Copyright Blackwell Munksgaard 2005

Acta Neurol Scand 2005: 112 (Suppl. 181): 3639

All rights reserved

ACTA NEUROLOGICA
SCANDINAVICA

Diagnosing and predicting refractory

epilepsy
Brodie MJ. Diagnosing and predicting refractory epilepsy.
Acta Neurol Scand 2005: 112 (Suppl. 181): 3639. Blackwell
Munksgaard 2005.
Over 30% of people with epilepsy will never achieve remission with
antiepileptic drug (AED) therapy. These individuals are often severely
disabled by their condition, have an unsatisfactory quality of life, and
are at increased risk of sudden unexpected death. Early identication
of refractory epilepsy would allow prompt referral to specialist
services, where the diagnosis can be conrmed, seizures and syndromes
classied, AED therapy optimized, and suitability for surgery assessed.
Recent studies suggest that patients with symptomatic or cryptogenic
epilepsy, those who experience multiple seizures before AED treatment
initiation, and those with febrile convulsions, a family history of
epilepsy, or psychiatric comorbidities are least likely to respond to
drug therapy. Failure to achieve good seizure control with the rst one
or two AED monotherapies is usually sufcient to highlight the
possibility of subsequent refractory epilepsy. For most of these
individuals, combination therapy using AEDs with complementary
modes of action is the recommended treatment approach.

Despite the introduction of many novel antiepileptic drugs (AEDs) over recent years, approximately one-third of people with epilepsy will never
achieve remission (14). Medically refractory epilepsy is increasingly accepted as a distinct, multifaceted condition that is associated with intractable
seizures, an excessive drug burden, and signicant
cognitive deterioration (Table 1) (5). Lifestyle
restrictions resulting from decades of imperfect
seizure control frequently lead to psychosocial
dysfunction (6, 7), an unsatisfactory quality of
life (8), and a drain on healthcare resources (9).
Perhaps more worryingly, frequent uncontrolled
seizures also increase the risk of suicide (10), and
sudden unexpected death (11, 12).
The biologic basis of refractory epilepsy has not
been well established. There is good evidence that
pharmacoresistant seizures may be self-perpetuating in some individuals, potentially causing irreversible neuroplastic changes including dendritic
sprouting, synaptic reorganization, glial proliferation, and neuronal cell death (13). Pharmacologic
refractoriness may be genetically determined as a
consequence of ion channel mutations (5) or
overexpression of multidrug resistance genes
(14). Other possible contributory factors include
36

M. J. Brodie
Epilepsy Unit, Division of Cardiovascular and Medical
Sciences, Western Infirmary, Glasgow, UK

Key words: antiepileptic drugs; diagnosis; epilepsy;

prognosis; refractory; seizures
Martin J. Brodie, Epilepsy Unit, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT, UK
Tel.: +44 141 211 2572
Fax: +44 141 334 9329
e-mail: martin.j.brodie@clinmed.gla.ac.uk

syndrome classication, causative neuropathology,

and reactive autoimmunity (Table 2).
Early identification of refractory epilepsy

There is increasing evidence that patients with

refractory epilepsy can be identied early in the
course of their illness, and could, potentially, be
spared damaging years of avoidable seizures and
the resultant downward spiraling in quality of life
(15). Identication of such individuals should
encourage their prompt referral to specialist centers, where they can have the diagnosis conrmed,
seizures and syndromes classied, AED therapy
optimized, and suitability for surgery assessed.
Individuals with temporal lobe epilepsy are particularly strong candidates for resective surgery, with
more than 60% of suitable patients being rendered
seizure-free after anterior temporal lobectomy (16).
Neural stimulation offers a promising new technique for the treatment of intractable seizures, and
has produced good results in selected patients (17).
Recent studies have attempted to identify reliable prognostic indicators for treatment-refractory
epilepsy (3, 1822). Outcome studies in Glasgow
have shown that response to the rst or second

Diagnosing and predicting refractory epilepsy

Table 1 Dimensions of refractory epilepsy
Intractable seizures
Excessive drug burden
Cognitive decline
Psychosocial dysfunction
Dependent behavior
Restricted lifestyle
Unsatisfactory quality of life
Worsening morbidity
Increased mortality

Table 2 Factors contributing to the biologic basis of refractoriness

Syndromic classification, e.g. childhood epileptic encephalopathies
Causative neuropathology, e.g. mesial temporal sclerosis
Hyperexcitable and disinhibited neuronal network
reorganization, e.g. mossy fiber sprouting
Altered neurotransmitter receptors, e.g. composition/
functioning of GABA/glutamate receptors
Ion channelopathies, e.g. sodium, calcium, potassium channels
Reactive autoantibodies, e.g. glutamic acid decarboxylase, glutamate receptors
Impaired drug penetration, e.g. P-glycoprotein expression at bloodbrain barrier

AED appears to be one of the most consistent

predictors of prognosis, and these studies have
conrmed that around 30% of patients are inherently pharmacoresistant (3). In one study, which
involved 470 newly diagnosed, previously
untreated adolescent and adult patients, 60% had
their seizures controlled with AED monotherapy;
47% became seizure-free on their rst AED, and a
further 13% were controlled with their rst alternative monotherapy. Only 3% responded to polytherapy. Similar ndings have been reported by
other investigators (6, 22).
Early response to AED treatment is not, however, the only factor predictive of refractory
epilepsy. Patients with symptomatic or cryptogenic
epilepsy are more likely to be medication-resistant
than those with idiopathic epilepsy (1, 3, 6, 19, 23,
24). In the Glasgow population, 43% and 39% of
patients with symptomatic epilepsy and cryptogenic
epilepsy, respectively, continued to have seizures
despite AED therapy, compared with just 26% of
patients with idiopathic epilepsy (3).
Patients experiencing a large number of seizures
before treatment initiation also appear to be more
likely to be unresponsive to AED therapy (3, 18,
19). Our initial study reported a signicant linear
trend in the proportion of patients with uncontrolled epilepsy; only 15% of patients who experienced two pretreatment seizures did not respond to
AED therapy, whereas 51% of those who experienced >20 seizures before treatment was initiated
developed refractory epilepsy (Fig. 1).
We have recently completed an analysis of
outcomes in 780 patients given a diagnosis of

Figure 1. Outcome in patients according to number of seizures

before treatment. The percentages of patients with uncontrolled epilepsy are shown within the bars (P < 0.001 for the
comparison with patients who were seizure free). Reproduced
from Kwan and Brodie (3), with permission from Massachusetts Medical Society.

epilepsy and started on their rst AED at the

Epilepsy Unit of the Western Inrmary in
Glasgow, UK, between July 1982 and May
2001; some patients have now been followed for
more than 20 years (25). Overall, 59% of patients
had a good prognosis, with 31% of the total
population responding immediately to therapy by
having no further seizures after taking the initial
AED dose. Most patients who entered remission
did so with their rst AED (46%) or second
treatment schedule with an alternative monotherapy or a combination (10%). Only a further
3% of patients achieved remission with subsequent drug regimens.
Patients with the best response to AED treatment in our latest analysis were those with
idiopathic epilepsies (66% remitted compared
with 57% and 56% of patients with cryptogenic
or symptomatic epilepsies, respectively), those
reporting fewer seizures before starting treatment,
elderly individuals, and patients with underlying
cerebrovascular disease, thus conrming and
extending our previous observations. Febrile convulsions, a family history of epilepsy, and psychiatric co-morbidity were all associated with a higher
probability of refractory epilepsy (25).
Rational approach to refractory epilepsy

The ndings from these studies can be used to

formulate practical guidelines for the diagnosis and
management of patients with refractory epilepsy. It
is clear that the majority of individuals who do not
attain good seizure control with their rst or
second treatment schedule can condently be given
a diagnosis of refractory epilepsy, and at this point
they should be referred to an epilepsy service for
further evaluation.
37

Brodie
The initial choice of AED is critical, as life-long
treatment may be required, even in patients with
only mild epilepsy (26). The most suitable AED for
each patient should be selected to maximize the
chance of remission without producing intolerable
side effects (27). In this respect, not all rst-line
AEDs are the same (28).
If the rst drug produces a rash or another
idiosyncratic reaction, side eects at low or
moderate dosage, or worsens or fails to improve
seizure control, an alternative AED should be
substituted. If the rst or second choice is well
tolerated, the dose can be increased by increments
toward the limit of tolerability, aiming for optimal control. If control is greatly improved but
seizure freedom is elusive, another AED with a
dierent or multiple mechanisms of action should
be added. The dose of the original drug may need
to be reduced, particularly if the patient develops
side eects. If seizures are not fully controlled on
the rst two drugs as monotherapy, or the initial
drug and the rst combination, epilepsy surgery
should be considered, especially if a potentially
operable structural abnormality such as mesial
temporal sclerosis has been identied.
One of the greatest remaining challenges facing
clinicians today is how to improve the outlook for
those patients who do not respond to AED
monotherapy. As most individuals with epilepsy
cannot be cured by surgery, eective combination
therapy using modern AEDs with complementary
modes of action at moderate doses remains the best
therapeutic approach (29). Recommendations for
combining AEDs are beyond the scope of this
paper, but have been published recently elsewhere
(30).
Conclusions

Despite optimal use of modern agents, over 30% of

people with epilepsy never achieve remission with
AED therapy and these individuals are at great risk
of psychosocial dysfunction, poor quality of life,
and increased mortality. The prognosis for most
people with newly diagnosed epilepsy, whether
good or bad, usually becomes apparent within a
few years of starting treatment. Those experiencing
fewer seizures at diagnosis, those with idiopathic
epilepsies, and the elderly are more likely to have a
better outcome than the rest of the population.
Patients who do not achieve long-term seizure
freedom with their rst two AED regimens are
unlikely ever to have a useful period of remission.
These individuals should be given a diagnosis of
refractory epilepsy and referred for specialist evaluation with the aim of conrming the seizure and
38

syndrome classication, optimizing pharmacotherapy and, if appropriate, considering epilepsy

surgery.
Acknowledgement
This paper was supported by a grant from UCB.

References
1. Annegers JF, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia
1979;20:72937.
2. Cockerell OC, Johnson AL, Sander JWAS, Hart YM,
Shorvon SD. Remission of epilepsy: results from the
national general practice study of epilepsy. Lancet
1995;346:1404.
3. Kwan P, Brodie MJ. Early identication of refractory epilepsy. N Engl J Med 2000;342:3149.
4. Mattson JH, Cramer JA, Collins JF. Prognosis for total
control of complex partial and secondary generalised
tonic-clonic seizures. Neurology 1996;47:6876.
5. Kwan P, Brodie MJ. Refractory epilepsy: a progressive,
intractable but preventable condition? Seizure 2002;11:77
84.
6. Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term
prognosis of seizures with onset in childhood. N Engl J
Med 1998;338:171522.
7. Kwan P, Brodie MJ. Neuropsychological eects of epilepsy
and antiepileptic drugs. Lancet 2001;357:21622.
8. Cramer JA. Quality of life for people with epilepsy. Neurol
Clin 1994;12:113.
9. Devinsky O. Patients with refractory seizures. N Engl J
Med 1999;340:156570.
10. Nilsson L, Ahlbom A, Farahmand BY, Asberg M, Tomson T.
Risk factors for suicide in epilepsy: a case-control study.
Epilepsia 2002;43:64451.
11. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T.
Risk factors for sudden unexpected death in epilepsy: a
case-control study. Lancet 1999;353:88893.
12. Pedley TA, Hauser WA. Sudden death in epilepsy: a wakeup call for management. Lancet 2002;359:17901.
13. Meldrum BS. Why and when are seizures bad for the brain?
Trends Pharmacol Sci 2001;22:4456.
14. Kwan P, Brodie MJ. Potential role of drug transporters in
the pathogenesis of medically intractable epilepsy. Epilepsia 2005;46:22435.
15. Trevathan E, Gilliam F. Lost years. Delayed referral for
surgically treatable epilepsy. Neurology 2003;61:4323.
16. Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized,
controlled trial of surgery for temporal-lobe epilepsy.
N Engl J Med 2001;345:3118.
17. Theodore WH, Fisher RS. Brain stimulation for epilepsy.
Lancet Neurol 2004;3:1118.
18. Collaborative Group for the Study of Epilepsy. Prognosis of
epilepsy in newly referred patients: a multicenter prospective study of the eects of monotherapy on the longterm course of epilepsy. Epilepsia 1992;33:4551.
19. Sillanpaa M. Remission of seizures and predictors of
intractability
in
long-term
follow-up.
Epilepsia
1993;34:9306.
20. Shorvon SD. The epidemiology and treatment of chronic
and refractory epilepsy. Epilepsia 1996;37(Suppl. 2):S13.
21. Perucca E. Pharmacoresistance in epilepsy: how should it
be dened? CNS Drugs 1998;10:1719.

Diagnosing and predicting refractory epilepsy

22. Dlugos DJ, Sammel MD, Strom BL, Farrar JT. Response to
rst drug trial predicts outcome in childhood temporal
lobe epilepsy. Neurology 2001;57:225964.
23. Berg AT, Levy SR, Novotny EJ, Shinnar S. Predictors of
intractable epilepsy in childhood: a case-control study.
Epilepsia 1996;37:2430.
24. Semah F, Picot M-C, Adam C et al. Is the underlying cause
of epilepsy a major prognostic factor for recurrence?
Neurology 1998;51:125662.
25. Brodie MJ. Glasgow outcome studies. Epilepsy Res
2004;60:967.
26. Brodie MJ, French JA. Management of epilepsy in adolescents and adults. Lancet 2000;356:3239.

27. Brodie MJ, Kwan P. The star systems. Overview and use in
determining antiepileptic drug choice. CNS Drugs
2001;15:112.
28. Kwan P, Brodie MJ. Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology
2003;60(Suppl 4):S2S12.
29. Deckers CLP, Czuczwar SJ, Hekster YA et al. Selection
of antiepileptic drug polytherapy based on mechanisms
of action: the evidence reviewed. Epilepsia 2000;41:1364
74.
30. Brodie MJ. Medical therapy of epilepsy: when to initiate
treatment and when to combine? J Neurol 2005;252:125
30.

39