Reversible Methotrexate‐Induced Dementia: A Case Report

To the Editor: Low-dose oral methotrexate is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis, but its mechanism of action for these indications remains unclear.1 Folate antagonism and inhibition of polyamines are known to contribute to the antiproliferative effects.2 In patients with hematological cancer, methotrexate is known for its central neurotoxic side effects after long-term intrathecal administration, ranging from acute aseptic meningitis to delayed toxicities comprising cognitive deficits and progressive dementia, but all these cases concerned long-term intrathecal administration in children.3, 4 A case with reversible dementia after withholding low-dose oral methotrexate for the treatment of rheumatoid arthritis is reported. A 78-year-old man was treated with 15 mg of methotrexate once a week in combination of 2.5 mg of folic acid 6 days a week after a diagnosis of rheumatoid arthritis. His medical history included periods of major depression. Eleven months after starting methotrexate, he was hospitalized on a psychiatric ward because of mood and behavioral disorders and cognitive disturbances. Methotrexate was continued. After 3 weeks of clinical observation (including comprehensive neuropsychologic testing and magnetic resonance imaging (MRI) of the brain) and treatment with nortriptyline 75 mg once a day, a diagnosis of dementia syndrome, probably symptomatic frontal lobe, was made, with a Clinical Dementia Rating (CDR) severity of 1. The cognitive domain of the CDR was 2. Four months later, he visited the memory clinic for a second opinion. Cognitive disturbances (Montreal Cognitive Assessment 20/30) and symptoms of frontal lobe dysfunction such as agitation, lack of empathy, and inappropriate and rude reactions were seen. After consulting the rheumatologist, methotrexate was withdrawn. Four weeks later, the neuropsychological tests started to improve (e.g., Mini–Mental State Examination (MMSE) score 26), and his symptoms of frontal lobe dysfunction decreased. He had no symptoms of depression. One year after withdrawal of methotrexate, his MMSE score was 30, with a clinical diagnosis of multidomain mild cognitive impairment. The behavioral disturbances no longer existed. This case-report describes a 78-year-old mean with a dementia syndrome, symptomatic frontal lobe, after the use of low-dose oral methotrexate that was reversed upon withdrawal of the methotrexate. In the literature, reversible cognitive disturbances after start and rechallenge with low-dose methotrexate were described 25 years ago in older adults with mild renal insufficiency,5 but a case of methotrexate-induced dementia is not described in the literature. In the Netherlands, seven cases (aged 52–77) with cognitive disturbances after the start (latency time 1–24 months) of low-dose oral methotrexate (5–32.5 mg once a week) were reported to the Netherlands Pharmacovigilance Centre Lareb, which is responsible for the collection and analysis of spontaneously reported adverse drug reactions in the Netherlands. The cognition of three of these individuals recovered after withdrawal of methotrexate. Like the case described herein, improvement of an adverse reaction after withdrawal of a suspected drug without additional treatment points to a causal relationship between the suspected drug and the adverse reaction. The reason methotrexate affects cognition is not clear. There may be several mechanisms. One explanation is depletion of folic acid. Methotrexate is a folic acid antagonist, and the addition of folic acid with the use of methotrexate is standard care. Older people are especially vulnerable to cognitive problems caused by folic acid deficiencies, and the administration of methotrexate may enhance this.6 Furthermore, folate deficiency induces several pathophysiological changes that are supposed to be pathogenetic in Alzheimer's disease, such as mitochondrial dysfunction, loss of calcium regulation, neuronal and synaptic impairment, and accumulation of hyperphosphorylated tau and β-amyloid.7 Another explanation for the effect of methotrexate on cognition is the effect of methotrexate on polyamines like putrescine, spermidine, and spermine seen in rodents.8 Polyamines influence the aggregation of amyloid-beta (Aβ) peptides into fibrils, known as a risk for Alzheimer's disease.9 Polyamines have recently been recognized as important elements in the development of many brain diseases.10 Finally, the man describe herein had had several bouts of depression. Depression and frontal lobe dementia decrease the function of the prefrontal areas,11 so this man might have been prone to the potential negative effect of methotrexate on cognition. This case shows that in cases of vulnerability, older people or people known to have depressed periods, low-dose methotrexate can cause cognitive disturbances and even the clinical syndrome of dementia. If low-dose oral methotrexate is needed in these individuals, screening cognitive functions before and during methotrexate treatment may be useful. Perhaps in these individuals, the recommended dose of additional folic acid needs to be increased. Conflict of Interest: Paul J. L. Dautzenberg is on the 2012 advisory board for Eli-Lilly and the 2012 advisory board for Novartis; received sponsorship for a memory congress from 2001 to 2013 from Novartis; and participated in Phase III medication trials for MSD, Novartis, and Janssen-Cilag during the conduct of the study. All other authors declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. Author Contributions: All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the drafting of the manuscript. Data collection: Dautzenberg. Study supervision: Keijsers. All authors approved the final version. Sponsor's Role: No sponsor.

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