Recurrent stupor is a common neurologic problem and is usually due to seizures, intox ications, sleep

INTRODUCTION

RECURRENT STUPOR IS A COMMON NEUROLOGIC

PROBLEM AND IS USUALLY DUE TO SEIZURES, INTOX-

ICATIONS, SLEEP

DISORDERS, OR METABOLIC

ENCEPHALOPATHIES.

1

Idiopathic recurrent stupor associated

with elevated levels of an endogenous benzodiazepine-like agent

was first described by the Balogna group,

2-4

and they then pub-

lished a definitive study of 20 patients with the condition from all

parts of Italy.

5

The cases comprised 16 men and 4 women; the

age range was 24 to 69 (mean 50.6) years. There was no diurnal

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

2

saturation > 90%),

even in those patients with some evidence of respiratory disease.

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 

γ-aminobutyric acid

(GABA)-A receptor.

6,7

Between attacks, serum (9 subjects) and

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-

por, constituted a novel though not so rare syndrome that they

now prefer to call endozepine stupor. The condition has also been

reported in the elderly

8

and in children.

9

There have been 2 cases

reported outside Italy.

10,11

COVERT BENZODIAZEPINE ADMINISTRATION

In late 1998, the same Balogna group

12

reported 9 patients pre-

senting with recurrent stupor, which proved to be due to exoge-

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

1597

Endozepine Stupor: Disease or Deception? A Critical Review

REVIEWS

Ron Granot

1

; Samuel F Berkovic, MD

2

; Scott Patterson; Malcolm Hopwood, MD

3

; Olaf H. Drummer, PhD

4

; Rod Mackenzie, MD

1

Institute of Neurological Sciences, Prince of Wales Hospital; 

2

Epilepsy Research Institute, Department of Medicine (Neurology), University of

Melbourne; 

3

Department of Psychiatry, University of Melbourne; 

4

Victorian Institute of Forensic Medicine, Australia

Abstract: Presentation of patients with recurrent stupor associated with

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.

Key Words: coma, recurrent stupor, idiopathic stupor, Munchausen syn-

drome by proxy, benzodiazepine, endozepine.

Citation: Granot R; Berkovic SF; Patterson S et al.  Endozepine stupor:

disease or deception? A critical review.  SLEEP 2004;27(8):1597-9.

Disclosure Statement

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.

Submitted for publication May 2004

Accepted for publication June 2004

Address correspondence to: Ron Granot, Unit 904/8 Spring St, Bondi Junction

NSW 2022; Tel: [phone]; E-mail: [e-mail]

inal cases had been imperfect and “the endozepine origin of the

stuporose episodes in previously reported patients...should be

considered as still unproven.” 

OTHER CASES

Since 1998, there have been only 2 more case reports relevant

to this condition. French investigators

13

reported a patient with

typical features of endozepine stupor who had been prescribed

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. 

We reported

14

the case of a 71-year-old man with a 16-year his-

tory of recurrent episodes of stupor and coma. The diagnosis of

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). 

BENZODIAZEPINE DETECTION

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

are 

ω-1 specific to GABA-A receptor; they will cause sedation in

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.

15

The Balogna group

12

subse-

quently used LCMS to identify the surreptitious administration of

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-

azepines.

16

ENDOZEPINES

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.

17

They act via the GABA-A

receptor.

18-21

They are also found in peripheral organs, in partic-

ular liver, kidneys, adrenal glands, and testis.

17,22

They are

thought to have various neuroregulatory functions.

22,23

It has

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.

5

Similarly, its affinity for the

hippocampal GABA receptors might explain the prominent dis-

turbances of memory that has been observed in patients with

recurrent stupor. 

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.

20,23,24 

Furthermore, intracerebroventricu-

lar injection of endozepines in rodents promotes opposite physi-

ologic effects to diazepam, including anxiogenic effects,

25

pro-

conflict behavior,

26

and both anxiety and depression

27

in rats or

no change in pigs

28

; it has also been shown to reverse the anti-

conflict action of diazepam. 

29

These behavioral data suggesting

endozepines may act as inverse agonists on central-type benzodi-

azepine receptors are now supported by biochemical animal

work.

30

It has even been shown that endozepines reduce the hyp-

notic action of pentobarbital in mice.

31

There are no examples in

animal or human literature of tumors or other pathologic states

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.

COULD MSP EXPLAIN ENDOZEPINE 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.

32-35

However, MSP involving adult victims

does occur, and we have found 5 previous examples in the liter-

ature of adult MSP involving conditions other than benzodi-

azepine administration.

36-40

Patients in the original Balogna series

were adults from all parts of Italy with no family history of recur-

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

12

were not given; however,

the fact that these presentations occurred in a restricted rural area

in Tuscany raises the possibility that they were examples of

learned behavior. 

Little follow-up has been given in these or other reports. No

deaths have been reported, consistent with the benign prognosis

of benzodiazepine intoxication.

CONCLUSION

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

SLEEP, Vol. 27, No. 8, 2004

1598

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