El Burnout y la relación con el apoyo social

Investigations are carried out to support the diagnosis of epilepsy and to identify aetiology. The investigative modalities in epilepsy include electroencephalography and neuroimaging.

2.8.1 Electroencephalography

Electroencephalography (EEG) is a recording of the electrical activity of the cerebral cortex, through electrodes placed on the scalp. EEG can be used to support the diagnosis in

patients with a clinical history suggestive of an epileptic seizure or epilepsy.^43,69

The distribution of epileptiform discharge helps in classification of epileptic seizures and syndrome, prognosticate and to determine appropriate medication. For instance the presence of 3per second spike and wave discharges which can be precipitated by

hyperventilation on EEG is diagnostic of absence seizure in a child with repeated episodes

of loss of awareness. Furthermore studies have shown that different epileptic seizures or syndromes have different pharmacoresponse. ^43,69

It is useful in evaluation of unexplained coma to exclude a non-convulsive seizure. In addition, it may help in anatomical localization of an underlying cerebral pathology, though

neuroimaging

techniques are superior in localization and diagnosis of underlying pathology. ⁴³

EEG has a sensitivity of about 25–56% in detecting epileptiform activities in patients with epilepsy. Sensitivity increases with repeated readings, and only about 10% of patients with epilepsy have normal EEG after repeated recordings. Specificity however is about 78–98%

and only about 0.5% of adults and 2-4% of children without epilepsy have EEGs showing epileptiform discharges.⁷⁰ Epileptiform discharges include abnormal spikes, polyspike discharges, and spikewave complexes.⁴³ EEG readings in patients with epilepsy may also show non-specific abnormalities like focal slow wavesa.^43,70

EEGs in epileptic patients may be obtained in the ictal or interictal state. In patients with unclassifiable seizures, sleep EEGs and video EEG recording of attacks are used to classify seizures and exclude pseudo seizures. Recordings are usually extracranial however intracranial readings may be indicated in patients planned for epilepsy surgery to localize epileptic foci.⁴³

Aina et al reported abnormal interictal EEG in 52% of subjects with epilepsy with about 48% having normal reading.⁷¹ Ahmed and Obembe also reported normal EEGs in about 25% of the patients in a tertiary centre in Northern Nigeria. The abnormal records in this study were associated with generalized seizure and participants under 20 years of age.⁷² Another study in Tanzania reported that 86% of the study participants had abnormal EEG.

The study also included paediatric population.⁷³ Thus the possibility of finding an epileptiform discharge in patients with epilepsy depends on demographic and clinical characteristics of the patient, semiology of seizures, the use of antiepileptic drugs and the duration between the last seizure and time of recording. ⁴³

2.8.2 Imaging modalities in epilepsy.

Imaging modalities include magnetic resonance imaging (MRI), computed tomographic (CT) scan, positron emission tomography (PET), and cerebral angiography.

MRI scanning is the modality of choice in the investigation of patients with epilepsy.⁶⁹ It is superior to CT scan in detecting and localizing small lesions that are less than 0.5cm. On the other hand CT scan may be employed in situations when urgent neuroimaging is required and when there are contraindications to MRI. Contraindications to MRI include use of pacemakers and cochlear implants. CT scan of the brain is also superior in

diagnosing focal calcific lesions hence it is useful in detection of intracranial calcifications in the early stages of Sturge Webers syndrome.

43, 69

The recent National Institute of Clinical Excellence (NICE) guideline recommended the use of MRI in age of seizure onset of less than 2 years, in the presence of focal seizures and when patients fail to respond to first line drugs. ⁶⁹ The American Academy of Neurology

(AAN) recommended that brain imaging with computed tomographic (CT) scan or magnetic resonance imaging (MRI) should be considered as part of the routine neurodiagnostic evaluation of adults presenting with an apparent unprovoked first seizure. It is done to exclude symptomatic causes of epilepsy..⁶⁹ Other indications for neuroimaging include loss of seizure control after a period of remission, change in seizure pattern and in the presence of focal neurological deficit or persistent alteration in higher mental state.⁴³ Neuroimaging may not be justified in patients with idiopathic/genetic generalized

epilepsy. 69

MRI is also important in localizing lesions in patients being worked up for epilepsy surgery.

It is pertinent to know that the presence of a lesion on imaging may not be the focus of ictal discharges, thus functional studies are very useful in localizing epileptic foci.

Functional imaging studies include functional MRI.⁴³

Other investigative imaging modalities include magnetic resonance spectroscopy (MRS), singlephoton emission computed tomography (SPECT) and positron emission tomography

(PET) which maps cerebral glucose metabolism. They help delineate epileptic foci by differential concentration of biological molecules, uptake of radiolabelled ligands and differences in regional blood flow as a result of pathological changes.⁴³ These imaging modalities are particularly useful in situations where epileptic surgeries are planned. They are used both in the preoperative periods and post operatively to determine the outcome of surgery.

A study on the imaging findings in patients with seizures was significantly abnormal in 10%

of the patients studied.⁷⁴ Specific abnormal findings on neuroimaging in people with

epilepsy include tumour (primary and secondary), hippocampal sclerosis and vascular malformations (carvernomas and arteriovenous malformations). Malformations of cortical development like focal cortical dysplasia polymicrogyria and periventricular heterotopia may also be seen. ⁴³ Other pathological lesions that may be seen include areas of focal or diffuse cortical damage that occur following trauma, or infarctions. Findings on

neuroimaging following CNS infections may manifest with areas of focal or diffuse damage or manifest as an intracranial space occupying lesion like neurocysticercosis and

tuberculoma.⁴³

2.9 TREATMENT

In previous guidelines treatment is indicated when a diagnosis of epilepsy is made, however the recent operational definition of epilepsy has made some modifications. The diagnosis of epilepsy does not justify the use of antiepileptic medications. Patients with infrequent seizures at very long intervals and mild attacks treatment may not be

commenced on treatment.²

Patients should be evaluated for a previous history of myoclonic, absence and focal seizures after presenting with the first episode of generalized tonic clonic seizure to

determine the need to commence antiepileptic medication. Antiepileptic medications may also be considered following a first seizure if the EEG shows epileptiform discharges, in the presence of a neurological deficit, abnormal imaging findings and if the patient considers the risk of recurrence unacceptable.

Antiepileptic drugs are also used in acute symptomatic seizures when seizures occur during a

systemic illness and in the setting of a recent brain pathology. ^69,75

The goal of treatment is restoration of patient to normal life through complete control of seizure with no side effect. Patients should be educated on the indication for drug therapy, the need for compliance, possible side effects of medications and prognosis. Risk

assessment should be carried out on all patients and such patients should be counselled on the issues related to safety like driving,

living alone, swimming and occupation. ^69,75

Drug treatment is the first option in treatment of epilepsy. About 70% of patients respond to drug therapy while the remaining is intractable. ⁵ Medically intractable seizure is considered when there is failure of two monotherapy drugs and a two-drug trial at the therapeutic level. ⁷⁶ This may necessitate surgical intervention.

Other indications for surgery include the presence of a single epileptogenic focus amenable to resection, focal epileptogenic structural lesion and surgically remediable syndrome (e.g.

unilateral mesial temporal sclerosis, focal cortical dysplasia or hypothalamic hamartoma).⁷⁶ Surgical techniques include temporal lobectomy, selective amygdalohippocampectomy, division of the corpus callosum and vagus nerve stimulation.⁷⁶

Vagus nerve stimulation is used as adjunctive treatment in people greater than 12 years old for the treatment of both focal and generalized epilepsies which are resistant to drug treatment but not suitable for resective surgeries. Outcome studies have shown 50%

reduction in seizure frequency in 55% of the study population. Furthermore improvement in depressive symptoms has been

reported. 69, 77

Electro-stimulation which involves deep brain stimulation (DBS) and responsive nerve stimulation (RNS) at seizure foci are other therapeutic options in patients with drug resistant epilepsy who are not candidates for surgical resection. This modality involve implanting electrodes in intracranial sites like the anterior thalamic nucleus, sub-thalamic nucleus, centro-median nucleus of the thalamus and hippocampus. Deep brain stimulation of the anterior thalamic nucleus and RNS have been found to be effective in reducing seizure frequency in patients on short term and long term basis.⁷⁸ Further studies are ongoing to determine the effectiveness of DBS at other sites.⁷⁹ Other ancillary treatment methods include use of ketogenic diet in children and psychotherapy. The use of ketogenic diet is not recommended in adults with epilepsy. ⁶⁹

2.9.1 Antiepileptic drugs.

Antiepileptic drugs (AEDs) are indicated for the control of seizures either in acute

symptomatic seizures or in epilepsy. Their mechanism of actions permits their use in other conditions like migraine and pain syndromes. They act at ion channels and receptors on the neuron favouring inhibitory neurotransmission over neuroexcitation, thus preventing the generation of epileptic seizures but they have no effect on the process of

epileptogenesis.⁷⁵ These channels include sodium, calcium and potassium channels, while the receptors they act on are gamma-aminobutyric acid (GABA) and glutamate receptors.

Drugs acting on sodium channels suppress rapid repetitive firing of neurons by prolonging closure of sodium channels (e.g. phenytoin, carbamazepine, valproate, lamotrigine) and

blockage of voltage sensitive calcium channels (e.g.ethosuximide, dimethadione,

valproate).⁸⁰ Recently retigabine a voltage-sensitive potassium channel opener has been added to the AEDs. ⁸¹ They also enhance GABA-mediated inhibitory neurotransmission by acting directly as agonists on the GABA-receptor-chloride channel complex (e.g.,

benzodiazepines, barbiturates), inhibiting the metabolism of GABA (e.g., vigabatrin, valproate) and increasing the release of GABA (e.g., gabapentin). Another mechanism is attenuation of excitatory transmission (e.g., phenobarbital, topiramate) by blockage of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Felbamate, remacemide, an investigational drug) and N-Methyl-D-aspartate (NMDA)

receptors. ⁸⁰

Antiepileptic drugs are generally subdivided into the first-generation antiepileptic drugs (phenytoin, carbamazepine, phenobarbital, primidone, valproate, ethosuximide, and the benzodiazepines), and the second-generation drugs (felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin). ⁸² The newer antiepileptic drugs have similar efficacy as the older medication but have superior drug –drug interaction, adverse effect profile and teratogenicity potentials. Some are used as first line in the management of specific epilepsies but majority are used as adjuncts to older generation

drugs. ⁸²

The seizure type, epilepsy syndrome and co-morbidities are strong consideration before choosing an AED. Other factors that must be considered include cost, availability, other medications taken concomitantly, the individual’s lifestyle and the preferences of the

individual and their family.⁶⁹ Patients must be educated on the risk and benefits of therapy including possible adverse effects from medications and the need for drug compliance. Life threatening reactions like rashes must be

reported as an emergency.⁶⁹

Treatment is initiated with a single drug at the lowest dose and titrated upwards until seizure control is achieved. However if seizures are uncontrolled or intolerable adverse effect develop, medications are changed to another monotherapy agent. After two failed monotherapy a second agent may be added as an adjunct to the first medication.⁶⁹ Evidence supports the use of one of carbamazepine, phenytoin, levetiracetam and zonisamide as first line drug in the management of partial onset seizures in adults while the use of carbamazepine, lamotrigine, oxcarbazepine, valproic acid and topiramate is supported in generalized onset tonic- clonic seizures in adults. Older drugs like phenytoin and phenobarbitone have also been found to be equally effective in generalized onset tonic clonic seizures in adults.⁸³

Antiepileptic drug (AED) may be discontinued after 2-3 years of seizure freedom. Drugs are withdrawn slowly over 2-3 months while watching out for recurrence of symptoms.⁶⁹ Studies show that the risk of seizure recurrence after drug withdrawal is related to factors such as a longer duration of epilepsy, an abnormal neurologic examination, an abnormal EEG, certain epilepsy syndromes and frequency of seizures prior to control.⁸⁴

Adverse effects occur commonly in patients taking antiepileptic medications and it has implications for drug compliance which ultimately affects seizure control and quality of life of the patient.⁸⁵ WHO defined adverse effects as “a response to a drug that is noxious and

unintended and it occurs at doses normally used in man for prophylaxis, diagnosis and therapy of diseases or for modification of physiological function.” ⁸⁶

Adverse effect can be classified into five groups based on the pathophysiologic mechanism, manifestations, time to onset and individual and population differences. ⁸⁵

Type A adverse effects occur as a result of the mechanism of action of the drug. It occurs in the setting of introduction of a new drug, high doses, rapid and recent drug dose escalation and patients usually develop tolerance to these effects.⁸⁵ The clinical manifestation

commonly involve the central nervous system and the gastrointestinal system.

Manifestations of acute drug reactions include somnolence, dizziness, ataxia, blurring of vision, fatigue, nausea, vomiting, diarrhoea, dizziness, anorexia, and abdominal pain.

These acute reactions can be reduced by introducing drugs at small doses, increasing drug doses at a slow rate (usually over weeks) and usually the lowest effective maintenance dose.⁸⁵

Type B reactions are idiosyncratic reactions which are based on immunological and genetic mechanisms. They are rare host specific and occurs during the first few weeks of

treatment. Drug molecules interact with endogenous proteins and are presented as haptens to T-lymphocyte. This elicits an immune response which may be life threatening.

Since they are not dose related,

treatment is by withdrawal of the offending drug. ^{85, 87}

Idiosyncratic effects include, rashes, Steven-Johnson’s Syndrome, lupus like reactions, pseudolymphoma, hepatitis, blood dyscrasias, aplastic anaemia and leukopenia.⁸⁷

HLA-B*1052 haplotype is linked to the development of Steven Johnsons syndrome in people of Asian descent, this gene was found in all the patient who developed Steven Johnsons’

syndrome after the use of carbamazepine in Hong Kong and Taiwan.⁸⁸

Type C effects are chronic adverse effects occurring after prolonged duration of treatment and are more diverse compared to acute effects, involving multiple organs. They occur as a result of cumulative toxicity and individual variations in drug response causing

neuropsychiatric, gastrointestinal, hematologic, metabolic, endocrine, dermatologic, and systemic consequences.^85,

86

Teratogenic and carcinogenic potentials are the type D adverse effects. This is very important because epilepsy affects women of childbearing age and the teratogenic potentials of these

medications should be considered when prescribing drugs for women in this age group.⁸⁵ Teratogenicity has been reported following the use of AEDs. The use of first generation antiepileptic drug and polytherapy doubles the risk of congenital abnormalities in babies born to mothers with seizure disorder. There is a paucity of data regarding newer

generations of AEDs. This risk is highest with valproate and the old phenobarbital, while the risk is relatively lower with carbamazepine, lamotrigine and phenytoin. The use of folic acid supplement has not been found to reduce the risk of teratogenicity in patients on valproate.^85,89

These defects are intrauterine growth retardation, delay in cognition, dysmorphism and major congenital abnormality. Fetal anticonvulsant syndrome include a combination of dysmorphic features, cognitive, behavioural and major abnormality in children exposed to carbamazepine, phenytoin and valproate. Heart defects are seen in patients exposed to barbiturates, phenytoin and carbamazepine. The use of carbamazepine and valproate is associated with neural tube defect. Valproate is also associated with skeletal abnormality and hypospadias.⁹⁰

The AAN recommends the avoidance of valproate and antiepileptic drug polytherapy during the first trimester of pregnancy to decrease the risk of major congenital

malformations. ⁹¹ It also recommended that the avoidance of valproic acid, phenytoin, phenobarbital and antiepileptic polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes.⁹¹ Finally type E effects are due to drug-drug interactions. Antiepileptic drugs have low therapeutic index, furthermore they are enzyme inducers and inhibitor and because they are used for a prolonged period of time they are likely to be co-prescribed with other medications. All these factors contribute to the risk of adverse effects in patients on these medications. An important reaction in antiepileptic drug is the prescription of lamotrigine with valproic acid. The combination of the two leads to toxic levels of lamotrigine. ⁸⁵

Studies in Nigeria have reported impairment in cognitive function in patients on antiepileptic

drugs.92,93.

2.9.2 Management issues for women with epilepsy

The choice of medication is an important consideration in managing women with epilepsy because of teratogenic potentials of these medications, contraception, fertility and

cosmetic issues. Reports have shown higher abortion rates in women taking antiepileptic medications compared to the

general population.⁸⁵

Furthermore, because of the enzyme inducing properties of antiepileptic drugs, the choice of contraceptives should be a medication that will have a favourable drug-drug reaction.

Carbamazepine, phenytoin, phenobarbital and primidone induces the metabolism of hormonal

contraceptives which could lead to unwanted pregnancy.^85,90

Chronic adverse effects like weight gain has been reported with use of medications like valproic acid, gabapentin, pregabalin, and less commonly carbamazepine, while topiramate and zonisamide may lead to weight loss. Prolonged use of phenytoin is associated with gingival

herperplasia. These effects may be undesirable for women because of cosmetic appearance.^85,90

2.9. 3 Carbamazepine

Carbamazepine (5H-dibenzazepine-5-carboxamide) is an iminostilbene derivative with a tricyclic structure. It is an antiepileptic drug widely used for treatment of partial seizures, trigeminal neuralgia, and bipolar affective disorder. ⁹⁴

It is contraindicated in patients with absence and myoclonic seizures, which may be exacerbated with carbamazepine use ⁸² Carbamazepine selectively inhibits high frequency epileptic foci while

normal neuronal activity remains undisturbed. ⁹⁴

Carbamazepine is absorbed erratically after oral administration because of its lipophilic nature. Treatment with carbamazepine should be initiated at low dose to allow tolerance of its central nervous system side effects to develop. The initial starting dose is 400mg/day increasing at 200mg weekly till desired response is obtained. Maximum dose is 1200mg in adults. ⁹⁵ It has a large volume of distribution; peak plasma levels occur 4-8 hours post ingestion but may take up to 24 hours to peak. Its half-life is 30hours when given as a single dose. With repeated use half-life is reduced to about 15 hours because it is a strong enzyme inducing agents. ⁹⁴ Steady state is achieved within 2-4 days of initiation of

treatment, but may be up to 5 weeks due to auto induction. ⁹⁵

The therapeutic range is 4-12mg/l though marked variations have been reported.⁹⁵ The primary site of metabolism is the liver; its metabolite carbamazepine-10, 11-epoxide, also is active, which may increase duration of the symptoms of toxicity.⁹⁵

The tablet is formulated in the form of immediate and controlled release form. The use of longacting formulations of carbamazepine enables the use of twice-per-day dosing, rather than the 3- to 4-times-per-day dosing that would otherwise be necessary because of the

short half-life of carbamazepine. It may minimize these side effects because a steady serum concentration is maintained over the course of the day.⁹⁶

The common side effect developed are dizziness, sleepiness, ataxia, abdominal discomfort, blurred vision, double vision, nystagmus and headaches. These effects are known to occur acutely in the course of therapy. ⁹⁵ With prolonged use individuals may develop

hyponatremia and mild neutropenia.⁹⁵ Other less common adverse effects include nausea, vomiting, diarrhoea, constipation and behavioural changes.⁹⁵

Rarely, idiosyncratic reactions like Steven Johnson’s syndrome and severe leukopenia (with leukocyte counts < 2, 5000/mm) develop which may necessitate discontinuation of

therapy. Hepatic failure, osteoporosis and aplastic anaemia are also rare idiopathic complications of carbamazepine. ⁹⁵

Carbamazepine induces hepatic enzyme metabolism. Clearance of other drugs like theophylline, oral contraceptives, warfarin, and haloperidol may therefore increase. This also affects other antiepileptic drugs when given concurrently with carbamazepine, at times causing difficulty in attaining therapeutic levels. In turn, carbamazepine clearance increases when given with these drugs. Inhibition of hepatic metabolism by erythromycin, isoniazid, propoxyphene, diltiazem, verapamil and cimetidine may cause an increase in carbamazepine levels. ⁸²