the Management of Epilepsy in Egypt

Section I: Definition and classification of epilepsy

To determine whether the patient might have had an epileptic seizure, the patient's and eyewitness's (where possible) detailed histories should be taken . (strong recommendation)  (high quality evidence) [1].

A  neurological examination  should be performed since recurrence can be predicted through an abnormal examination after a first seizure . (strong recommendation)  (high quality evidence) [1].

In children and young people, a specialist neurologist with good training and expertise in epilepsy should establish the diagnosis of epilepsy  (strong recommendation) (high quality evidence) [2].

We recommend referral to a more specialized Epilepsy clinic If the epilepsy diagnosis cannot be definitely confirmed. (strong recommendation) (high quality evidence) [2].

·   Electroencephalography for epilepsy diagnosis

 Normal EEG should not exclude the diagnosis of epilepsy . (strong recommendation)   (high quality evidence) [3] .

Epilepsy is a clinical diagnosis; however, EEG can be indicated  .(conditional recommendation)   (high quality evidence) [1] .

If  there is clinical doubt, EEG  should be used to classify epileptic seizures and epilepsy syndromes . (strong recommendation) (low quality evidence) [4] .

In case of equivocal epilepsy diagnosis or suspected non-epileptic events, refer to tertiary center (strong recommendation)   (low quality evidence) [5] .

When findings of a standard EEG have not supported epilepsy diagnosis or classification, a sleep EEG should be performed . (strong recommendation) (low quality evidence) [6] .

Increasing recording time to 60 minutes on conventional EEG is a more convenient and cost-effective method of enhancing the EEG diagnostic yield compared to multiple conventional EEGs (strong recommendation)  (high quality evidence) [7] .

In the case of patients with a likelihood of a non-convulsive epileptic seizure, as suggested by the clinical history, the finding of epileptiform abnormalities in EEG is specific to assess the risk of seizure recurrence . (strong recommendation)   (high quality evidence) [8] .

We strong recommend using 21 electrodes and should be used (10-20 system) periods when the eyes are closed and open should be included in the recordings (strong recommendation) (low quality evidence) [9] .

During EEG Photic stimulation, sleep deprivation, and hyperventilation can be used routinely (unless contraindicated ) (conditional recommendation)  (low quality evidence) [9] .

·   Electrocardiography for epilepsy diagnosis

In all patients with blackouts,  we recommend the 12-lead electrocardiography (ECG) in  older age groups with blackouts (strong recommendation) (high quality evidence) [10] .

Consider ECG as a routine channel during EEG recording and should be performed as a baseline before starting ASM (conditional recommendation) (low quality evidence) [9] .

·  Magnetic resonance imaging for epilepsy diagnosis

Magnetic resonance imaging (MRI) epilepsy protocol should follow the ILAE consensus on the"recommendations for using structural MRI in the care of PWE" (strong recommendation) (moderate quality evidence) [11] .

 We recommend MRI  for brain imaging in PWE (before the age of two years and in adults)

         (strong recommendation) (high quality evidence) [1] . Any patient with focal onset on 

         history, EEG, or examination (unless clear evidence of   benign focal epilepsy) is indicated

         for MRI (strong recommendation) (high quality evidence) [1] .

·  Neuropsychological assessment

We recommend Referral for neuropsychological for any PWE who is suffering from learning or occupational challenges and as a part of the pre-surgical evaluation (strong recommendation) (high quality evidence) [12] .

· Laboratory studies

In adults, appropriate blood tests should be considered (complete blood count (CBC), glucose, calcium, thyroid-stimulating hormone (TSH), plasma electrolytes) to specify possible causes and/or any significant comorbidity(strong recommendation) (high quality evidence) [1].

In adolescents and adults, urine toxicology screening should be done if addiction is suspected (strong recommendation) (high quality evidence) [1] .

We recommend lumbar puncture (LP) for a child <6 months, a patient who fails to return to baseline /meningeal signs, or suspects high intracranial pressure (imaging before LP is mandatory) (strong recommendation). (high quality evidence) [1] .

In children and young people, other investigations should be considered in special situations (including urine and blood biochemistry) to identify an underlying cause of epilepsy and exclude other diagnoses (strong recommendation). (high quality evidence) [1] .

Section II: Choice of Anti-Seizure Medication (ASM)

1.     General Considerations for choosing the ASM:

In case of failure of the initial ASM (due to continued seizures or adverse effects), initiation of an additional drug should take place and then escalate up to an adequate or maximum tolerated dose (this drug may be an alternative first‐line or second‐line drug). Afterward, slow tapering off the first drug should be done and caution is needed during the changeover period (strong recommendation) (high quality evidence) [13] .

In case the second drug is worthless, consider tapering of it or the first drug  (conditional recommendation) (low quality evidence) [14] .

We recommend combination therapy with the newer antiepipetic drugs in  patients who do not achieve seizure freedom on monotherapy . (strong recommendation) (high quality evidence) [13] .

We recommend Drug withdrawal  after a minimum of 2-5 years without a seizure based on risk of seizure recurrence. Gradual withdrawal over 2-6 months is recommended. If seizures recur, the effective well tolerated drug previously used should be restarted using the last effective dose . (strong recommendation) (moderate quality evidence) [15,16] .

2.  Choice of ASM According to Different Epileptic Syndromes in Different Age Groups (after excluding treatable metabolic causes):

2.A. Self-limited epilepsy with centrotemporal spikes:

First line: carbamazepine, oxcarbazepine, valproate.

            Adjuvant therapy: eslicarpazepine, lacozamide, lamotrigine, levetiracetam, zonisamide.

            (strong recommendation) (high quality evidence) [17-21].

2.B. Self-limited epilepsy with autonomic seizures

            First line: carbamazepine, sodium valproate.

            Adjuvant therapy: eslicarpazepine, lacozamide, lamotrigine, levetiracetam, zonisamide.

            (conditional recommendation) (low quality evidence) [22].

2.C. Childhood occipital visual epilepsy

             First line: carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, valproate.

             Adjuvant therapy: eslicarpazepine, lacozamide, lamotrigine, levetiracetam, zonisamide.

           (strong recommendation) (high quality evidence) [23] .

2.D. Photosensitive occipital lobe epilepsy

            First line: avoid factors that provoke seizures, valproate.

           Adjuvant therapy: benzodiazepines, levetiracetam.  (strong recommendation)

            (high quality evidence) [23] .

2.E. Childhood absence epilepsy

First line: ethosuximide, valproic acid.

Adjuvant therapy: a combination of ethosuximide and valproic acid or lamotrigine  (strong recommendation) (high quality evidence) [24] .

2.F. Epilepsy with myoclonic absence

First line: ethosuximide, valproic acid.

Adjuvant therapy: a combination of ethosuximide and valproic acid.

Other options: lamotrigine  (strong recommendation) (high quality evidence) [25].

2.G. Epilepsy with eyelid myoclonia

First line: ethosuximide, valproic acid.

Adjuvant therapy: clonazepam, ethosuximide, valproic acid.

(conditional recommendation) (low quality evidence) [26] .

2.H. Myoclonic atonic epilepsy

First line: valproate in GTCS, ethosuximide in absence seizures, steroids in the periods with multiple atonic seizures, and frequent, prolonged episodes of nonconvulsive status.

Adjuvant therapy: lamotrigine, ketogenic diet.

(conditional recommendation) (low quality evidence) [27].

2.I. Lennox-gas taut syndrome

First line: lamotrigine, topiramate, valproate.

Adjuvant therapy: lamotrigine, topiramate, valproate, rufinamide.

(strong recommendation) (high quality evidence) [28-30].

2.J. Developmental and/or epileptic encephalopathy with spike-wave activation during sleep

First line: standard ASMs, VPA, benzodiazepines, ethosuximide, ACTH or prednisone, high-dose benzodiazepines, intravenous immunoglobulins, epilepsy surgery.

Other options: acetazolamide, clobazam, lacozamide, lamotrigine, levetiracetam.

 (conditional recommendation) (low quality evidence) [31] .

2.K, Febrile infection-related epilepsy syndrome

First line: benzodiazepines and barbiturates for treatment of the acute event.

Adjuvant therapy: ketogenic diet.

Other options: IVIG, cannabidiol, anakinra, immunomodulation such as tocilizumab or canakinumab, epilepsy surgery.(strong recommendation) (high quality evidence) [32].

2.L. Hemiconvulsion, hemiplegia epilepsy syndrome

First line: Steroids, NMDA receptor blocker as memantine, amantadine.

Adjuvant therapy: carbamazepine, phenytoin in cases of persistent seizures.

Other options: lamotrigine, perampanel, rufinamide, topiramate, valproate, epilepsy surgery.(conditional recommendation) (low quality evidence) [33].

II.3. Choice of ASM According to Different Epileptic Syndromes in Adolescents:

3.A. Juvenile absence epilepsy (JAE)

First line: ethosuximide, lamotrigine, sodium valproate.

Adjuvant therapy: a combination of any of the first lines.(strong recommendation) (high quality evidence) [34].

3.B. Juvenile myoclonic epilepsy (JME)

First line: sodium valproate, topiramate.

Adjuvant therapy: acetazolamide, lamotrigine, levetiracetam .

(strong recommendation) (high quality evidence) [35,36].

3.C.Idiopathic generalized tonic–clonic seizures

First line: lamotrigine, sodium valproate.

Adjuvant therapy: consider carbamazepine, oxcarbazepine (exacerbating myoclonic and absence seizures). (strong recommendation) (high quality evidence)[37].

II.4. Choice of ASM According to Seizure Type:

4.A. Focal aware and impaired awareness seizures

First line: carbamazepine, eslicarpazepine acetate, lacozamide, lamotrigine, levetiracetam, oxcarbazepine, sodium valproate.

Adjuvant/ Add-on: lamotrigine, phenobarbital, phenytoin, topiramate, vigabatrin, zonisamide (strong recommendation) (high quality evidence) [18].

4.B. Focal to bilateral tonic-clonic seizure and generalized onset tonic-clonic seizure

First line; lamotrigine, sodium valproate.

Adjuvant/ Add-on: levetiracetam, topiramate  (strong recommendation) (high quality evidence).[38,39].

4.C. Generalized non-motor (Absence) seizures

First line: ethosuximide, sodium valproate

Adjuvant: clonazepam, lamotrigine, levetiracetam, topiramate, zonisamide  (strong recommendation) (high quality evidence) [24].

 

4.D. Myoclonic seizures

First line: levetiracetam, sodium valproate, topiramate.

Adjuvant: clonazepam, levetiracetam, piracetam  (strong recommendation) (high quality evidence) [35,36].

$.E. Tonic & atonic seizures

First line: sodium valproate

Adjuvant: lamotrigine, topiramate  (strong recommendation) (high quality evidence) [28-30]

Section III: Status Epilepticus (SE)

III.1. Diagnosis and Evaluation of SE:

The diagnostic evaluation begins in parallel with Emergent Initial Therapy.

For diagnosis, finger stick glucose should be checked, pulse oximeter and cardiac monitoring should be started as soon as possible. Blood and serum laboratory evaluation typically includes a CBC, basic metabolic panel, calcium and magnesium determinations (conditional recommendation) (low quality evidence) [40].

In the case of febrile patients or if there is a suspected subarachnoid haemorrhage or central nervous system infection, LP should be performed, preferably after obtaining the CT scan. Non-contrast CT of the brain is the first imaging study to be considered in the Emergency Department (ED) if MRI is not feasible (conditional recommendation) (low quality evidence).[40].

III.2. Emergent treatment of SE:

Emergent prehospital treatment with benzodiazepines is needed while assessing any abnormalities (hypoxia, hypoglycemia, or hypotension must be managed accordingly).

(strong recommendation) (high quality evidence) [41,42].

If benzodiazepines are not administered to the patient before ED arrival and are still seizing, IV benzodiazepines should be included in the initial dosing when IV access is immediately available.

 (strong recommendation) (high quality evidence) [43].

When IV access is not available, IM, per rectum (PR), buccal, or intranasal benzodiazepines should be administered together with IV placement (strong recommendation) (high quality evidence)[44].

Unless IV access is immediately available, initiate IM. In adults or children over 40 kg, IM midazolam 10 mg. In children 13–40 kg, the IM midazolam dose is 5 mg, and in children <13 kg, the IM midazolam dose is 0.2 mg/ kg  (strong recommendation) (high quality evidence)[44].

Among second-line ASMs, the first-line choice will be either phenytoin or levetiracetam in their standard loading doses. Also lacosamide can be used if the previous ASM failed or is unavailable. It would be better to start the second line simultaneously with the initial benzodiazepine rather than waiting for a response for benzodiazepine.(strong recommendation) (high quality evidence)[45].

If seizures have stopped after the initial ASM, and the patient had awakened, a maintenance dose of loading ASMs should be started if indicated and can be given either orally or intravenously

(strong recommendation) (high quality evidence) [45].

III.3. Treatment of Refractory SE:

Early (within one hour) drug-induced coma with continuous IV infusion of an anaesthetic drug is recommended for RSE with EEG target of burst suppression (strong recommendation) (high quality evidence) [46].

The recommended loading dose of IV midazolam infusion is 0.2 mg/kg at 2 mg/min. Then, repeated boluses every 5 min of 0.2–0.4 mg/kg should be administered until the seizures stop, up to a maximum loading dose of 2 mg/kg. Then, a continuous infusion at 0.05–2 mg/kg/h should be started (strong recommendation) (high quality evidence) [47].

Propofol IV infusions are an alternative at 1–2 mg/kg IV over 3–5 min as a loading dose and then repeated boluses every 3–5 min of the same amount until the seizures stop. The propofol infusion at a rate of 30–200 mcg/kg/min should then be maintained  (strong recommendation) (high quality evidence) [48].

Pentobarbital at 5 mg/kg as a loading dose, which is followed by a maintenance infusion of 1–3 mg/ kg may be used in children with refractory SE more frequently because of adverse effects with propofol  (strong recommendation) (high quality evidence) [49].

III.4. Treatment of Super-Refractory SE:

Thiopental should be initiated in the recommended dose with progressive weaning of the previous anesthetic over the following 24 hours  (conditional recommendation) (low quality evidence) [50].

If a burst-suppression EEG pattern without epileptic activity has been achieved during 24 hours under thiopental and SE recurs after thiopental weaning, adding phenobarbital should be considered in therapeutic dose for at least 24 hours, after which weaning should again be tried (conditional recommendation) (low quality evidence) [51].

If SRSE recurs after weaning of thiopental in association with phenobarbital or if it persists under thiopental anesthesia (epileptiform discharges), then ketamine in the recommended dose should be associated with thiopental  (conditional recommendation) (low quality evidence) [52].

In case of persistence or recurrence of SRSE despite the adoption of all previous recommendations; then the patient should be maintained in burst suppression under combined anesthesia with thiopental and ketamine, and all of the following therapeutics should be considered (according to availability and applicability):

·       A. magnesium sulfate – intravenous bolus (4 g) followed by a continuous infusion (2 - 6 g/h) aiming for plasma levels of 3.5 mmol/L (conditional recommendation) (low quality evidence) [53].

·       B. Immunotherapy  (conditional recommendation) (low quality evidence) [54].

·       C. Ketogenic diet  (conditional recommendation) (low quality evidence) [55].

·       D. Vagus nerve stimulation (conditional recommendation) (low quality evidence) [56].

·       F. Epilepsy surgery  (conditional recommendation) (low quality evidence) [57].

·        G. electroconvulsive therapy  (conditional recommendation) (low quality evidence)  [58].

Section IV: Drug-Resistant Epilepsy (DRE)

IV.1. Characteristics of a specialized/tertiary epilepsy facility

Patients with focal DRE should be referred for evaluation in a specialized/tertiary epilepsy care facility. The expertise of multidisciplinary teams should include psychology, psychiatry, neuroradiology, social work, counseling, clinical nurse specialists, occupational therapy, neurology, neuroanesthesia, neurophysiology, and neurosurgery  (conditional recommendation) (low quality evidence) [40].

Once referred to a specialized/tertiary epilepsy facility the patient should undergo

A. Video-EEG to characterize the epilepsy types and rule out PNES [23] (conditional recommendation) (low quality evidence).

B. Imaging (MRI- HARNESS protocol) studies must be scrutinized once epilepsy diagnosis is confirmed to ascertain the presence of an epileptogenic focus and facilitate a possible surgical work-up  (conditional recommendation) (low quality evidence) [59][11] .

C.    In presence of high suspicion of focal seizures; if no epileptogenic lesion is found on MRI, other ancillary tests include:

1.     Ictal single-photon emission computed tomography (SPECT) (conditional recommendation) (low quality evidence) [60].

2.     Positron emission tomography (PET). (strong recommendation) (high quality evidence) [61].

3.     Functional MRI for eloquent regions of the brain  (strong

 recommendation) (high quality evidence) [62].

 4.  Invasive EEG can be considered in case of unclear  localization, or in case a more precise definition of the relationship of the eloquent cortex to the epileptic cortex is  needed (strong recommendation) (high quality evidence) [63].

IV.2. Epilepsy surgery referrals in Egypt:

In case of the localized epileptogenic zone (i.e. for lesional focal epilepsy in concordance with semiology and EEG, or non-lesional focal epilepsy with the localized epileptogenic zone); For extra-temporal lobe epilepsy related to eloquent areas but not included in the epileptogenic zone; awake craniotomy, mapping techniques, and ECoG guided resection should be applied (conditional recommendation) (low quality evidence) [64].

In case of the localized epileptogenic zone (i.e. for lesional focal epilepsy in concordance with semiology and EEG, or non-lesional focal epilepsy with the localized epileptogenic zone); For extra-temporal lobe epilepsy with eloquent areas included in the epileptogenic zone; implementation of procedure such as MST, VNS, or RNS should be applied  (strong recommendation) (high quality evidence).[65]

In case of the localized epileptogenic zone (i.e. for lesional focal epilepsy in concordance with semiology and EEG, or non-lesional focal epilepsy with the localized epileptogenic zone); For unilateral temporal lobe epilepsy with lateral temporal involvement, ATL should be applied (strong recommendation) (high quality evidence) [66].

In case of the localized epileptogenic zone (i.e. for lesional focal epilepsy in concordance with semiology and EEG, or non-lesional focal epilepsy with the localized epileptogenic zone); For unilateral temporal lobe epilepsy with no lateral temporal involvement, either surgical procedures (ATL or SAH) or minimally invasive procedures (LITT or SRS) should be applied  (strong recommendation) (high quality evidence) [66].

In the case of the localized epileptogenic zone (i.e. for lesional focal epilepsy in concordance with semiology and EEG, or non-lesional focal epilepsy with the localized epileptogenic zone); For bilateral temporal lobe epilepsy, either VNS or RNS should be applied [67, 68] (conditional recommendation) (low quality evidence).

In the case of hemispheric generalized or multifocal epilepsy, either hemispherectomy (anatomical or functional) or VNS should be applied [69] (conditional recommendation) (low quality evidence).

In the case of generalized poorly localized epilepsy with mostly atonic attacks, palliative management with corpus callosotomy should be applied (conditional recommendation) (low quality evidence).[70]

In case of generalized poorly localized epilepsy with minor atonic attacks, palliative management with VNS.[71] or DBS of the anterior nucleus of the thalamus should be applied (strong recommendation) (high quality evidence) [72].

Implementation consideration

It is advised to provide training courses for the physicians at the centers that diagnose and treat epilepsy and in neurophysiology units too .

Clinical indicators for monitoring

For monitoring of the implementation of the guidelines, the files of the patients presenting with the status epilepticus event should include:

-  The date of onset of first seizure

-  ABCD evaluation

-  Treatment of status according to:

 First line : Midazolam iv injection or im.

Second line : Phenytoin or levetiracetam.

 Third line : midazolam infusion , propofol or phenobarbital in children.

Fourth line : thiopental , ketamine or combined thiopental and ketamine.