Recurrent Catatonia Pre- and Postorthotopic Liver Transplant

Catatonia is a heterogeneous neuropsychiatric syndrome characterized by several psychomotor disturbances, including stupor, negativism, waxy flexibility, stereotypy, echolalia, and echopraxia, among others (1). Catatonia is associated with both primary psychiatric illness (including psychotic and affective disorders) and acute medical conditions (2). Recurrent or periodic catatonia refers to a relapsing-remitting course of the syndrome (3) that may be associated with unique biological abnormalities (4). Although a phenomenon of clinical relevance, there is a dearth of literature pertaining to diagnostic, pathophysiologic, and treatment considerations for recurrent catatonia (5, 6). In fact, the possibility of repeated catatonic episodes is not acknowledged in DSM-5 (1), let alone the characterization of differences in longitudinal presentation (1, 5). In the absence of data from large-scale controlled trials, clinical observations can help refine understanding about recurrent catatonia and offer guidance to the practicing clinician (7). The present case report describes a patient with recurrent catatonia in the setting of end-stage liver disease (ESLD) and subsequent orthotopic liver transplant. Several important considerations are highlighted, including inherent vulnerability to catatonic states, heightened risk in the posttransplant period, and overlap of catatonia with delirium.

Case Report

“Ms. Z” is a 47-year-old female with a history of ESLD secondary to primary biliary cirrhosis who was admitted to the inpatient general medical service for altered mental status. The patient’s pertinent medical history included familial hyperlipidemia and coronary artery disease with two bypass graft placements 2 years prior to presentation. She had no personal or family history of psychiatric illness. Her ESLD was complicated by gastric varices, hyponatremia, and hepatic encephalopathy that had been well controlled with lactulose. Symptoms documented on admission by the treatment team included confusion, verbigeration, and decreased spontaneous speech, and her presentation was thought to be atypical for hepatic encephalopathy given a lack of asterixis and undetectable ammonia levels. Hepatic encephalopathy was formally ruled out after aggressive treatment with rifaximin and lactulose resulted in minimal benefit, and psychiatry was consulted on day 3 of her hospitalization. On evaluation, symptoms of excitement (e.g., getting up repeatedly during interview and opening doors), echopraxia, echolalia, verbigeration (repeating “this is not what I can do”), impulsivity, gegenhalten, and perseveration were noted, raising concern for catatonia (Bush–Francis Catatonia Rating Scale score of 13, although assessment was limited). Benzodiazepine challenge with 2 mg of intravenous (IV) lorazepam resulted in marked improvement in her attention, alertness, behavioral regulation, rigidity, and ability to answer questions and was subsequently scheduled at a dose of 1 mg IV twice daily. The patient continued to improve over the next 3 days and was discharged with an oral lorazepam taper. At her outpatient psychiatry follow-up appointment approximately 1 month later, her catatonia remained resolved, and her sleep had improved with doxepin, which was initiated by the transplant hepatology team. She was not taking maintenance benzodiazepines.

The patient returned to the hospital approximately 1 month after her psychiatry appointment following 6 days of worsening altered mental status, characterized by initial hyperactivity at home (repeatedly calling emergency services, throwing away medications, and combativeness with family members) that progressed to hypoactivity with minimal responsiveness. Psychiatry was consulted, and her presentation again was felt to be consistent with catatonia, with evaluation notable for immobility, mutism, staring, catalepsy, stereotypy (continuously scratching her head and rubbing her hands against her arms), mannerisms (fixed upward gaze with rapid blinking), verbigeration (repeating “okay”), negativism, waxy flexibility, perseveration, and autonomic abnormality (mild tachycardia), as well as a documented Bush–Francis Catatonia Rating Scale score of 21. The patient was rechallenged successfully with lorazepam 1 mg IV, which resulted in positive effects on cognitive and psychomotor symptoms similar to those observed during her first presentation. She was restarted on scheduled lorazepam 0.5 mg IV in the morning and 1 mg in the evening, with full resolution of symptoms, and she was discharged home on oral lorazepam at this dose. She followed up with psychiatry 5 days following her discharge, and a 1-month oral lorazepam taper was planned.

Twelve days following her outpatient psychiatry follow-up appointment, she was hospitalized for an orthotopic liver transplant. The transplant surgery was without complication. Immunosuppressive therapy following the transplant included tacrolimus, mycophenolate, and prednisone; the patient was not restarted on benzodiazepines. Eight days after surgery, the transplant team noted decreased responsiveness and engagement with care, and a psychiatric consult was ordered. Examination by the psychiatry team was notable for immobility, mutism, staring, posturing/catalepsy (holding her arms in an elevated position), grimacing, echopraxia, stereotypy (touching her arms), mannerisms (unusual upper-extremity movement), negativism, withdrawal, automatic obedience, mitgehen, and grasp reflex, as well as a Bush–Francis Catatonia Rating Scale score of 23. The patient’s family noted that her presentation was similar to previous episodes of catatonia. Lorazepam challenge (2 mg IV) was again successful, with noted improvement in responsiveness, and she was started on scheduled lorazepam 1 mg IV every 8 hours. The dose of lorazepam was increased to 2 mg every 6 hours given her incomplete response. Although her catatonia improved, she developed symptoms consistent with delirium, including marked confusion, disruption of her sleep-wake cycle, and intermittent agitation. Delirium was distinguished from catatonia by the absence of previously identified psychomotor findings. Olanzapine was started and titrated to 10 mg at bedtime to address agitation and insomnia, with positive effect. Lorazepam was then tapered and discontinued. She was discharged home 24 days posttransplant on olanzapine 5 mg at bedtime, which was continued due to beneficial effect on sleep.

She has had no reemergence of catatonia since her discharge. Olanzapine was discontinued by the outpatient psychiatry team in favor of mirtazapine for ongoing treatment of insomnia, to which the patient has responded well.

Discussion

With recent estimates suggesting that catatonia is both prevalent and underdiagnosed in the medical setting (8–10), a better understanding of the longitudinal course of this complex neuropsychiatric syndrome is of clinical importance. There are several important teaching points in this case report. The first is that catatonia is an independent phenomenon that transcends medical and psychiatric diagnoses (11), meaning that susceptibility may render specific individuals prone to developing symptoms under a variety of psychiatric and nonpsychiatric conditions. In the present case, these included both ESLD and orthotopic liver transplant. Reports of recurrent catatonia suggest that this vulnerability can extend beyond acute psychiatric and medical conditions (5, 12, 13). Clinicians should be aware that not only is relapse possible following an initial episode of catatonia, but specific triggers may vary with subsequent episodes; in certain instances, causes may not be identifiable. It should be noted that it is unclear whether there are meaningful phenotypic differences between catatonia secondary to medical illness (as in the above case) and catatonia secondary to psychiatric illness or idiopathic catatonia (14). Although benzodiazepines and electroconvulsive therapy are first-line treatments regardless of etiology, it appears that catatonia secondary to schizophrenia is less responsive to these treatment modalities than other forms of catatonia (15–18), and symptom presentation may vary depending on underlying causes (19–21). Further work is needed to establish whether there are discrete neurobiological subtypes associated with catatonia that influence presenting symptoms, treatment response, and likelihood of recurrence.

The second point pertains to the association between catatonia and orthotopic liver transplant. As described by Tatreau and colleagues (22), there is an elevated risk of developing catatonia in the period immediately following liver transplant. Awareness of increased vulnerability to catatonia during the posttransplant period can facilitate rapid diagnosis and treatment, reducing hospital stays and mortality. In terms of pathophysiology, catatonia is thought to occur as a result of impaired gamma‑aminobutyric acid (GABA)-ergic function and increased glutamatergic function globally in the brain (23). GABA activity is increased in ESLD (i.e., prior to transplant) due to decreased clearance of GABAergic compounds (including ammonia) (24), upregulation of GABA receptors and GABAergic neurosteroids in the brain (24, 25), and an increased permeability of the blood-brain barrier to peripherally circulating GABA (25). Orthotopic liver transplant abruptly reverses these effects, producing a relative GABA deficiency and higher likelihood of related pathology. Additionally, immunosuppressive agents (particularly tacrolimus and cyclosporine) have been shown to inhibit GABA function and potentiate N-methyl-d-aspartate receptor activity (26). It should be noted that the patient in the present case developed catatonia following orthotopic liver transplant, which would be expected, as well as prior to orthotopic liver transplant, when GABAergic function is purportedly increased. While dysfunction in GABA signaling is currently the most widely accepted theory regarding the pathophysiology of catatonia (2), the true biological underpinnings (and how implicated systems interact with hepatic function) remain poorly understood. It is also interesting that this patient required an increased dose of lorazepam to treat catatonia posttransplant. Theoretically, lorazepam is metabolized by phase II glucuronidation and should not be affected by liver function (27). However, small changes in lorazepam pharmacokinetics have been observed in ESLD (28). It could additionally be speculated that the relative deficit in GABA function was higher following the transplant and immunosuppressive treatment (due to the above-mentioned factors), requiring higher doses of GABAergic medication to counteract it.

Finally, the patient in the above case developed delirium immediately after resolution of catatonic symptoms during the posttransplant period. In DSM-5, delirium and catatonia are considered mutually exclusive diagnoses in the context of medical illness (1), although recent research and clinical experience have suggested that they often coexist in medically ill persons and may share an underlying pathophysiology (29, 30). Consideration for emergence of symptoms of either catatonia or delirium in cases of altered mental status in hospital settings is therefore recommended for appropriate flexibility in clinical management. While benzodiazepines are used in catatonia but avoided in delirium (31), and antipsychotics are used in delirium but considered potentially harmful in catatonia (32), the above case suggests that judicious concurrent use can produce successful outcomes. Although there are no formal guidelines or treatment recommendations for overlapping delirium and catatonia, the approach utilized with this patient points to a potential benefit of frequent monitoring (she was evaluated daily while symptomatic), with adjustment of medications based on the presence or absence of overlapping delirium and catatonia symptoms and the trajectory of the clinical course.

Key Points/Clinical Pearls