barbiturate-refractory epilepsy - SciELO

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E i g h t p a t i e n t s w e r e o n p h e n o b a r b i t o n e a t a d o s e o f 1 2 5 ± 2 0 rag daily (mean±standard deviation). Two were on primidone 750 and 1000 ...
BARBITURATE-REFRACTORY EPILEPSY SAFE

SCHEDULE FOR

ANA

MARIA

CARLOS PAULO

E.

THERAPEUTIC

GORZ S.

ROGÉRIO

SUBSTITUTION

*

SILVADO M.

** BITTENCOURT

*

Barbiturates are the main line of antiepileptic drug therapy in many third world countries due to a traditional prescribing habit which survives to this day in relation to factors such as low cost and simplicity of use. An over-simplification of epilepsy as a uniform clinical entity allows usage of a single treatment at any age without regard to specific types of seizure disorders. There is also widespread belief that there are no side-effects of considerable importance associated with barbiturates, completing an illusory picture of a simple medical problem, epilepsy, which may be solved by a simple therapeutic manoeuvre, barbiturates. The frequency of barbiturate side-effects is high, but they may go unnoticed by physicians because they affect mood and intellect in a relatively subtle manner. In children the frequency of hyperkinetic behaviour varies from 8% to 4 2 % in different studies . The latter may be a more correct estimate related to increased awareness by more recent inves­ tigators. In adults there is evidence that barbiturates impair sustained attention and memory function . Some of these effects are related to serum concentrations and their severity decreases as the drug is withdrawn . Sedation, psychomotor slowing and depression of mood are the most common observations during chronic therapy, although tolerance usually develops at least partially as time g o e s on 8. Tolerance appears to develop to the therapeutic as well as to the side-effects of phenobarbitone 3 . Patients tolerate progressively higher doses which are needed to maintain seizure control 3,5. Rebound increase in seizure frequency is the rule on withdrawal of barbiturates . Varying rates of development of tolerance probably underlie the difficulty in establishing rela­ tionships between serum concentration and affect on central nervous system (CNS) function . 9..13

6

7

6,10

4,5,10

11

W e have studied a population of epileptic patients who became refractory to barbiturates after varying amounts of time. Their types of seizures and the seizure frequency during replacement of barbiturates by therapy drugs with other drugs were evaluated in a prospective manner with the objectives of clarifying which patients tend to become refractory and what may be an appropriate schedule for withdrawal. U n i d a d e d e N e u r o l o g i a Clínica, H o s p i t a l N o s s a S e n h o r a d a s Graças * e D e p a r t a m e n t o d e C l í n i c a M é d i c a , H o s p i t a l d e C l í n i c a s d a U n i v e r s i d a d e F e d e r a l d o P a r a n á **, C u r i t i b a , Paraná,

Brasil.

PATIENTS Approximately clinic

of

the

1982 a n d basic

April

data

were

epilepsy

seen

with

of

these

in

carbamazepine

If

drugs

(generalized

The new drug w a s adjusted the

were

barbiturate

changed

depended jf

one

to

was

an

on the

The

of

Neurology

do

Parana

study

seizures,

they

seizures

designed

were

with

or

equivalent

dose

of

on

For

to

mono­

generaliza­

types)

or

pharmacological

this

phenobarbitone.

of s e i z u r e s b u t u s u a l l y

patients

reduced without

until clinical toxicity or seizure control

frequency

standard

any

seizures).

while

withdrawn.

obtain

When

T h e procedure for w i t h d r a w a l w a s

progressively

April

to

established

the a b s e n c e or m y o c l o n i c

seizures

out-patients

between

monotherapy.

tonic-clonic

uncontrolled

the

protocol

achieving

(partial

seizures

in

Federal

prospective

uncontrolled

barbiturate drugs these were withdrawn.

which

a

of

generalized

with

assessed

Brazil (1,2).

phenytoin

(primary

patients presented

in

objective

with

or

were

included

the

METHODS

Universidade

southern

on polytherapy

three

da

were

with

tion), sodium valproate

patients

Clinicas

They

procedures

first

therapy

epileptic de

1984.

on

therapeutic

600

Hospital

AND

was achieved,

purpose

The

it w a s

rate

reduced

doses

all

of

by

of

standardized. after

barbiturates

dose

reduction

50% at

intervals

month. RESULTS

Fifty-two

patients

cases

withdrawal

none

needed

Their

age

level

or

family

to

completed

be

illiterate,

two

partial

of

t h e 10 p a t i e n t s .

A

focal

to

an

these

years.

had a specific Five

with

The

withedrawal

increase

patients

deviation)

neuro-psychiatric

two

seizures

generalization.

barbiturate

due

Four

had

and

the

meningo-encephalitis).

simple

with

enter

(mean±standard

for epilepsy

and

had

agreed not

admission.

24±8

were

history

seizures of

hospital

was

hemiplegia three

could

male

had

disturbances, etiology

6

a

complex

and

two

found

female.

two

had

was

had

positive (infantile

partial

seizures,

had

complex

was

abnormal

in

5

partial in

patients,

were

on

had

barbiturate

epilepsy

monotherapy.

valproate.

Taken

together

deviation)

years.

Eight

daily The

(mean±standard monthly

increased two

seizure

seizure

when

they

barbiturate barbiturates

was

they

Five

patients

frequency

not

had

increased

to

on

Two

of

follow

were

been

were

of

drug

the

on

on

the

previous

for at

primidone was

10.

barbiturate

initial

to

achieved,

these patients wil

Twenty-four

female

successful

barbiturate

deviation),

with

a

primary

a range

educational

and

18

not

be

male

withdrawal.

considered patients

Their

o f 15 t o 64 y e a r s . level

or

were

age

any

(81%) was

dose

of

and

1000

and

further of

Eighty-eight

illiterate,

17%

the

had

per

on

mg

decreased,

patient after

small

initial years of

when

the

the

dose

of

number

and

to

successful (Table

rag

daily.

developed

been

one

cent

sodium

125±20

patients

had

settled

their

29±13

one

The

patients

(mean±standard

a

their characteristics w h i c h w e r e similar to those patients in w h o m was

Four

750

Seven

They

Due

and 7±6

dose

correctly dose.

step.

years.

phenytoin

phenobarbitone

regimen

25% of t h e

deviation)

barbiturates

10 p a t i e n t s

50%

the

also

on

were

these

when

reached

(mean±standard

had

deviation).

frequency did

dose

for 1 2 ± 6

9

other

foca.1 a b n o r m a l i t i e s i n t w o a n d g e n e r a l i z e d a b n o r m a l i t i e s i n t h e r e m a i n i n g t w o c a s e s . 10 p a t i e n t s h a d

10 but

educational

patients

abnormality

and

for their epilepsy

(EEG)

In

frequency

primary

generalization

lobe

schedule.

seizure

were

All

electroencephalogram

temporal

in

withdrawal

1). group

achieved

(mean ± standard the patients

neuro-psychiatric

had

associated

features was of

and

found severe

one

had

severe right

24% had

in

hypoxia a

middle

Routine

EEG

temporal

lobe

abnormalities in the

9%

presence

disturbance

the

one

artery.

records

showed

abnormality were

of

a

(focal

found

for

Six

time

meningitis,

and

cerebral

generalized

or w i t h o u t

of

injury,

history

(40.4%).

around

history

head

a positive

17 p a t i e n t s

of

one

patient The

their was

had

was

areas.

discharges

focal

lesion

spikes

generalization

or

slowing)

(71.4%).

in

In

in

54.6%

seizures) the

and

his

of

the or

for

head

the is

the

started

territory

shown

In

clinical

with

evidence

had

partial

the 2).

A

focal

18.2%

focal

slowing

Combining

42 p a t i e n t s

after of

(Table

patients.

EEGs.

6

hemiplegia,

generalized

EEG

epilepsy injury,

infantile epilepsy

on

types

52% of

etiology severe

had

infarct

focal

found.

of

had

seizures

18.2%

were

of

two

an

features

(partial 30

of

specific

history

hemophiliac

frequency

spike-wave brain

birth,

demonstrated

other

A

had

sustained

epileptogenic

in

epilepsy.

patients

and

evidence of

of

a

focal

epilepsy

with

por

The

42 p a t i e n t s

6±6

years

monotherapy 57%

took

mazepine 113±39

phenytoin and

as

a

phenytoin.

(mean±standard

barbiturates subsequent

at

for

the

6±6

barbiturate were

(22.5%),

respectively

and/or

change Time

The

Four

of

15 ± 9

750 a n d

13±7

withdrawal over

at

dosages the

and/or

over from barbiturate

to

time

sodium

barbiturates withdrawal

1000

mg

The

started 1.7

monotherapy of 7 5 2 ± 2 4 5

patients

were

had

cent

of

carbamazepine

daily. for

per

and

were

latter

took

carba-

15%

withdrawal

The

had

42 p a t i e n t s

of

was

per

333±39

5;r3

seizures frequency month

mg

daily

been

patient

seizures

(Table or

was

patients

months

per of

(67.5%)

polytherapy

on

Of t h e

Two

carbamazepine

to

barbiturates

i n 40 p a t i e n t s .

The

patient

and

changed

on

patients

before

withdrawal

7.1.

with mg

used

frequency

was

been the

on poly therapy.

barbiturates

necessary

became

and

phenobarbitone

months. were

per

50% w e r e took

of

of

years

Fifty

19%

dose

mg

The

was

of

drug,

daily

deviation) dose

changed

phenytoin

of

for

deviation).

drug changes

patients

deviations).

epilepsy

second

years.

follow-up

before the

complete

had

with a barbiturate and the other

took primidone

month

had

(mean±standard

3).

on and per

after Forty

phenytoin

(means±standard

with

carbamazepine

valproate.

to

carbamazepine, varied. COMMENTS

phenytoin

or

sodium

valproate.

The results demonstrate that withdrawal of barbiturate with concomitant replacement by efficient antiepileptic drug therapy is possible in 4 out of 5 patients with uncontrolled epilepsy. The absence of complications such as status epilepticus was possibly due to the progressive nature of the drug change. Besides making possible the withdrawal of medication which w a s not efficient any longer- this manoeuvre improved seizure control in 42 of 52 patients. Few similar studies have been published. Theodore and Porter reported the results of withdrawal of benzodiazepine and barbiturate drugs in 78 patients with intractable epilepsy i . In 48 cases this was accomplished while patients were admitted to a specialized epilepsy unit and in the 30 remaining cases the change-over w a s carried out on and out-patient basis. Seizure frequency, signs of central nervous system toxicity and in some cases performance at school improved in subjective criteria used by the investigatores. Our results suggest that hospitalization is not generally necessary for withdrawal of barbiturates. 2

The 42 patients in whom successful withdrawal w a s achieved had a history of brain injury due to trauma, hypoxia, infection or other causes in 40% of the

cases, as compared to similar etiology in 30% of the general epileptic population of Curitiba . The frequency of patients with partial seizures is higher in the barbiturate refractory group (74.4%) than in the general epileptic population 60%!, using similar definitions. The frequency of abnormal EEGs w a s higher in the present group (52% as compared to 4 0 % ) . There was a high frequency of temporal lobe epileptogenic abnormalities (55% of abnormal EEGs). 1

The group of barbiturate refractory patients is characterized by long-standing epilepsy, the diagnosis having been made approximately 15 years before they entered the study. They had been on barbiturates for approximately 6 years but the study did not show how long after beginning barbiturates patient.; became refractory. Evidence from earlier studies 4 , 5 , 1 0 s well as from these results indicate that the antiepileptic effect of barbiturate drugs may decrease during chronic therapy, specially in cases of partial epilepsy with or without generalization when a temporal lobe abnormality is found in the EEG. The amount of time necessary for development of tolerance is not clear, but is under 6 years in average. The difficult situation then achieved may be improved significantly by a progressive decrease of barbiturates drugs over a period of in average 5 months on an out-patient basis, in the majority of cases. As most patients which become refractory suffer from partial epilepsy, carbamazepine and phenytoin seem the most appropriate drugs to be instituted. a

Serum concentrations were not measured in this study because they are not available routinely in most third world countries. As demonstrated previously (Bittencourt et al. 1 9 8 3 ) tailoring the dosage through close clinical observation of seizure frequency and signs of CNS toxicity appears to suffice in the majority of cases, if pharmacokinetic principles are kept in mind. Although formal assessment of neuro-psychological function w a s not carried out, there w a s a generalized feeling among patients and physicians that irritability, slowness of thought, depressed mood and generalized viscosity of behaviour improved significantly as patients became free of barbiturate drugs. These uncontrolled observations are in agreement with similar observations of Theodore and Porter 12 and with a number of previous studies showing impairment of various aspects of higher brain functions by barbiturate drugs 6 , 7 , 9 , 1 0 . 2

Taken together, the development of tolerance and the resulting reapperance of seizures with the impairment of brain functions seem to contra-indicate barbiturates as first-line antiepileptic drugs, contrary to widespread and traditional practices in third world countries. SUMMARY

Barbiturates are considered first line antiepileptic drugs in third world countries due to traditional and economic reasons. This prospective uncon­ trolled study of 52 patients aged 15 to 64 years (mean 24) demonstrates that patients who become refractory to barbiturates are mainly those with partial seizures with or without generalization or with a focal EEG abnormality ( 7 1 % ) . Seizures tend to become refractory approximately 6 years after barbiturates were started. Progressive barbiturate withdrawal over a period of two to 8

months (mean 5) with institution of treatment with carbamazepine, phenytoin or sodium valproate allowed complete barbiturate withdrawal in 42 of the 52 patients ( 8 1 % ) . Furthermore monthly seizure frequency in those in whom barbiturates were withdrawn decreased from 7.1 to 1.7 per patient. An improvement in mental status w a s observed but not measured. These results show that barbiturates should not be first-choice drugs in patients who have a chronic disease such as epilepsy, and indicate a schedule for barbiturate withdrawal Which is safe and independent of hospitalization or monitoring of antiepileptic drug serum concentrations. RESUMO

Epilepsia terapêutica.

refrataria

a barbitúricos:

esquema

seguro

para

substituição

de

Barbitúricos são considerados tratamento anti-epiléptico de primeira escolha em países do terceiro mundo devido a razões econômicas e tradicionais. Este estudo prospectivo e não-controlado de 52 pacientes com idades entre 15 e 64 anos (média de 24) demonstra que pacientes que se tornam refratários a barbitúricos são principalmente aqueles com crises parciais com ou sem generalização secundária ou com uma anormalidade focal no eletrencefalograma ( 7 1 % ) . As crises parecem se tornar retratarias aproximadamente 6 anos após o início do tratamento com barbitúricos. Retirada progressiva em um período de dois a 8 meses (média de 5) com início de tratamento com carbamazepina, difenil¬ -hidantoína ou valproato de sódio permitiu retirada completa dos barbitúricos em 42 dos 52 pacientes ( 8 1 % ) . Além disso a frequência mensal de crises naqueles de quem barbitúricos foram retirados diminuiu de 7,1 para 1,7 por paciente. Melhora no estado mental foi observada, porém não medida. Estes resultados indicam que barbitúricos não deveriam ser drogas de primeira escolha em pacientes com doença crônica tal como epilepsia, e indicam uma forma de retirada de barbitúricos que é segura e independente de hospitalização ou de monitorização de níveis séricos de drogas anti-epilépticas.

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Unidade 80510 -

de Neurologia Curitiba, PR

-

Clínica, Brasil.

Hospital

N. S.

das

Graças

— Rua

Alcides

Munhoz,

433

-