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Footage of the first Parkinson’s treatments was rediscovered by Marcelo Miranda, a researcher at Clinica Las Condes in Santiago, Chile and uploaded to YouTube. In this exclusive interview, he tells us how he came across the video and the historic impact Dr George Cotzias’s first levodopa trials have had on Parkinson’s research
How did you discover the footage?
I decided to speak about the seminal contribution of Ismael Mena and George Cotzias’s work on manganic parkinsonism and its role in the development of levodopa for Parkinson’s disease. I found the video in the files of one of Dr Mena’s friends. It’s the only document available depicting the first patients affected by a secondary cause of parkinsonism as is manganism and their response to levodopa.
This footage shows the clinical features and the levodopa effect of patients affected with manganic parkinsonism – exposure to the metal manganese that causes tremors and other neurological symptoms that closely resemble Parkinson’s Disease – and not that of classical Parkinson’s disease.
How does it help our understanding of Parkinson’s back then compared to now?
Classical Parkinson’s disease shares some similarities but big differences with manganese parkinsonism: the work of Cotzias and Mena on these patients clearly show that levodopa introduced in a slow manner up to very high doses was effective: at that time there were no carbidopa nor benserazide (which inhibit the breakdown of levodopa) which now allow the use of less levodopa dose to reach the brain.
What do the videos show about Parkinson’s treatments back then and the history of neurology?
This video is important because shows some of the first patients treated with levodopa. Cotzias was working at that time in the development of levodopa, he had already treated some patients with Parkinson’s disease and reported his work in New England Journal, but the outbreak of manganic patients in a Chilean mine in 1960s allowed him to test his hypothesis that a toxin could also cause symptoms of Parkinson because of its interaction with melanin – manganese is a melanin trapper, and melanin is a precursor of levodopa – he initially thought that loss of melanin was a key factor in the cause of the disease but later he realised that this was not the case.
How can we explain the apparent success of Cotzias’s investigation?
The success was due to his perseverance and that he used higher doses of levodopa than tried before, in order to gain a clear response, as he finally demonstrated in his papers.
Was Cotzias’s work with levodopa known prior to discovering the videos?
He is part of the history of Neurology! He started working in 1950s in New York and during the following decades he devoted to find a treatment for Parkinson’s disease. He made many seminal publications during the 1960s reporting his findings, including those in Neurology in 1967 and ‘New England Journal of Medicine’ in 1970, which relate to the footage.
Would there have been a high level of risk involved with adverse side effects in such experiments at that time?
As he introduced levodopa very slowly and increased the dose gradually, he could get unusual high doses that were well tolerated in manganic patients. But he realised that patients (with typical Parkinson’s disease) developed dyskinesia and fluctuations of motor responses.
Initially he tested other formulations of ‘-dopa’ that caused blood disorders and he also tested a melanocytic hormone as he suspected loss of melanin was a cause – but the treatment caused skin to darken without a motor effect.
How has levodopa developed over the last 50 years?
In the 1970s levodopa was associated with an inhibitor of its metabolism allowing the use of smaller doses of levodopa.
How far have we come since those initial experiments with Parkinson’s treatments in general?
In the 1970s and 1980s and last decades other dopaminergic drugs were introduced with longer-lasting effects than levodopa, but not better than it. After 50 years, levodopa remains the main treatment for most patients with Parkinson’s. Other alternative therapies are available for those who have developed a more severe disease with dyskinesia and motor fluctuations, for example deep brain stimulation (DBS).
At the moment there is no neuro-protective therapy available: a major field of current investigation is devoted to finding a therapy that can be used in the very early stages of Parkinson’s disease – even before the classical motor symptoms emerge – to avoid the development of the disease.
Why is it important for future medical advances to document historic medical archives like this?
Because it documents a historical advance – the initial steps in the introduction of levodopa. Furthermore, it supports the notion that even secondary causes of Parkinsonism – such as manganism – may respond to levodopa. This finding was very controversial in the last decades, but this video clearly supports it.
Credit: ‘Neurology Journal’ YouTube channel
Authors: Marcelo Miranda, M. Leonor Bustamante, Francisco Mena, and Andrew Lees
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