Issues of Medical Intractability for Surgical Candidacy
Patrick Kwan
Martin J. Brodie
INTRODUCTION
Although the effectiveness of epilepsy surgery for patients with surgically remediable syndromes refractory to antiepileptic drug (AED) treatment, in particular anterior temporal lobectomy for mesial temporal lobe epilepsy, has been demonstrated in uncontrolled studies (1,2) and confirmed in a double-blind, randomized, controlled setting (3), controversies over the selection criteria for surgical candidacy continue. One of the prerequisites for epilepsy surgery is demonstrated “medical intractability” (4). The term is often used interchangeably with “medical refractoriness” or “pharmacoresistance.” The Oxford English Dictionary defines “intractable” as “not easily treated or dealt with; resisting treatment effort.” Although the concept may appear to be self-explanatory and intuitive at first glance, the precise definition of “medical intractability” has remained elusive (5,6). This chapter aims to explore the issues surrounding the definition of intractable epilepsy, with particular reference to its relevance to selection of surgical candidacy.
PSEUDORESISTANCE
The term “pseudoresistance” has been introduced to describe the condition in which seizures persist because the disorder has not been adequately or appropriately treated (5). It may arise in a number of situations, and must be excluded or corrected before AED treatment can be declared as having failed.
Incorrect Diagnosis
If a patient does not have epilepsy, AED therapy is unlikely to be helpful. A wide range of conditions can mimic epileptic seizures and must be considered in the differential diagnosis. Syncopal attacks, during which there may be clonic movements and incontinence, are commonly misdiagnosed as epileptic seizures (7). Pseudoseizures or nonepileptic psychogenic seizures are estimated to account for 10% to 45% of patients with apparently refractory epilepsy (8). Diagnosis can be challenging, as nonepileptic attacks often co-exist with epilepsy or may develop as a substitute for seizures once the epilepsy is controlled (9). Mistaking other conditions for epilepsy can lead to unnecessary and potentially harmful treatments and delays in initiating appropriate therapy (7).
Incorrect Drug Choice or Inadequate Dosage
Incorrect classification of syndrome/seizure type is another common cause of drug failure. The profile of activity against different seizure types varies among the AEDs (10,11). Certain epilepsy syndromes and seizures have been found to be particularly responsive to specific AEDs, whereas others may be exacerbated by incorrectly chosen agents (12,13). A notable example is juvenile myoclonic epilepsy, which responds well to sodium valproate even at low doses (14). The syndrome is often misdiagnosed (15), however, leading to an erroneous choice of drug (e.g., carbamazepine or phenytoin), which can exacerbate myoclonic jerks and absence seizures (16). It is not uncommon at an initial clinic visit to be uncertain whether a young patient
is reporting generalized absence or short-lived complex partial seizures.
is reporting generalized absence or short-lived complex partial seizures.
In some circumstances, failure of an AED is not due to an incorrect drug choice for a particular seizure type(s), but rather because the agent is not prescribed at optimal dosage. Because of genetic and environmental factors, wide interindividual variability exists in the dosages at which beneficial and toxic effects are observed (17). Patients are often switched to an alternative treatment before the maximum tolerated dose (MTD) of their current AED is reached, resulting in persistent seizures that could have been controlled at higher dosages. One of the reasons for failure to optimize the dose in an individual patient is injudicious reliance on monitoring serum drug concentration, including a “therapeutic range” that can be interpreted as dictating dosage adjustment without adequate clinical correlation (18). Although “therapeutic” or “target” ranges are often quoted for established AEDs in standard textbooks (19), these should only be used as an aid in dosage adjustment. The treating clinician must realize that some patients will do well below the lower limit of the range, whereas others will tolerate higher levels with benefits and without toxicity.
In a study of 30 patients with serum phenytoin concentrations >20 mg/L (the widely quoted upper level of the target range), 17 patients became seizure free or had a significant reduction in seizure frequency from a baseline of one or more seizures per week when their dose was increased to achieve this high serum level (20). In another study of 74 consecutive patients referred for epilepsy surgery for presumed drug resistance, a systematic protocol to titrate their AED to the MTD, regardless of serum levels, resulted in a greater than 80% reduction in seizure frequency and cancellation of planned surgery in seven patients (9.5%) (21). An individualized approach must, therefore, be adopted when titrating an AED to the MTD before being declared a failure.
Imperfect Compliance or Inappropriate Lifestyle
As with other chronic medical conditions, imperfect adherence to the therapeutic regimen is one of the most common factors resulting in epilepsy treatment failure. AED noncompliance remains the most frequently identified etiology of status epilepticus in adults (22). The reasons for noncompliance are multifactorial, including socio-economic, racial, and family factors (23). A survey of 232 adolescents identified support from the treating physician as the most powerful predictor of compliance with treatment regimens (24). Adherence to treatment may also be improved by simplifying the dosing regimen. Cramer and colleagues found that compliance rates in patients with epilepsy decreased as the frequency of drug administration increased, from 89% with once-daily dosing to 81% with twice-daily drug administration, 77% with 3-times-daily administration, dropping to only 39% with 4-times-daily administration (25).
Abuse of alcohol and recreational drugs can cause seizures and nonadherence to AED treatment. Similarly, sleep deprivation and stress are common precipitants. Social and lifestyle factors should, therefore, be considered when evaluating the efficacy of pharmacologic treatment.
INTENDED CONTEXT OF DEFINITION
Before the criteria for defining medical intractability are discussed, it should be emphasized that, by default, intractability is a relative concept rather than an absolute designation, which is influenced by the context in which it is intended to apply. A practical definition of medical intractability is required for three main purposes: (a) selection of patients for epilepsy surgery, (b) recruitment in experimental drug trials, and (c) identification for inclusion in epidemiologic studies. Because of these varying purposes, the definition may vary widely in different settings. For instance, since industry-sponsored regulatory add-on trials of experimental agents are typically of relatively short duration, the definition of refractory epilepsy for enrollment purposes usually requires high baseline monthly seizure frequency in order to achieve adequate statistical power with minimum sample size (26). In epidemiologic studies, the definition of medical intractability should reflect the outcome of epilepsy in response to treatment—that is, the likelihood of success or failure with successive AED regimens. This requires an understanding of the natural history of treated and untreated epilepsy, which remains poorly documented (27).
The relativity of any definition of medical intractability is particularly poignant in the context of candidacy for potentially “curative” resective epilepsy surgery. Aided by technical advances in neuroimaging and video electroencephalographic (EEG) monitoring, improvements in technique, and a better understanding of the anatomic and pathophysiologic bases of the epilepsies, resective surgery has become a highly effective and safe treatment modality for certain remediable syndromes, the prototype of which is mesial temporal lobe epilepsy (28,29). With a reported remission rate of 60% to 70% from centers across the world, mortality close to zero, and permanent neurologic morbidity less than 5%, anterior temporal lobectomy has made mesial temporal lobe epilepsy, an often medically intractable condition, highly surgically treatable in appropriately selected patients (30). A clinically relevant, pragmatic definition of drug resistance for patients with this epilepsy syndrome must, therefore, take into account the potential success of surgical treatment. Indeed, since the effectiveness of surgery may vary for different types of epilepsy, syndrome-specific predictive models may be required (31). Such definitions will have to be updated periodically, with the availability of new AEDs and improvement in surgical techniques and outcomes.
ELEMENTS OF THE DEFINITION
Bearing in mind the aforementioned considerations, a discussion of the criteria used in defining medical intractability, with particular reference to epilepsy surgery, will follow. Although the definitions of medical intractability found in the medical literature seem to be highly variable (Table 72.1), sometimes even from the same authors, three key elements need to be incorporated: number of AEDs failed, frequency of seizures, and duration of treatment (3,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42).
Number of Drugs Failed
An implicit assumption in any definition of medical intractability is that remission will not or is very unlikely to be attained with further manipulation of AED treatment. Therefore, the most important element in defining medical intractability is the number of AEDs failed at optimal dosage. Any definition must be based on an assessment of the probability of subsequent remission after each drug failure. Until recently, clinicians have had a relatively limited therapeutic armamentarium with which to treat epilepsy. With the approval of ten new AEDs in the past decade, the choice has been substantially widened and the number of possible combinations is now almost limitless. No patient will be able to try all AED regimens. A number of questions remain to be answered: How many trials of single AEDs should be used before a patient is treated with polytherapy? How many AEDs, either singly or in combination (and in how many combinations), have to fail before a seizure disorder can be recognized as medically refractory and surgery considered? At what stage does epilepsy become pharmacoresistant to AED treatment? Are there clinical features that will allow prediction of subsequent refractoriness? Answers to these questions depend on an understanding of the natural history of treated epilepsy, in particular its progress in response to treatment.
TABLE 72.1 SELECTED DEFINITIONS OF MEDICALLY INTRACTABLE EPILEPSY FROM MEDICAL LITERATURE | ||||||||||||||||||||||||||||||||||||||||||
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