Sleepless and paranoid

The authors’ observations

American Psychiatric Association practice guidelines³ do not support first-line use of benzodiazepines for non-alcohol withdrawal-related delirium. Benzodiazepines are ineffective for treating delirium and may exacerbate symptoms.⁴ Laboratory evidence confirmed Mr. Q has no history of alcohol or benzodiazepine use. Although treating the underlying cause of delirium is essential, prescribing a sedative-hypnotic medication such as zolpidem for Mr. Q’s insomnia may worsen his condition. These agents are known to impair cognition and may induce or intensify psychosis.⁵ Melatonin and melatonin receptor agonists, such as ramelteon, promote sleep by regulating the sleep-wake rhythm through their action on melatonin receptors in the hypothalamus.⁶ Recently, a randomized control trial (RCT)⁷ found melatonin protected against delirium in hospitalized patients age ≥65. However, no RCT has examined use of exogenous melatonin or melatonin receptor agonists to treat delirium. In Mr. Q’s case, we chose to administer haloperidol. First- and second-generation antipsychotics have shown efficacy in treating acute delirium. Although more clinical experience has accumulated using first-generation agents such as haloperidol, a 2007 Cochrane meta-analysis⁸ demonstrated equal benefit with second-generation antipsychotics, while noting a decreased incidence of adverse effects.

TREATMENT: Adverse effects

Mr. Q receives an IM injection of haloperidol, 5 mg, for severe agitation, followed 15 hours later by IM aripiprazole, 9.75 mg. Within hours of receiving aripiprazole, Mr. Q develops hyperkinetic perioral and tongue movements. He initially is diagnosed with acute reactionary dystonia, although closer examination reveals myoclonus consistent with his overall presentation. Additionally, his QTc interval increases by 120 ms. Subsequently, all antipsychotics are stopped. We prescribe lorazepam, 1 mg IM every 4 hours as needed, for agitation. Mr. Q receives 2 consecutive doses of lorazepam, although neither effectively reduces his agitation or promotes sleep. Mr. Q is not assessed with positron-emission tomography (PET) or polysomnography.

The authors’ observations

There was no evidence of neurologic disease on Mr. Q’s CT scan and EEG was within normal limits. Other imaging and laboratory studies did not reveal possible infection, malignancy, or cardiovascular disease. Despite its rarity, we considered the possibility of a prion disease, given Mr. Q’s unique presentation and family history. Familial fatal insomnia (FFI) is an autosomal dominant disease caused by a point mutation in the prion protein gene. Prion proteins are theorized to play a role in myelin stability. The aberrant isoform produced in FFI is structurally misfolded so that it resists degradation by proteolytic enzymes. The accumulation of irregular prion proteins in the medial thalamic nucleus results in progressive neurodegeneration. Patients with FFI present with increasingly severe insomnia, mild fever, dysautonomia, spontaneous myoclonus, cognitive dysfunction, and hallucinations.⁹ Generally, patients die from sudden cardiorespiratory failure or ensuing infections 9 to 24 months after symptom onset. In vivo, FFI diagnosis is suggested by a loss of sleep spindles on polysomnogram and by decreased thalamic metabolism on PET scan. Other imaging modalities and testing, including EEG and CSF analysis, lack sensitivity and/or specificity.¹⁰

OUTCOME: Improvement, discharge

On his fourth hospital day, Mr. Q’s symptoms begin to remit spontaneously. His gastrointestinal (GI) upset improves and the following night he sleeps for approximately 4 hours. As his sleep improves, his delusional thinking and hallucinations resolve. Orientation, memory, and concentration gradually improve. Before discharge, his MMSE score is 24 out of 30, indicating improved cognition. His heart rate, blood pressure, and body temperature normalize and his myoclonus improves. Mr. Q is discharged after 6 days in the hospital and returns home. He follows up with his primary care physician, denies any recurrence of sleep disturbance, and reports that his cognition and perception have returned to his baseline.

The authors’ observations

Spontaneous resolution of Mr. Q’s symptoms excludes an FFI diagnosis. We reconsidered the possibility of substance-induced insomnia. Most compelling was how quickly Mr. Q’s insomnia abated after hospitalization, even though he received no specific treatment. His protracted nausea and vomiting resolved just before his overall condition improved. We hypothesized that Mr. Q’s GI upset may have impaired absorption of his prescribed opioid, leading to acute withdrawal symptoms (Table 3).¹¹ Symptoms of severe opioid withdrawal include psychosis, autonomic instability, and myoclonus.¹² Another possibility is that opioid withdrawal may have caused Mr. Q’s GI upset, in which case we would search for a cause of decreased intestinal absorption or suspect a history of opioid abuse. Mr. Q’s daily marijuana use raises the risk of comorbid substance abuse or dependence. Chronic pain and long-term opioid use can result in chronic insomnia, which may account for Mr. Q’s sleep disturbance in the months before his presentation.