Case of neuromyelitis otica: bilateral sensorineural hearing loss and transverse myelopathy following intrathecal chemotherapy

Background

Neurotoxicity of chemotherapeutic agents is well recognised, with the route of administration and the agent used being the main determinants of toxicity.1 In the case of intrathecal chemotherapy (ITC), serious neurological adverse events have been reported in around 8.3% of patients, and in 3.1% of treatments.2 However, myelopathy has been reported as the most frequent complication, particularly after methotrexate (MTX) administration.1 3 Although cytarabine (ARA-C) is another agent frequently associated with myelopathy, it’s neurotoxicity is not exclusive of IT administration.4 Ascertaining chemotherapy as the cause of myelopathy requires a careful and thorough evaluation to rule out infectious (eg, HIV or syphilis), metabolic (eg, cobalamin or copper deficiency, excess zinc intake), vascular (dural arteriovenous fistula), autoimmune or paraneoplastic causes. Hearing loss represents unusual toxicity, which has been rarely associated with MTX and ARA-C.5 6 We present the case of a 21-year-old male with acute lymphoblastic leukaemia, who developed acute transverse myelitis and bilateral sensorineural hearing loss following five rounds of intrathecal methotrexate and cytarabine, (along with intravenous doxorubicin and vincristine), a previously unreported association, without initial evidence of injury by imaging or audiometry, but further documented by neurophysiological studies.

Case presentation

A 21-year-old male was diagnosed with acute lymphoblastic leukaemia (ALL) and received five chemotherapy sessions with intravenous doxorubicin and vincristine, and intrathecal MTX, ARA-C and dexamethasone. During the fifth ITC administration, he reports to have developed dizziness and headache, and after the administration had finished, he lost consciousness. On regaining consciousness he was completely deaf, paraplegic with abolished sensory modalities up to his chest and unable to control sphincters. Chemotherapy was halted and the patient was diagnosed with an acute medullary syndrome of unknown (non-infectious neither neoplastic) aetiology; thus prednisone (1 mg/kg) was prescribed during 21 days, without improvement.

During the following 4 months, the patient had incomplete recovery of motor (MRC 2/5) and sensory function (sustained absent pain, temperature, vibration and joint position sense), hearing loss and sphincter control remained unchanged. He was referred to our hospital, to continue treatment for ALL. Haematological consultation ruled out an active neoplastic process, and the patient was referred to the neurology outpatient clinic to determine the cause of the myelopathy.

Neurological examination was carried out through a series of written commands and questions to the patient who after reading them, would then answer loud and clear or perform what was requested. Mental status examination and higher cortical functions were unremarkable. On cranial nerve examination bilateral complete sensorineural hearing loss was found. Upper limbs were normal, lower limb evaluation revealed a spastic paraparesis with bilateral increased tone, 1/5 strength, hyperreflexia and sensory level at T5 with loss of all sensory modalities below this level with bilateral extensor plantar responses. Gait and coordination could not be evaluated. Anal tone was severely diminished. At follow-up 1 month later, strength had improved to 3/5, but patient was unable to weight bare and sphincter function was unchanged.

Investigations

Neuroimaging of the brain and complete spinal cord at the time the patient was evaluated at our hospital was unremarkable (figure 1), as was the imaging done initially. HIV and syphilis were ruled out through antibody testing (fourth-generation ELISA, and anti-treponemal antibodies). Lumbar puncture revealed an absent cell count, with a normal level of glucose, proteins and lactate. Somatosensory evoked potentials were performed revealing an impairment of nerve conduction at spinal cord level (figure 2), and auditory brainstem response evoked potentials revealing bilateral impairment of conduction at the cochlear nerve level (figure 3), confirming thus the presence of damage at both levels.

Differential diagnosis

The differential diagnosis was narrow because of the likelihood of an adverse drug reaction was, according to the scale designed by Naranjo et al: previous (but separate) reports of myelopathy or hearing loss with intrathecal chemotherapeutics, the close cause-effect relationship between administration and onset of symptoms and the improvement of the symptoms after discontinuation of chemotherapy, (reasonable) exclusion of alternative causes and the objective evidence of injury with evoked potentials.

Given the rarity of the case, it was discussed among the Neurology Service Faculty and Residents. It was concluded that the patient developed acute transverse myelopathy and bilateral sensorineural hearing loss as a consequence of intrathecal chemotherapy. It was also considered that vascular, infectious and inflammatory or autoimmune aetiologies were unlikely, because of normal imaging and cerebrospinal fluid (CSF) profile, and the absence of systemic signs and symptoms (such as fever, malaise, weight loss). Metabolic causes, such as cobalamin, folate or copper deficiency (or excess zinc intake), were considered also unlikely because of the transverse nature of myelopathy without the involvement of upper limbs, against the selective involvement of dorsal column in the above-mentioned myelopathies, as well as the lack of haematological abnormalities. The possibility of neoplastic or paraneoplastic causes was also considered, but considered less likely given the negative CSF results.

Treatment

Supportive care, with physical therapy and rehabilitation. The patient was referred to a hearing loss clinic to be assessed to receive a hearing-aid device.

Outcome and follow-up

At 1 month follow-up (via text message), the patient reported he was able to walk aided (modified Rankin scale 3), but the hearing loss was unchanged.