Chapter 5
Drug-Resistant Epilepsy
CQ 5-1

What is the definition of drug-resistant epilepsy?
Summary
Clinically, drug-resistant epilepsy is defined as the epilepsy which cannot be controlled for a certain period (atleast 1 year or 3 times the longest interval between seizures) by using two appropriately selected antiepileptic drugs(whether as monotherapy or combination therapy), with sufficiently high blood concentrations but without adverse
events.

Comment
Since not all the epilepsies that cannot be controlled by antiepileptic drugs are intractable epilepsies (only some are
intractable), “intractable epilepsy” that was used in the previous edition is replaced by “drug-resistant epilepsy” in the 2018
edition. Some subtle seizures that do not impede daily life and recur several times a year are drug resistant, but not intractable.
Even when antiepileptic drugs fail to control seizures, if the seizure frequency is 1‒2 times a year, the patient is not indicatedfor surgery. However, if seizure frequency is 1‒2 times a month, the patient has an intractable epilepsy in whom surgicaltreatment should be considered.
The definition of drug-resistant epilepsy depends on the use situation and we have no universal definition. The ILAE
proposed the above definition so that it can be applied to various situations1). This definition is intended not only for clinicalsettings but also for purposes such as designing clinical trials, clinical research, and facilitating referral of the patients tospecialized facilities. Referral to specialized facilities is recommended if seizures are not controlled by two appropriately
selected drugs at adequately high doses.
The evidence for two drug regimens was provided by a study of 1,098 adolescent or adult patients with untreated epilepsy.
The seizure-free rate was 50% after the first drug regimen, 13% after the second regimen of monotherapy or combination
therapy, but only 5% after the third to ninth regimen of monotherapy or combination therapy. Since there is very low
possibility of achieving seizure-free status by continued drug therapy after failure of 2 regimens of antileptic drugs asmonotherapy or combination therapy, epilepsy uncontrollable by 2 appropriate drugs as monotherapy or combination
therapy can be regarded as drug resistant2).
The evidence of at least one year is based on community-based studies showing that one or more seizures in the past two
years have various impact such as psychological symptoms or disadvantages in daily life. In addition, being seizure-free forat least one year is a requirement for acquiring a driver’s license in many countries. However, in a long-term follow-up (2-22years, median 6.1 years) study of 780 adolescent-adult patients with untreated epilepsies, out of 462 patients whose seizures
were controlled for more than 1 year at the time of the final observation, 74% had seizures controlled within one year, and
11% within two years after the treatment started. In another definition, drug resistance was defined as seizures persisting
after at least two years of treatment, in addition to control failure with two drugs. This is because the possibility of drug
resistance is high if seizures are not controlled after two years of treatment3).
However, these definitions do not always apply to children, and there are many pediatric patients in whom seizures arewell controlled by three or more drug regimens. In a cohort of 613 children with epilepsy prospectively followed for 13 years
at the longest (median 9.7 years), 128 children who did not respond favorably to two drugs were treated with the third or
more drugs (median 3 drugs). After treatment for 1-14 (median 10.1) years, seizures were controlled for at least 1 year during
this period in 57% of the patients, and seizures were controlled for more than 1 year at the final observation in 38%4).
Therefore, for children, drug resistance must not be defined only by seizures not controlled by two drug regimens, or notcontrolled after 1‒2 years of treatment.
According to the guideline of the Japan Epilepsy Society for the purpose of considering surgical indication, the criterion

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

of drug-resistant epilepsy is seizures not controlled after more than 2 years of treatment even with 2‒3 kinds of appropriate
drugs5).
It should be noted that there are many patients with pseudo-drug-resistant epilepsy due to misdiagnosis (see CQ5-3 onpage 47).

▪ References
1) Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission
on Therapeutic Strategies. Epilepsia. 2010; 51(6): 1069-1077.
2) Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012; 78(20): 1548-1554.
3) Hitiris N, Mohanraj R, Norrie J, et al. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007; 75(2-3): 192-196.
4) Berg AT, Levy SR, Testa FM, et al. Remission of epilepsy after two drug failures in children: a prospective study. Ann Neurol. 2009; 65(5): 510-519.
5) Mihara T, Fijiwara T, Ikeda A, et al. Guideline on indications for epilepsy surgery. Tenkan Kenkyu. 2008; 26(1): 114-118 (in Japanese).

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((refractory/AL and (epilepsy/TH or epilepsy/AL)) and (definition/AL or classification/TH or classification/AL)))) and (DT = 2008:2015 and PT =excluding proceedings) = 27
No references that could serve as evidence were found in Ichushi Web.

Chapter 545

CQ 5-2

What are the true drug-resistant epilepsies in adults?
Summary
Drug-resistant epilepsies in adults include symptomatic partial epilepsies with intracranial lesions (including
cerebrovascular disorder, cerebral dysplasia, brain tumor, hippocampal sclerosis, encephalitis or encephalopathy,
and systemic diseases) on MRI and other imaging studies; cryptogenic partial epilepsies including temporal lobe
epilepsy; symptomatic generalized epilepsies with degenerative disorders such as dentatorubral pallidoluysian
atrophy (DRPLA) or metabolic disorders; various childhood onset epilepsies uncontrolled even in adulthood such as
Lennox-Gastaut syndrome; and epilepsies associated with autoimmune encephalitis.

Comment

In one study, out of a total of 2,200 outpatients (partial epilepsy 1,369 cases, generalized epilepsy 473 cases, andundetermined epilepsy 358 cases) aged 16 years and above, 1,696 patients were treated and followed for 1‒7 years. Amongthem, 45% were seizure-free for one year or longer. By epilepsy classification, the seizure-free rate was 27% in symptomatic(with a definitive cause of epilepsy) or cryptogenic (cause of epilepsy suspected but not definite) generalized epilepsy, 82% in
idiopathic generalized epilepsy, 35% in symptomatic partial epilepsy, 45% in cryptogenic partial epilepsy, and 11% in partial
epilepsy with hippocampal sclerosis. Among the partial epilepsies, seizure-free rate was 20% in temporal lobe epilepsy and
36% in non-temporal lobe epilepsy. For temporal lobe epilepsy, the seizure-free rate was 10% when accompanied byhippocampal sclerosis, and was 31% when not accompanied by hippocampal sclerosis. There was no difference in the seizurefree rate between temporal lobe epilepsy without hippocampal sclerosis and non-temporal lobe epilepsy. The seizure-free rate
was markedly low in hippocampal sclerosis, dual pathology (hippocampal sclerosis + other lesions), and cerebral dysgenesis(11%, 3% and 24%, respectively)1).
In a prospective study of 550 adolescent and adult patients with partial epilepsy treated with antiepileptic drugs, 312(57%) patients were seizure-free for at least 1 year at the last follow-up. The seizure-free rate was 42% in patients with mesial
temporal sclerosis, 78% with cerebral arteriovenous malformation, 67% with cerebral infarction, 63% with brain tumor,
57% with gliosis, 55% with cerebral atrophy, and 54% with cortical dysplasia. Patients with mesial temporal sclerosis werethe most intractable. There was no difference in seizure-free rate between patients with symptomatic partial epilepsy andthose with cryptogenic partial epilepsy2). In patients with Lennox-Gastaut syndrome (mean age 28.6 years) observed for an
average of 16 years, seizures were controlled in only 5% of the patients3).
Among 780 adolescent and adult patients newly diagnosed with epilepsy and followed long-term after treatment initiation(2–22 years, median 6.1 years), 318 (41%) patients did not achieve seizure control at least for the last 12 months of follow-up.
These patients frequently had (1) symptomatic or cryptogenic epilepsy; (2) more than 10 seizures before treatment initiation;(3) a family history of epilepsy, previous febrile convulsion, and traumatic brain injury; (4) nonadherence or irregular use ofantiepileptic drugs; and (5) prior or current psychiatric comorbidity (especially depression)4). The presence of these factors
may predict a high possibility of drug-resistant epilepsy.
Some autoimmune encephalitis-related epilepsies such as autoimmune limbic encephalitis and anti-NMDA receptor
encephalitis are highly drug-resistant and require immunotherapy5). Furthermore, although not an epilepsy, psychogenic
nonepileptic seizure is also highly drug resistant and is difficult to diagnose and treat.

▪ References
1) Semah F, Picot MC, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology. 1998; 51(5): 1256-1262.
2) Stephan LJ, Kwan P, Brodie MJ. Does the cause of localization-related epilepsy influence the response to antiepileptic drug treatment? Epilepsia.
2001; 42(3): 357-362.
3) Yagi K. Evolution of Lennox-Gastaut syndrome: a long-term longitudinal study. Epilepsia. 1996; 37(Suppl 3): 48-51.
4) Hitiris N, Mohanraj R, Norrie J, et al. Predictors of pharmacoresistant epilepsy. Epilepsy Res. 2007; 75(2-3): 192-196.
5) Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and neural cell surface proteins. Neurology. 2011; 77(2):179-189.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((refractory/AL and (epilepsy/TH or epilepsy/AL)) and (definition/AL or (classification/TH or classification/AL)))) and (DT = 2008:2015 and PT= excluding proceedings) = 27

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 5-3What are the drug-resistant epilepsies in children?
Summary
Drug-resistant epilepsies in children include epileptic encephalopathies with infant and early childhood onset,
such as West syndrome; cerebral dysplasia; chromosomal abnormalities such as 4p minus syndrome; neurocutaneous
syndromes including tuberous sclerosis; post-encephalitis/encephalopathy; post-hypoxic ischemic encephalopathies
such as severe neonatal asphyxia; epilepsy associated with cerebral degenerative/metabolic disorders; and autoimmune
encephalitis-related epilepsy.

Comment

1. Causes of drug resistanceIn one 2-year follow-up study of 381 children with newly diagnosed epilepsy, 75 patients (19.7%) were found to have drugresistant epilepsy. Neuroimaging abnormalities, some abnormalities found in clinical neurological examination, and focal
seizures were associated with drug resistance. Despite treatment of these patients with appropriate drugs for an average of
11.7 years, 49% remained drug resistant, and the resistance was mostly associated with neuroimaging abnormalities1). In
another study, among 459 patients with childhood epilepsy treated for 2‒14 years (mean 7.5 years), 87 patients (19%) were
drug resistant. The factors associated with the drug resistance were age younger than 4 years, developmental delay or motor
deficit, brain structural abnormality, and specific epileptic syndromes2).

2. Relation of drug resistance with epilepsy syndromes or underlying diseases3)
In children, there are drug-resistant epilepsies specific to age of onset4, 5). Infantile epileptic encephalopathies (including
early-stage myoclonic encephalopathy, Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, Westsyndrome, and Dravet syndrome) and early childhood onset epileptic encephalopathies (Lennox-Gastaut syndrome,
myoclonic encephalopathy in non-progressive diseases, and myoclonic absence seizure) are extremely drug resistant. In these
epilepsies, seizure control is almost impossible except for West syndrome, in which seizures could be controlled inapproximately 50% of the cases.
As in adults, seizures caused by localized cortical dysplasia in children are drug resistant, but some childhood-specificepilepsies such as epilepsies associated with unilateral megalencephaly, lissencephaly, and holoprosencephaly are markedly
severe and seizures cannot be controlled by antiepileptic drugs.
Among chromosomal abnormalities, seizures associated with ring chromosome 20 syndrome are intractable, and seizures
associated with 4p minus syndrome (Wolf-Hirschhorn syndrome) are also highly drug resistant.
Among neurocutaneous syndromes, seizures associated with Sturge-Weber syndrome and linear nevus syndrome are notcontrolled by drugs. Tuberous sclerosis is accompanied by epileptic seizures at a very high rate (approximately 85%), andmost cases are West syndrome. West syndrome caused by tuberous sclerosis responds well to vigabatrin, but rarely responds
to other antiepileptic drugs.
Epileptic seizures associated with destructive lesions in the brain caused by hypoxic ischemic encephalopathies such as
encephalitis/encephalopathy, meningitis, and severe neonate asphyxia; as well as seizures associated with neurodegenerationsin the brain such as metabolic neurological diseases and neurodegenerative diseases (including DRPLA, Krabbe disease,neuronal ceroid lipofuscinosis, and GLUT-1 deficiency) are drug resistant, and seizures related to autoimmune encephalitis
are also drug resistant in children.

▪ References
1) Wirrell EC, Wong-Kisiel LCL, Mandrekar L, et al. What predicts enduring intractability in children who appear medically intractable in the first
2 years after diagnosis? Epilepsia. 2013; 54(6): 1056-1064.
2) Ramos-Lizana J, Rodriguez-Lucenilla MI, Aguilera-Lopez P, et al. A study of drug-resistant childhood epilepsy testing the new ILAE criteria.
Seizure. 2012; 21(4): 266-272.
3) Ohtsuki Y, et al. (ed.) Clinical Practice Manual for Rare Refractory Epilepsies. Tokyo: Shindan To Chiryosha, Inc. 2013. (in Japanese)4) Bureau M, Genton P, Dravet C, et al eds. Epileptic syndromes in infancy, childhood and adolescence. Montrouge: John Libbey Eurotext, 2012.
5) Duchowny M, Cross JH, Arzimanoglou A eds. Pediatric Epilepsy. New York, McGraw Hill, 2013.

Chapter 547

Figure 1. Ages of children and specific epilepsy syndromes.

(Modified from: Bureau M, Genton P, Dravet C, et al. eds. Epileptic syndromes in infancy, childhood and adolescence.
Montrouge: John Libbey Eurotext, 2012./ Duchowny M, Cross JH, Arzimanoglou A eds. Pediatric Epilepsy. New York, McGraw
Hill, 2013.)

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Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 5-4

What is pseudo-drug-resistant epilepsy?
Summary
Pseudo-drug-resistant epilepsy arises when appropriate antiepileptic drugs are not used at adequate doses, which
may be due to misdiagnosis of the epilepsy or seizure type, wrong choice of antiepileptic drugs, wrong dosage, orpoor adherence.

Comment
When epilepsy is found to be drug resistant, it may be truly drug resistant; that is, not responding to appropriately selected
antiepileptic drugs at adequate doses, or it may be pseudo-resistant because appropriate drugs are not used at appropriate
doses.

1. In the case of inappropriate choice of drugs(1) The most common cause is misdiagnosis of non-epileptic seizures as epilepsy, such as psychogenic non-epileptic seizures(PNES), syncope, and arrhythmia. (2) Inappropriate drugs are selected due to wrong diagnosis of epilepsy syndrome or
seizure type. (3) The antiepileptic drugs are inappropriate for the correct diagnosis of seizure type or epilepsy syndrome, suchas using carbamazepine for myoclonic seizure leading to exacerbation1).
In one study in which 1,590 patients underwent simultaneous EEG-video monitoring, 32.3% were found to havepsychogenic seizures2). In another study, 46 (25%) of 184 patients treated for epilepsy did not have epilepsy, and 12 (13%) of
94 patients who were regarded as having intractable epilepsy did not have epilepsy3).

2. In the case of drug resistance despite using appropriate drugs
The cause may be due to pharmacokinetics, such as (1) the blood concentration may be low because the dose is inadequate,
or may not be much enough because not titrating the dose to the maximum tolerable level paying too much attention to thetherapeutic range of blood concentration; (2) inappropriate multidrug therapy including a combination of drugs showinginteractions (see Table 1 of CQ 12-4 on page 109) that lower the blood concentration; and (3) occurrence of drug tolerance(including benzodiazepines and acetazolamide).

3. In the case of drug resistance despite prescription of appropriate antiepileptic drugs at adequate doses
The causes may include (1) poor adherence due to a lack of understanding and motivation of epilepsy treatment by thepatient or the family, or excessive anxiety over antiepileptic drugs; (2) induction of seizures by alcohol or drug abuse, andpoor adherence; (3) inappropriate time of drug taking or irregular time of drug taking due to irregular life rhythm such asnight shift; and (4) lifestyle problem such as shift work causing disturbed circadian rhythm, sleep deprivation, and fatigue1).

▪ References
1) Kwan P, Schachter SC, Brodie MJ. Drug-resistant epilepsy. N Engl J Med. 2011; 365(10): 919-926.
2) Martin R, Burneo JG, Prasad A, et al. Frequency of epilepsy in patients with psychogenic seizures monitored by video-EEG. Neurology. 2003;
61(12): 1791-1792.
3) Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. Q JM. 1999;
92(1): 15-23.

Chapter 549

CQ 5-5

How to manage drug-resistant epilepsies?
Summary
The first step to manage drug-resistant epilepsy is finding the cause. After reviewing the seizure symptoms, epilepsy
diagnosis and etiology of epilepsy, assess whether the case is truly drug resistant or pseudo-resistant. In the case ofpseudo-resistance, remove the causative factors (see CQ 5-4 on page 50). In the case of true resistance, review the
drug therapy (diagnosis, choice of drugs, dose, use of antiepileptic drugs based on pharmacokinetics, rational use ofmultidrug combinations, etc.) and consider other treatment options such as surgery and immunotherapy.

Comment

1. Are the choices of drug and dose appropriate?
Confirm the seizure symptoms, medical history, situations when seizures occur, interictal EEG (sleep EEG essential), andbrain MRI. Examine the underlying disease (family history, past history, present illness, general physical findings, andneurological findings). Based on the above, determine whether the case is truly epilepsy or not, and diagnose the seizure typeand epilepsy syndrome, and investigate the etiology of epilepsy. Next, examine the type of antiepileptic drug and dose, andblood concentration. Interview, gesture mimicking seizure symptoms, and video recording by family members are useful toconfirm seizure symptoms.

2. Identification of pseudo-drug resistance and management
a. Differentiation between epilepsy and confounding seizure symptoms (see CQ1-4 on page 10, and CQ1-5 on page 11)
Confirmation of seizure symptoms (from home video if possible), interview (especially the situation of seizure occurrence),
interictal sleep EEG, and video-EEG monitoring are useful.
b. Review diagnosis of epilepsy, epilepsy syndrome and related seizure disorders, as well as seizure type
The procedures are similar to those described above (a). Juvenile myoclonic epilepsy is sometimes misdiagnosed as partial
epilepsy and treated with carbamazepine or phenytoin, which may exacerbate the seizures1).
c. Review the choice of drug and the dose
Examine whether the drug is appropriate for the epilepsy syndrome and seizure type (see Table 1 in CQ4-6 on page 42
and Table 1 in Chapter 6 on page 54), whether the drug is used sufficiently (dose and blood concentration), and whether
tolerance occurs. In the case of multidrug therapy, examine whether each drug is appropriate for the seizure type, whether
there is drug interaction that lowers blood concentration, and whether drugs with the same mechanism of action are used in
combination.
From the above information, switch to the appropriate drug, up-titrate until the maximum tolerated dose with bloodconcentration exceeding the therapeutic range, and confirm the effect. Conduct rational multidrug therapy by selecting
drugs appropriate for each seizure type, increase or decrease the doses considering drug interactions, and use drugs withdifferent mechanisms of action in the combination.
d. When poor adherence is suspected
Confirm the situation of drug taking (time of drug taking, missed doses), lifestyle and rhythm, as well as time andsituation at which seizures often occur. Monitoring blood concentration is useful for detecting habitual poor adherence.
To prevent lowered adherence, explain to the patient and the family about the following: (1) the nature of epilepsy fromthe viewpoint of epilepsy syndrome and the prognosis, (2) the necessity of treatment, (3) caution in daily life, and (4)properties of the drugs being taken (half-life, interaction with other drugs or foods, possible adverse effects and theirfrequency and severity). Also, adjust the time of drug taking considering the patient’s lifestyle such as night shift.

50Part IThe Clinical Practice Guidelines for Epilepsy 2018

3. True drug-resistant epilepsy(1) If MRI detects an intracranial lesion, evaluate for epilepsy surgery soon.
(2) Select first-line or second-line drug that is deemed appropriate, and increase the dose up to the maximum tolerated
dose. As long as adverse effects are not induced, up-titrate to blood concentrations exceeding the therapeutic range. When
adverse effect appears, reduce the dose.
Despite the above procedures, if seizures remain uncontrolled, conduct rational multidrug therapy considering interactionsof antiepileptic drugs (see Table 1 of CQ12-4 on page 109) and the mechanisms of action. Add a drug that has different
mechanism of action from the drug currently being used or a drug with multiple mechanisms of actions2). An effective
combination is to use a Na+ channel blocker and a GABAergic inhibition enhancer. Although the therapeutic effect isincreased by combining two drugs that both enhance GABAergic inhibition, or combining two glutamate receptor inhibitors(such as AMPA antagonist and NMDA antagonist), tolerability is often reduced. Combination of two Na+ channel blockers
not only has limited effectiveness, but also causes adverse effects such as exacerbating dizziness3).
(3) Consider referral to or consultation with epilepsy specialists, measurement of autoimmune antibodies, andimmunotherapies (including intravenous immunoglobulin, steroids, and immunosuppressants), and consider surgicalindication even though MRI shows no intracranial lesions.

▪ References
1) Sazgar M, Bourgeois BF. Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol. 2005; 33(4): 227-234.
2) St. Louis EK. Truly “rational” polytherapy: maximizing efficacy and minimizing drug interactions, drug load and adverse effects. Curr
Neuropharmacol. 2009; 7(2): 96-105.
3) Brodie MJ, Sills GJ. Combining antiepileptic drugs—rational polytherapy? Seizure. 2011; 20(5): 369-375.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015(((intractable [TIAB] OR refractory [TIAB]) AND “Epilepsy/therapy” [majr])) AND “treatment outcome” [mh] Filters: Review; Publication datefrom 2008/01/01 to 2015/12/31; Humans; English; Japanese = 112

Chapter 551

CQ 5-6

What are the intellectual prognosis and social prognosis of drugresistant epilepsy?
Summary
Both intellectual and social prognoses are poorer than people without epilepsy, and there are major disadvantagesin academic, employment, and marriage aspects. These two outcomes are especially poor when seizures are notcontrolled. The rate of sudden death is also higher among people with epilepsy than the general population.

Comment

1. Socioeconomic situation
For people with drug-resistant epilepsy, even when they have no intellectual problems and are in general employment,
their work contents are sometimes restricted. In addition, if seizure occurs at work, they often lose their jobs. They also often
have difficulty in marriage. In the United States, the total household annual income of people with epilepsy is 93% of theaverage annual income of the whole population, their unemployment rate is 25%, the high school graduation rate of those
aged 25 years and above is 64% (82% in the United States in general), and the marriage rate of those aged 19 years and above
is 51% for men and 48% for women (63% and 59%, respectively, in the United States in general)1). This data is for all
epilepsies including treatable epilepsies, and these figures would be even worse in people with drug-resistant epilepsy.

2. Intellectual prognosis
In a study of 136 adults with various epilepsies who had uncontrolled seizures, WAIS-R was performed twice with aninterval of 10 years or longer. The mean verbal IQ decreased from 90.3 to 82.3, performance IQ decreased from 91.0 to 84.5,
and full scale IQ decreased from 91.0 to 84.5, and the frequency of generalized tonic-clonic seizure was most strongly related
to the cognitive decline2).

3. Social prognosis
Among 102 patients (mean age 28.6, range 15‒60 years) with Lennox-Gastaut syndrome followed long-term for 10‒20(mean 16.3) years, 12 patients worked normally, 36 worked part-time or at a sheltered workshop, and the remaining 54 were
under home care or institutionalization3). Most of the 12 patients in normal employment were seizure-free for at least 1 year
or had only tonic seizures during sleep.
Ninety-nine patients with uncomplicated childhood epilepsy (onset age younger than 16 years) followed for 27‒31 years
were compared with controls matched for sex, age, and birthplace. The relative risk of completing primary education only
was 2.1-fold, not married was 3.5-fold, no children was 3.0-fold, and unemployed was 3.8-fold4).

4. Sudden unexpected death in epilepsy (SUDEP)
SUDEP refers to death for which no cause can be found besides suffering from epilepsy.
Patients with epilepsy have high mortality rate and high SUDEP rate. The standardized mortality rate for SUDEP was
24-fold compared to the general population, accounting for 2‒17% of all-cause deaths in epilepsy patients5).
The mortality rate of 2,689 patients with chronic epilepsy who had been followed for 20 years was 2.05 times the mortality
rate of the general population in Scotland matched for sex and age6). The incidence of SUDEP per 1,000 person-years was
0.35‒1.5 cases in a population-based incidence cohort of epilepsy, but increased to 1.2‒3.8 cases in persons with chronic
epilepsy and further to 3.5‒9.3 cases in persons with intractable epilepsy. Seizure frequency is the strongest risk factor for
SUDEP, and other risk factors are onset at an early age and long duration of disease7). The risk of SUDEP increases if
generalized tonic-clonic seizures are not controlled.

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▪ References
1) Fisher RS, Vickrey BG, Gibson P, et al. The impact of epilepsy from the patient’s perspective I: descriptions and subjective perceptions. Epilepsy Res.
2000; 41(1): 39-51.
2) Thompson PJ, Duncan JS. Cognitive decline in severe intractable epilepsy. Epilepsia. 2005; 46(11): 1780-1787.
3) Yagi K. Evolution of Lennox-Gastaut syndrome: a long-term longitudinal study. Epilepsia. 1996; 37(Suppl 3): 48-51.
4) Sillanpää M, Jalava M, Kaleva O, et al. Long-term prognosis of seizures with onset in childhood. N Engl J Med. 1998; 338(24): 1715-1722.
5) Ficker DM, So EL, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology. 1998; 51(5): 12701274.
6) Mohanraj R, Norrie J, Stephen L, et al. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet
Neurol. 2006; 5(6): 481-487.
7) Tomson T, Walczak T, Sillampaa M, et al. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia. 2005; 46(Suppl11): 54-61.

▪ Search formula and secondary reference sources
PubMed search: June 29, 2015((((intractable [TIAB] OR refractory [TIAB]) AND “Epilepsy” [majr])) AND (((“Intelligence” [Mesh] or “Intelligence Tests” [Mesh])) OR “Social
Adjustment” [mh])) AND (“prognosis” [MeSH] OR “cohort studies” [MeSH] OR “follow-up studies” [MeSH]) Filters: Publication date from2008/01/01 to 2015/12/31; Humans; English; Japanese = 36

Chapter 553