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INVITED REVIEW
Year : 2008  |  Volume : 3  |  Issue : 1  |  Page : 35-40
 

Management in refractory epilepsy: Beyond epilepsy surgery...


Consultant Neurologist, P. D. Hinduja National Hospital, Veer Savarkar Marg, Mahim, Mumbai - 40016, India

Correspondence Address:
Roop Gursahani
2101, Hinduja Clinic, P. D. Hinduja Hospital, Veer Savarkar Marg, Mahim, Mumbai - 400016
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1817-1745.40588

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   Abstract 

Although definititions of refractory epilepsy vary, about 40% of prevalent cases of epilepsy are not controlled by anti-epileptic drugs. A substantial proportion of this population requires palliative therapy since only a minority are candidates for epilepsy surgery. Drug therapy can be optimised after accurate classification of the epilepsy. Monotherapy is often as effective as polytherapy with fewer adverse effects. Depression and CNS adverse effects significantly impact quality of life and must be systematically screened for and treated. The ketogenic diet and vagal nerve stimulation provide substantial seizure control in a significant number of cases and may be used synergistically. Deep brain stimulation is another promising modality.


Keywords: Refractory epilepsy, intractable epilepsy, pharmacoresistant epilepsy, epilepsy, depression, ketogenic diet, vagal nerve stimulation


How to cite this article:
Gursahani R. Management in refractory epilepsy: Beyond epilepsy surgery... J Pediatr Neurosci 2008;3:35-40

How to cite this URL:
Gursahani R. Management in refractory epilepsy: Beyond epilepsy surgery... J Pediatr Neurosci [serial online] 2008 [cited 2019 Dec 16];3:35-40. Available from: http://www.pediatricneurosciences.com/text.asp?2008/3/1/35/40588



   Introduction Top


Epilepsy is probably the commonest serious neurologic disorder in most populations. Early literature in the 19 th century and the beginning of the 20 th century considered it a refractory and largely progressive disease. Gowers [1] is credited with the notion that 'the spontaneous cessation of the disease (i.e., epilepsy) is an event too rare to be reasonably anticipated' and that 'seizures beget seizures.' It is often presumed that modern medicine has substantially changed this grim scenario. Hauser [2] in 2006, estimated that about 5-10% of all incidence cases of epilepsy eventually become refractory. Cumulatively, these patients eventually perhaps account for about 40-50% of epilepsy prevalence. If it is presumed that about 60% of this is partial epilepsy, of which perhaps half are reasonable surgical candidates, that still leaves large numbers for whom the only option is optimal medical therapy and palliation. Extrapolating from conservative prevalence figures of epilepsy in India (about 3/1000) suggests about 28,000 persons of the Mumbai population (total population 13 million) suffering from 'incurable' epilepsy. This paper summarizes currently available options for these patients.


   Identifying Refractory Epilepsy Top


It has been presumed that the outcome of the epilepsy syndrome in a given patient can be determined fairly early in the course of the disease. Kwan and Brodie [3] followed up 525 patients with newly diagnosed epilepsy for over a decade and concluded that an early response and a response to the first antiepileptic drug (AED) were powerful predictors of a good outcome. The converse assumption that poorly controlled epilepsy is evident early in the course of the illness is commonly held. However, matters are not so clear-cut. A study of 333 patients undergoing epilepsy surgery showed that a large minority failed their second drug trial up to ten years after the onset of epilepsy, [4] showing that not all cases of refractory epilepsy (RE) are identifiable in the first few years after diagnosis. Intractability can also sometimes be a temporary phenomenon, and an initial poor prognosis can change. Thus the refractoriness of the condition in a given patient is an evolving diagnosis and must be open to revision.

Medically, refractory (or pharmacoresistant) epilepsy has been defined in numerical terms. For instance, one study identifies children with RE if they meet the following requirements: (a) failure of two appropriate AEDs, (b) the occurrence of an average of one seizure per month for 18 months or more and (c) not more than a 3-month seizure-free hiatus during this period of 18 months. [5] It must be remembered that these are definitions for research purposes. In clinical practice, early identification of a feasible surgical target such as a cavernoma or mesial temporal sclerosis (with concordant semiology) may result in a lowering of the bar for defining medical refractoriness. In less developed countries, limited expertise and surgical facilities also contribute to a reluctance to confront the issue of identifying RE, simply because not much can be done.

From the patient's perspective, the absolute seizure count may not mean much. The subjective handicap, i.e., the individual's own perception of how her illness limits life and its opportunities, is more relevant. Although quality of life has multiple determinants, seizure worry is one of the most important in patients with RE. [6] This contributes to a perceived loss of independence and is an important concern that is not easily evaluated. Most patients find it difficult to accept the limitations and risk following on from even one complex partial seizure in the past 6 months. [7]


   Accurate Diagnosis and Classification Top


Over a period of time, in any chronic illness both patient and family lower expectations. This therapeutic pessimism soon affects the clinician managing the patient, who may even reinforce it. This attitude needs to be challenged when the patient is referred for specialist opinion. One method is to set a therapeutic goal of seizure freedom at the end of one to two years, depending on the seizure frequency. This can also be the first step to counseling the patient about the possibility of a surgical option at the end of this period. In less sophisticated patients, a discussion of epilepsy surgery is best deferred till both patient and epileptologist have established sufficient rapport.

A thorough analysis of the history and investigations will show whether the epilepsy syndrome has been accurately classified or not. Review of the MRI scans with a neuroradiologist will confirm if a fresh study is essential at this stage. Sleep-deprived EEG recordings are very useful for excluding idiopathic generalized epilepsies; [8] and if the suspicion of idiopathic generalized epilepsy (IGE) is still high, overnight EEG recording may be a useful intermediate step before video-EEG. At some stage, if not already performed, all unclassified patients must be offered prolonged video-EEG monitoring and the seizures documented. Video-EEG is consistently used as a pre-surgical tool to determine whether the epilepsy is localization-related or generalized and to differentiate among localization-related epilepsies, between mesiotemporal and extratemporal/neocortical epilepsy. [9] Video-EEG is also an essential tool to identify nonsurgical candidates by diagnosing generalized epilepsies and non-epileptic seizures.

Psychogenic non-epileptic seizures account for about 20% of all intractable seizures referred for comprehensive epilepsy care, with an annual incidence perhaps about 4% of true epilepsy. These episodes may be more frequent, severe and disabling than even true epilepsy, with a much poorer quality of life. [10] This diagnosis should be confirmed by video-EEG even if the clinical impression of psychogenic seizures is very strong. Family members and fellow clinicians, especially psychiatrists may not be convinced without documentation. These events may be difficult to control and require treatment for the primary psychiatric issues.


   Optimizing Medical Therapy Top


Most clinicians are alert to the possibility of idiosyncratic side effects of antiepileptic drugs. In comparison, neurotoxic adverse effects are relatively insidious and are often missed. In a busy practice, teasing adverse effects out from frequently associated depression and the cognitive implications of multiple seizures can be a difficult undertaking. Multiple studies have shown that adverse effects significantly impact quality of life and can contribute to failure of therapy. This evidence is substantial for the older AEDs. Mattson et al . [11] in 1985, in an early multi-center, double-blind trial, showed that amongst patients on carbamazepine, phenytoin, phenobarb and primidone, over 40% of patients on each medication experienced significant toxicity. Systematic screening with an Adverse Events Profile questionnaire identified tiredness in 45-55%, sleepiness in 30-40% and memory problems in 30-48% of patients on carbamazepine, phenytoin, phenobarbital and valproate monotherapy. [12]

Can anything be done to reduce the burden of AED adverse effects? Awareness of the magnitude of the issue in a given patient can often guide appropriate modifications in the drug regimen. In a randomized trial, [13] Gilliam et al . used a self-administered screening questionnaire (the Adverse Events Profile). Physicians who were informed about their patients' adverse events profile (AEP) scores could reduce the adverse effect burden without affecting seizure control. Yet another approach is to convert from polytherapy to monotherapy. In a retrospective chart review, Pirio Richardson et al . [14] studied 35 patients with medically refractory epilepsy who had been converted from polypharmacy to monotherapy and maintained on monotherapy for at least 12 months. None of the 35 patients had worsening of their seizure frequency after the conversion to monotherapy; and in fact, 14 (40%) became seizure free.


   Depression in Epilepsy Top


Depression is probably the commonest associated illness in epilepsy. In a population survey, adults with active epilepsy were three times as likely to report depression and twice as likely to have anxiety in the preceding year as were adults without epilepsy. [15]

The lifetime prevalence of epilepsy in depression has been estimated at between 6% and 30% in population-based studies and up to 50% among patients followed in tertiary centers. [16] There is an association with refractory epilepsy: in one study, 44% and 21% of individuals with frequent seizures (>1/month) were anxious and depressed respectively. [17] This is a serious issue because of the association of depression with the risk for suicide. In people with epilepsy, 5-7% of deaths are due to suicide. [18]

The significance of depression in the management of refractory epilepsy is best exemplified by Boylan et al .'s prospective study of 122 patients admitted for video-EEG monitoring. [19] Depression was a powerful predictor of quality of life, outperforming all other variables. In these patients, depression was common (54%), severe (19% with suicidal thoughts), underdiagnosed (37%) and largely untreated (17% on antidepressants). Other studies too have found that depression was the single strongest predictor for each domain of health-related quality of life (QOL). The significant association of depression with health-related quality of life (HRQOL) persists after controlling for both seizure frequency and seizure severity. [20],[21] Seethalakshmi and Krishnamoorthy [22] in a recent review analyzed published material on the multiple etiologies and risk factors for depression in epilepsy. They discussed the possible roles of male gender, left-handedness, structural etiologies for epilepsy, family history of depression, structural changes in the medial temporal lobe, learning disability and stigma. The unpredictability of epilepsy leads to 'learned helplessness' when individuals are exposed to adverse events on a random basis. Antiepileptic drugs also contribute; and vigabatrin, tiagabine, topiramate, phenobarbital and levetiracetam are termed 'depressogenic.'

Being aware of the issue is not enough. Diagnosis is not difficult with self-administered screening questionnaires being easily available. [21] These should be routinely administered to patients with difficult-to-control epilepsy. Screen positives could then be referred for formal psychiatric consultation. The major issue in management is the choice of drugs. The newer non-MAOI, selective serotonin reuptake inhibitors (SSRI) antidepressants such as citalopram, paroxetine, mirtazepine and sertraline all lower the seizure threshold. However, in patients with depression alone (without epilepsy), the risk of a seizure with the use of these drugs is generally considered to be low (0.0-0.4%) and not very different from the incidence of first seizure in the general population (0.07-0.09%). [23] Risk with tricyclic antidepressants at effective therapeutic doses is relatively high (0.4% to 1-2%). Seizure following overdose is a significant and relatively frequent event for some antidepressants. Unfortunately, the evidence base for managing depression in epilepsy is very limited. Nevertheless, it can be recommended that selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) are to be preferred. [24] Although one open-label study of sertraline in epilepsy did show worsening of seizures in 6% of patients, given the morbidity and mortality associated with untreated depression, this risk is probably acceptable. Pharmacokinetic drug interactions between SSRIs and antiepileptic drugs are rare, with the exception of inhibition of carbamazepine and phenytoin metabolism by fluvoxamine. [24] SSRIs can potentiate the tendency of oxcarbazepine to cause hyponatremia. There is a suggestion that higher doses and polypharmacy may be required for successful treatment of depression in many epilepsy patients. [21] Electroconvulsive therapy (ECT) is not necessarily contraindicated in epilepsy and can be lifesaving, particularly for patients with psychotic depression. [24] Other approaches to treatment are also discussed in Seethalakshmi and Krishnamoorthy's review. [22]


   Choosing Antiepileptic Drugs in Refractory Epilepsy Top


Most patients will have been tried on multiple drugs before reaching an epileptologist. This section summarizes a personal approach in patients at this stage.

For partial epilepsies, unless otherwise contraindicated (drug rash, etc.), the base drug is carbamazepine. This can be titrated up to a trough serum level of 10-12 mg/l. The controlled-release version helps smooth out the peaks to avoid intermittent diplopia. For generalized epilepsies, valproate is the main drug, with a target dose of 20 mg/kg to begin with. Higher doses may be required, especially in children and in patients on enzyme-inducing AEDs. The usual therapeutic range for valproate serum levels is 50-100 mg/l, but levels up to 150 mg/l may be tolerated. It must be understood that some patients may tolerate doses that produce levels higher than the usually quoted upper limits for the therapeutic serum level. A systematic protocol to identify the maximum tolerated dose may produce remissions in patients previously thought to be difficult. In one study of patients referred for epilepsy surgery, this approach produced greater than 80% reduction in seizure frequency in 7 of the 74 patients; although complete seizure control was not obtained in any. [25] There are risks involved with sustaining these doses in the long term, especially with valproate; and fatalities have been reported, for instance, due to hemorrhagic complications. [26]

Add-on options for partial epilepsies include phenobarb and clobazam amongst the older drugs. Of the newer ones, a comparison of six-month seizure-freedom rates showed that levetiracetam and topiramate are probably the most effective; although levetiracetam is far better tolerated. [27] Pregabalin may also be emerging as a significant add-on of last resort. [28]

For the generalized epilepsies, information about add-ons to valproate is relatively scantier; but zonisamide, levetiracetam and lamotrigine are possible options. [29],[30] Unfortunately, valproate and topiramate cannot be combined because of a risk of hyperammonemia, [31] while the combination of levetiracetam and zonisamide has been shown to worsen seizure control. [29]

A possible approach is to systematically explore the maximum tolerated dose of the main drug as monotherapy. Patients who still continue to have seizures should then be started on a carefully chosen add-on drug, taking into consideration the patient profile, especially including the socioeconomic status.


   Ketogenic Diet Top


It has been known since biblical times that fasting improves seizure control. In 1921, Geyelin published systematic observations on the effect of fasting, and this was followed soon after by Wilder's suggestion of a high-fat diet, ketogenic diet, to simulate the effect of starvation. [32]

Based on clinical experience, any diet that produces sustained ketonemia and lowers blood sugar has an anticonvulsant effect. Chronic ketosis is thought to modify the tricarboxylic acid cycle to increase GABA synthesis in the brain. In addition, reactive oxygen production is reduced and energy production is enhanced in brain tissue. Hypothetically, the limited glucose and enhanced oxidative phosphorylation can also hyperpolarize neurons and glia. These and other diverse changes stabilize synaptic function and increase the resistance to seizure generation throughout the brain. [33]

In most epilepsy centers, the diet is initiated in-hospital. After initial screening for metabolic disorders (pyruvate carboxylase deficiency and porphyria are absolute contraindications), it begins with a 24-hour period of fasting, during which the patient is monitored for symptomatic hypoglycemia. Over the next 2-3 days, the diet is gradually introduced to build up to the requisite total calorie count which is based largely on anthropometric measurements. The diet is high in fat content and low in carbohydrate and to some extent protein content, with a typical ratio of 3:1 or 4:1 (by weight). Supplements of vitamins, calcium and micronutrients are required; and if there is a possibility of nephrolithiasis, citrate is added as well. It takes about 3-6 months for the efficacy of the diet to be established; but once that happens, antiepileptic drugs may be tapered. [34]

Because randomized controlled trials of the diet are not possible, the Cochrane database terms it a 'possible option.' A systematic review of the use of the diet in patients under 18 years of age showed complete control of seizures in 15.6% of children and greater than 50% reduction in 33%, [35] but the author also noted the bulk of the material was uncontrolled and retrospective. Adverse events were not frequent, but there were 16 deaths while on the diet. The largest single-institution intention-to-treat (which lists dropouts for any reason) prospective study of 150 patients at the Johns Hopkins Hospital showed that at 12 months, with 83 patients remaining on the protocol, 7% were free of seizures, 20% had a greater-than-90% reduction and 23% had a 50-90% reduction. [36] A multicenter study showed no effect of age (all children under eight), sex, principal seizure type or EEG findings. [37] A small study of 11 adults also showed promising results, [38] although there is an impression that complex partial seizures probably do not respond well. [34]

The ketogenic diet is not a benign therapy, although most side effects are predictable and treatable. [34] These include acidosis, weight loss, inadequate growth, symptomatic nephrolithiasis (6%), hyperlipidemia, hypoglycemia, hyperuricemia, GI symptoms and easy bruising. The efficacy figures, however, are largely comparable to any of the new AEDs available. In a small group of patients, the combined use of the ketogenic diet and vagal nerve stimulation appeared synergistic and yielded rapid benefits. [39]


   Vagal Nerve Stimulation Top


Since the initial reports of the use of vagal nerve stimulation for intractable epilepsy [40] in the early 1990s, this has become a widely used mode of palliative therapy. The vagus nerves have extensive projections to the thalamus, amygdala and forebrain through the nucleus tractus solitarius and to other cortical areas via the medullary reticular formation and can possibly widely modulate cortical excitability. [41] Thalamocortical relay neurons may play a crucial role in influencing the generation of primary generalized seizures, as well as the secondary generalization of partial epilepsies; and thalamic activation has been linked to success with vagal nerve stimulation (VNS).

The stimulation device (similar to cardiac pacemaker) is implanted under the left clavicle, and two helical bipolar stimulating electrodes are placed around the left vagus nerve (never the right because of possible cardiac effects) distal to the branching of recurrent laryngeal nerve. [42] The whole procedure can be done under either local or general anesthesia on an outpatient basis and takes 1-2 hours. The starting level of stimulation is 025 mA, and this is increased to 125-200 mA over several weeks. Most common settings for the stimulator are a frequency of 20-30 Hz, pulse width of 250-500 ms, time-on of 30 seconds and time-off of 3-5 minutes. The rate of postoperative infections is 3-6% across series. The common side effects are all stimulation setting related and include voice alteration (50-60%) and cough, hoarseness, dyspnea, pain, paresthesia, headaches (15-20%). [42]

Because patients sense when VNS is active, traditional placebo-controlled trials are not practical. Instead, the pivotal trials [42] tried to show effectiveness by a 'high' dose versus 'low' dose. The mean reduction in seizure frequency was 25-30% for the high-dose group and 6-15% for the low-dose group. About 30-40% of the high-dose group and 15-20% of the low-dose group had a 50% or greater reduction of seizure frequency. More recent reports from other groups are summarized below. A retrospective study from seven epilepsy centers in Belgium followed 138 patients for a minimum period of one year. [43] Although overall AED usage did not change, mean monthly seizure frequency reduced by 51%, and 12 patients (9%) became seizure free. In another series from Ireland, [44] 48 patients were followed up over a median of 18 months, and 36.5% had a >50% reduction of seizure frequency. The seizure freedom rate was consistent across centers, with a figure of 6 of 47 (13%) patients implanted from Bethel, Germany [45] ; and 5 of 49 (10.1%) from Cleveland, USA. [46]


   Brain Stimulation Top


At present these are all largely experimental modes for palliative therapy. Although they do have an advantage over resective surgery by being reversible, the substantial expense is a major deterrent. The stimulation targets have included the cerebellum, caudate nucleus, the thalamus (most commonly the anterior nucleus, but also the centromedian) and the subthalamic nucleus. [41] A Belgian group has studied deep brain stimulation in the medial temporal lobe structures in patients with mesial temporal lobe epilepsy. [47] Even more interestingly, a Mexican group found >95% seizure reduction in five patients with normal MRI. [48]

Another brain stimulation modality that is getting attention is repetitive transcranial magnetic stimulation using external stimulators. [41],[49] As of now, the results can only be listed as 'promising'!

 
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    Abstract
    Introduction
    Identifying Refr...
    Accurate Diagnos...
    Optimizing Medic...
    Depression in Ep...
    Choosing Antiepi...
    Ketogenic Diet
    Vagal Nerve Stim...
    Brain Stimulation
    References

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