CURRENT ISSUES
------------------------------------- 3 Epilepsy: clinical questions and clinical outcomes - Heather Langtry-
T A ]hat outcomes of epilepsy treatment are important to patients and how can these be
" V measured by objective means? What makes epilepsy drug-resistant and how should intractable epilepsy be treated? These and other questions were raised at the 22nd International Epilepsy Congress [Dublin, Ireland; July 1997]. 'Seizures are the most commonly assessed endpoint in epilepsy', noted Dr Anne Berg from the US. However, seizure outcome is often an intermediate goal. She explained that health-related quality of life (HRQOL) is usually the ultimate goal of therapeutic interventions.
Looking at QaL The goal of treatment should not simply be to improve QOL, but to improve QOL by improving clinical status and functional ability, said Dr Berg. As it relates to daily clinical practice, assessing HRQOL is more complex and less easily measured than seizure parameters. To maximise the benefits to the patient, researchers must now correlate seizure outcomes with HRQOL outcomes, she added. Measuring QOL will be further refined in the future, according to Dr Bert Spilker from the Walton Centre of Neurology and Neurosurgery, Liverpool, UK. Although QOL is now the ultimate efficacy endpoint in clinical trials of most medical problems, it will eventually playa greater role in clinical practice than it does today, he added.
Which QaL measures? According to results from 2 clinical studies, QOL trials appear to be well-poised to answer the question: if treatment can't cure the disease, do patients think it at least makes it better?
Patient perceptions before and after 20 weeks of monotherapy with either lamotrigine 500 mg/day or valproic acid 1000 mg/day were assessed in adults with partial seizures using the Liverpool Seizure Severity Scale. With lamotrigine, ictal/postictal measures improved both in patients with major seizures and in those with minor seizures, according to Dr Linda Bryant-Comstock of Glaxo Wellcome, US. In addition, there were improvements in both seizure severity and behaviour associated with major seizures. In contrast, valproic acid did not alter major seizure severity, although minor seizures were perceived as less severe, she added.
Impact of lamotrigine on QaL In the second study, the Aberrant Behaviour Checklist and a disease-specific QOL questionnaire were used to assess the effects of lamotrigine on seizure severity, mood and behaviour of 33 adults and children with learning disabilities, according to Dr Gus Baker from the Walton Centre of Neurology and Neurosurgery. Caregivers were surveyed before and after 3, 6 and 9 months of open add-on lamotrigine treatment. Significant reductions in seizure severity and improvements in perceived control were reported for those patients who did not become seizure-free. Behaviour, mood, lethargy, and hyperactivity also improved after addition of lamotrigine. The caregivers also reported
Results from selected outcomes studies reported at the 22nd International Epilepsy Congress. Studv
Pellocla, et aI.
1
FowIef, et aI.2
PaIenU
Protocol
Outcome-.
FIndInge
ChlIdr8n with per1lal epilepsy (n:8)
Patients _ evaluated befo(e and after 6 ITIQrlths of IarnotrIgIne treatment
Stanford-Blnet and behavioural ques1lonnalres
LMnotrll;ne lmproYed 8Ilenllve
Adolescents wI1h epilepsy and
Baseline _ t and follow-up assessment after a mean 0119 wMks of toplramate treatment BaselIne .....,.,.,. and follow-up aft8f .. months 01 I8mo4rIglne lnI8lment
Rutter BehavIour SC8Ies A end B AIigrlltlc31t na-ln
learning cisablllties (n : 16)
Placi
Patients wI1h drug-reslstant epIepsy (n =13)
Rosenfeld, et aI.~
Patients wI1h epiIeptly receiving phenytoin, valprolc acid 01'
C8ltlBmazeplne (n
=40)
reported negdYe behaviour
on topIl'lIl'lllltlt
lMnotrlglne lncnIeIed REM Ileep wI1h no change In daylIme IIeepi-.
TopIlMl8Ie ... s;ven as
MlitipIe Sleep l..UIncy Teet and Stanford SIeeplneu Sc:aIe and ~ Bodywelg1t
GABA IIMIls m.acnd In
Nudear m«gnelIc I8llONII\C8
Gab8pentIn lhefapy . . . ueoclated wI1h good control In pallenta wIltl above normal brain IeYels 01 GABA
Quantitallve ~ racIogrBptIy
S91IfIcan1Iy I8duced lumbar Bnd temoraI bone mineral density In patients than controls
add-on lherapy to Olher drugs known to be auocIal8d wIltl weight g8Irt
Mattson, et aI.5
Patients wI1h complex partial selzures (n 18) receiving gabapenlln and controls (19)
KIfIme, et a1.'
Patients wI1h epIlep1y who _ L.umb8r spine end lemor8l neck medicated for ~ 5 yea" (n 45) bone mineI'aI density aueseed Bnd age-matched controls without epilepsy (62)
Galli, et aI?
Pallenta wI1h per1lal epilepsy
=
betlaVIcu' and lid not alleet IQ
14an' 8I'8ll 01 oocipItaIlobe
=
8aMllne .....,.,.,. and again attsr 2 monltla 0I18molrIgIne lherapy
1173-550319710130-0003l$O1.000 Adl. Inl8mlltionlll limited 1llll7. All rights ..-YlId
speclrometet
01 bone densiIy
Mt,;tIpIe Sleep Latency Teet
Add-on toplramate lhenIpy was
ueoclated wI1h weiglt Io8s but not below lde8I ~t
No daytime aomnolence effects wI1h~
PharmacoEconomics & Ou1comes News 20 Sep 111117 No. 130
CURRENT ISSUES
4
Epilepsy: clinical questions and clinical outcomes - continued that their own levels of anxiety decreased during lamotrigine treatment. Since the disease process associated with epilepsy can affect psychosocial and cognitive functioning, drug trials need to make comparisons with a baseline as well as with control groups. Changes from baseline can help to detennine whether an effect is due to the drug or the disease. However, practice effects are a common problem in clinical trials which assess the cognitive effects of drugs. A systematic review of randomised controIled trials of the effect of anticonvulsant medication on neuropsychological outcomes also highlighted the need for an agreed protocol for assessing the outcome of anticonvulsant drug treatment on cognitive functioning.' Although clinical trials usually examine seizure outcomes, several recent trials have assessed other outcome measures [see table on the previous page). In these trials, efficacy and tolerability of drug treatment were measured using checks on behavioural or cognitive function and effects on sleep or physiology.
Drug-resistant or not? Clinical trials of new anticonvulsant drugs are generally conducted in patients with intractable or drug-resistant epilepsy. Only recently, however, has much attention been paid to the question: how do you define drug resistance? Several ideas exist. • Is it when patients have ~ 1 seizure(s) per month over 2 years? • Is it when trials of ~ 3 drugs have failed to control seizures? • Is rt when patients have seizures that persist after treatment wrth ~ 1 primary drug at its highest tolerated dose?
Proposed definitions of drug resistance, as they affect inclusion criteria for add-on trials, were discussed by Professor Emilio Perucca of the University of Pavia, Italy. Controversies in defining drug resistance generally relate to factors such as whether resistance is a function of time, age, natural history or the duration of epilepsy. Additional factors include how many drugs have already been tried and whether the drugs have been tried at the appropriate dosages. 'The likelihood of controlling epilepsy in a patient who has failed on 1 drug is greater than in a patient
Pharm8eoEeonomics & Outcomes News 20 Sep 1997 No. 130
who has tried 10 drugs andfailed', according to Professor Perucca A system of grading drug resistance should be agreed upon and put to use in clinical trials. He added that using this type of grading system would aid comparability across clinical studies, avoiding reports of 'drug-refractory patients' in whom the severity of drug resistance is unclear.
How to handle intractable epilepsy A fuIl analysis and precise diagnosis of epilepsy type along with optimal use of appropriate therapeutic agents may make intractable epilepsy tractable, according to Dr Korn-Merker and coIleagues from the K1inik Kidron, Gennany. Evidence for this assertion comes from their study of 110 children with 'intractable' epilepsy.9 After careful assessment and changes to the drug therapy regimens, about one-third of patients became seizure-free and none had daily seizures (down from two-thirds of patients at baseline). 'Take quality of life into account when you can't do anything about a patient's severe epilepsy', advised Dr D Smith from the Walton Centre of Neurology and Neurosurgery, Liverpool, UK. Patients with drugresistant epilepsy should be reviewed for suboptimal drug treatment and noncompliance. When seizure control cannot be achieved, optimal drug combinations of new or older drugs should be used and realistic treatment goals must be set including consideration of the psychosocial needs of the patient, he urged. 1. Baker GA. et aI. A systematic review of neuropsychological outcomes of randomised clinical trials of antiepileptic medication. Epilepsia 38 (Suppl. 3): 60-61. 1997 2. Pelliccia A. et al. Behavioural improvement in epileptic children treated with lamotrigine. Epilepsia 38 (Suppl. 3): 130. 1997 3. Fowler M. et aI. Effects of topiramate on behaviour in adolescents with learning disability. Epilepsia 38 (Suppl. 3): 131. 19974. Placidi F. et aI. Effect of chronic treatment with lamotrigine on nocturnal sleep and daytime sleepiness of epileptic patients. Epilepsia 38 (Suppl. 3): 58, 1997 S. Rosenfeld WE. et aI. Weight loss with topiramate therapy. Epilepsia 38 (Suppl. 3): 58. 19976. Mattson RH. et aI. Gabapentin: a GABA active drug. Epilepsia 38 (Suppl. 3): 65-66. 1997 7. Kifune A. et aI. Bone mineral densities in epileptic patients taking antiepileptics - a study by quantitative digital radiography. Epilepsia 38 (Suppl. 3): 70. 1997 8. Galli R. et al. Correlation between multiple sleep latency test and plasmatic drug concentrations in epilepsy patients treated with lamotrigine monotherapy. Epilepsia 38 (Suppl. 3): 79. 1997 9. Korn-Merker E. et aI. Intractable epilepsies - are they really intractable' Epilepsia 38 (Suppl. 3): 13. 1997 .... '87]2
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