RECURRENT STUPOR IS A COMMON NEUROLOGIC
PROBLEM AND IS USUALLY DUE TO SEIZURES, INTOX-
DISORDERS, OR METABOLIC
Idiopathic recurrent stupor associated
was first described by the Balogna group,
and they then pub-
parts of Italy.
The cases comprised 16 men and 4 women; the
pattern of presentation, and onset was not related to activities of
daily living or to psychological factors. The altered state of con-
sciousness had persisted for 2 to 120 hours. Patients could have
fairly frequent episodes (> 6 per year) or rare attacks (1-6 per
year). In nine patients, the episodes had disappeared sponta-
neously 2 to 6 years previously, after 1 to 6 years of recurring
episodes. At the time of onset of the stuporous episodes, all
patients were in good mental and physical condition, and none
were receiving medical treatment. No patient had a previous his-
tory of psychiatric disorder, and there was no family history of
sleep disorder. Blood, urine, and cerebrospinal specimens were
taken and were unremarkable during all instances of stupor.
Blood oxygen always remained normal (O
saturation > 90%),
Brain structural studies were normal during and between attacks.
Urine immunoassays and blood gas-chromatography mass spec-
trometry (GCMS) were negative for benzodiazepines, barbitu-
rates, tricyclic antidepressants, ethanol, opiates, and cocaine. The
electroencephalogram (EEG) was normal between attacks but,
during altered consciousness, was characterized by diffuse low-
amplitude unreactive activity with a peak at 13 to 16 Hz.
Intravenous administration of 0.5 to 2.0 mg flumazenil, a benzo-
diazepine antagonist, under EEG monitoring, led to a transient
reappearance of 8- to 12-Hz EEG alpha activity associated with
behavioral awakening or arousal; however, this reversal lasted
only 10 to 15 minutes. Interictal polygraphy showed normal
sleep patterns. Daytime somnolence, measured by the Multiple
Sleep Latency Test, was normal in 17 and borderline in 3 cases.
The investigators reported that high-performance liquid chro-
matography (HPLC) showed an elevation of serum and cere-
brospinal fluid levels of endozepine-4, an endogenous ligand for
the benzodiazepine recognition site of the
cerebrospinal fluid (4 subjects) HPLC endozepine-4 levels were
no different from controls, but they rose to more than 4000 times
normal (cerebrospinal fluid ) and 20,000 times normal (serum)
during episodes of stupor. The investigators thought that such
cases, which they had originally termed idiopathic recurrent stu-
now prefer to call endozepine stupor. The condition has also been
reported in the elderly
and in children.
There have been 2 cases
reported outside Italy.
In late 1998, the same Balogna group
reported 9 patients pre-
nous benzodiazepine administration. The patients had all pre-
sented over a short period of time to hospitals in a restricted rural
area of Tuscany. Except for the extraordinary clustering in time
and space, these patients were similar to the sporadic cases. They
had the same clinical picture and EEG pattern during stupor and
a reversal of these states after flumazenil administration. Again,
toxicologic immunoenzymic tests failed to detect even traces of
synthetic benzodiazepines. However, since the original report, a
newer more specific toxicologic assay, liquid-chromatography
mass spectroscopy (LCMS) had become available, and this test
detected lorazepam in the blood of all the Tuscan patients. The
investigators diagnosed fraudulent lorazepam intoxication in
these patients and excluded an endogenous benzodiazepine
(endozepine) origin of the stupor. It was conceded that the chem-
ical tests used to exclude exogenous benzodiazepines in the orig-
Endozepine Stupor: Disease or Deception? A Critical Review—Granot et al
SLEEP, Vol. 27, No. 8, 2004
Endozepine Stupor: Disease or Deception? A Critical Review
; Samuel F Berkovic, MD
; Scott Patterson; Malcolm Hopwood, MD
; Olaf H. Drummer, PhD
; Rod Mackenzie, MD
apparently elevated levels of an endogenous benzodiazepine-like agent,
endozepine-4, has been reported from several centers, and a new syn-
drome, endozepine stupor has been proposed. We recently reported a
case with typical features of this syndrome, which proved to be an exam-
ple of surreptitious administration of exogenous benzodiazepine. This and
other examples of clandestine drug use, together with uncertainties about
the validity of tests used to distinguish exogenous and endogenous ben-
zodiazepines, prompted us to undertake a reappraisal of this clinical syn-
drome by proxy, benzodiazepine, endozepine.
disease or deception? A critical review. SLEEP 2004;27(8):1597-9.
Dr. Hopwood has received research support from Pfizer, GlaxoSmithKline, Bristol
Myers Squibb, and Brain Resource Company Pty Ltd.; and has participated in
paid speaking engagements supported by Eli Lily, Pfizer, and Wyeth. Drs.
Berkovic, Patterson, Granot, Drummer, and Mackenzie have indicated no finan-
cial conflicts of interest.
Address correspondence to: Ron Granot, Unit 904/8 Spring St, Bondi Junction
NSW 2022; Tel: 61 2 9386 0290; E-mail: firstname.lastname@example.org
stuporose episodes in previously reported patients...should be
considered as still unproven.”
Since 1998, there have been only 2 more case reports relevant
to this condition. French investigators
reported a patient with
zolpidem, a nonbenzodiazepine hypnotic for insomnia, prior to
presenting with 5 episodes of stupor over a 5-month period. The
search for poisons, including benzodiazepines, was negative and
HPLC was biologically normal. Although these authors were sus-
picious that an exogenous poison may have been involved and
raised some doubts about the authenticity of endozepine stupor,
they ultimately concluded that “an endogenous intoxication” was
likely. The episodes ceased spontaneously.
the case of a 71-year-old man with a 16-year his-
endozepine stupor was regarded as secure over many years (2
positive toxicologic assays were attributed to prescribed benzo-
diazepine) until upon further inquiry, the patient’s wife admitted
administering lorazepam to her husband, causing his episodes of
stupor and coma. This was thus an adult example of Munchausen
syndrome by proxy (MSP).
In cases of benzodiazepine intoxication where the subject or
other perpetrator denies the use of these drugs, the absence of
benzodiazepines on a routine “drug screen” may falsely reassure
the clinician. There are a number of benzodiazepines that are
very difficult to detect using conventional techniques such as
immunoassay screening, GCMS and HPLC. These include tria-
zolam and bromazepam, as well as lorazepam; this last substance
is the only 1 known to chromatograph in the vicinity of
endozepine-4, although other substances may do so.
Nonbenzodiazepines such as zopiclone, zolpidem, and zaleplon
the same way as conventional benzodiazepines, but thin-layer
chromatography cannot reliably detect these substances.
The initial and subsequent reports of endozepine stupor all
used immunoassay, GCMS, and HPLC. These methods are now
known to show false-negative results in the presence of certain
benzodiazepines, especially lorazepam, and fail to distinguish
lorazepam from endozepine-4.
The Balogna group
lorazepam in cases initially suspected of having endozepine stu-
por. This technique and other more sophisticated GCMS tech-
niques are required to detect low concentrations of benzodi-
Studies in a number of vertebrate species have established the
presence of a family of peptides, which have become known as
endozepines. They are widely distributed, especially in glial cells
in the central nervous system—in particular cerebellum, amyg-
dala, hippocampus, hypothalamus, and substantia nigra—and are
evenly distributed in the spinal cord.
They act via the GABA-A
ular liver, kidneys, adrenal glands, and testis.
been suggested that the high affinity of endozepine-4, like syn-
thetic benzodiazepines, for the GABA-A receptor might explain
its apparent ability to induce coma.
Similarly, its affinity for the
turbances of memory that has been observed in patients with
However, experimental work has shown that the effects of the
endozepines are mediated not only through central benzodi-
azepine receptors, but also through peripheral-type receptors and
a metabotropic receptor.
lar injection of endozepines in rodents promotes opposite physi-
ologic effects to diazepam, including anxiogenic effects,
and both anxiety and depression
in rats or
no change in pigs
; it has also been shown to reverse the anti-
These behavioral data suggesting
azepine receptors are now supported by biochemical animal
It has even been shown that endozepines reduce the hyp-
There are no examples in
causing an alteration in levels of endozepine or any alteration in
clinical status. These facts raise uncertainties about the likelihood
of elevated endozepine levels causing stupor.
MSP involves the deliberate exaggeration, fabrication, or
induction of physical or psychological symptoms in others. It
usually involves an adult, most commonly the parent, perpetrat-
ing the act on a child.
does occur, and we have found 5 previous examples in the liter-
ature of adult MSP involving conditions other than benzodi-
Patients in the original Balogna series
ring stupor and no history of psychiatric disorders; social and
psychiatric factors were not detailed in other case reports of
endozepine stupor. The ages and social circumstances of the 9
cases that are known to be fraudulent
were not given; however,
in Tuscany raises the possibility that they were examples of
Little follow-up has been given in these or other reports. No
deaths have been reported, consistent with the benign prognosis
of benzodiazepine intoxication.
The clinical and biochemical similarities between cases of
endozepine stupor and exogenous benzodiazepine administra-
tion, the difficulty in conclusively ruling out the involvement of
exogenous benzodiazepines, and uncertainties about the patho-
physiologic role of the endozepines, all make it more likely that
most if not all of these cases are due to exogenous drug adminis-
tration. This may well include further examples of MSP. In our
opinion, the concept of endozepine stupor, on current evidence,
cannot be sustained.
Endozepine Stupor: Disease or Deception? A Critical Review—Granot et al
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