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 discernible 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 administration 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 HPLCESI-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 proxy4 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 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
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