Could low-dose oral methotrexate cause extrapontine myelinolysis?/nA 67-year-old man with somewhat

Fråga: Could low-dose oral methotrexate cause extrapontine myelinolysis?

A 67-year-old man with somewhat high alcohol consumption is treated with methotrexate due to seronegative rheumatoid arthritis. He is also treated with acetaminophen (Alvedon), tramadol (Tradolan), prednisolone (Prednisolone) 2.5 mg qd, simvastatin 40 mg, metoprolol (Seloken ZOC), losartan (Cozaar) and cyanocobalamin (Betolvex).

For seven months he has had severe neurological symptoms and an MRI has shown disseminated white matter changes. The changes are spread both supra and infratentorial and affects pons, cerebellum, the corona radiata, the centrum semiovale and so on. Methotrexate was withdrawn at least four months ago and some clinical improvement has been noted during the last two months. Cerebrospinal fluid had no pleiocytosis, but some oligoclonal bands.

Sammanfattning: Leukoencephalopathy with or without pontine involvement is a known side-effect of intrathecal methotrexate, and has also been described in connection with oral methotrexate in a few cases. A causal relationship cannot be established from these case reports only.

Svar: Central pontine myelinolysis is classically characterised by a sharply demarcated myelin loss extending from the midline of the basis pontis. Sometimes, however it extends up to the midbrain, cerebrum and cerebellum, but rarely down into the medulla oblongata. The disorder is then called extrapontine myelinolysis (1). Pontine and extrapontine myelinolysis is classically caused by rapid correction of hyponatremia, but other riskfactors involve chronic alcoholism (even without hyponatremia), liver transplantation, hepatic cirrhosis, burns, diabetes mellitus, AIDS and hyperemesis gravidarum (2).

Methotrexate is a hydrophilic compound and does not readily penetrate the blood-brain barrier. Therefore it is given intrathecally to treat various malignancies affecting the CNS. Leukoencephalopathy is a well-known, but rare, side effect of intrathecal methotrexate administration (3). However, there are a few reports of white matter disease in patients treated with low-dose oral methotrexate.

Worthley and McNeil were the first to describe a case of leukoencephalopathy in a patient on oral methotrexate (10-20 mg/week for 3 years). The symptoms were impaired short term memory and unsteadiness of gait. MRI showed extensive white matter disease, mainly in the parietal and occipital lobes, but also in the internal capsule, basal ganglia and brainstem. The symptoms were not reversible upon three months follow-up (4).

The Swedish adverse drug reactions register has one report of leukoencephalopathy in a 47-year-old man treated with oral methotrexate and etanercept. The neuroradiological changes are sketchily described as spread changes in both hemispheres and a finger-like edema. There were no pathological changes in the cerebrospinal fluid (CSF) (5). Etanercept, however, has also been associated with demyelinating disease (6).

Yokoo et al describe a Japanese 68-year-old woman who after two years treatment with oral methotrexate (4 mg/week) developed fatigue, progressive pareses, restricted visual field, mental confusion and deteriorating consiousness and eventually death. CSF showed some pleiocytosis and elevated protein, but no oligoclonal bands. Autopsy revealed diffuse, symmetrical, myelinolytic leukoencephalopathy involving large parts of the cerebral and midbrain white matter, while cerebellum was grossly spared (3).

Rahavendra et al describe an Indian 59-year-old woman who after five years of oral methotrexate 7.5 mg/week) developed visual blurring, transient disorientation and sensory impairment. Her CSF showed mild pleiocytosis, but was otherwise normal; nothing is written about immunoglobulins or oligoclonal bands. Neuroradiology showed symmetrical parieto-temporo-occipital white matter lesions. A stereotactic biopsy showed extensive demyelinisation. The patient recovered, but relapsed four months later and subsequently died from septicemic aspiration pneumonia (7).

The case of a Dutch 49-year-old woman on oral methotrexate (7.5 mg/week) since seven years differs from the above cases in that she only had white matter changes in the occipital lobes (posterior leukoencephalopathy) with no involvement of the crus cerebri or other parts of the cerebrum (8).

The WHO adverse drug reactions register has 83 reports of demyelinating disorders on methotrexate, 7 of which are reported for the oral route (9).

In this particular case, however, the patient´s alcohol intake is the most well-established risk factor for extrapontine myelinolysis.

We still recommend this case to be reported as a suspected adverse drug reaction. Kleinschmidt-Demasters BK, Rojiani AM, Filley CM. Central and extrapontine myelinolysis: then...and now. J Neuropathol Exp Neurol 2006;65(1):1-11 Lampl C, Yazdi K. Central pontine myelinolysis. Eur Neurol 2002;47(1):3-10 Yokoo H, Nakazato Y, Harigaya Y, Sasaki N, Igeta Y, Itoh H. Massive myelinolytic leukoencephalopathy in a patient medicated with low-dose oral methotrexate for rheumatoid arthritis: an autopsy report. Acta Neuropathol 2007;114(4):425-430 Worthley SG, McNeil JD. Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid arthritis. J Rheumatol 1995;22(2):335-337 Sweweb (cited 2009-03-11) Drugline no 23239 (year 2007) (cited 2009-04-07) Raghavendra S, Nair MD, Chemmanam T, Krishnamoorthy T, Radhakrishnan VV, Kuruvilla A. Disseminated necrotizing leukoencephalopathy following low-dose oral methotrexate. Eur J Neurol 2007;14(3):309-314 Renard D, Westhovens R, Vandenbussche E, Vandenberghe R. Reversible posterior leucoencephalopathy during oral treatment with methotrexate. J Neurol 2004;251(2):226-228 Vigibase: WHO:s adverse drug reactions database (cited 2009-04-07).