420
Convulsions after
enflurane in a
schizophrenic patient
receiving neuroleptics
A schizophrenic patient suffered from an episode of unexpected
grand mal seizure following an enflurance anaesthetic for bi-
opsy of an orbital lesion. The seizure was brief and subsided
spontaneously. An assessment of the anaesthetic technique and
a thorough neurological examination which included a CTscan
and an EEG, failed to demonstrate any obvious cause for the
convulsion. The patient was not an epileptic and was receiving
neuroleptic drugs preoperatively for the treatment of schizo-
phrenia. A synergistic role of enflurane and neuroleptic drugs
in producing seizure activity in this patient is a distinct pos-
sibility. Caution is therefore recommended when administering
enflurane to patients on neuroleptic drugs.
Un patient schizophr~ne est saisi d'un accbs de grand real d
la suite d'une anesthdsie ~ l'enflurane pour la chirurgie d'une
Idsion orbitaire. La crise a dtd brbve et s'est rdsolue sponta-
ndment. La rdvision de la technique anesthdsique et I'examen
neurologique complet avec tomodensitomdtrie et EEG n'ont
pas rdvdl~2la cause de la convulsion. Le patient n~tait pas ~pi-
leptique et recevait auparavant un neuroleptique pour le trai-
tement de sa schizoph~nie. I1 est possible que l'association de
l'enflurane et du neuroleptique ait jou~ un r6le dans le d~clen-
chement de la crise convulsive. La prudence est recommandde
quand on administre de I'enflurane d u n patient sous neu-
roleptique.
Key words
ANAESTHETICS,VOLATILE:enflurane;
ATARACTICS:phenothiazines, thioxanthines;
COMPLICATIONS:convulsions.
From the Department of Anaesthesia, Manchester Royal
Infirmary, Manchester, U.K.
Address correspondence to: Dr. S.B. Vohra, Department of
Anaesthesia, Manchester Royal Infirmary, Oxford Road,
Manchester MI3 9WL, U.K.
Acceptedfor publication 26th January, 1994.
C A N J A N A E S T H 1994 / 41: 5 / pp420-2
S.B. Vohra MBBS MD FFARCSI
Enflurane is one of the many anaesthetic agents known
to produce convulsive effects. These effects are precip-
itated at high concentrations especially in the presence
of hypocarbia as the seizure threshold is lowered, i Ad-
ditive and synergistic roles of various drugs or their me-
tabolites, in potentiating seizure activity produced by en-
flurane have been suggested. 1-5 A case of possible
synergism between enflurane and phenothiazines and thi-
oxanthines in producing convulsions is reported.
Case report
A 39-yr-old 50-kg man was admitted for investigation
of a left orbital lesion associated with pain, photophobia
and redness of the eye of one week duration. There were
no symptoms or signs of intracranial extension. He was
a known schizophrenic who had been treated with electro-
convulsive therapy and chlopromazine 100 mg four times
a day for five years. Flupenthixol 40 mg On every two
weeks had then been added to his regimen and chlor-
promazine reduced to 50 mg three times a day. This ther-
apy continued for ten years. At the time of admission,
the patient had been taking chlopromazine irregularly,
parenteral flupenthixol being continued as before. There
was no history of epilepsy in the family. He had had
two other uneventful general anaesthetics in the past for
minor procedures.
Preoperative systemic examination, biochemical studies
including thyroid function tests and haematology were
all normal. A provisional diagnosis of orbital lymphoma
or a pseudotumour was made. An ultrasound examina-
tion of the eye and CT scan of the brain were carried
out to exclude an intracranial extension. A biopsy of the
mass was scheduled for the following week. The day be-
fore surgery he took 100 mg of chlopromazine at 15.00
hr and again at 22.00 hr.
The patient was premedicated with lorazepam 2 mg
two hours before the operation. Intravenous access was
established with an indwelling cannula. Anaesthesia was
induced with thiopentone 300 mg and fentanyl 100 ~g,
and muscle relaxation was achieved with atracurium 25
mg. The trachea was intubated with a 9 mm cuffed tube.
Anaesthesia was maintained with nitrous oxide 4
Vohra: CONVULSIONS FOLLOWING A N A E S T H E S I A
L" min -l, oxygen 2 L" min -1. Enflurane 1% from En-
flurotec Mark 3 vaporiser was added to the breathing
mixture. Intermittent positive pressure ventilation was
carried out using a Manley ventilator (tidal volume 550
ml approximately, respiratory rate 11 min-t). Monitoring
consisted of NIBP, ECG and SpO2. As a capnograph
was not available, end tidal COz concentrations could
not be monitored. The operation lasted 30 min during
which the inspired concentration of enflurane was ad-
justed between I-1.5% as required. The haemodynamic
parameters were within normal limits as were his SpO2
observations.
The residual neuromuscular blockade was reversed
with neostigmine 2.5 mg and atropine 1.2 rag. The tra-
chea was extubated after a few breaths of a mixture of
oxygen 7 L. min -t and CO2 0.5 L-rain -I. The vital
signs (heart rate, blood pressure and peripheral oxygen
saturation) were satisfactory. At this point the patient had
regained his protective reflexes. His respiratory rate and
pattern were satisfactory and he was receiving oxygen
(6 L. min-t) by M e mask. About five minutes after ex-
tubation he had a classical grand real seizure lasting 30
sec. The seizure subsided spontaneously but the patient
became apnoeic and unresponsive to external stimuli al-
though his pupils were normal in size. The trachea was
reintubated and 100% oxygen was administered for the
next ten minutes following which he recovered sufficiently
to allow extubation. Oxygen was continued by mask and
the subsequent recovery was uneventful. There was no
neurological deficit postoperatively. After a normal EEG
and CT scan, he was discharged on the ninth postop-
erative day. There was no neurological deficit at six
months followup.
Discussion
One of the side effects of anti-psychotic drugs such as
phenothiazines and thioxanthenes is lowering of the sei-
zure threshold. 6 This has been shown in animal exper-
iments using chlorpromazine at low and intermediate dos-
ages. 7 The usual electroencephalographic (EEG) effect of
these drugs is diffuse slowing of activity. Chlorpromazine
reduces the frequency of alpha waves but increases the
frequency of theta and delta waves, s This kind of activity
is not pathological but other types of EEG patterns pro-
duced during antipsychotic drug treatment may have clin-
ical importance. These are transient, ranging from dys-
rhythmic groups and sharp potentials to spike and dome
complexes and may be associated with epileptic seizures.
These EEG changes are commonly accentuated during
initial period of treatment, sudden dose changes or fol-
lowing an abrupt withdrawal. 9 Aliphatic phenothiazines
and thioxanthenes are more epileptogenic than the pip-
erazine derivatives. Furthermore, combinations of anti-
421
psychotic drugs produce an additive and possibly syn-
ergistic effect on the spike activity. 7 Epileptics are par-
ticularly susceptible to the increased paroxysmal activity
produced by chlopromazine and frank seizures have been
reported after chlopromazine in epileptics stabilized on
anticonvulsants and free from fits. ~0
Enflurane is known to cause cerebral stimulation. Deep
levels of enflurane anaesthesia produce EEG changes
characterized by low voltage, fast frequency waves pro-
gressing through spikes and dome complexes. These al-
ternate with electrical silence and may finally produce
a frank seizure activity pattern. ~ They originate in the
limbic system and then spread to all other areas. 2 These
changes may persist for as long as 30 days following en-
flurane anaesthesia, t2 The factors suspected of predis-
posing to seizures are pre-existing neurological disorders,
high (>2-3%) inspired concentration of enfhirane, and
drug interactions with diazepam, amitriptyline, tetrahy-
drofuran, ketamine and althesin. ~-5 There may be a syn-
ergistic role for laudanosine, a metabolite of atracurium,
as high plasma concentrations of laudanosine have been
shown to produce seizure activity in animals. Hyperven-
tilation and a respiratory alkalosis have potentiating ef-
fects on the seizure activity produced by enflurane. 2
The patient described in this case report was not an
epileptic and had no family history of epilepsy. Diazeparn
was not used as a premedicant, the dose of atracurium
was modest so that a laudanosine-induced interaction is
unlikely. Previous animal research suggests that nitrous-
oxide confers some protection against enflurane-induced
hyperexcitability unless the duration of anaesthesia is pro-
longed. During prolonged anaesthesia a state of tolerance
develops and sudden cessation of nitrous-oxide induces
hyperexcitability. 13 The duration of this case was half an
hour so that nitrous-oxide withdrawal-induced hyperex-
citability is unlikely.
The inspired concentration of enflurane was no more
than 1.5%, and there were no undue photic or auditory
stimuli in the immediate postoperative period. ~4The pa-
tient was unlikely to be hypocarbic at the time of seizure
as CO2 had been added to the breathing mixture before
extubation. Also an intracranial extension of the orbital
tumour had already been excluded by a normal CT scan
of brain.
Thus, one explanation for the cause of the epileptic
seizure in this patient appears to be the synergistic activity
between enflurane and the antipsychotic drugs. As noted
in the history, the dosage regimen for chlorpromazine was
irregular. The patient was receiving chlorpromazine and
flupenthixol concurrently though somewhat inconsist-
ently. He had been given an additional dose of chlor-
promazine on the evening before the surgery. Since com-
binations of antipsychotic drugs have an additive effect
422 CANADIAN JOURNAL OF ANAESTHESIA

on the spike activity and, furthermore, the sudden al- 14 DeWolfe AM, Chang JL, Larson CE, Caparosa RJ.
teration of doses is known to lower the seizure threshold, Enflurane induced grand mal seizure during optic micro-
it is possible that the stage was already set for seizure surgery. Anesthesia Progress 1984; 31: 136-7.
when another potentially epileptogenic drug (enflurane)
was added.
In conclusion, the possibility of an interaction between
antipsychotic drugs and enflurane should be considered.
This is especially relevant if the prescribed dosage regimen
has not been consistent and if there is any doubt about
compliance on the part of the patient. Thus, this might
be considered when choosing an inhalational agent for
the patients on antipsychotic therapy.

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