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: giuseppe.plazzi@unibo.it
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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