Sleep, Vol. 37, No. 1, 2014

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SLEEP, Vol. 37, No. 1, 2014

211

Letter to the Editor—Plazzi et al

The World Wide Web has become a default source for medical 

information, especially in cases of rare diseases or when the 

diagnosis is ambiguous. Recurrent hypersomnia and recurrent 

episodes of stupor are rare, and they are diagnoses of exclusion 

whose pathophysiologies are not well understood. Idiopathic 

recurring  stupor  (IRS)  was  identified  as  a  new  syndrome  in 

1992, in which spontaneous stupor lasting from hours to days 

occurred unpredictably and in the absence of readily discern-

ible toxic, metabolic, or structural causes. Individuals otherwise 

appeared normal between episodes. Electroencephalography 

(EEG) during events exhibited activity patterns reminiscent 

of benzodiazepine (BZD) overdose, but traces of BZDs were 

found in plasma in only a proportion of cases.

1,2

 Stupor resolved 

and the EEG normalized for tens of minutes with administra-

tion  of  the  BZD-antagonist  flumazenil.  The  syndrome  was 

attributed  to  elevated  plasma  and  cerebrospinal  fluid  (CSF) 

levels of an endogenous BZD-like substance (viz., endoze-

pine-4), which binds competitively for the BZD recognition site 

of the γ-aminobutyric acid (GABA) A receptor subtypes, and 

enhanced receptor function by positive allosteric modulation.

1

The turning point in understanding this puzzling condition 

came when IRS was suspected in a group of close neighbors 

living near Lucca, Italy. Traditional gas-chromatographic-mass-

spectrometric methods (GC-MS) did not detect BZDs or their 

metabolites. However, more sensitive high performance liquid 

chromatographic-mass-spectrometry  (HPLC-ESI-MS)  run  in 

parallel with a radioreceptor-binding assay, detected lorazepam 

and its metabolites in patients’ plasma.

3

 Reanalysis by HPLC-

ESI-MS of plasma collected and banked from our patients during 

episodes of IRS, and previously negative for BZDs by GC-MS, 

confirmed  the  presence  of  exogenous  BZDs.  Thus,  the  above 

evidence suggested that IRS, at least in these cases, was not a disease 

sui generis caused by endozepines, but rather, it was secondary to 

malicious administration of BZDs. In addition to cases of covert 

intoxications,  a  Munchausen  syndrome  by  proxy

4

 has been 

documented in a case previously diagnosed as IRS. Spontaneous 

IRS is therefore an unproven and indeed questionable entity.

3

 

Upon informing our previously diagnosed patients, one of them 

sued for damages, claiming that the diagnosis of IRS amounted 

to  malpractice.  Moreover,  we  were  recently  alerted  by  our 

National  patients’  hypersomnia  association  (AIN-Associazione 

Italiana Narcolettici ed Ipersonni, www.narcolessia.it) to online 

LETTER TO THE EDITOR

http://dx.doi.org/10.5665/sleep.3342

Idiopathic Recurrent Stupor: Munchausen by Proxy and Medical Litigation

Giuseppe Plazzi, MD

1,2

; David Rye, MD

3

; Luca Vignatelli, MD

4

; Roberto Riva, MD

1,2

; Elio Lugaresi, MD

1

1

DIBINEM, Alma Mater Studiorum, University of Bologna, Bologna, Italy; 

2

IRCCS Istituto delle Scienze Neurologiche, Bologna, Italy; 

3

Department of 

Neurology, Program in Sleep, Emory University School of Medicine, Atlanta, GA; 

4

Department of Primary Care, Local Health Trust, Bologna, Italy

Submitted for publication February, 2013

Submitted in final revised form April, 2013

Accepted for publication June, 2013

Address correspondence to: Giuseppe Plazzi, MD, Dept. of Clinical Neu-

rology, University of Bologna, via Ugo Foscolo, 7, Bologna, 40123 Italy; 

E-mail: [e-mail]

material suggesting that IRS remains a recognized entity in 

some nosological schemes for recurrent hypersomnia. On the 

rare disease European portal (www.orpha.net), a webpage is 

dedicated  to  IRS,  where  it  is  classified  as  rare  neurological 

disease, with links to expert centers, research projects, as well 

as patient organizations. This is not supported by the scientific 

evidence. Since implicating endozepine-4 as a cause of IRS in 

1998, we are unaware of any new cases of apparent IRS that 

have been attributed to an endogenous molecule with BZD-like 

bioactivity. That being said, recent meticulously conducted 

analyses  of  plasma  and  CSF  from  patients  with  a  persistent 

primary hypersomnia with the highest sensitivity toxicological 

methods have detected BZD-like bioactivity that is clinically, 

pharmacologically, and molecularly distinct from endozepine-4.

5

 

It remains to be determined if this new, genuine biology might 

underlie recurrent episodes of hypersomnia that more closely 

mimic the clinical picture of presumed IRS.

When managing a patient with isolated or recurrent episodes 

of disabling sleepiness, it is first mandatory that one rule out 

toxic hypersomnia.

6

 The diagnosis of IRS should not be made 

without performing sophisticated toxicological tests to rule out 

exogenous BZDs.

Doing so may distress patients, lead to inappropriate treatments, 

and may have legal repercussions for the treating physicians.

CITATION

Plazzi G; Rye D; Vignatelli L; Riva R; Lugaresi E. Idiopathic 

recurrent stupor: Munchausen by proxy and medical litigation. 

SLEEP 2014;37(1):211.

DISCLOSURE STATEMENT

Drs. Plazzi and Rye have participated in advisory boards of 

UCB Pharma and Jazz pharmaceuticals. The other authors have 

indicated no finacial conflicts of interest.

REFERENCES

1.  Rothstein JD, Guidotti A, Tinuper P, et al. Endogenous benzodiazepine 

receptor ligands in idiopathic recurring stupor. Lancet 1992;340:1002-4.

2.  Lugaresi E, Montagna P, Tinuper P, et al. Endozepine stupor. Recurring 

stupor linked to endozepine-4 accumulation. Brain 1998;121:127-33.

3.  Lugaresi E, Montagna P, Tinuper P, Plazzi G, Gallassi R. Suspected covert 

lorazepam administration misdiagnosed as recurrent endozepine stupor. 

Brain 1998;121:2201.

4.  Granot  R,  Berkovic  SF,  Patterson  S,  Hopwood  M,  Drummer  OH, 

Mackenzie R. Endozepine stupor: disease or deception? a critical review. 

Sleep 2004;27:1597-9.

5.  Rye  DB,  Bliwise  DL,  Parker  K,  et  al.  Modulation  of  vigilance  in  the 

primary  hypersomnias  by  endogenous  enhancement  of  GABA-A 

receptors. Sci Transl Med 2012;4:161ra151.

6.  American Academy of Sleep Medicine. The international classification of 

sleep disorders: diagnostic and coding manual, 2nd ed. Westchester, IL: 

American Academy of Sleep Medicine, 2005.

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