Department of Neurology , 
Medical College , Calicut

Address for Correspondence

Professor AS Girija
Head of the Department
Dept of Neurology , 
Medical College , Calicut
KERALA

ABSTRACT

The overall prevalence of epilepsy is 5.3 / 1000 Antiepileptic drugs(AED) render most of the epilepsy patients seizure free. Approximately 80% will be controlled with single drug and 10-15% require combination therapy. Despite optimal therapy, a sizeable number of patients exhibit chronic recurrent seizures. Detailed history with review of the past drug records, detailed Clinical examination and thorough workup is mandatory before planning the management of Epilepsy.Many patients with chronic epilepsy comply poorly with their prescribed medication, particularly if seizures are uncontrolled and if dosing is complicated, involving many doses per day, or causing adverse effects. It is necessary to establish a positive rapport with the patient, to explain the rationale, expectations and limitations of treatment, and the need to take medication regularly.

KEYWORDS: Epilepsy, Classification, Management, Pharmacotherapy

Introduction:

Considering that the overall prevalence of epilepsy is 5.3 / 1000 (1) 9,00,000 people suffer from medically intractable epilepsy.in India. Antiepileptic drugs(AED) render 70-80% of epilepsy patients seizure free. Approximately 80% will be controlled with single drug and 10-15% require combination therapy. Despite optimal therapy, 20-25% exhibit chronic recurrent seizures.
If 100 subjects have first seizure, approximately 60 subjects will develop recurrence. Out of this 48 persons go into remissions and approximately 12 will go on to develop medically refractory epilepsy(2).

Intractable Epilepsy - is defined as two or more seizures per month for a period of 2 years or more despite supervised trials (six month each twice with monotherapy and once with polytherapy. (3). Yet another definition is occurrence of one or more seizures per month on follow up of one year or more with an adequate trial of two primary AED (Carbamazepine(CBZ), Phenytoin(PHT),Valproate(VAP),) and one or more of the new antiepileptic drugs)(4,5). Another approach scores intractability by the number of drugs tried in mono and polytherapy regimens (6). 
These definitions and criteria are of specific use in research purposes. The Neurologist is more concerned with chronic uncontrolled epilepsy.

Approach to the Problem:

Detailed history with review of the past drug records is mandatory. Detailed clinical examination has to be done to exclude neurological deficit. Patients should be requested to keep seizure diary.Ideally patient may be admitted and investigated.
The important investigation in intractable epilepsy (IE) is:

1) Detailed metabolic work up
2) EEG - Telemetry which can be considered as a gold standard.
3) This should be followed by MRI using 1.5 Tesla which helps to exclude surgically amenable lesions (Table I)(7,8). By the end of these investigations, it will be possible to classify the epilepsy into syndromic diagnosis.

Surgically Treatable Causes:
Mesial Temporal lobe epilepsy
Benign neoplasms
Ganglioglioma
Dysembryoplastic neuroepithelial tumours
Low grade astrocytoma
Oligodendroglioma

Developmental lesions
Glioneuronal Hamartoma
Focal cortical dysplasia
Heterotopias
Hemimegalencephaly

Other lesions
Vascular malformations
Atrophic scars
Rasmussen's encephalitis

Having excluded the surgically amenable conditions, the cases of IE have to be dealt with as follows. Is there associated Non epileptic seizure (NES) ?
Identification of NES is best done by witnessing attacks and by EEG telemetry. NES constitutes 25-50% of cases of IE referred to a Neurologist or epilepsy center(9).
2) Avoidance of precipitating factors is very important. Topmost in this category is 

I. Non compliance 
Many patients with chronic epilepsy comply poorly with their prescribed medication, particularly if seizures are uncontrolled and if dosing is complicated, involving many doses per day, or causing adverse effects. It is necessary to establish a positive rapport with the patient, to explain the rationale, expectations and limitations of treatment, and the need to take medication regularly.

It should be made clear to the patient that it is understood that it is hard to take medication that appears ineffective and causes problems, and that the aim is to improve control of the epilepsy with a simplified regimen and minimum adverse effects. Patients should be encouraged to report any dissatisfaction with their therapy.

Prescribing more than two doses of medication per day strains compliance, particularly for the middle-of-the-day doses, and polytherapy is less likely to be taken accurately. Poor memory is often a contributory factor to poor compliance. A written summary of dosing instructions, a preset alarm and a drug wallet in which the doses for an entire week may be placed in individual compartments, so that it is clear to the patient and their carers whether a particular dose has been taken or not, are frequently useful.
In addition to asking the patient and his/ her carers, compliance can be checked by tablet-counting, if dispensing is from one source. It is helpful to check serum concentrations of AEDs unexpectedly, to determine whether there are inappropriately low serum concentrations for the prescribed doses. A microchip device built into the tops of drug containers, which registers when medication has been taken, has been developed and used in clinical trials and can also be useful in assessing compliance(10).

2. Sleep deprivation, alcohol intake, precipitating factors like sunlight in photosensitive epilepsy have to be avoided.

Review drug history

Time spent ascertaining what AEDs have been used in the past, in what doses, and the evidence for beneficial and adverse affects often pays dividends. As a result of such a review, it should be possible to identify a list of AEDs that have not been used to their full potential, which may be appropriate to try. This process requires a history from patient and relatives and careful inspection of previous medical records. It may, for example, be a patient's understanding that he is allergic to carbamazepine, whereas review of records may indicate that the starting dose was 200mg thrice daily (much too high) and that the drug was discontinued after 2 days because of nausea.


Form treatment strategy

A treatment plan should be made, based on the types of seizure and epilepsy and by review of all the AEDs that have and have not been used to their maximum tolerated doses, those that may have shown some benefit, those that have not been used at all, and those that it would be appropriate to try. It is then possible to select the AED that is most likely to be efficacious and to have the fewest side-effects and to adjust the dose of this drug to the optimum. This drug will usually be chosen on the grounds that it has previously not been used to its full potential and / or appears to have had a definite beneficial effect.

Taper unhelpful AEDs

AEDs that have not aided seizure control and have produced adverse effects should then be gradually tapered and discontinued. Seizures may worsen at this time and the strategy may need revision. Frequently, however, reduction of the number of AEDs results in fewer adverse effects, improved seizure control and better compliance.(11).
Subsequent strategy

If seizures remain uncontrolled, other first-line and second-line drugs that have been identified as being possibly helpful, and surgical treatment, should be considered, as for newly diagnosed patients. It is important, however, to recognize the limits of the efficacy of currently available AEDs and the need to avoid intoxication. 

AEDS in IE:
1) Is the drug appropriate for the type of epilepsy
2) Has the drug been used in adequate dose
3) Is there unfavourable interactions.

AED choice based on seizure type (12).

Seizure Type First Choice Other options
Infantile spasm Corticotrophin TopiramateZonisamideVigabatrin(VGB)
Absence EthiosuximideSodium valproate LamotrigineZonisamide(ZNS)
Atonic Valproate TopiramateLamotriginePhenytoin(PHT)Phenobarb(PHB), ZNSFelbamate
Tonic Valproate TopiramateLamotriginePHT, PHBZNS, Felbamate
Myoclonic Valproate TopiramateLamotriginePHB, ZNSFelbamateLevitiractem
Tonic-Clonic Valproate TopiramateLamotriginePHT, PHBZNS, Felbamate
Partial generalized Carbamazepine(CBZ) Oxcarbazepine(OXC)LamotrigineTopiranatePHT, LevitiracetumZNS, Tiagabin(TGB)Gabapentin(GBP)VAP, PHBFelbamate



Idiopathic Generalised Epilepsy and the Choice of AED In general, Idiopathic generalized epilepsy (IGE) respond to treatment with 80-90% becoming fully controlled(13). Some AEDS are not optional choice for IGE. These non broad spectrum AED include PHT, CBZ, OXC, GBP, TGB and Vigabatrin (14). Poor choice of AED in IGE can be a cause of intractability. The assumption that IGE is rare beyond childhood is not true.
35% of IGE occurs after 18 years of age
28% occurs after 20 years(15). Thus identification of IGE as a group is important.

Useful combination of AEDS in IE:
Combination of VAP and Ethosuximide is useful in suppressing atypical absence seizures refractory to either drug alone. Combination of CBZ & VAP leads to enhanced therapeutic index unlike combination of CBZ & PHB.

Vigabatrin (Increase inhibition by ­GABA) and Lamotrigine (¯ excitation by ¯ Glutamate )have complimentary action and is of use.
Valproate & Lamotrigine combination is of benefit
Myoclonic seizures may respond to combination of VAP and Clonazepam.

Role of Polypharmacy:
A number of placebo controlled trials have shown that addition of a second or even a third anticonvulsant does produce a statistically significant decrease in frequency of seizures. This usually comes to <10%. If by addition of multiple drugs, there is no significant decrease in seizure frequency, but adds only to toxicity, and expenditure, monotherapy need be introduced or a maximum of two drugs may be given in conditions like Tuberous sclerosis, mental retardation etc. as a palliative measure. Very high dose of phenytoin & CBZ can increase seizure frequency due to proconvulsant action (16). PHB, PHT & CBZ are enzyme inducer and can reduce levels of VAP, LTG, TP, TG (17).


Alternate modes of treatment of IE:
Diet
Ketogenic Diet:
This is a high fat, low protein, low carbohydrate diet developed in 1921.It mimics the effect of starvation. It is used as an add in treatment in children with IE. There has been renewed interest for this since last decade. The cost for initiation is high. It has been found to be effective in all types of IE in children(18). Generalised, partial & infantile spasms respond (19). it may be continued for 1-2 years. The side effects include dehydration, GI symptoms, hypoglycemia, carnitine and vitamin deficiency, osteoporosis, protein deficiency (20). Corn oil which is cheaper and now available in India can be used as a substitute for medium chain fatty acids in ketogenic diet.

Alkins diet as therapy for IE:
This restricts carbohydrates but does not restrictive consumption of calories or proteins. This was originally used for weight reduction. There is a preliminary report of its effectiveness in reducing seizures in IE (21).
Steroids in IE:
Steroids have been found to be of use in West syndrome, Lennox Gestant syndrome and other IE of childhood. The dosage is 1mg/Kg x 6 wk and alt. days for next 6 weeks (22).
ACTH was initially introduced in the treatment of West syndrome. It stimulates production of deoxycorticosteroids which is then converted to Tetrahydroxydeoxy corticosterone (THDOC), a neurosteroid that lacks classical hormonal properties and acts as a modulator of GABA receptors (23,24).

Ganaxolone is a synthetic neurosteroid analog which is of use in infantile spasm. It is a novel positive allosteric modulator of the Gaba A receptor complex(25). It is of benefit in partial and Generalized epilepsies. Dose : 36mg/Kg/day. It may be given for 4 wks and then maintenance at reduced dose for total of 8 weeks and tapered.

Immunoglobulins in IE:
Unknown efficacy and unknown mechanism of action.
Rasmussen encephalitis(RE) is an example of an autoimmune disorder of CNS in which antibodies to Glutamate receptor, GluR are present in serum (26).
A recent report recommends Immunoglobulins in1) late onset RE with slower and milder course; 2) Dominant hemisphere involvement; 3) Suspected RE in whom neurologic deterioration has not occurred; 4) Bilateral RE
Therapeutic plasma exchange and protein A immunoglobulin G (IgG) immunoadsorption (PAI) have been tried in RE (27).
Immunoglobulins have been used in West syndrome, and Lennaux Gestaut syndrome(LGS) with good results. Randomized multicentral double blind trial were started in 1993 including patients with WS and LGS. These showed a trend in favour of IV Immunoglobulin but lacked statistical significance (28). More controlled multicentric trials are required.Dosage : 0.4mg/kg/day x 5 days once in 2 wks x 3 months

Pyridoxin : Use of Pyridoxin in pyridoxin dependency convulsions which can present as recurrent status and IE is well known (29,30).
Outcome in Epilepsy is determined by Aetiology

4 prognostic groups in the epileptic syndromes have been identified (31).

Group-I:
Excellent prognosis
Benign focal epilepticus. Acute symptomatic seizures (30%).

Group-II: (30-40%) Good prognosis
Childhood absences
GTCS in awakening
Localisation related & acute symptomatic seizure
AEDS can be tapered off.

Group-III: 10-20%. Uncertain prognosis and tendency to recur without AEDS.
Most of localization related epilepsies, JME.

Group-IV: 20%-30%. Poor prognostic group. AEDS have palliative effect in this group with tendency for seizures to recur.
a) In children and adolescence - this comprise:
1) The progressive myoclonic epilepsies and progressive myoclonic encephalopathy
2) Age dependent epileptic encephalopathies (O Wahara's, West's & Lennox Gestant syndromes)
3) Rasmussen's syndrome & Acute infantile Hemiplegia
4) Tuberous sclerosis
5) Cerebral malformations and disorders of neuronal migration
6) Cerebral palsy
7) Other localization related epilepsies (both symptomatic and cryptogenic)

b) Refractory epilepsies of adult onset are mostly localization related, both remote symptomatic and cryptogenic. These include (32).
1) Hippocampal sclerosis or mesial temporal lobe sclerosis - commonest in this group
2) Cerebral cortical dysgenesis (abnormalities of gyration, heterotopia, tuberous sclerosis, focal cortical dysplasia)
3) Vascular malformations including cavernous & AVMS
4) Indolent tumours - gliomas, meningiomas, dysembryoplastic neuroepithelial tumours (DNET)
5) Granulomas - Tubercular & Cysticercal
6) Scars - areas of acquired cerebral damage, eg: vascular, traumatic, post meningitis.

Multivariate analysis reveal certain independent predictors of intractability (33,34).

These include:
1) Poor short term outcome of therapy. Failure of initial AED. Even in this 40% of patients go on to achieve remission with adequate therapy with an alterate AED.
2) Occurrence of status epilepticus either at the onset or subsequently during the course of the illness.
3) High initial seizure frequency
4) Symptomatic aetiology
5) Onset at age <1 yr.


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