All-trans retinoic acid-induced multiple mononeuropathies

Abstract

All-trans retinoic acid (ATRA) is widely used as a differentiation therapy to induce a complete remission in patients with acute promyelocytic leukemia (APL) [1]. The major adverse effect during ATRA therapy is an increase of leukocytes, which is often accompanied by retinoic acid syndrome [2]. This reaction is characterized by fever, respiratory distress, radiographic pulmonary infiltrates, pleural effusions, and weight gain [3]. It has also been reported that ATRA-associated neurological symptoms such as headache and pseudotumor cerebri [4] are mainly caused by intracranial hypertension. We describe a patient who developed multiple mononeuropathies during ATRA therapy for APL.A 23-year-old Japanese female was admitted with fever and purpura in November 1997. APL with disseminated intravascular coagulation was diagnosed. She received ATRA (45 mg/m 2 /day) with chemotherapy including daunorubicin (40 mg/m 2 /day, on days 9, 10, 21, and 22) and behenoyl cytarabine (200 mg/m 2 /day, on days 9, 10, 11, 21, 22, and 23), and supportive therapy for disseminated intravascular coagulation. She had a slight headache after administration of ATRA, but there were no findings on the neurological examination and computed tomography scan of the brain. On the seventeenth day after admission, a neurosurgical operation was performed because of acute subdural hematoma. Although ATRAassociated headache persists, no symptoms remained, which were caused by intracranial hemorrhage and operation. Furthermore, she complained of diplopia, and burning pain and contact dysaesthesiae at the dorsum of the left hand and the right foot on day 21 of the ATRA treatment. She also had weakness in the same extremities. Tendon reflexes were normal. Electrophysiologic study revealed a decrease of right peroneal nerve conduction velocity and amplitude. Although right abducens nerve palsy and visual disturbance were present, there were no papilloedema and abnormalities on magnetic resonance imaging of the brain. Lumbar puncture showed normal cerebrospinal fluid with normal pressure. She had no manifestation of autonomic disturbances. ATRA was discontinued because a complete remission was achieved on day 51 after administration of ATRA. Total dosage of ATRA was 3,390 mg. She received three times the intensive postremission chemotherapy (daunorubicin, cytarabine, mitoxantrone, mercaptopurine, and prednisolone). Symptoms of peripheral neuropathy and findings on electrophysiologic study gradually improved as well as headache and dry skin after discontinuation of ATRA, in spite of additional chemotherapy. The right abducens nerve palsy also partially improved.To the best of our knowledge, this is the first report of ATRA-induced multiple mononeuropathies. Neurological symptoms might be considered as atypical pseudotumor cerebri with focal neurological sign [5]. However, there was no evidence of intracranial hypertension. Furthermore, we carefully excluded a possibility that other medication including anticancer drugs induced peripheral neuropathy. Clinicia...

Effects of oral isotretinoin therapy on peripheral nerve functions: a preliminary study

“…Peripheral neurophysiological abnormalities are not usually discussed in reviews of adverse effects to systemic isotretinoin. However, peripheral sensory, motor or sensorimotor neuropathies have been reported in several cases in association with short‐ and long‐term oral‐retinoid treatments 2–11 . In these reports, complete remission of neuropathy has occurred in 2 weeks to 2.5 years after cessation of oral retinoid therapy, and clinical or electrophysiological peripheral neuropathies have been detected in 10 days to 4 years after onset of therapy.…”

“…Sensory nerve fibres are more susceptible to oral synthetic retinoids than are motor fibres. Reversible myopathy associated with oral isotretinoin treatment has been reported in only four cases in the literature 2–11 (Table 1). To the best of our knowledge, this study is the first to detect the electrophysiological evidence of peripheral sensory neuropathy under oral isotretinoin therapy.…”

“…A broad spectrum of neurological adverse reactions, almost exclusively concerning the central nervous system, has been observed under oral treatment with synthetic retinoids, especially isotretinoin and acitretin/etretinate 1 . Several cases of peripheral neuropathy (mainly sensory) associated with short or long‐term etretinate 2–7 and all‐ trans retinoic acid therapy 8 have been reported previously. A MedLine search (1966 to January 2006) revealed no reports of peripheral neuropathy due to isotretinoin 9–11 .…”

Potential Neurologic Side Effects of Oral Isotretinoin: A Case of Peripheral Neuropathy

“…After three weeks of ATRA therapy, the patient complained of diplopia as well as dysesthesia of the dorsum of the left hand and right foot. The patient also showed weakness in these extremities and a decrease in right peroneal nerve conduction velocity and amplitude during electrophysiologic study 9 . The mechanism by which isotretinoin may cause peripheral neuropathy is still unknown, but Aydogan and Karli hypothesize that nerve conduction is negatively affected by changes in lipid composition of peripheral nerve membranes secondary to isotretinoin therapy.…”