There is speculation that Adolf Hitler may have had encephalitis lethargica when he was a young adult (in addition to the more substantial case for Parkinsonism in his later years). Mervyn Peake (1911–1968), author of the Gormenghast books, began his decline towards death which was initially attributed to encephalitis lethargica with Parkinsons disease–like symptoms, although others have later suggested his decline in health and eventual death may have been due to Lewy body dementia. Those described in the book Awakenings by the British neurologist Oliver Sacks. Jane Norton Grew Morgan, wife of J. P. Morgan Jr., died of encephalitis lethargica in 1925. At the time, doctors attributed her encephalitis to having contracted influenza during the 1918 pandemic. References
Further reading
Crosby, Molly Caldwell (2010). Asleep: The Forgotten Epidemic that Remains One of Medicines Greatest Mysteries. New York: Penguin/Berkley. – Describes the history of the disease, and the epidemic of the 1920s. Reid, A.H.; McCall, S.; Henry, J.M. ; Taubenberger, J.K. (2001). "Experimenting on the Past: The Enigma of von Economos Encephalitis Lethargica". J. Neuropathol. Exp. Neurol. 60 (7): 663–670. doi:10.1093/jnen/60.7.663. PMID 11444794. Sacks, Oliver (1990). Awakenings. Vintage Books. ISBN 978-0-375-70405-5. OCLC 21910570. Sacks O (1983). "The origin of Awakenings". Br. Med. J. (Clin. Res. Ed.). 287 (6409): 1968–1969. doi:10.1136/bmj.287.6409.1968. PMC 1550182. PMID 6418286. Vilensky, J.A. ; Foley, P.; Gilman, S. (2007). "Children and Encephalitis Lethargica: A Historical Review". Pediatr. Neurol. 37 (2, August): 79–84. doi:10.1016/j.pediatrneurol.2007.04.012. PMID 17675021. Vilensky, Joel A., ed. (2010). Encephalitis Lethargica: During and After the Epidemic. Oxford, UK: Oxford University Press. ISBN 978-0190452209.
Proton-pump inhibitors such as omeprazole and the anticonvulsant valproate have been found to increase the plasma concentrations of methotrexate, as have nephrotoxic agents such as cisplatin, the GI drug colestyramine, and dantrolene. Mechanism of action
Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. The affinity of methotrexate for DHFR is about 1000-fold that of folate. DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate. Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is essential for purine and pyrimidine base biosynthesis, so synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins.For the treatment of rheumatoid arthritis, inhibition of DHFR is not thought to be the main mechanism, but rather multiple mechanisms appear to be involved, including the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function. Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor.