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 Some of these effects are related to serum concentrations and their severity decreases as the drug is withdrawn .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
-