Epilepsy Surgery, Department of Neurology, Postgraduate Medical School, Thomayer's Teaching Hospital, Prague

OTHER CONTRIBUTORS MUDr. Jan BOHÁČ Department of Assessment Medicine, Institute of Postgraduate Medical Education, Prague MUDr. Jindřiška BUDEŠOVÁ Department of Neurology, Faculty of Medicine, Palacký University and University Hospital, Olomouc MUDr. Marie KOLÍNOVÁ Department of Neurology, 1st Faculty of Medicine, Charles University and General University Hospital, Prague MUDr. Hana KRIJTOVÁ Centre for epilepsies, Department of Neurology, 2nd Faculty of Medicine, Charles University, University Hospital Motol, Prague MUDr. Robert KUBA, Ph.D. Centre for epilepsies, 1st Department of Neurology, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno. MUDr. Iva MAREČKOVÁ Centre for epilepsies, Department of Neurology, Na Homolce Hospital, Prague Prof. MUDr. Soňa NEVŠÍMALOVÁ, DrSc. Department of Neurology, 1st Faculty of Medicine, Charles University, General University Hospital, Prague MUDr. Tomáš NEŢÁDAL Centre for Neuropsychiatry and Epileptology, Department of Neurology, Na Františku Hospital, Prague MUDr. Irena NOVOTNÁ Centre for epilepsies, 1st Department of Neurology, Faculty of Medicine, Masaryk University, St. Anne's University Hospital, Brno. MUDr. Martin TOMÁŠEK Centre for epilepsies, Department of Neurology, 2nd Faculty of Medicine, Charles University, University Hospital Motol, Prague

CONTENTS MAIN AUTHORS AND EDITORS .......................................................................................4 OTHER CONTRIBUTORS................ .....................................................................................5 CONTENTS ..............................................................................................................................6 INTRODUCTION ....................................................................................................................7 1.1 MINIMAL DIAGNOSTIC STANDARD FOLLOWING THE FIRST EPILEPTIC SEIZURE ............................................................................................................................8 1.2 MINIMAL DIAGNOSTIC AND THERAPEUTIC STANDARD IN SUSPECTED NON-EPILEPTIC SEIZURES ...........................................................................................9 1.3 MINIMAL DIAGNOSTIC STANDARD IN PATIENTS WITH SUSPECTED MEDICALLY REFRACTORY EPILEPSY .....................................................................11 1.4 PHOTIC STIMULATION .................................................................................................12 1.5 NEUROIMAGING ............................................................................................................15 1.6 PSYCHOLOGICAL EXAMINATION IN EPILEPTOLOGY .........................................16 1.7 EPILEPSY AND SLEEP ...................................................................................................17 2.1 FIRST AID IN EPILEPTIC SEIZURE .............................................................................20 2.2 PROPHYLACTIC TREATMENT ....................................................................................21 2.3 GENERAL PRINCIPLES OF THERAPY..... ..................................................................23 2.4 TREATMENT OF EPILEPSY ACCORDING TO SEIZURE TYPE ..............................26 2.5 RATIONAL PHARMACOTHERAPY IN AGE-RELATED EPILEPTIC SYNDROMES ..................................................................................................................27 2.6 TREATMENT IN SPECIFIC SITUATIONS ................................................................. 28 2.7 STATUS EPILEPTICUS AND ITS TREATMENT ........................................................31 2.8 SURGICAL TREATMENT OF EPILEPSY ....................................................................34 3.1 CONTRACEPTION .........................................................................................................37 3.2 PREGNANCY AND DELIVERY ...................................................................................39 3.3 PERIMENOPAUSE AND POSTMENOPAUSE ............................................................42 3.4 EPILEPSY AND EPILEPTIC SEIZURES IN THE ELDERLY.......................................44 4.1 CRITERIA FOR DETERMINING THE LEVEL OF EPILEPSY CONTROL................47 4.2 ABILITY TO DRIVE MOTOR VEHICLES IN PATIENTS WITH EPILEPSY. SITUATION IN THE CZECH REPUBLIC............................................................................48 4.3 ASSESSMENT OF THE ABILITY TO HOLD OR CARRY WEAPON AND AMMUNITION IN PATIENTS WITH EPILEPSY................................................................50 4.4 SOCIAL AND LEGAL MINIMUM .................................................................................51 4.5 ASSESSMENT OF PATIENTS WITH EPILEPSY IN TERMS OF GAINFUL ACTIVITIES AND DISABILITY PENSIONS (ID), CURRENT SITUATION...................55 LIST OF ABBREVIATIONS..................................................................................................59 EPILOGUE ..............................................................................................................................60

INTRODUCTION Dear colleagues. We present you the revised and expanded edition of "Minimal Diagnostic and Therapeutic Standards" prepared by the EpiStop Working Group. Aim of all EpiStop activities is the improvement of care in patients with epilepsy, and thereby - as we hope - improvement of their quality of life. Three years have passed since the last edition of “Epi-Standards” and many amendments were needed to keep the text in line with new findings and recommendations. The text is intended to serve not only to neurologists and paediatric neurologists, but also to general practitioners and other clinicians (e.g. internal medicine specialists, neurosurgeons, gynaecologists, anaesthesiologists), and, last but not least, to patients and their families. Individual recommendations should reflect current situation in epileptology, as well as personal experience and consensus of leading Czech epileptologists. Views and statements presented in this book should not be taken as strict recommendations or guidelines. Rather, their intent is to provide basic information about preferred approach to particular clinical situations. We must emphasise the importance of tailoring the care to meet the needs of individual patients, especially as far as treatment is concerned. We greatly acknowledge the work of all authors and reviewers of individual sections who also took part n the completion and final processing of the whole text. We are especially thankful to K. Koubková, who hugely contributed in the preparation of all editions of epi – standards. Allow us to conclude by (traditionally) dedicating even this edition to J. Dolanský, the founder of EpiStop and author of the first diagnostic and therapeutic standards. For the EpiStop authors, Vladimír Komárek and Petr Marusič

1.1 MINIMAL DIAGNOSTIC STANDARD FOLLOWING THE FIRST EPILEPTIC SEIZURE Minimal standard care is administered by treating physicians, i.e. general practitioners, paediatricians, internal medicine specialists, neurologists and paediatric neurologists. Mandatory examinations: 1. Neurological 2. General physical 3. Basic laboratory 4. EEG 5. Neuroimaging: 

always in adults



according to paediatric neurologist in children



in non-acute situations, MRI is preferred over CT (see standard 1.5)

1.2 MINIMAL DIAGNOSTIC AND THERAPEUTIC STANDARD IN SUSPECTED NONEPILEPTIC SEIZURES In some cases, it is very difficult to differentiate epileptic and non-epileptic seizures. The situation is complicated by relatively frequent co-incidence of non-epileptic and epileptic seizures in the same patient. Incidence of non-epileptic seizures is high especially in patients treated as medically refractory epilepsy. Consultation in a dedicated centre with the availability of video-EEG monitoring is indicated when the cause of seizures is dubious. Non-epileptic seizures can be divided, according to aetiology, into somatic and psychogenic. Somatic non-epileptic seizures:  Syncope of various causes (esp. convulsive syncope) 

Cardiovascular diseases, esp. arrhythmia



Sleep disorders (narcolepsy-cataplexy, somnambulism, pavor nocturnus, iactatio capitis nocturna, enuresis nocturna, etc.)



Paroxysmal dystonia, and paroxysmal kinesiogenic chorea



Sleep-related physiological myoclonus, other non-epileptic myoclonias



Tetany



Migraine (esp. when headaches are minimal or absent)



Benign paroxysmal vertigo



Transitory ischemic attack



Transient global amnesia



Paroxysmal endocrine dysbalance



Others

Psychogenic non-epileptic seizures:  Dissociative seizures 

Panic attacks



Malingering



Behavioural disorders



Münchhausen syndrome



Münchhausen syndrome by proxy

Diagnosis  Thorough history, include objective data 

Neurological examination



EEG, including activation methods



Brain MRI



Long-term video-EEG monitoring with recording of patient's habitual seizures



Psychological examination



Psychiatric examination



General physical examination and, if needed, cardiological evaluation (Holter monitoring of blood pressure and ECG, orthostatic tests, head-up-tilt table test). Metabolic and endocrinological examination may also be performed if needed.

Therapy  In case of proven non-epileptic aetiology of seizures, the treatment is governed by the underlying cause. Also, gradual discontinuation of antiepileptic therapy is indicated. 

In case of combination of epileptic and non-epileptic seizures, both types of seizures have to be adequately treated.



In psychogenic non-epileptic seizures, long-term complex psychiatric care (psychotherapy, pharmacotherapy, family therapy) is needed.

Correct and early identification of non-epileptic seizures can prevent iatrogenic harm caused by inadequate therapy.

1.3 MINIMAL DIAGNOSTIC STANDARD IN PATIENTS WITH SUSPECTED MEDICALLY REFRACTORY EPILEPSY Insufficient or absent response to antiepileptic treatment warrants evaluation in a dedicated epilepsy centre. Time to evaluation should not exceed one year since symptom onset. 1. Thorough evaluation of disease course (history and diagnostic findings) 2. Complete neurological and general physical examination with laboratory tests including antiepileptic drugs plasma levels. 3. EEG studies with increasing complexity: 

Routine EEG with photic stimulation, and also sleep deprivation where indicated.



Long-term EEG



Video-EEG monitoring, with reduction of medication where indicated.

4. Brain MRI and other structural or functional imaging of the brain when needed. 5. Neuropsychological examination 6. Other relevant exams to ascertain aetiology (i.e. metabolic, genetic, immunological, endocrinological and electrophysiological studies) – according to the differential diagnostic evaluation In a case of proven medically refractory epilepsy*, the treating physician should refer the patient to a dedicated epilepsy centre to evaluate the possibility of surgical treatment, in no longer than two years since the onset of symptoms. * Note. A patient is considered to be “medically refractory (pharmacoresistant)”, when seizure freedom is not achieved despite the use of at least two appropriately chosen antiepileptic drugs given at maximum tolerated doses (in monotherapy or combined therapy), and the persisting seizures significantly influence the patient’s quality of life.

1.4 PHOTIC STIMULATION Intermittent light (both artificially created and naturally occurring) may provoke epileptic seizures. Photosensitivity Photosensitivity denotes abnormal sensitivity of the brain to visual stimuli. Physical characteristics of these stimuli are most important, not their cognitive content. Photosensitivity manifests:  Clinically - as reflex seizures induced by visual stimuli  Electrophysiologically – as epileptiform activity in scalp EEG, i.e. photo-paroxysmal response (PPR)* Different clinical situations may occur. 1. The patient has epilepsy and is photosensitive (PPR in EEG; seizures occur spontaneously; the patient may have experienced a seizure induced by photic stimulation). 2. The patient has photosensitive epilepsy (PPR in EEG; seizures mostly evoked by photic stimulation) 3. The patient does not have epilepsy, but is photosensitive (PPR in EEG; no seizures) PHOTIC STIMULATION DURING EEG (Recommended technical parameters and methodology - international standard - consensus meeting, May 1996, Netherlands) Montage  At least 16 or 21 EEG channels 

Bipolar or source montage



Photic stimulation should not start earlier than 3 minutes after the end of hyperventilation

Distance of the stimulation lamp  30 cm from nasion Room  Dimmed light, but enough to allow direct observation of the patient Frequency  Optimum range1-60 Hz , e.g.: Binnie I protocol - for patients without known photosensitivity: 18, 2, 6, 8, 10, 15, 20, 30, 40, 50, 60 Hz Binnie II protocol - for patients with known photosensitivity: 2, 6, 8, 10, 15, 18, 20, 30, 40, 50, 60 Hz Kasteleijn-Nolst Trenité protocol - 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20 – 60, 50, 40, 30, 25 Hz Stimulation  10 s at each frequency; pauses of at least 7 s 

Must be stopped when a clinical seizure or PPR occurs. In this case, the continuation of photic stimulation must be consulted with a physician.

Technician notes  Clinical signs and symptoms (e.g. myoclonias, absences) induced by photic stimulation must be noted by the technician. Photo-paroxysmal response Rhythmical generalised spikes and waves (PSW – polyspike-wave, SW – spike-wave); usually out of phase with the stimuli; may have posterior predominance. When PPR continues after stimulation ceases, the likelihood of epilepsy exceeds 90 %. Other responses  Occipital spikes mostly occurring at low frequencies; in phase with the stimulation frequency  Photic driving (frequency take-up); often supra- or sub-harmonic 

Evoked potentials (low stimulation frequency)



Photomyogenic response - rhythmical action potentials from eye muscles (and other muscles of the face), synchronised with stimulation flashes

These responses are physiological; their presence does not indicate photosensitivity. The presence of occipital spikes suggests some form of occipital cortex hyperexcitability, which, however, may not be clinically relevant.

Sources of visual stimuli (intermittent light and patterns)  TV (> 60 % first seizures) 

Flashing light, especially red colour (sun, stroboscope, disco light effects)



Video games and computer games



Patterns - Venetian blinds, escalators - moving stairs, propellers, fans

Prevention  Avoid combination of risk factors 

Watch TV from a distance of at least 2,5 m for a 19 " screen in a well lit room. Use remote control.



Cover one eye in case of photic stimulation.



Use polarised glasses; tinted glasses (especially blue tones) are more effective



Use TV screens with a frequency of 100 Hz or an LCD display



PC and video games: smaller monitor, avoid playing or working more than one hour; avoid playing and working when tired, fasting, or sleep deprived. In patients with proven photosensitive epilepsy, the presence of another trained person is advised.

In patients without clinical or EEG signs of photosensitivity, blanket restriction of using PC or watching TV is not substantiated. Treatment of photosensitive epilepsy  AEDs in a dose needed to prevent clinical seizures. Do not aim at the cessation of EEG signs.  Use AEDs with documented efficacy in photosensitive epilepsy (VPA, LTG, LEV, CLZ, PRM). * The presence of photo-paroxysmal response in EEG does not necessarily mean epilepsy the patient may not have epileptic seizures. The occurrence of photo-paroxysmal response can be influenced by sleep deprivation, drugs, season, and, in women, the phase of menstrual cycle. PPR disappears spontaneously by the 2nd or 3rd decade in 25% of patients.

1.5 NEUROIMAGING 1) The aim of neuroimaging (MRI, CT) is to establish aetiology and specify classification of epilepsy or epileptic syndrome. In non-acute cases  Magnetic resonance imaging (MRI) is the method of choice.  CT is the alternative method when MRI is contraindicated.  MRI should be repeated in patients with worsening of disease course or a change in seizure characteristics suggesting progressive lesion. In acute cases (acute symptomatic seizures)  CT is regarded as sufficient investigation in acute cases, when MRI is not rapidly available or is contraindicated.  MRI is the method of choice in acute cases during pregnancy. 2) Functional neuroimaging (SPECT, PET, functional MRI and MR spectroscopy) is performed only in patients included in an epilepsy surgery programme.

1.6 PSYCHOLOGICAL EXAMINATION IN EPILEPTOLOGY Comprehensive care for patients with epilepsy aims not only to favourably affect seizures, but also to address other somatic, psychological and social problems. Psychological examination is indicated:  At the beginning or during the course of the disorder according to the decision of the treating neurologist.  When subjective or clinically evident cognitive changes (e.g. in memory) occur. 

In disorders with deficit of attention, concentration, emotion, behaviour, personality or sociability.

Neuropsychological examination:  Helps to assess and delineate the epileptogenic zone or the functional deficit zone. 

Is indicated in the differential diagnosis of epileptic and non-epileptic seizures.



Is indicated for the purposes of expert assessments.

Possible psychological problems should be identified among the patient's close friends and relatives as well. Psychological examination may be followed by psychiatric consultation.

1.7 EPILEPSY AND SLEEP Sleep activates many epileptic syndromes, either on the level of interictal epileptiform activity, or in terms of clinical seizures. This effect is especially pronounced in NREM sleep and, in some cases, during arousal. A. Epileptic syndromes related to sleep or arousal  Age-related idiopathic partial epilepsies, especially benign partial epilepsy with rolandic spikes (BERS).  Other age-related syndromes. Electrical status epilepticus in sleep (ESES) and LandauKleffner syndrome (LKS) are developmental disorders of electrogenesis combined with impairment of speech and (usually) cognition.  Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterised by repeated short nocturnal motor seizures which lead to arousal. It manifests in adolescence. Hereditarz and sporadic cases occur.  Idiopathic primarily generalised epilepsies - juvenile myoclonic epilepsy (JME) and epilepsy with grand mal seizures on awakening (GMA). The occurrence of seizures is more of less limited to first hour or two following arousal. Seizures are frequently provoked by afternoon naps.  Symptomatic epilepsies with partial seizures. NREM sleep typically provokes frontal hypermotor seizures with striking and sometimes bizzare motor features, as well as seizures originating in supplementary motor area characterised by short asymmetrical tonic postures, frequently with mimic muscles involvement and vocalisation.

B. Differential diagnosis  NREM parasomnias Somnambulism, disorientation on awakening (sleep drunkenness) and pavor nocturnus may resemble complex partial seizures. Diagnosis of epilepsy is more likely when the paroxysmal events: 1. Occur frequently. 2. Do not occur exclusively in the first third of the night. 3. Have stereotypical semiology. Enuresis. May be both epileptic or non-epileptic. Iactatio capitis and bruxism may sometimes be confused with epilepsy.

 REM parasomnias. REM sleep behavior disorder (RBD) may have motor symptoms similar to frontal lobe epilepsy. Retained memory of a specific dream is typical for RBD – it is an important differentiating feature compared to epilepsy. Diagnosis is always established by polysomnographic recording, which proves lack of muscle atonia during REM sleep. In case of nightmares, the memory of a specific dream may be retained as well. Sleep paralysis may be differentiated by thorough history.  Hypnagogic jerks and benign sleep myoclonus are usually differentiated based on history but monitoring is sometimes needed.  Non-epileptic psychogenic seizures. May also occur at night from a state that resembles sleep, but arousal preceding the seizure can be documented by monitoring. The differentiation from epilepsy may be difficult without video-EEG monitoring.  Sleep apnoea. Sometimes, sleep apnoea provokes genuine epileptic seizures. On the other hand, ADNFLE may have features resembling sleep apnoea.  Periodic limb movement in sleep. A condition close to restless legs syndrome. Both these states may give rise to a suspicion of epilepsy. However, it should not survive the first well performed history-taking. C. Diagnosis.  History Precise description of the event emphasizing responsiveness during the seizure and retention of a memory of the seizure. Seizure frequency and exact time of seizure occurrence during night-time. If available, a home video of the event may be conclusive.  Physical examination

 EEG. Better yield when patient is sleeping during the examination.  Neuroimaging (see standard 1.5)  Psychological examination when needed.

ď&#x201A;ˇ Night-time video-EEG monitoring possibly combined with polysomnography is performed in: Patients with history of unexplained repeated nocturnal movements (for differential diagnostic reasons). In seemingly well-compensated patients with epilepsy complaining of excessive daytime sleepiness. To attribute this sleepiness invariably to side effects of antiepileptic medication is a mistake. It may be related to sleep fragmentation caused by clinically unremarkable seizures, subclinical epileptiform activity, or by a concomitant sleep disorder not related to epilepsy (e.g. obstructive sleep apnoea). For the same reasons, sleep video-EEG monitoring is indicated in epilepsy patients with unexplained cognitive deficit.

2.1 FIRST AID IN EPILEPTIC SEIZURE 1. Remove all objects which could cause injury. Transfer the patient to another place only when absolutely necessary. Support the patient's head, loosen the clothing around the neck. 2. Do not try to stop jerks or tonic spasms. Do not prevent automatisms unless there is a risk of injury or damage to things. Do not try to open the patient's mouth by force. Wait until the seizure stops. 3. In lasting impairment of consciousness, put the patient into stabilised position. Slightly open the patient's mouth, clean the oral cavity and push forward patient's jaw. Wait until the patient regains consciousness. 4. During postictal confusion: try to talk to the patient and calm him down. Do not restrain the patient's movements unless absolutely necessary. 5. Examine the patient for injuries (particularly head, tongue and vertebrae). 6. Determine the patient's history. Transportation to a hospital is not necessary when the patient is already on treatment, has no injury that would need medical attention, and there is no continuing disorientation. Transportation is indicated in following cases:     

First seizure. Seizure cluster (except for repeated habitual partial seizures routinely managed by the patient or relatives) Status epilepticus (see standard 2.7). Persisting disorientation or repeated generalised seizures (impending status epilepticus). The patient suffered an injury that needs medical attention.

2.2 PROPHYLACTIC TREATMENT Prophylactic treatment in febrile seizures  There is no evidence that treatment with AEDs after a febrile seizure prevents later development of epilepsy.  To minimise the risk of febrile seizure recurrence, intermittent administration of diazepam during the next infectious/febrile illness is indicated.  Recommendation: diazepam 0,5-0,7mg/kg PO or PR divided into three doses a day, given during the first three days of the illness.  Vaccination may be hazardous in children with a history of febrile seizure. Consultation with paediatric neurologist is mandatory. Prophylactic treatment in traumatic brain injury (TBI)  The administration of AEDs immediately after severe TBI can lower the incidence of early epileptic seizures in the first 24 hours or first few days after the injury. This treatment is indicated in patients in which seizure occurrence would carry a risk of significant worsening of existing systemic or intracranial impairment.  Prophylactic treatment with AEDs has no influence on the development of posttraumatic epilepsy; on the contrary, the administration of some AEDs can worsen the cognitive performance of patients following TBI.  Long-term prophylactic treatment is not indicated even if acute symptomatic or early seizures occur. Prophylactic treatment in inflammatory, vascular or neoplastic CNS disorders  Similarly as in TBI, prophylactic treatment with AEDs has no influence on the development of symptomatic epilepsy.  In indicated cases, short-term prophylaxis of early seizures (several weeks) can be administered.  Long-term prophylactic treatment is not indicated even if acute symptomatic or early seizures occur.

Prophylaxis after brain surgery  Early prophylaxis is administered in high-risk patients according to the neurosurgeon and the type of operation.  Long-term prophylactic treatment is not indicated even if early postoperative seizures occur.  Treatment with AEDs is usually indicated already after the first unprovoked epileptic seizure following surgery. Treatment is always indicated in case of epilepsy.

2.3 GENERAL PRINCIPLES OF TREATMENT Correct classification of seizures is mandatory for successful treatment (see Standard 1.2) When to start treatment?  When the diagnosis of epilepsy is definite. The question whether to start treatment already after the first seizure or only in case of seizure recurrence must be settled on an individual basis; the benefit of treatment should always outweigh the potential risks. The risk of seizure recurrence and potential hazards for the patient in such a case are of crucial importance. These factors are influenced mainly by the type of seizure and epileptic syndrome, aetiology, patient age and comorbidities. The possible impact of side effects is also very important.  In rare situations, when the diagnosis of epilepsy is highly probable, and the risk of seizure recurrence outweigh the risk of therapy (e.g. elderly, patients living alone, etc.).  For mandatory diagnostic tests see Standard 1.1 The choice of AED  According to seizure type (see Standard 2.4).  According to the epileptic syndrome (see Standard 2.5).  Broad-spectrum AEDs are preferred when precise classification of seizures or epilepsy is not possible, when several types of seizures occur, or when a narrow-spectrum AED can possibly worsen one of the seizure types.  The AED must be chosen on an individual basis, according to the patient's biological, somatic and psychological condition.  At the beginning of treatment, the choice of AED and its dosing must be especially considered in the following groups of patients: children; women with child-bearing potential; women taking contraceptives; women in the menopause (see Standard 3); elderly; patients with significant comorbidities and polytherapy; patients with neuropsychological deficit and/or psychiatric comorbidity.

Aims of treatment  Optimal quality of life and functional status of the patient.  Control of the seizures (especially severe types) and good?optimal interictal somatic and psychic condition of the patient, without unacceptable side? effects of the therapy.  The benefit of treatment must outweigh its risk. Strategy of treatment  Treatment initiation - discuss with the patient (parents) the real possibilities of treatment and their expectations. Motivation to treatment is the key to good compliance.  First step – initial monotherapy respecting the titration schemes; start with low dose. The optimum therapeutic dose is individual, recommended daily doses only serve as a guidance. The aim is to reach an effective and well-tolerated dose. Under-dosing, as well as avoiding maximal tolerated dose (MTD) is a mistake. The easiest possible dosing scheme is recommended (controlled-release formulations).  Second step - alternative monotherapy; especially in case of side effects or low efficacy of initial monotherapy. Rational polytherapy can be considered already at this point, when the initial monotherapy is well tolerated and has a significant effect.  Third step - rational polytherapy: combination of drugs with different (synergistic) pharmacodynamic actions, without adverse pharmacokinetic interactions.  Referral to a dedicated centre should not be delayed in case of pharmacoresistance (see Standard 1.3). For other non-pharmacological modes of treatment see standard 2.8. Treatment monitoring  Treatment efficacy should be assessed both objectively and subjectively (by the patient).  For the criteria used to determine control of epilepsy see Standard 4.1  Interictal somatic and psychic condition of the patients (quality of life).  Use laboratory testing according to the type of medication and somatic condition of the patient.  Monitoring the AEDs plasma levels yields information about an individually effective dose. AED plasma level examination is indicated when the treatment is problematic (lack of effect despite adequate dosing, compliance concerns, possibility of auto-induction in previously effective treatment, symptoms of overdose, presumed pharmacokinetic interactions, etc.). Free drug levels are more significant.



Follow-up EEG is indicated mainly in patients with uncontrolled epilepsy, especially when seizures worsen or change, new type of seizure occurs, or the somatic or psychic condition of the patient deteriorates. It is also indicated in case of presumed neurotoxicity, after making changes in the treatment, during treatment discontinuation and in some legal issues (e.g. assessment of the eligibility to drive).

Treatment termination  Usually, the treatment lasts at least two years.  It can be shorter in childhood idiopathic benign syndromes with age-dependent clinical manifestation.  In other cases, the decision to stop treatment is always individual. Both medical and psychosocial risk of possible seizure recurrence must be considered in the same way as it was assessed at the beginning of treatment (aetiology, type of epileptic syndrome, EEG findings in some cases, etc.).  The prognosis must be discussed with patients (their parents), and their decisions must be respected and recorded.

2.4 TREATMENT OF EPILEPSY ACCORDING TO SEIZURE TYPE The following table is based on published recommendations taking into consideration the current practice in the Czech Republic. It is intended as a guide when the epileptic syndrome is not precisely identified, but the type of seizures is known. Type of seizures

First choice

Second choice*

Focal (partial) or secondarily generalised tonic-clonic

CBZ, GBP, LEV, LTG, VPA, TPM

ESL, LCM, PGB, ZNS

Primary generalised tonic-clonic

LTG, VPA, TPM

LEV

Absence

ETS**,LTG, VPA

TPM

Myoclonic

LTG***, VPA

BZD, LEV

Note Individual drugs are listed in alphabetical order and each can be used as a first choice. Explanation * drugs of second choice can be used as first choice with respect to the patient's medical condition and the type of epileptic syndrome. ** only in childhood absence syndrome *** not in severe myoclonic epilepsy of infancy (SMEI - Dravet syndrome) Abbreviations are explained in the Appendix.

2.5 RATIONAL PHARMACOTHERAPY IN AGE-RELATED EPILEPTIC SYNDROMES

First choice

Second choice*

West syndrome (WS)

ACTH, VGB

BZD, LEV, steroids, TPM, VPA

Lennox-Gastaut syndrome (LGS)

LTG, TPM, VPA

BZD, FBM, LEV, RUF

Myoclonic-astatic epilepsy (MAE; Doose syndrome)

VPA

BZD, ETS, LTG

Childhood absence epilepsy (CAE)

ETS, VPA

LEV, LTG

Juvenile absence epilepsy (JAE)

LTG, VPA*

ETS, LEV, TPM, ZNS

Epilepsy with grand mal seizures on awakening (GMA)

LTG, VPA*

LEV, PRM, TPM, ZNS

Juvenile myoclonic epilepsy (JME)

LEV, LTG, VPA

CZP, PRM

Benign partial epilepsy with rolandic spikes (BERS)

sultiam, VPA

CBZ, GBP

Landau-Kleffner syndrome (LKS)

ACTH or steroids, diazepam, VPA

LEV, sultiam

Note Drugs are listed in alphabetical order and each can be used as first choice. Drugs of second choice can be used as first choice with respect to the patient's state of health and the type of epileptic syndrome. Treatment of WS, LKS and CSWS should be reserved for specialised centres. * VPA is used as second choice in young females.

2.6 TREATMENT IN SPECIFIC SITUATIONS Perioperative treatment with AEDs  Operations not involving gastrointestinal tract. In planned operations, administer the usual evening and morning PO medication (morning dose sufficiently in advance) with a small amount of fluid. Benzodiazepines may be added according to the anaesthesiologist. If the postoperative state precludes oral intake, AEDs can either be administered via nasogastric tube, or in parenteral formulations.  Gastrointestinal surgery. When available, use parenteral formulations of chronically administered AEDs (PHT, VPA, LEV, PB, CZP). If parenteral formulation does not exist for the given AED, use an alternative drug with respect to the type of seizures (e.g. BZD, PHT, VPA, LEV). Treatment in liver or renal failure  Requires understanding of the changes in AED pharmacokinetics in these disorders. Plasma drug level monitoring may be helpful. Renal failure  Impairment of renal functions (decreased glomerular filtration and tubular secretion) can lead to accumulation of AEDs excreted by the kidney (GBP, PGB, VGB, TPM, LEV, PHT). Hypalbuminemia increases free drug fractions of AEDs. Possible gastroparesis and oedema of intestinal mucosa result in slower and decreased absorption of AEDs.  Dose reduction or prolongation of the intervals between the doses is often neccessary.  AEDs with low protein binding (GBP, PGB, VGB, TPM, PB, LEV) are cleared from circulation by dialysis (up to 50 % during standard four-hour dialysis). Therefore, an extra dose is often needed at the end of dialysis. Supplementation of AEDs with significant protein binding (VPA, PHT) is usually not needed. Effect of peritoneal dialysis is unpredictable, and measuring of AEDs plasma levels can be helpful, especially in this case.  Acute symptomatic seizures may occur as a result of uremic encephalopathy, disorders of ion and glucose metabolism, disorders of acid-base balance, dialysis encephalopathy or complications of renal failure (malignant hypertension, intracranial hemorrhage).

Liver failure  Hepatic failure decreases biotransformation of some AEDs and leads to hypalbuminemia  Avoid potentially hepatotoxic AEDs (VPA, FBM). VPA is an inhibitor of hepatic enzymes and it can increase its own concentration and toxicity, especially when administered in combination with other enzyme inhibitors. As an idiosyncratic reaction, VPA can cause Reye's syndrome, especially in children younger than two years, with inborn metabolic disorders, mental retardation or polytherapy. Idiosyncratic hepatotoxicity is also a concern of treatment with FBM.  The treatment of choice can be an AED with low protein binding and low rate of hepatic metabolism (GBP, PGB, LEV, TPM)  In patients with porphyria, GBP, PGB, OXC or LEV can be used. Organ transplantation  Occurrence of epileptic seizures in patients after organ transplantation can indicate a complication. Fast and detailed diagnostic evaluation is needed: EEG (to rule out nonconvulsive status epilepticus), CT or MRI (stroke, venous sinus thrombosis, cerebral abscess, CNS lymphoma), laboratory testing, which may include the plasma levels of immunosuppressive drugs (metabolic and toxic encephalopathies, sepsis)  Most seizures after transplantations are sporadic (either one or only a few seizures in the peri-transplantation period), and do not require long-term treatment with AEDs. Generally, long-term treatment is indicated when the cause of the seizures persists (e.g. refractory metabolic disorders), especially in severely ill patients, in whom seizures represent another significant health hazard.  It is not advised to use enzyme inducing drugs because of the risk of interactions with immunosuppressive and other drugs, and also because of higher probability of idiosyncratic reactions. TPM should be avoided in kidney transplant recipients, especially those with history of nephrolithiasis.  Avoid AEDs that may damage the transplanted organ. For example, after liver transplantation, choose AEDs that are not metabolised in the liver. Following kidney transplantation, adjust the doses of AEDs excreted by the kidney according to the current renal functional capacity.  In liver transplant recipients, recommended drugs include LEV, PGB and GBP; in patients after kidney transplantation, VPA is the drug of first choice.

Surgical treatment of an epileptogenic lesion with sporadic seizures prior to surgery  If AED treatment was started before the operation, it is advisable to continue with it for at least one week after surgery. If radiotherapy follows the operation, AED treatment can be maintained throughout its course.  For management of patients not treated with AEDs prior to surgery see standard 2.2. prophylactic therapy. The decision about further treatment is individual and depends on the type of lesion and the extent of the resection.  Treatment is usually indicated after the first unprovoked seizure and always after seizure recurrence.  Enzyme inducing drugs may lower the efficacy of chemotherapeutic agents and corticosteroids. Conversely, chemotherapy may lower the plasma levels and efficacy of AEDs. The use of enzyme inhibitors (e.g. VPA) may lead to toxicity of both chemotherapy and AEDs. During radiotherapy, PHT, and to a lesser extent, PB and CBZ, can cause severe and potentially fatal mucocutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). Epilepsy surgery  Therapy should be adjusted to rational mono/polytherapy before the operation.  Do not change the therapy following the operation, unless the change is unavoidable due to the need of parenteral AED administration.  In seizure free patients, it is possible to consider a gradual dose reduction and eventual withdrawal of treatment, usually one or two years after the surgery. The decision about further treatment is individual and depends on the type of lesion, the extent of the resection and patient's preferences.

2.7 STATUS EPILEPTICUS AND ITS TREATMENT Any kind of seizure may develop into status epilepticus (SE). SE is broadly divided into convulsive and non-convulsive type. Convulsive SE is further divided into partial and generalised. Non-convulsive SE can be divided (mainly with the aid of EEG) into absence status and complex partial status. Non-convulsive status may also occur in comatose patients. Generalised tonic-clonic SE is associated with the highest morbidity and mortality. Therefore, it must be regarded as an acute and life-threatening condition. Approximately 70 % of all SE occur in children. Generalised convulsive SE occurs when an isolated seizure fails to stop after 30 minutes, or when several seizures arise during this period and the patient does not regain full consciousness between them. SE can be a manifestation of acute brain injury or a symptom of epilepsy (e.g. first epileptic seizure in the form of SE or SE due to inappropriate treatment withdrawal). In differential diagnosis, it is necessary to consider non-epileptic psychogenic seizures, which may manifest in the form of status as well (see Standard 1.2). Most seizures stop spontaneously within five minutes. With longer duration, the probability of spontaneous termination decreases. Seizures lasting longer than five minutes should therefore be regarded as an impending SE. Management of status epilepticus (particularly generalised tonic-clonic SE) 1. Check and stabilise vital functions, prevent hypoxia (position, oxygenation), perform basic physical examination, establish venous access, order basic laboratory tests including AED plasma levels and, in some cases, toxicology. In presumed hypoglycaemia, administer 50 ml 40% dextrose in adults, along with 100mg thiamine. In children, give 35mg/kg 25-30% dextrose - maintenance dose is 0,5-1,0 g/h.

2. Stop the seizure - see "Treatment". 3. Ascertain and treat the aetiology of SE (perform CT of the brain and, when necessary, CSF examination). 4. Maintain metabolic homeostasis and treat possible complications (hypotension, arrhythmia, hyperthermia). Treat cerebral edema. Admit the patient to ICU (artificial ventilation must be readily available). 5. EEG monitoring is needed to evaluate the efficacy of SE treatment, especially in case of refractory status and pharmacologically induced coma (convulsions may disappear despite ongoing electrographic epileptic activity). 6. Prevent seizure recurrence (early administration of long-term oral therapy; via nasogastric tube initially). Treatment of tonic-clonic SE or prolonged seizure Time (min) 5-10 Diazepam 10-20mg (0,2mg/kg/dose) IV over two minutes in adults. Children younger than three years: 0.5mg/kg/dose. Older children: 0.3mg/kg/dose. If lacking IV line, administer diazepam 10mg PR in adults; 5 mg PR in children under 15 kg body weight. Alternative: midazolam 5-15mg i.m. in adults; 0.2-0.3mg/kg/dose in children. 10-30 Phenytoin 15-20mg/kg IV (total dose 1000-2000mg in most adults). Rate of administration: 50mg/min. Only the first 250mg can be administered faster over two minutes. For children younger than 12 years the saturation dose of phenytoin is 20-30mg/kg IV at rate of 25mg/min. Do not dissolve in dextrose! Blood pressure and ECG monitoring is imperative during phenytoin administration (risk of bradycardia or cardiac arrest). Alternative: valproate 15-20mg/kg IV (first 800mg can be given over two minutes). Repeat benzodiazepine administration - same or half of the previously calculated dose. 30-70 Start EEG monitoring (if SE continues and the patient does not regain consciousness). Phenobarbital 20mg/kg IV, 50mg/min. Note: Watch out for possible inhibition of ventilation and hypotension in patients chronically treated with barbiturates or after repeated administration of benzodiazepines!

Komentář [D1]: Hezký, ale hovorovější.

If SE lasts longer than one hour, induction of pharmacological coma is indicated. After establishing artificial ventilation, administer thiopental 100-250mg IV in one dose and then 50mg every 2-3 minutes until the seizure stops. Continue with thiopental infusion (usually at a rate of 3-5mg/kg/hour) with thiopental plasma level monitoring and dose adjustment according to EEG (achieve and maintain burst/suppression pattern). Thiopental doses should be decreased gradually, start no sooner than 12 hours since the last seizure; decrease the infusion rate by 1mg/kg/hour every 6 hours. Alternative: midazolam - saturation dose 0.15-0.20mg/kg followed by continuous infusion 0.05-0.30 mg/kg/hour with EEG monitoring and interruption of the infusion at least every 12 hours. Alternative: propofol - saturation dose 2.0-2.5mg/kg, followed by 5-10mg/kg/hour to achieve burst/suppression pattern. Maintenance dose 1-3mg/kg/hour. Doses of anticonvulsant drugs in children. In children younger than three years IV diazepam is administered at the dose of 0.5mg/kg, in older children 0.3mg/kg. Recommended dose for rectal application in children under 15 kg body weight is 5 mg; 10mg in children over 15 kg. Maximal single dose of diazepam in older children usually does not exceed 10mg and the total daily dose 20-40mg. Single IV dose of midazolam for children under three years is 0.15-0.3 mg/kg, 0.1 mg/kg for older children. In acute situations, midazolam can be administered intramuscularly (0.2-0.3 mg/kg/dose), nasally, buccally or rectally. The IV dose of clonazepam approximates 1/10 of the dose of diazepam - i.e. 0.05 mg/kg under three years, 0.03 mg/kg in older children. Phenytoin is given in children at the saturation dose 20-30mg/kg IV, recommended infusion rate is slower than in adults (25mg/min). In children, IV dose is 20mg/kg for phenobarbital and 25-30mg/kg for valproate. In children younger than 18 months, pyridoxin at the dose of 100-200mg i.v. is recommended.

2.8 SURGICAL TREATMENT OF EPILEPSY Basic requisites for epilepsy surgery  Refractory epilepsy (see Standard 1.3)  Expected increase in quality of life after seizure suppression  Potential risk of surgery does not outweigh expected benefit  Positive motivation of the patient or his legitimate representative Contraindications of epilepsy surgery:  Concomitant progressive severe disease, including neurodegenerative and neurometabolic disorders.  Lack of patient motivation or lack of compliance, precluding the completion of necessary pre-surgical epileptological evaluation and the assurance of adequate postoperative care. Pre-surgical evaluation: Basic  Detailed history, excluding "pseudopharmacoresistance"  Neurological evaluation  Interictal EEG  Satisfactory brain MRI examination  Non-invasive or semi-invasive video-EEG monitoring with recording of typical seizures.  Neuropsychological evaluation.

Facultative  Inter-ictal PET  Ictal/inter-ictal SPECT (or SISCOM)  Intra-carotid amobarbital (Wada) test.  MR spectroscopy  Invasive video-EEG examination  Functional MRI  Perimeter  Intraoperative electrocorticography Surgical procedures:  Resections - anteromedial temporal lobe resection (AMTR), selective amygdalohippocampectomy (AHE), extended lesionectomies, focal cortical resections  Calosotomy  Hemispherectomy  Multiple sub-pial transsections  VNS implantation (vagus nerve stimulation)  Stereotactic radiosurgery Postoperative care:  Regular neurological follow-up, with repeated evaluation of postoperative seizure control (Engel classification - see below) and the impact of surgery on patient's quality of life.  Follow-up brain MRI no sooner than three months and no later than 1 year after surgery (does not apply to VNS patients)  Follow-up neuropsychological evaluation (ideal timing one year after surgery)  Follow-up perimeter examination in indicated cases.  Postoperative rehabilitation in indicated cases. Every patient with refractory epilepsy who agrees with surgical treatment should be evaluated at a dedicated epilepsy centre as soon as possible (in less than two years). The centre must be able to perform valid pre-surgical evaluation and successful epileptosurgical treatment (number of operations in such centres exceed 25 per year).

Appendix 1 - Engel’s Classification of Postoperative Outcome Class I: Free of disabling seizures (excludes early postoperative seizures - first few weeks) A. Completely seizure-free since surgery B. Nondisabling simple partial seizures only since surgery C. Some disabling seizures after surgery, but free of disabling seizures for at least two years D. Generalised convulsions with AED discontinuation only. Class II: Rare disabling seizures ("almost seizure-free") A. Initially free of disabling seizures but has rare seizures now. B. Rare disabling seizures since surgery C. More than rare disabling seizures since surgery, but rare seizures for the last two years D. Nocturnal seizures only Class III: Worthwhile improvement (determination of “worthwhile improvement” will require quantitative analysis of additional data such as percentage seizure reduction, cognitive function, and quality of life) A. Worthwhile seizure reduction. B. Prolonged seizure-free intervals amounting to greater than half the followed-up period, but not longer than two years Class IV: No worthwhile improvement A. Significant seizure reduction B. No appreciable change C. Seizures worse Appendix 2 – ILAE classification of postoperative outcome 1 Completely seizure free; no auras 1a – same class, but for the whole time since surgery 2 Only auras; no other seizures 3 One to three seizure days per year; ± auras 4 Four seizure days per year to 50% reduction of baseline seizure days; ± auras 5 Less than 50% reduction of baseline seizure days to 100% of baseline seizure days; ± auras 6 More than 100% increase of baseline seizure days; ± auras - Situation over the passed year is evaluated, always to the date of surgery or closest followup visit, with the exception of 1a class.

3.1 CONTRACEPTION Already at the first visit, it is necessary to ask adolescents and women of child-bearing age about contraception, inform them about the importance of family planning, and discuss the pros and cons of individual methods of contraception. Hormonal contraceptives are not contraindicated in patients with epilepsy. In women with epilepsy, specific factors influence the choice of a suitable method of family planning:  High reliability is a crucial factor. Unwanted pregnancy can unfavourably influence the course of epilepsy, AEDs taken during pregnancy carry higher risk of teratogenicity.  Use of combined oral contraception can lead to lowering of LTG plasma levels.  Several AEDs may lower the reliability of some methods of contraception (oral contraception, implants). The main reason is an increase in the activity of hepatic enzymes leading to more rapid metabolism of ethinylestradiol (documented for PB, PHT, PRM, CBZ, ETS and TPM at doses >200mg/day).  Age-specific factors must be taken into consideration when choosing the method of contraception.  In adolescence, contraception is influenced by several well-described factors: worse compliance leading to significantly lower reliability; worse tolerance of unwanted effects; more partners; lower financial resources; worse co-operation with the treating physician. I. Combined oral contraception (COC)  Monophasic formulations with the same oestrogen and progestogen dose throughout the whole cycle are appropriate. These formulations also allow the use of the so called continual scheme in patients with catamenial epilepsy (i.e. use of several packages in sequence without the seven pill-free days to allow withdrawal bleeding).  In patients using hepatic enzyme inducing drugs (see above), intermediate-dose contraceptives should be used (30-37.5μg of ethinylestradiol). Ineffectiveness of COC is indicated by breakthrough bleeding. In this case, contraception with 50μg ethinylestradiol is needed.



Low-dose estrogen formulations (15-20 μg) are generally not suitable in patients with epilepsy.

II. Intrauterine device (IUD)  Recently, medicated devices are most popular; the device is coated with copper, gold or releases a low amount of gestagene (Mirena®)  Hormonal IUD is a very reliable method. The likelihood of influencing the local effect of hormones by concomitant medication is very low.  Contrary to combined oral contraception or implants, the amount of gestagene released into the circulation is significantly lower.  Absence of higher risk of pelvic inflammation makes IUD a suitable method also for women, who have not yet delivered. III. Vaginal ring (Nuvaring®)  New method of contraception  Elastic medicated ring with gestagene (etonogestrel 11,7 mg) and ethinylestradiol (2,7mg). On average, the ring releases 0,120 mg of etonorgestrel and 0,015 mg ethinylestradiole over 24 hours.  It is inserted for 3 weeks, followed by a week without the ring during menses. Hormonal levels remain stable due to constant rate of release from the ring. IV. Implants  Based on the available evidence, this method is not recommended for women using AEDs. IV. Depot progestogen contraception (Depo-Provera inj.®, Sayana®)  Advantages include high reliability and low cost  Disadvantages include high frequency of unwanted effects, especially irregular bleeding, which, in most women, occurs for several months. Other adverse effects characteristic for progestogen contraception are also common: weight gain, headache, breast tension, mood changes. Frequently, after treatment withdrawal, the onset of regular menstrual and ovulation cycle is delayed, which also influences the chances of conception.  Long-term application lowers bone density in young women and increases the life-long risk of osteoporotic fractures. V. Female sterilization  Due to its reliability and safety, sterilization is a suitable method for those women with epilepsy who have already fulfilled their reproduction plans, or in whom the severity of epilepsy does not allow pregnancy.

3.2 PREGNANCY AND DELIVERY Pregnancy can affect the course of epilepsy - either worsen it (approximately 1/5 of cases) or alleviate it (approximately 1/5 of cases). In most cases however, no change in the course of epilepsy is observed during pregnancy. Epilepsy worsens most frequently during the first and third trimester and during lactation. Women with focal epilepsy, long duration of epilepsy and inadequate compensation prior to conception are at greater risk. One of the reasons for worsening of epilepsy during pregnancy may be AED plasma level reduction. Lamotrigine monotherapy carries an especially high risk from this perspective. If a patient is stabilized for a period of 9 months or more prior to conception, an uncomplicated course of pregnancy caqn be expected (almost 90% probability) Epilepsy influences the course of a pregnancy. Pregnancy should be planned for a period of optimal seizure control. During pregnancy, generalised convulsive seizures carry the highest risk for fetus. The risk of seizures surmounts the risk associated with AED administration. Other types of generalised seizures (absence, myoclonic) and focal seizures are not associated with increased risk for the fetus. Preconception period  Establish definite diagnosis of epilepsy. Precise classification of seizures, epilepsy and its aetiology. Neuroimaging - preferably MRI of the brain.  Compensation with a suitable monotherapy at the lowest effective dose, suppressing especially generalised convulsive seizures.  AEDs plasma levels and EEG.  Inform the patient about possible unwanted effects of AED therapy and epilepsy on pregnancy and vice versa.  Genetic testing.  It is advisable to eliminate or compensate other risk factors, not always related to epilepsy or AEDs: obesity, malnutrition, B12 deficiency in vegetarian patients, smoking, alcohol, X-ray exposure, other drugs than AEDs, other disorders, e.g. diabetes, hypertension etc.  Folic acid supplementation 5mg/day (e.g. Acidum folicum 1 drg on alternate days), at least three month prior to conception.

Prenatal period  From the viewpoint of comprehensive care, pregnancy in a patient with epilepsy is considered as a high-risk pregnancy.  Folic acid supplementation continues at least until the end of the first trimester.  Screening for congenital defects of the fetus (Down syndrome and severe fetal malformations) During 10–11th week by measuring PAPP-A (pregnancy associated plasmatic protein A) and beta-HCG (free chorionic gonadotropine) in the mothers' serum. 11th to 13th week: transvaginal ultrasonography 16th week: the so-called tripple test (serum alfa-fetoprotein, total HCG and estriol in the mothers' serum). In women with a higher risk one of the following invasive diagnostic methods is offered: chorion villi biopsy (first trimester), amniocentesis (after 15th week), cordocentesis (after 20th week). 18th to 20th week: fetal echocardiography and a thorough ultrasonographic examination.  Follow-up AED plasma levels should be ordered on an individual basis.  When epilepsy develops during pregnancy, it is advisable to postpone (if possible) the initiation of AED treatment to the end of the first trimester. MRI is the method of choice when neuroimaging is needed. When there is no danger of delay, it is safer to perform MRI after the first trimester  Seizures during pregnancy can be caused by: Decrease of AEDs plasma levels due to: Inadequate compliance (fear of teratogenicity). Increase in the volume of distribution (water retention, bodyweight increase). Lower absorption (changes in gastric pH, slowing of gastrointestinal motility, vomiting). Increased clearance (due to increased blood flow through the liver and enhanced activity of enzymes). Lower protein binding and thus faster elimination. Hormonal changes. Increased stress and anxiety. Sleep deprivation. 

Most clinically significant reduction in LTG plasma levels occurs up to the 30 th week of pregnancy.

Delivery Before the delivery, the treating neurologist should provide a report for the obstetrician, including the patient's type of epilepsy, type of seizures and AEDs taken. It should also contain the information about possible precautions and arrangements during and after the delivery, as well as the information whether breast feeding is allowed.  Epidural analgesia is not contraindicated.  Prolonged hyperventilation should be avoided in patient in whom it was clearly identified as a provocation factor for epilepsy (history, EEG).  The AED treatment should continue also on the day of delivery. After delivery the doses can be adjusted when needed (especially after a previous increase during pregnancy).  Sleep deprivation should be prevented.  No other special arrangements are needed. In case of a seizure, use benzodiazepines (diazepam 10mg IV or rectal, midazolam 5-10mg IM or bucal).  Planned cesarean section is indicated (from a neurological point of view) only in patients with: High risk of generalised seizures or status epilepticus. Focal/partial seizures that are prolonged or occur in clusters. Postnatal period and lactation.  Breast feeding is not contraindicated.  Withdrawal syndrome may occur in children withheld from breast feeding whose mothers were exposed barbiturates and benzodiazepines during pregnancy.  Sleep deprivation should be prevented (help of a third person during the night is advisable).  Prevent injury of the new-born or infant in case of mother's seizure. Breast feed while supine or in other position secure in case of falling. The presence of another person is advisable during bathing of the child, precautions should be taken to avoid injury in case of falling (bathing outside the basin, the basin situated on the floor, etc.) Secure the pram from leaving its place in case of seizure.

3.3 PERIMENOPAUSE AND POSTMENOPAUSE* ď&#x201A;ˇ Primenopause "Hyperoestrogenic" state during perimenopause can lead to worsening of epilepsy (especially in women with catamenial seizures), or to de novo onset of epilepsy. Apart from adjusting the AED treatment, it is possible to consider decreasing the hormonal dysbalance and alleviating the signs and symptoms of perimenopause by combined oral contraception with the so-called very low dosing (15-20 ug ethinylestradiole) or continuous dosing. Efficacy of combined oral contraception is lowered by enzyme inducing AEDs, but that is not a concern in this clinical situation.

ď&#x201A;ˇ Postmenopause Chronic epilepsy may improve during postmenopause, especially in women with catamenial seizures. If epilepsy worsens, AED plasma levels should be monitored, both total and free levels when available. In postmenopausal women, the following metabolic changes influencing the levels of AED may occur: decrease of liver and renal functions, worsening of gastrointestinal absorption, the change in the muscle to fat mass ratio. All these factors can influence AED levels and cause either toxicity, or worse seizure control. Treatment see 2.3, 2.4 Postmenopausal women are at greater risk of a decrease in bone mass (osteopenia, osteoporosis, osteomalacia), and, as a consequence, the risk of fractures compared to men of the same age is almost three times higher. In women with epilepsy, the risk of bone metabolism impairment is even higher. Long-term treatment with first or second generation AEDs depresses bone metabolism and may lead to a decrease in bone mass. Predisposition to falls, but also muscle spasms during GTCS, represent independent risk factors for fractures. In disabled and hospitalised patients, the risk of osteoporosis and fractures is even higher (lack of sunlight, physical inactivity, malnutrition).

Early examination, diagnosis and treatment may prevent hip, vertebral body and forearm fractures, which represent a significant health and social problem, and, in some patients, may even be fatal. Preventive measures in all patients treated with AEDs (same as in general prevention of bone mass decrease) include: appropriate physical activity and balanced diet with sufficient intake of calcium. Daily calcium intake should be at least 1000 to 1500 mg. When we presume that the treatment with hepatic enzyme inducing drugs (see 2.3) will last more than six months, 1000 IU of vitamin D (Vigantol 2 drops) daily should be added in persons under 65 years, and 1000-2000 IU daily in persons older than 65 years and hospitalised (without sunlight exposition). It is mandatory to actively search for women with a higher risk of AED-induced osteopathy, and perform testing of the calcium-phosphate metabolism in these patients. Appropriate treatment should be discussed with an endocrinologist, osteologist. ď&#x201A;ˇ Hormone replacement therapy (HRT) Apart from epilepsy decompensation in women with epilepsy the transition period between child-bearing age and postmenopause may be accompanied by uncomfortable symptomes of vegetative syndrome. Therapeutic options for problems in perimenopause and postmenopause include, apart from the above-mentioned low-dose combined oral contraception, hormonal therapy, non-hormonal therapy and changes to lifestyle and diet. From the epileptological perspective, studies showing both worsening and alleviating of epilepsy during HRT administration in postmenopause were published. Available data show that combined HRT is less hazardous for seizure provocation than purely estrogenic treatment. Menopause - starts with the date of the last menstruation, which can be identified retrospectively after one year. In some women with poorly compensated epilepsy and high seizure frequency, the menopause occurs sooner than in the general population. Perimenopause - period preceding the menopause, physiologically, it can last several years. Characteristics: irregular menstruation, anovulatory cycles, relative hyperosetrogenism, increased level of FSH and decreased or absent production of progesterone. Climacteric syndrome with vegetative (hot flushes, night sweats, dry skin) and psychic components (mood changes with a predisposition to depression) is variably pronounced in each patient. Postmenopause - period after the menopause.

3.4 EPILEPSY AND EPILEPTIC SEIZURES IN ELDERLY Epilepsy is a relatively frequent condition in the elderly, especially after 65 years of age (approximately 30% of newly diagnosed epilepsies). Acute symptomatic (provoked) seizures are also common. Aetiology  Newly diagnosed epilepsies in the elderly are symptomatic or cryptogenic. Elucidation of treatable causes of epilepsy is important. Idiopathic epilepsies in the elderly usually do not occur de novo, rather, they persist or recur.  Most common causes of epilepsy in the elderly vascular disorders (30-50%) brain tumors (5-15%) neurodegenerative disease (7-14%) traumatic brain injury (3-5%)  Most common causes of acute symptomatic seizures acute brain disorders (stroke including TIA, traumatic brain injury - surgically treatable subdural hematoma is especially diagnostically important, etc.) metabolic and toxic causes (uremia, hypoglycaemia, ionic dysbalance in renal disorders, liver disorders, alcohol abuse, withdrawal syndromes, etc.) drugs with proconvulsive effect (more often in higher doses), especially older psychiatric agents - tricyclic antidepressants, classic neuroleptics; aminophyllin; some analgesics (tramadol, non-steroid anti-inflammatory drugs); baclofen; some anticholinergic drugs (benzatropine); cholinesterase inhibitors (donepezil); penicilin; izoniazid; vincristin, etc.

Clinical considerations  Range of seizure types is more narrow partial (esp. complex partial) seizures are the most frequent; auras are less common secondarily generalised tonic-clonic seizures without a clear transition from a partial seizure GTCS during sleep is more common non-convulsive status epilepticus (NCSE) can manifest as fluctuating confusion or delirium  Postictal phenomena are generally longer and more pronounced in the elderly Todd´s hemiparesis can be mistaken for TIA. postictal confusion can persist for several hours or days and can be misdiagnosed as psychiatric disorder (dementia, delirium, etc.) seizures during night-time can alter patient’s condition during the day.  History has a lower information yield Elderly patients are often not aware of their seizures (up to 30%, especially those living alone) Depreciation of seizures by the patient due to fear of hospitalisation, loss of self-sufficiency, stigmatisation and social isolation. Diagnosis  Ask for possible falls (even from the bed), injuries (including tongue biting), sphincter symptoms (bed wetting), repeated transitory symptoms - weakness of the extremities, confusion, memory loss, muscle pain in the morning, disarranged bed, etc.  Exclude comorbidity: cardiovascular disorders (syncope due to fluctuation in blood pressure, arrhythmia); cerebrovascular disorders (TIA); metabolic disorders (hypoglycaemia or hyperglycaemia, ionic? dysbalance); vertigo; transitory global amnesia; non-epileptic psychogenic seizures (dissociative, panic disorder) etc. It is important to consider combination of epilepsy and non-epileptic paroxysmal events (somatic or psychogenic).  Carotid and vertebral artery ultrasonography and Holter ECG monitoring is indicated on an individual basis apart from basic examinations (see 1.1).  EEG has lower yield in recording epileptiform activity in the elderly (approximately 6070% EEGs are negative). However, EEG is crucial in differential diagnosis of NCSE.

Treatment  General guidelines of treatment has the same validity in the elderly as in other patients see standard 2.3  Specific considerations apply to pharmacodynamics and pharmacokinetics in the elderly: drugs are effective already in low doses; patients are more sensitive to possible side effects, especially neurotoxicity; free drug levels can be higher; AED clearance may be decreased and plasmatic half-life of drugs prolonged.  Attention should be given to overall health condition of the patient (esp. renal and hepatic functions, psychiatric condition) and to potential drug interactions due to polytherapy. When evaluating non-compliance, a specific phenomenon of "repetitive medication" (repeated use of a drug, fluctuating side effects), apart from failing to take a dose, occurs in the elderly. It is recommended to use a dosing device.  The aim and way of treatment has to be slowly, clearly and repeatedly explained; the patient should be asked to repeat the information. At the beginning, more frequent followup visits are recommended to evaluate efficacy, tolerance and compliance.  Treatment should be initiated already after the first unprovoked epileptic seizure. Risk of repeated seizures and injury is relatively high. In the elderly, treatment of epilepsy is often life-long.  Monotherapy is preferred over polytherapy.  Simple dosing scheme, in one or two daily doses.  Very slow titration to lowest effective doses Treatment of choice is usually CBZ and VPA - target doses of CBZ approx. 400 mg/day, VPA approx. 500-600mg/day. New AEDs can be used as well: GBP, LTG, LEV, in refractory patients TPM and PHT.  Treatment of epilepsy in the elderly is usually successful. Similar to younger patients, in case of treatment failure, early re-evaluation of the diagnosis and treatment is advisable – see 1.2., 1.3.

4.1 CRITERIA FOR ASSESSMENT OF EPILEPSY CONTROL EpiStop conceived the following version of epilepsy control scale according to the Methodology guideline Nr.1/1989 of the Czech Ministry of Health "The evaluation of children, adolescents and adults with epilepsy based on the level of epilepsy control" (LP/2264â&#x20AC;&#x201C;06/04/1989/75/2). Patients with epilepsy are divided into four basic groups: I. Fully Controlled Epilepsy

Seizure free for two or more years with or without therapy

II. Controlled Epilepsy

Seizure free for one year with or without therapy

III. Partially Controlled Epilepsy

Usually seizure free for more than one month (usually less than 12 seizures a year); quality of life altered by epilepsy

IV. Uncontrolled Epilepsy

Seizures occur more frequently than once a month (usually more than 12 seizures a year); quality of life significantly altered by epilepsy

The diversity of epilepsies and epileptic syndromes prevents the identification of a single criterion that would precisely describe the level of epilepsy control together with the limitations caused by epilepsy in each individual patient. However, there is an unequivocal need to define different levels of epilepsy control for everyday practice. Seizure frequency is one possible measure. Only the treating neurologist (who follows the patient for at least six months) can classify the patient according to the levels of epilepsy control. Seizure frequency does not have to be the sole criterion. Other important factors include severity of the seizures, type of epileptic syndrome, EEG findings, neuropsychological status of the patient, etc. The main purpose of defining different levels of epilepsy control should be the possibility to evaluate the patient's ability to participate in the normal daily life. Other important issue is a need for simple classification of patients with epilepsy according to the severity of the seizure disorder and unified application of such a classification into the legislation. Isolated epileptic seizure without epileptiform activity in the EEG or without a proven structural lesion of the brain is not classified as epilepsy. Acute symptomatic seizure caused by factors no longer persisting (e.g. a trauma, stroke, exogenous or endogenous intoxication, brain oedema, etc.) is not classified as epilepsy.

4.2 ABILITY TO DRIVE MOTOR VEHICLES IN PATIENTS WITH EPILEPSY. SITUATION IN THE CZECH REPUBLIC. The assessment of the ability to drive motor vehicles in patients with epilepsy is regulated by the following legislation:  Regulation No. 277/2004 (Ministry of Health), which, in order to maintain the same conditions in all EU countries, is currently novelised by the incentive of european directive. Because it is suspected that, at the beginning of 2011, the novelised Regulation will already be valid, we refer to this new version below.  Act No. 361/2000 Coll. According to the Act No. 361/2000, the evaluating physician can be a) registering general practitioner, b) preventive care physician of a company, or c) any general practitioner in case of a patient who does not have a registering general practitioner or a company preventive care physician. To evaluate the ability of patients with epilepsy, a statement of a neurologist is needed. The statement is based on the patient's history, clinical examination, EEG results and evaluation of possible cognitive side effects of AEDs. For the purposes of the statement, the neurologist may ask for other necessary examinations (neuroimaging, psychology, psychiatry, video-EEG monitoring, etc.). In equivocal cases, a statement of an epileptologist may be asked. If a driver acquired a driving license according to current legislation, and a physician finds out or suspects that the driver's ability to drive is not in line with Regulation No 277/2004, he or she is required to inform the driver and the evaluating physician by means of a written notice (if he or she is known to him). Explanatory notes to Table on p49: - For the purpose of this Regulation, the term “Epilepsy” denotes two or more epileptic seizures, which occurred in the person under assessment within an interval of 5 years at most. - The length of seizure-free period is validated by the applicant’s signature. - Regular follow-up is a requisite for granting ability to drive. Follow-up evaluations are provided as part of regular follow-up visits scheduled by law; this does not apply in case of earlier expiration of expert statement validity.

Licence group 1 (A, B, B+E, AM and sub-groups A1 and B1) Diseases, handicaps and states excluding the ability to drive

Diseases, handicaps and states in which it is possible to grant ability to drive, based on expert statement

Epilepsy, seizure-free period shorter than 12 months.

Licence group 2 (vocational, „OSVČ“ – e.g. taxi, ambulance, firemen etc., C, C+E, D, D+E a T, C1, C1+E, D1 a D1+E) Diseases, handicaps and states listed in group 1, if not stated otherwise.

Isolated or first unprovoked epileptic seizure leading to a decision to start medication, for a period of 12 months.

Epilepsy with a seizure-free period less than 10 years after antiepileptic drug withdrawal.

Isolated or first unprovoked epileptic seizure not leading to a decision to start medication, for a period of 6 months. Epilepsy, seizure-free period longer than 12 months.

Isolated unprovoked epileptic seizure without medication, for a period of 5 years since this seizure. months. Diseases, handicaps and states listed in group 1, if not stated otherwise.

Epilepsy with seizures occurring exclusively in sleep; no seizures ever occurred in the waking state and the duration of epilepsy is no less than 12 months. Epilepsy with seizures not influencing ability to drive; no seizures ever occurred other than those in which lack of influence on driving ability was proven and the duration of epilepsy is no less than 12 months. Epileptic seizures occurring due to change of antiepileptic medication advised by the treating physician; if previously effective treatment is resumed, the applicant most not drive for a period of 3 months.

Isolated or first unprovoked epileptic seizure leading to a decision to start medication, for a period of 12 months since this seizure; for a period of 6 months if medication was not started

Isolated unprovoked epileptic seizure not leading to a decision to start medication, with no seizurerelated brain pathology found on neurological examination and no epileptiform activity found on EEG, after 5 years since this seizure. Epilepsy or epileptic seizure leading to a decision to start medication, 10 years after antiepileptic drug withdrawal; in case of favorable prognosis, e.g. benign epilepsy with rolandic spikes, 5 years after antiepileptic drug withdrawal. Seizure provoked by an identifiable causative factor, which does not generally occur while driving.

Diseases with increased risk of epileptic seizures, even if actual seizures did not occur; in structural brain lesions with increased risk of seizures the estimated risk must be less than 2% a year.

Seizure provoked by an identifiable causative factor.

4.3 ASSESSMENT OF THE ABILITY TO HOLD OR CARRY WEAPON AND AMMUNITION IN PATIENTS WITH EPILEPSY Weapon licences and their categories according to the Act No. 119/2002 Coll. ("Firearms and Ammunition"): A - for collectors' purposes B - for sporting purposes C - for hunting purposes D - occupational requirement E - for the protection of life, health or property Assessment of the health status is, according to the Firearms Act, one of the prerequisites to hold or carry a weapon or ammunition. The assessment is issued upon the applicant's written request. The assessment is based on medical examination carried out by the evaluating physician (the applicant's general practitioner) and, if needed, on a psychological or other necessary examinations ordered by the evaluating physician, if not stated otherwise. In the following cases, the evaluating physician must obtain an appropriate expert evaluation prior to issuing of the medical assessment: 1. The medical condition of the applicant warrants such approach. 2. The applicant is in care of another physician or psychologist. See Regulation 493/2002.