Dr Lazar Remen (1907–74): a forgotten pioneer in the treatment of myasthenia gravis

摘要

Dr Lazar Remen (1907–74) was the first, in 1932, to describe the beneficial effect of prostigmine on a myasthenia gravis patient. His observation actually preceeded by two years Mary Broadfoot Walker's (1888–1974) paper, which is considered to be the landmark article on this association. nnMary Broadfoot Walker (1888–1974) is regarded as the discoverer of prostigmine therapy in myasthenia gravis (MG)1 when she showed that a subcutaneous dose of physostigmine and of neostigmine temporally restored muscle function. In the five years after 1934, she and others provided clinical evidence suggesting that transmission failed due to acetylcholine deficiency and that physostigmine delayed its destruction.2 A film from the London County Hospital 1935 shows an item on Youtube illustrating the myasthenia treatment. She also described the association between familial periodic paralysis and hypokalaemia. nnPearce3 also mentioned that ‘the German physicians Erb in 1879 and Goldflam in 1893 later reported new and detailed expositions of MG’. In fact, Samuel Goldflam (1852–1932) was not a German but a Jewish-Polish neurologist, and a friend and colleague of the founder of Polish neurology, Edward Flatau (1869–1932). Heinrich Erb (1840–1921) was an eminent German neurologist. Carl Weigert (1845–1904) was a German-Jewish pathologist who noted the association of MG with hypertrophy of the thymus.4 nnRemen's 1932 paper has received scant acknowledgement although both Finger and an internet site devoted to the history of MG5,6 notes: ‘In 1932, Lazar Remen, a little known German physician reported that a patient he had treated could stretch his hands, open his eyes better, and eat without choking after an injection of neostigmine. But, because Remen was more interested in other things, his comments about the drug were brief [dosage was not even mentioned] and limited to a short paragraph in a thirteen page paper on a different subject’. Lazar Remen was not German. Finger7 mentions Remen as do others.8 nnThis author met Remen's son, Danny Remen, MD (from Arizona) and his daughter, Yona Laor MD (from Cincinnati and Israel) and they presented the family archives. Lazar (Eliezer) was a Polish Jew born in 1907 in Bialystok, Poland. He went to Jena to study medicine and after graduation (the thesis was presented in Koln, Department of Gynaecology) worked in Munster under Professor F Kehrer and in Berlin under Professor G Rosenow. While in Germany, he published many works on creatine and creatinine, and other subjects in internal medicine, gynaecology and neurology (he published a historical article on the treatment of MG). He started his gynaecological career in Germany but, after the Nazis took over, Remen, his wife and their daughter emigrated to Palestine in 1933 and there he became established in the town at Petach Tikya Maternity Hospital. His wife served as the Matron-nurse and two of his sons were born there. By this time he had published several papers.9–17 nnLater a surgeon, a paediatrician and an internist joined him. Injured soldiers from the ETZEL (Irgun) were clandestinely treated there until the British authorities revealed it, arrested Remen in 1939 and turned the hospital to their purposes. During the war, like many others, Remen volunteered for the British Forces and served in Malta for two years. The hospital was bought by The Workers Compensation Sick-Fund and became Hasharon Municipal General Hospital. Remen continued to work as gynaecologist in his private clinic until his death in 1974 and was very active in his community. nnIn his myasthenia paper, Remen described a myasthenic patient. He actually searched for creatine metabolic disturbances. The aetiology of the disease was still obscure – ?neurological, ?metabolic, ?vascular – but, Remen wrote, that it was known that histological examination of myasthenic muscles revealed various pathologies. Was it myositis? He quoted Marinescu who thought the disease is caused by a ‘neuro-muscular irritation’ or by changes in calcium metabolism, Herzog who related the myasthenia to a muscular disorder and Chvostek who hypothesized some connection with blood vessel epithelium! Remen also mentioned another hypothesis: perhaps myasthenia was caused by amino acid metabolic disturbances? His mentor, Professor Kehrer, suggested treatment with glykokol (glycine). Remen had noticed that a high meat diet and glykokol induced some clinical improvement among myasthenic patients.18 nnTreatment with glycine was tried in various situations.19–22 Then, in his paper he mentioned the treatment of MG with intramuscular or oral prostigmin (neostigmine bromide). Temporary improvement was noticed. Prostigmin, an anticholinesterase agent, is now recognized as the treatment of MG and the edrophonium test23 has largely been superseded by a trial of oral anticholinesterase. nnIn February 1965, the Third International Symposium on MG took place at the Waldorf Astoria Hotel, New York, where Dr Henry R Viets24–26 was asked to give the opening remarks. He was aware of Dr Remen's paper, found him in Israel and invited him to be credited at the meeting. He wrote to Remen from Boston (on 24 July 1964): ‘If I read your paper correctly, the director of the nerve clinic was more interested at that time in the glycine and you and he followed that unprofitable pattern, either missing or misinterpreting the results of prostigmin’.