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A 17-year-old boy with a history of anxiety was transported from a juvenile detention center for altered mental status, including hallucinations and agitation. What's the diagnosis?
A 17-year-old boy with a history of anxiety was transported from a juvenile detention center for altered mental status, including hallucinations and agitation.
Four days prior, he had arrived at the center in his usual state of health. Upon arrival, he was placed in a solitary isolation room due to a pending coronavirus disease 2019 (COVID-19) test. Three days later he was found to be diaphoretic with visual hallucinations, paranoia (asking to change rooms, describing “snipers on the roof”), physical agitation, and bizarre behavior, including attempting to drink out of the toilet bowl.
He was then taken to a community emergency department (ED), where he had a normal noncontrast head computed tomography (CT) scan. There he received lorazepam, diphenhydramine, and haloperidol, after which he became less physically agitated but remained significantly altered. He was then transferred to our tertiary care children’s hospital.
It was difficult to obtain an initial medical history from the patient due to his altered mental status. He did admit to some substance use, including alcohol, marijuana, and benzodiazepines, prior to detention. His grandmother, with whom he lived, had also found a “green pill” in the house, which she could not identify and had flushed down the toilet. She also reported that her grandson had been anxious but otherwise well prior to entering the juvenile detention center. According to his grandmother, and staff at the juvenile detention center, he had not had any known fevers, headache, blurry vision, gait instability, head trauma, or loss of consciousness. His family history was notable for depression, anxiety, and substance use disorders.
The patient’s initial exam in the ED was notable for an elevated blood pressure of 132/60 mmg Hg, a heart rate of 62/min, and temperature of 37.5 °C. His pupils were 1 to 2 mm in diameter and reactive to light; no Kayser-Fleischer rings were noted. The skin exam was notable for alopecia of the scalp. His neck was supple without goiter. There were no focal neurologic deficits; he had normal deep tendon reflexes without clonus, asterixis, or truncal or appendicular ataxia, although his exam was limited by his right upper extremity being handcuffed to the bed. His mental status was alert and oriented to self and place (he was unsure of the date). It was notable for describing seeing “virtual currency,” hearing “things through his AirPods” even when he was not using them, and tangential thought content without pressured speech. In sleep, he was observed to have frequent bilateral upper extremity myoclonic jerking and unintelligible utterances. Sleep appeared to be fragmented into 15- to 20-minute segments.
Initial laboratory evaluation demonstrated normal serum electrolytes and tests of renal function, with elevated serum aspartate aminotransferase/alanine aminotransferase levels of 143/43 u/L with normal serum ammonia. His complete blood count displayed a mildly elevated white blood cell count (11 K/uL) with 71.9% neutrophils; inflammatory markers were normal. A serum drug screen was negative for alcohol, acetaminophen, and salicylates. A urine immunoassay drug screen was positive for cannabinoids but otherwise negative, including for amphetamines, benzodiazepines, cocaine, and opiates. A broad serologic laboratory work-up was sent, which included an autoimmune encephalitis panel, oligoclonal bands, antinuclear antibody (ANA), rheumatoid factor (RF), copper, ceruloplasmin, vitamin B12/folate, thyroid-stimulating hormone (TSH), and rapid plasma regain (RPR)/HIV. A lumbar puncture and empiric antimicrobials were deferred given lack of infectious signs or symptoms.
The patient was given empiric thiamine for possible Wernicke encephalopathy.
Diagnostic test results
Video electroencephalogram (EEG) and brain magnetic resonance imaging were performed and were normal. The autoimmune encephalitis panel, oligoclonal bands, ANA, RF, copper, ceruloplasmin, B12/folate, TSH, and RPR/HIV returned negative.
Further history: The key to the diagnosis
On hospital day 2, the patient’s mother disclosed that the patient had previously informed her of 3 to 4 months of daily alprazolam use, as much as 2 to 3 “xanny bars” per day, which he was obtaining from friends or via social media. In light of the clinical history of acute onset diaphoresis, psychosis, sleep abnormalities, psychomotor agitation, and hypertension in the setting of recent incarceration, and a history of regular benzodiazepine use, his presentation was felt to be most consistent with alprazolam withdrawal.
A trial of alprazolam was administered to see if it would reverse the presumed withdrawal symptoms. After serial 1-mg alprazolam doses (total, 3 mg over 4 hours), the patient had a return of normal mental status and significant subjective improvement in perceptual disturbances, without sedation. Of note, a “xanny bar” is a 2-mg dose formulation of alprazolam; the patient had complete resolution of symptoms with a dosage comparable to what he had reportedly been taking at home. He was then started on a clonazepam taper, with good effect, including sustained normal mental status, normalization of blood pressure, and resolution of sleep disturbance. Several days later, gas chromatography/mass spectroscopy analysis of his urine, which had been added on to the urine sample collected on the day of presentation, was positive for alprazolam and alprazolam metabolites. This confirmed the patient’s reported history of alprazolam use. He was discharged back to the custody of the juvenile detention facility following successful completion of the taper, with outpatient supports for behavioral health and substance abuse treatment.
The use of benzodiazepines, although prevalent among adults (12.6% in recent estimates, highest among ages 50-65 years), is presumably less common in the pediatric population; however, relevant data are sparse. Notably, younger adults (ages 18-25 years) have higher rates of benzodiazepine misuse despite lower rates of overall use. Younger adults or adolescents (18-24 and 13-17 years of age, respectively) are more likely to use alprazolam than diazepam without a medical purpose.4,5 Alprazolam in particular has a higher misuse liability compared with other benzodiazepines, and is associated with more severe withdrawal syndromes, including delirium, psychosis, and even catatonia.6,7
The diagnosis of benzodiazepine withdrawal must be made clinically in order to provide timely treatment. In the setting of a substance use history, particularly with a trigger for abrupt cessation of use such as placement in a detention facility, and without other clear organic etiologies, the constellation of abrupt onset of autonomic instability, diaphoresis, and perceptual mood disturbances was consistent with benzodiazepine withdrawal in this patient. This was despite the initial negative urine screen. The inadequate response to lorazepam was likely related to alprazolam’s distinct structure. As a triazolobenzodiazepine, it has unique action at the gamma-aminobutyric acid (GABA) receptor, making trials of lorazepam, or diazepam, less effective in treating alprazolam withdrawal.3 A poor understanding of the drug’s unique structure may lead to a missed diagnosis.
In this case, the initial urine drug screen (an enzyme immunoassay) was negative for benzodiazepines; however, the extended panel (an immunoassay with reflex to mass spectrometry) was positive for both alprazolam and alprazolam metabolites. Confirmatory testing by mass spectrometry is often helpful. Compared to enzyme immunoassays, mass spectrometry identifies a broader range of compounds at lower concentrations. This is especially relevant when substance use may be more remote, such as when there is suspicion for withdrawal or in the setting of illicit substance use, which is more likely to include a wider variety of less common compounds.8 If there is concern for toxic exposure or withdrawal, saving a specimen from the earliest possible date is crucial.
In this case, treatment was initially trialed with alprazolam, and clonazepam taper was initiated following our patient’s stabilization. Case series suggest that clonazepam may be effective in treating alprazolam withdrawal, particularly compared to diazepam, which has not been found to be as effective. Although uncontrolled alprazolam withdrawal may initially prove recalcitrant to nontriazolo-benzodiazepines, transitions to longer-acting benzodiazepines can be effective once withdrawal symptoms are under good control. A longer-acting benzodiazepine and gradual taper is likely safer and more effective in preventing breakthrough withdrawal symptoms due to the accumulation of metabolites over time.3
There are no specific guidelines around benzodiazepine tapers to treat withdrawal. Most weans in children and adolescents are in the setting of prescribed use for prolonged or severe illness, often concomitantly prescribed with sedatives or opiates. In comparison, this case lacked clarity in terms of dosage and frequency of use from which to initiate a wean. No specific assessment tools have been validated for benzodiazepine withdrawal, although some studies of benzodiazepine withdrawal use Withdrawal Assessment Tool, version 1 (WAT-1), which has been validated for opioid withdrawal in pediatric patients. Of note, our patient had WAT- 1 scores of 2 to 3 prior to treatment initiation, and 0 after treatment initiation. Wean trials typically last 5 to 10 days, weaning at a rate of 10% to 20%; however, there are no standardized recommendations and clinical practice is often variable.9 Our patient completed a 12-day wean, weaning at a rate of 30% to 50% approximately every 3 days.
Our patient’s withdrawal was precipitated by incarceration in a juvenile detention center. He and his family indicated that his initial alprazolam use was related to insomnia and anxiety over entering detention while awaiting adjudication for a nonviolent offense. Detained adolescents, who are often awaiting their court date as this patient was, can spend periods of time ranging from days to months in custody. Juvenile detention includes physical and emotional separation from caregivers and communities during a developmentally vulnerable time, as well as exposure to potentially violent and chaotic environments. Detention also may preclude access to what is already limited mental health and substance misuse treatment resources.10
This young man was at risk of potentially life-threatening consequences of withdrawal while in physical and social isolation. Alternative solutions may include substance use rehabilitation programs, home confinement, or other community- or family-based interventions. This approach may have provided an avenue to a safe taper without a severe withdrawal syndrome for our patient.
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10. Holman B, Ziedenberg J. The dangers of detention: the impact of incarcerating youth in detention and other secure facilities. Justice Policy Institute. November 28, 2006. Accessed January 15, 2021. http://www.justicepolicy.org/uploads/justicepolicy/documents/dangers_of_detention.pdf