LESSON OF THE MONTH
Idiopathic recurrent stupor: a warning
R Granot, S F Berkovic, S Patterson, M Hopwood, R Mackenzie
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J Neurol Neurosurg Psychiatry 2004;75:368–369. doi: 10.1136/jnnp.2003.021691
A proposal that an endogenous benzodiazepine-like agent
named endozepine-4 might be responsible for presentations
of recurrent stupor has gained wide acceptance. A case of
recurrent stupor over two decades is presented with many
similarities to previous cases of ‘‘endozepine stupor’’. This
case, however, was caused by exogenous benzodiazepine
administration and serves as a warning to clinicians to
beware of this diagnosis.
s clinicians we have been taught to always first exclude
common causes before considering rare ones. Doctors,
especially specialists, like to make exotic diagnoses as a
part of the intellectual games we play. In the case to be
presented, the clinicians were seduced by an obscure but
plausible diagnosis when the clinical setting and test results
should have raised their suspicions.
A 71 year old man had a 16 year history of recurrent episodes
of stupor and coma. Initially these attacks occurred every
three to six months, but in recent years he had required up to
seven hospital admissions a year. The first attack occurred
when he was an inpatient at his local hospital for an
unrelated medical problem and witnessed the suicide of a
fellow patient; soon afterwards he lapsed into a coma from
which he recovered spontaneously. Subsequent attacks often
occurred in stressful situations—family disputes and medical
consultations related to his condition were common pre-
cursors. Typically, he would develop a gradually deepening
stupor over 20 minutes to several hours, often progressing to
coma with a Glasgow coma scale score as low as 4.
Hypoventilation (six to eight breaths a minute, occasionally
in a Cheyne–Stokes pattern) and mild hypotension with
bradycardia were common accompaniments. At times,
medical attendants had noted loss of oculo-cephalic, corneal,
and gag reflexes. His pupils were generally small but not
pinpoint, and were reactive. He had never shown any
convulsive movements, nor lost continence.
Several episodes of profound coma required intubation and
mechanical ventilation. Impairment of consciousness would
usually resolve over 12 to 36 hours, but occasionally recurred
one or more times over a period of one to two weeks.
Between attacks, the neurological examination was normal
except for right sensorineural deafness.
Over the course of multiple episodes at several different
hospitals, extensive investigations failed to reveal a cause.
Routine haematology and biochemistry including thyroid
function were normal. Blood lactate and ammonia levels
were normal both during and between attacks. Urine
immunoassays for opiates, ethanol, cocaine, benzodiazepines,
barbiturates, and antidepressants were done on many
occasions. These were usually negative, but on two occasions
when a positive result for benzodiazepines was found this
was thought to be caused by lorazepam prescribed by his
local doctor in case stress was triggering the attacks.
Electroencephalography (EEG) on several occasions was
unremarkable. Computed tomography of the brain and four
vessel angiography were normal. Examination of cerebrosp-
inal fluid (CSF) pressure and content was normal. Later in
the course of his illness, magnetic resonance imaging of the
brain revealed a small right acoustic neuroma, which
subsequently shrank with localised beam radiotherapy. The
attack pattern did not change with this successful treatment
and it was thought not to be relevant to his stupor episodes.
Finally, after nine years of such presentations, telemetric
EEG monitoring during coma revealed low amplitude
symmetrical beta activity of 16–18 Hz. Following the
administration of 0.5 mg of flumazenil intravenously, the
patient regained consciousness and medium voltage alpha
activity at 8–9 Hz returned. A diagnosis of ‘‘endozepine
stupor’’ was then made; this is a recently described syndrome
of recurrent stupor caused by an increase of an endogenous
benzodiazepine-like neuropeptide. The diagnosis was subse-
quently accepted by senior consultants in three other major
medical centres during recurrent admissions for stupor over
the next seven years. He was given intravenous flumazenil in
doses up to 5 mg daily for periods of up to two weeks on
Just before the last admission, one of us was informed that
the patient’s wife had confessed to surreptitious administra-
tion of lorazepam to her elderly mother during an admission
to the local hospital for suspected stroke. The nursing staff
had become suspicious when the patient’s condition deterio-
rated after each visit by the daughter. She had initially denied
administering the drug but, under threat of legal action, she
confessed to having done so. When her husband was later
admitted in stupor, urine gas chromatography mass spectro-
metry found a high level of oxazepam and when challenged
his wife confessed to having given oxazepam and lorazepam
to him over the period of his presentations. She often gave
the tablets disguised in his tea or his food, but may also have
openly given them to him on the pretext of ‘‘calming him
down’’. She herself had at least a 15 year history of
benzodiazepine dependence with multiple overdoses. She
worked at the local hospital and had been constantly in
attendance at her husband’s presentations and throughout
the course of his admissions. She agreed to undergo
This case, which had the typical features reported in
endozepine stupor, was eventually shown to be related to
exogenous benzodiazepine administration. However, this
possibility was completely overlooked by attending clinicians.
Presentation of a patient in stupor is a common diagnostic
problem for emergency departments everywhere. Recurrent
stupor is a less common disorder and has a wide differential
diagnosis including epilepsy, sleep disorders, and hepatic,
renal, or respiratory failure. Self administration of exogenous
benzodiazepines needs always to be excluded. Rarer causes
include migraine stupor, intermittent CSF obstruction, and a
variety of metabolic disorders. Endozepine stupor has
recently been added to this list,
characterised as a syndrome
of recurrent episodes of stupor or coma which are temporarily
reversed by the benzodiazepine antagonist flumazenil given
These episodes are thought to be caused by an
increase in endozepine-4,
one of a group of regulatory
peptides known as endozepines.
Munchausen syndrome by proxy (MSP) is a syndrome in
which caregivers deliberately invent, induce, or exaggerate
psychological or physical symptoms in others.
It seems that
the primary purpose for this superficially bizarre behaviour is
internal gratification of the perpetrator. The vast majority of
the reported cases involve the presentation of a child with the
symptoms and a parent, most often reported as the mother,
as the perpetrator. MSP involving adult victims is rare. We
have found five such cases in published reports.
the clinical setting of a pleasant elderly country gentleman,
always accompanied by his appropriately worried wife, gave
no reason for us to suspect drug abuse. The test results,
although on two occasions consistent with exogenous
benzodiazepine administration, were accepted as being part
of the exotic diagnosis of endozepine stupor. That the real
diagnosis was the apparently unbelievable MSP in adults
doubly conspired to confound us. In retrospect, the perpe-
trator took advantage of our vanity and we looked at the
literature instead of the patient and, more particularly, his
ever present partner.
. . . . . . . . . . . . . . . . . . . . .
R Granot, R Mackenzie,
Institute of Neurological Sciences, Prince of
Wales Hospital, Randwick, NSW, Australia
S F Berkovic, S Patterson,
Epilepsy Research Institute, Department of
Medicine (Neurology), University of Melbourne, Heidelberg, Victoria,
Department of Psychiatry, University of Melbourne
Competing interests: none declared
Correspondence to: Dr Roderick Mackenzie, PO Box 2043, Taren Point,
NSW 2229, Australia; email@example.com
Received 25 June 2003
Accepted 9 July 2003
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Eating fats may not affect risk of stroke in men after all
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long term prospective study has reported that eating fats—of whatever type—seems
not to affect risk of ischaemic or haemorrhagic stroke in men, even though the same
researchers earlier reported that omega 3 long chain fatty acids reduced the risk of
ischaemic stroke. Clearly, more research is needed.
The men were healthcare professionals aged 40–75 in 1986 in the United States.
Comprehensive data were obtained by validated questionnaires on their medical history,
diet, and lifestyle, regularly updated over the following 14 years. When fatal or non-fatal
strokes were reported a blinded physician assessed the risk factors from the medical notes.
Nearly 44 000 men were studied, after exclusions for prior diagnosis of cardiovascular
disease or diabetes mellitus, questionable energy intake, or incomplete data.
There were 725 cases of stroke—455 ischaemic, 125 haemorrhagic, 145 unknown—during
follow up. Neither total fat nor type of fat affected risk of ischaemic or haemorrhagic stroke
with data adjusted for known confounders. Long term effects, judged by comparing the
highest fifth of intake with the lowest fifth in each subject, did not alter the risk for total fat
or fats of different types—animal, vegetable, saturated, monounsaturated, polyunsaturated,
trans unsaturated—or cholesterol. Furthermore, red meats, high fat dairy foods, nuts, and
eggs had no effect.
Dietary fat intake is a big risk factor for heart disease but, apparently, not for stroke. Most
of the evidence has not explored whether there might be any differences in risk between
ischaemic and haemorrhagic strokes.
British Medical Journal 2003;327:777–781.
Idiopathic recurrent stupor: a warning