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All-Trans Retinoic Acid (ATRA) Syndrome Can Mimic Panic Disorder

TO THE EDITOR: The use of all-trans retinoic acid (ATRA) has proved extremely efficacious in the treatment of acute promyelocytic leukemia (APL). Since the mid-1980s, when ATRA was first used to induce remission, APL is now considered to be the most curable subtype of all the acute myeloid leukemias in adults.¹ A caveat to this success is that an estimated 25% of patients treated with this agent suffer a constellation of adverse effects that collectively constitute "ATRA syndrome."² Psychiatrists asked to consult on patients being treated for APL should be aware that the symptoms of ATRA syndrome may be misinterpreted as representing a primary psychiatric disorder.

Case Report

"Mr. M" was a 47-year-old married Caucasian man who was admitted to the oncology unit of a major tertiary-care hospital for acute abdominal pain and distension, in the setting of recently diagnosed APL. Work-up revealed a diagnosis of neutropenic enterocolitis, and Mr. M was ordered NPO (nothing by mouth) and started on broad-spectrum intravenous (IV) antibiotics for the colitis and on morphine PCA (patient-controlled analgesia) for management of his abdominal pain. His NPO status precluded administration of ATRA, which had been started 3 weeks before this admission, and is only available in an oral formulation. Mr. M had suffered headaches and fevers with the initiation of ATRA, but these symptoms had responded well to low-dose oral steroids.

Mr. M’s condition improved over the first several days of his hospitalization, prompting the reintroduction of ATRA on the fourth hospital day. Mr. M tolerated the oral administration of his medication without report of gastrointestinal pain or distress, but, 4 hours later, was noted to suffer a "panic attack," consisting of hyperventilation with desaturation to 80%. He was given IV lorazepam to treat these symptoms, and they were noted to resolve after the administration of two doses of 1 mg each. IV lorazepam was then started on a prn basis for anxiety. Twelve hours later, the Psychiatry Consultation Service was called emergently because the patient was acutely confused, attempting to leave the oncology unit and becoming combative when he was prevented from doing so. Mr. M responded well to reassurance and the administration of IV haloperidol. A diagnosis of delirium was made, and recommendations were made to hold those medications that could potentially aggravate his confusion; these including diphenhydramine, sertraline, and lorazepam. His delirium progressively resolved over the next 48 hours, and he was eventually discharged home on the 10th hospital day.

Discussion

Although hyperventilation is often a prominent feature of panic attacks, acute desaturation in the absence of preexisting pulmonary disease is unusual in panic episodes. The lack of any previous history of anxiety disorder and the temporal proximity of this episode to the reintroduction of ATRA raise suspicion for a possible link between the two. ATRA syndrome (retinoic acid syndrome), is defined as the presentation of any three of the following symptoms in the setting of ATRA administration: fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure.² The etiology of ATRA syndrome is poorly understood, although it is thought to be related to increased release of cytokines by APL cells.³ Treatment of ATRA syndrome typically consists of the administration of corticosteroids (which may also be beneficial as prophylaxis), cessation of ATRA, or addition of another antineoplastic treatment.³ Severe cases may require supportive measures, including intubation and mechanical ventilation.

Careful review of Mr. M’s vital signs revealed that he was intermittently febrile and hypotensive, in addition to the noted hyperventilation with desaturation, after the reintroduction of ATRA, although multiple chest x-rays revealed no sign of infiltrate or effusion. The symptoms of respiratory distress, fever, and hypotension would meet criteria for a diagnosis of ATRA syndrome.

In summary, ATRA syndrome is an unpredictable but frequent complication of the use of ATRA to treat APL. Prominent respiratory distress, with concurrent symptoms that are often less immediately appreciable, may lead to the misdiagnosis of a primary anxiety or panic disorder. The use of anxiolytic medications can further increase the risk for delirium already elevated by the cardiopulmonary compromise of ATRA syndrome. Clinicians treating patients with APL should be aware of this presentation to avoid such misdiagnosis and forestall subsequent mistreatment with anxiolytics.

REFERENCES

1. Tallman MS, Nabhan C, Feusner JH, et al: Acute promyelocytic leukemia: review of evolving therapeutic strategies. Blood 2002; 99:759–767[Abstract/Free Full Text]
2. De Botton S, Dombret H, Sanz M, et al: Incidence, clinical features, and outcome of all-trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia: The European APL Group. Blood 1998; 92:2712–2718[Abstract/Free Full Text]
3. Fenaux P, De Botton S: Retinoic acid syndrome (review): recognition, prevention, and management. Drug Saf 1998; 18:273–279[CrossRef][Medline]

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