Recurrent Stupor Research Articles

Idiopathic Recurrent Stupor, Still an Unsolved Issue

We report a case of unexplained recurrent stupor for which, given the current knowledge and the lack of easily available diagnostic tools, we were unable to reach a definite diagnosis. In the patient the syndrome was associated with an ominous prognosis. Worldwide accepted and easily available proceeding method is needed to manage patients with recurrent stupor for which a toxic origin may be supposed.

Idiopathic Recurrent Stupor: Munchausen by Proxy and Medical Litigation

Idiopathic Recurrent Stupor: Munchausen by Proxy and Medical Litigation

Endozepines in recurrent stupor

Stupor is a condition from which the subject can be aroused only by vigorous stimuli. Most patients with stupor have a diffuse organic cerebral dysfunction. Rarely stupor is recurrent and no specific causes can be found. Patients with idiopathic recurrent stupor were awakened by i.v. administration of an antagonist (flumazenil) of the benzodiazepine recognition site located in the GABA(A) receptor. Since no exogenous benzodiazepines were detected in plasma and cerebrospinal fluid by high performance liquid chromatography, an excess of endogenous benzodiazepine-like compounds (endozepines) was proposed as the cause of stupor. The existence of endozepines, their widespread distribution in the CNS and their involvement in hepatic encephalopathy are established. However, the origin of these compounds, how biosynthesis occurs and the mechanisms and causes through which they alter brain functions are poorly understood. The fact that a number of synthetic benzodiazepines are difficult to detect using conventional techniques and the discovery that some cases of recurrent stupor were caused by fraudulent administration of lorazepam question whether the concept of endozepine recurrent stupor can be sustained. This review summarizes the state of endozepine physiology and pharmacology and the clinical syndromes attributed to their involvement. A diagnostic work-up to define endozepine-induced recurrent stupor is suggested.

Recurrent stupor due to lysinuric protein intolerance

Recurrent stupor in children is an uncommon clinical problem with a wide differential diagnosis; inherited metabolic disorders account for a vast majority. We report a 9-year-old girl with recurrent episodes of stupor. Initial episode was treated as viral encephalitis and the second episode was managed as non-convulsive status epilepticus. Hyperammonemia was detected in the last episode. Metabolic work-up after dietary protein challenge revealed classical biochemical features of lysinuric protein intolerance. She was managed with protein-restricted diet, which resulted in marked neurological improvement. LPI is a rare inherited metabolic disorder due to membrane transport defect of cationic amino acids.

Endozepine Stupor: Disease or Deception? A Critical Review

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 syndrome, endozepine stupor has been proposed. We recently reported a case with typical features of this syndrome, which proved to be an example 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 benzodiazepines, prompted us to undertake a reappraisal of this clinical syndrome.

The effect of benzodiazepines and flumazenil on motor cortical excitability in the human brain

In the present study, the effects of benzodiazepines (diazepam) were evaluated in terms of cortical excitability changes, as tested with transcranial magnetic simulation (TMS). In particular, analyzed were drug-induced changes regarding two selected parameters of TMS: (1) the cortical excitability threshold and (2) the silent period duration (SP). For this purpose, we evaluated the effects of long-term therapy with diazepam in the patients affected by anxiety disorders and the changes induced by single oral doses of diazepam in both healthy controls and patients. In addition, we tested cortical excitability changes in two `extreme conditions' where a considerable concentration of serum benzodiazepine-like activity was reached, as represented by diazepam overdose and idiopathic recurrent stupor (IRS). In both groups of patients, a significant increment of motor threshold was found, while in the overdose patients, the SP was also increased. The administration of flumazenil in these two conditions was followed by a prompt reversal effect, consisting of a return to normal cortical excitability parameters. The long-term usage of diazepam in patients with anxiety disorders is associated with significantly increased threshold; the increased value of these parameters was temporarily further enhanced by the administration of a single oral dose of diazepam, which, in normal control subjects, is not associated with changes of cortical excitability. The results of this study reveal that different physio-pathological conditions induced by the influence of benzodiazepine and its antagonist are reflected in excitability changes which attest to the involvement and modification of cortical GABAergic activity.

Suspected covert lorazepam administration misdiagnosed as recurrent endozepine stupor

Istituto di Clinica Neurologica dell’Universita`di Bologna, Bologna, ItalyCorrespondence to: Professor Elio Lugaresi, Clinica Neurologica, Via Ugo Foscolo 7, 40123 Bologna, ItalyWe recently reported in Brain (Lugaresi et al., 1998) 20cases of idiopathic recurrent stupor due to endozepine-4accumulation in the blood. Samples obtained from nine ofthese patients were analysed by gas chromatography–massspectrometry to rule out contaminating synthetic benzo-diazepines (Rothstein et al., 1992). All these samplescontained endozepine-4 concentrations high enough toaccount for the stuporous state of the patients. The other 11cases of idiopathic recurring stupor were diagnosed on thebasis of clinical criteria alone since they were identical tothe patients with documented endozepine-4 accumulation.All presented the same clinical picture and EEG pattern (lowamplitude, unreactive, background activity) during stuporand a reversal of the stuporous state after flumazeniladministration (awakening and EEG normalization). Again,toxicological immunoenzymatic tests failed to detect eventraces of synthetic benzodiazepines.We subsequently investigated a cluster of nine patientspresenting recurrent stuporous attacks with almostsimultaneous onset which had occurred in a restricted ruralarea near Lucca in Tuscany. Except for the extraordinaryclustering in time and space, these patients were in allrespects similar to the sporadic idiopathic recurring stuporpatients previously encountered by us. The stuporous episodesin fact lasted 1–2 days and were followed by confusion andamnesia; ictal EEG was characterized by the typical lowvoltage, 13–14 Hz background activity, and flumazeniladministration led to transient awakening and EEGnormalization. Routine toxicological immunoenzymatic assayhad ruled out the presence of benzodiazepines.However, in the meantime, a newer more specific toxico-logical assay, liquid chromatography–mass spectrometry, hadbecome available to us. Because of the unusual epidemiology,we used this technique to re-analyse blood samples from theTuscan patients. This time we detected in the blood of all ofthese patients the benzodiazepine lorazepam which had not© Oxford University Press 1998been disclosed when we had used gas chromatography–massspectrometry analysis. We could therefore deduce a fraudulentlorazepam intoxication in these patients, and exclude anendogenous benzodiazepine (endozepine) origin of the stupor.Besides highlighting the difficulties inherent to theascertainment of surreptitious benzodiazepine administration,we wish here to offer also the following conclusions:(i) Toxicological immunoenzyme assays for benzo-diazepines currently implemented by the hospital emergencyservices, though they may reveal diazepam and otherbenzodiazepines, may prove negative if the drug present inthe blood is lorazepam.(ii) Biological tests on the chromatographic fractioncontaining endozepine-4 do not rule out that the episodes ofrecurrent stupor are due to lorazepam intoxication sincelorazepam migrates in the same chromatographic fraction asendozepine during high performance liquid chromatography.(iii) The agent responsible for recurrent stuporous attackscan only be identified by means of liquid chromatography–mass spectrometry.Finally, in the light of the above findings, the endozepineorigin of the stuporous episodes in the patients we recentlyreported in Brain (Lugaresi et al., 1998), especially in thosewho did not undergo gas chromatography–mass spectrometry,should be considered as still unproven.

3-50-02 An unusual case of idiopathic recurrent stupor with circadian rhythm — A new entity of the disease?

3-50-02 An unusual case of idiopathic recurrent stupor with circadian rhythm — A new entity of the disease?

Psychopharmacology of benzodiazepines—an update

Benzodiazepines are one of the classes of compounds which bind at the benzodiazepine site in the central nervous system. The benzodiazepine site is phylogenetically new and modulates allosterically the GABA-chloride ionophore. This complex is a pentamer surrounding the chloride channel and is made up of various combinations of alpha, beta and gamma subunits. The anatomical distribution of these subunits is diverse and underlies the differential binding of a number of benzodiazepine modulators in the brain. Other compounds which act at this complex include bicuculline, musicmol, ethanol and neurosteroids. Modulation at the benzodiazepine site is bidirectional. The net result of positive modulation is facilitation of conductance and thus hyperpolarisation i.e. an inhibitory effect, while negative modulation has the inverse effects. There is considerable receptor reserve at this complex, in addition since modulators depend on the presence of GABA for their effects, supraphysiological stimulation does not occur. These factors account for the extreme safety of benzodiazepines and explain the lack of selectivity of action of full agonists, since small increases in fractional occupancy are enough to produce the full gamut of effects. The same however does not apply to partial agonists which manifest the different actions at well separated receptor occupation. Endogenous ligands have not yet been found for these sites, although benzodiazepines have been found in brains collected prior to their pharmaceutic marketing—these probably originate from vegetable foodstuffs and gut bacteria. Changes in this site can be induced by stress, convulsions and repeated administration of modulators and animals bred for different sensitivity at the benzodiazepine site manifest consistent behavioural differences. These observations have instigated a search for potential endogenous inverse agonists in human anxiety disorders and epilepsy and for endogenous agonists in metabolic encephalopathies. While thus far this has not been successful the putative isolation of endozapines in the rare condition of idiopathic recurrent stupor indicate that this may be a useful line of research. In addition the emergence of partial agonists at these sites which have fewer side effects is likely to rekindle interest in the clinical use of such compounds in a variety of neurological and psychiatric syndromes.