Awakenings: Encephalitis lethargica and L-DOPA

This is the remarkable story of a group of patients who contracted sleeping-sickness during the great epidemic just after World War I. Frozen for decades in a trance-like state, these men and women were given up as hopeless until 1969, when Dr. Oliver Sacks gave them the then-new drug L-DOPA, which had an astonishing, explosive, “awakening” effect (the drama film Awakenings 1990).

The following text is an edited excerpt from an article by Foster and Hoffer [2004]:

 

“Encephalitis lethargica is a viral epidemic encephalitis that occurred in many parts of the world between 1915 and 1926. Also known as sleeping sickness or sleepy sickness, those who survived the initial infection typically displayed long term apathy, paralysis of the extrinsic eye muscles and extreme muscular weaknesses [Sacks 1982]. There is still disagreement over which virus was involved in this disease but the disorder often preceded Parkinsonism, suggesting that there must have been similarities in neurological damage. Although little or nothing has been published on the roll of oxidative stress in Encephalitis lethargica, damage by reactive oxygen species has been implicated in other forms of such disorders, as for example in Japanese encephalitis [Liao et al. 2003].”

“In 1969, Sacks [1983] began treating Encephalitis lethargica patients, some of whom had been catatonic for years, with high doses of L-DOPA. The dramatic improvements that followed were later documented in his book Awakenings and in a film of the same name [Sacks 1982, Awakenings 1990].”


Watch Awakenings

“It was discovered through the use of L-DOPA by Parkinson’s disease patients that, although its initial results were dramatically effective, a growing tolerance to it developed. This resulted in a need to increase dosages over time. Eventually side-effects of the drug, such as dyskinesias (abnormal movements), gastrointestinal symptoms, insomnia, hallucinations and even psychosis, became worse than its benefits [Katzenschlager and Lees 2002].”

“A similar picture emerged in the treatment of Encephalitis lethargica patients. Sacks [1982, screenplay Awakenings 1990] described treating 20 such patients with L-DOPA. The initial dose was 500 mg daily but, if required, was increased gradually to 6 g. Many patients showed great early progress, which Sacks termed an Awakening. Unfortunately, this dramatic improvement in health began to reverse. Sacks’ book Awakening first appeared in 1973. By the time his revised 1982 edition was published, seventeen of his patients were dead, mainly from Parkinsonism and all had relapsed. Sacks [1982] describes the experiences of an Encephalitis lethargica patient receiving high dose L-DOPA as follows:

For the first time, then, the patient on L-DOPA enjoys a perfection of being, an ease of movement and feeling and thought, a harmony of relation within and without. Then his happy state – his world – starts to crack, slip, break down, and crumble; he lapses from his happy state, and moves toward perversion and decay.”

“The evidence just presented suggests that dopamine deficiency probably plays an important role, not just in Parkinson’s disease, but also in Encephalitis lethargica” … “However, attempts to correct such deficiencies with L-DOPA, especially at high dosages, while initially beneficial appear to quickly produce a wide range of negative side effects.”

“The most logical interpretation of the L-DOPA experience is that patients with untreated Parkinson’s disease, Encephalitis lethargica” … “all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly improved by L-DOPA. A second set of symptoms, however, are the result of neurological damage caused by the metabolites of dopamine. The use of L-DOPA, therefore, increases the severity of these symptoms over time until they outweigh any improvement observed from the correction of dopamine deficiency. It is suggested that the damaging side-effects of L-DOPA’s use stem not directly from the drug but from its oxidation products which include dopachrome and other chrome indoles which are hallucinogenic, toxic to neurons and have been seen to hasten death in Parkinsonism patients [Graham 1978, Graham et al. 1978].”

“At least part of the neurological damage seen in Encephalitis lethargica” … “appears to be caused by dopachrome and other chrome indoles, produced by the oxidation of dopamine. The use of L-DOPA in these patients probably accelerates production of such neurotoxins. If this hypothesis is correct, it follows that combining L-DOPA with very high dose antioxidants may permit the beneficial use of this drug”.

… “high doses of natural methyl acceptors, such as thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3) and ubiquinone (Coenzyme Q10) should delay disorder progression. This is because they are capable of decreasing the conversion of dopamine to dopachrome and so preventing the toxic impacts of this and other chrome indoles [Hoffer 1998].”

 

References 

Awakenings (1990). Film. Directed by:  Penny Marshall. USA: Columbia Pictures.

Foster HD, Hoffer A (2004)  The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis. Medical Hypotheses 62: 177–181.

Graham DG (1978) Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Mol Pharmacol 14 (4): 633–643.

Graham DG, Tiffany SM, Bell WR, Gutknecht WF (1978) Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds towards C1300 neuroblastoma cells in vitro. Mol Pharmocol 14 (4): 644–653.

Hoffer A (1998) Vitamin B-3 Schizophrenia: discovery, recovery, controversy. Quarry Press, Kingston, Ontario.

Katzenschlager R, Lees AJ (2002) Treatment of Parkinson’s disease: levodopa as the first choice. J Neurol 249 (Suppl 2): 19–24.

Liao SL, Raung SL, Chen CJ (2003) Japanese encephalitis virus stimulates superoxide dismutase activity in rat glial cultures. Neurosci Lett 324 (2): 133–136.

Sacks O (1982) Awakenings. Pan Books. London.

Sacks O (1983) The origin of “Awakenings”. Br Med J (Clin Res Ed) 287 (6409): 1968–1969.

 

Eating flavonoids protects men against Parkinson’s disease

Men who eat flavonoid-rich foods such as berries, tea, apples and red wine significantly reduce their risk of developing Parkinson’s disease, according to new research by Harvard University and the University of East Anglia (UEA).

Published April 4 in the journal Neurology®, the findings add to the growing body of evidence that regular consumption of some flavonoids can have a marked effect on human health. Recent studies have shown that these compounds can offer protection against a wide range of diseases including heart disease, hypertension, some cancers and dementia.

This latest study is the first study in humans to show that flavonoids can protect neurons against diseases of the brain such as Parkinson’s.

Around 130,000 men and women took part in the research. More than 800 had developed Parkinson’s disease within 20 years of follow-up. After a detailed analysis of their diets and adjusting for age and lifestyle, male participants who ate the most flavonoids were shown to be 40 per cent less likely to develop the disease than those who ate the least. No similar link was found for total flavonoid intake in women.

The research was led by Dr Xiang Gao of Harvard School of Public Health in collaboration with Prof Aedin Cassidy of the Department of Nutrition, Norwich Medical School at UEA.

“These exciting findings provide further confirmation that regular consumption of flavonoids can have potential health benefits,” said Prof Cassidy.

“This is the first study in humans to look at the associations between the range of flavonoids in the diet and the risk of developing Parkinson’s disease and our findings suggest that a sub-class of flavonoids called anthocyanins may have neuroprotective effects.”

Prof Gao said: “Interestingly, anthocyanins and berry fruits, which are rich in anthocyanins, seem to be associated with a lower risk of Parkinson’s disease in pooled analyses. Participants who consumed one or more portions of berry fruits each week were around 25 per cent less likely to develop Parkinson’s disease, relative to those who did not eat berry fruits. Given the other potential health effects of berry fruits, such as lowering risk of hypertension as reported in our previous studies, it is good to regularly add these fruits to your diet.”

Flavonoids are a group of naturally occurring, bioactive compunds found in many plant-based foods and drinks. In this study the main protective effect was from higher intake of anthocyanins, which are present in berries and other fruits and vegetables including aubergines, blackcurrants and blackberries. Those who consumed the most anthocyanins had a 24 per cent reduction in risk of developing Parkinson’s disease and strawberries and blueberries were the top two sources in the US diet.

The findings must now be confirmed by other large epidemiological studies and clinical trials.

Parkinson’s disease is a progresssive neurological condition affecting one in 500 people, which equates to 127,000 people in the UK. There are few effective drug therapies available.

Dr Kieran Breen, director of research at Parkinson’s UK said: “This study raises lots of interesting questions about how diet may influence our risk of Parkinson’s and we welcome any new research that could potentially lead to prevention.

“While these new results look interesting there are still a lot of questions to answer and much more research to do before we really know how important diet might be for people with Parkinson’s.”

 

Reference

Gao X, Cassidy A, Schwarzschild MA, Rimm EB, Ascherio A. Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology, 2012 DOI: 10.1212/WNL.0b013e31824f7fc4

 

Intoxication With Heavy Metal As A Possible Cause Of Parkinson’s Disease

By veterinarian Hanne Koplev.

Hanne Koplev in the woods

A neurologist recommended in the year 1998, that I should be medicated against my tremor, but I said no thank you to his offer, as I preferred to be better diagnosed before starting medication.

The following year my symptoms increased, as I became more rigid and my tremor got worse and I therefore was easy to persuade by a new neurologist to try anti-Parkinson medication. Shortly after, I was scanned for Parkinson’s disease and the result was compatible with the diagnosis of Parkinson’s disease in the early stage.

Anti-Parkinson medication helped to decrease the symptoms, but soon I experienced more severe symptoms. At first I thought that it was the disease becoming more severe and this was confirmed by my neurologist who told me that it was unavoidable.

After one year on medication my neurologist recommended that I stopped medication before the next consultation. This became the start of a new phase in the way I coped with my disease, as without medication, I experienced that:-

–     The medication can result in abstinences when the medication is stopped.

–     Many of the symptoms, that I thought were Parkinson’s symptoms, were in reality side effects of the medication.

Therefore I decided to accept the symptoms of the disease instead of being burdened with adverse side effects of the medication. The outcome of this choice forced me to search for factors, which had influenced my symptoms.

In the year 2001 I was tested for Heavy Metal Toxicity in a private clinic in Aarhus, Denmark by Dr. Bruce Kyle and I was diagnosed with a combined toxic overload with mercury and copper.

I was treated at Dr. Bruce Kyle’s clinic with the Chelating Agent DMPS, with Vitamin-C infusions and different kinds of antioxidants and nutritional support. At the same time I had my amalgam fillings removed and had non-toxic, non-metal composites instead. This was done by a dentist with extra education in safe removal of amalgam. I also use saunas, which help detoxification by sweating out the toxins through my skin.

After some years of undergoing detoxifying treatments, I had fewer tremors and was less rigid, but I still suffered from fatigue. Allergic reaction against metals was suspect, and I undertook a MELISA-test.  My test showed an allergic reaction against gold, nickel and cadmium and treatment protocol was removal of a dental gold crown, which was replaced with plastic.  Now, I try to avoid nickel and to eat more organic food to avoid cadmium. Luckily I have been rewarded for my efforts as my fatigue has decreased.

Today I can honestly say that testing and treatments for my chronic cumulative toxicity has been successful for revealing some of the causes of my Parkinson’s disease. However, I still have slightly high levels of copper left and in autumn 2006 and spring 2008 tests show that I am also burdened with lead and aluminium.

I don’t dare to think about how my life would have been without detoxifying treatments!  When I look at other patients with Parkinson’s disease who are getting worse, I have even more reasons to be thankful for my health, which continues to improve as time goes on.

Where do these Heavy Metals come from?

In my case, mercury and copper were likely to have come from my amalgam fillings. Copper-amalgam contains a high percentage of copper and I had many fillings in my milk teeth. Even later in school I had many cavities, which were restored with amalgam. The dentist said that I had weak teeth.

As an adult, I have only had one cavity, so I might think that my parents were not good at helping me with tooth brushing and perhaps also the school dentist has been tempted to do fillings, which were not necessary as she was paid for the amount of pupils’ cavities that she restored.

In addition I have in my job as a veterinarian, been exposed to many thermometers, which sometimes break and where the mercury ended up in the bottom of the car. Veterinarians were not properly informed that this could constitute a health hazard at that time.

Moreover mercury can come from vaccinations containing the preservative thiomersal (ethyl-mercury). Mercury might also come from environmental pollution and intake of fish. Copper might come from use of copper spiral (anti contraceptive) and from drinking water and food. The Danish Agriculture Production uses 200 tons of copper yearly and this copper could be assumed to spread to the environment and end up in drinking water and food.

When a person is burdened with mercury toxicity, then the excretion of copper is decreased.

My toxicity burden with lead might perhaps come from common environmental pollution. My toxicity with aluminium probably came from years of injections with aluminium containing products against dust mite allergy.

My nutrition today contains more antioxidants (nutrients which protects the body against free radicals and oxidation), more vegetables (raw vegetables are chosen) and more fruits.  I have stopped eating unhealthy fats such as margarine, hard fats, corn oil, soy, sunflower etc. I try to eat more of the healthy fats such as fat fish (salmon), linseed, olives oil, nuts etc.

I take antioxidants as nutritional supplementation, also a multivitamin mineral pill without iron and copper, extra vitamin C and E, Lipoic acid, N-acetyl-cysteine, Echinacea, Ginkgo Biloba and Coenzyme Q10. I also use DMSA for mercury, copper and lead chelation.

Concerning the nutrition I would recommend the book by Jean Carper – “Your Miracle Brain.”

Physical activity has been an important part of my life. At the beginning of my disease I walked without swinging my right arm and I stumbled rather often. After years training trying to walk normally with swinging my right arm, I have succeeded, but only when I am not too stressed or exhausted. The principle is like this, if I can walk one step with swinging the arm, then I can also walk 3 steps….. or also walk 5 minutes…or 5 kilometres and so on.

I also use visualisation when training my movements.

People, who do not realise the effects that Parkinson’s disease has on their own body, often have problems understanding how demanding it is for a Parkinson patient to cope with conscious movements. Even something as banal as cleaning your shoes on a doormat is not necessarily functioning automatically but needs mental work, like steering a toy car with a joystick.

It is very common that a Parkinson patient with time develops a forward bending posture and some years ago I had thoracic Kyphosis and could not wear any of my shirts anymore. A physiotherapist has taught me some physical exercises, which I since have done every day.

Today my back is straight again, which makes me happy. People, who are happy, often have a straight posture, while sad and grieving people often have a crooked posture. By choosing body posture you can also indirectly choose your emotions.

I enjoy sending a signal that I am bubbling with joys of life.

I try to avoid, if possible, all kind of stress. Now I choose calm classical music instead of rock; I value tight relationships instead of having a circle of acquaintances with ‘small talk’ and I love being out in nature instead of taking city walks. It is a pleasure for me to do meditation and to sing.

I have also improved at listening to the signals from my body and I take care to rest and sleep when needed.  I have also improved at learning to avoid doing things, which I dislike and instead I do things that make me happy.

When being diagnosed with a chronic disease the patient often goes through a life crisis and so did I. The crises made me more religious and I learnt to pray to my God from the bottom of my heart – this has given me spiritual power to cope with life and the new circumstances.

‘Where there is willpower, there is a way to go.’ This phrase was said about me by a good friend, as a way to express how I cope with my disease.

Years ago the neurologists said several times that I had got Parkinson’s disease and that this disease is chronic, impossible to cure and progressive. I thought that it might be like this for other patients, but that it would not be like this in my case. By working and studying a lot and sometimes by choosing blind paths, I have succeeded in finding a tiny little path out of my disease. Today I have fewer symptoms than in the year 1998, which means that the expression ‘progressive’ cannot be used generally about all patients with Parkinson’s disease.

I retired in the year 2001 when I was 44 years old and although it was really a hard time, today I feel that I have a good life. To my co-patients I will say:-  “Search for knowledge and keep on trying to search for new possibilities.”

Generally I recommend neurological patients to be tested with a chelating agent for chronic toxicity with heavy metals. If this is diagnosed, then it is possible to detoxify, which can give hope to a future of increased health and decreased neurological symptoms.

If you want more information about toxicity with heavy metal and Parkinson’s disease then use the Internet.

Thank you for reading my case-story and I wish you all the best.

 

Read More

Bjørklund G.  Parkinson’s Disease and Mercury. Journal of Orthomolekulare Medicine 1995; 10: 147-148.

 

Glutathione And Parkinson’s Disease

“Dr. David Perlmutter, a board certified neurologist from Naples, Florida, started using intravenous glutathione in 1998 for his Parkinson’s patients after he did extensive research on Parkinson’s disease and effects of supplemental glutathione on improving the symptoms of Parkinson’s disease.  He is the pioneer in using intravenous glutathione in the treatment of Parkinson’s disease.  His research opened new doors in the treatment of Parkinson’s disease and other neurodegenerative diseases.  Dr. Perlmutter has successfully used intravenous glutathione in patients with significant improvement in the symptoms.  Although glutathione treatment cannot prevent the occurrence of symptoms, it significantly slows down the occurrence of symptoms with improvement in the existing symptoms.

Glutathione supplements do not directly raise the dopamine levels in the brain, instead they improve the efficiency of dopamine in the brain and also increase the sensitivity to dopamine and serotonin” (from the article Glutathione and Parkinson’s Disease by Zina Kroner).

 

 

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Link Between Parkinson’s Disease And Manganese Poisoning

The Yeast PARK9 protein (Ypk9) is localized to the vacuole membrane. Shown are yeast cells expressing Ypk9 fused to the green fluorescent protein.

A connection between genetic and environmental causes of Parkinson’s disease has been discovered by a research team led by Aaron D. Gitler, PhD, Assistant Professor in the Department of Cell and Developmental Biology at the University of Pennsylvania School of Medicine. Gitler and colleagues found in 2009 a genetic interaction between two Parkinson’s disease genes (alpha-synuclein and PARK9) and determined that the PARK9 protein can protect cells from manganese poisoning, which is an environmental risk factor for a Parkinson’s disease-like syndrome.

Manganism, or manganese poisoning, is prevalent in such occupations as mining, welding, and steel manufacturing. It is caused by exposure to excessive levels of the metal manganese, which attacks the central nervous system, producing motor and dementia symptoms that resemble Parkinson’s disease.

In Parkinson’s patients, the alpha-synuclein protein normally found in the brain misfolds, forming clumps. Yeast cells, the model system in which Gitler studies disease proteins, also form clumps and die when this protein is expressed at high levels. These are the same yeast cells that bakers and brewers use to make bread, beer, and wine.

As a postdoctoral fellow at the Whitehead Institute in Cambridge, Massachusetts, Gitler and colleagues started looking for genes that could prevent the cell death caused by mis-folded alpha-synuclein in yeast. Eventually they found a few genes to test in animal models and some were able to protect neurons from the toxic effects of alpha-synuclein. “One of the genes that we found was a previously uncharacterized yeast gene called YOR291W. No one knew what it did back in 2006,” he recalls.

Yeast PARK9 gene (YPK9) helps protect cells from manganese toxicity. Yeast cells missing the YPK9 gene (ypk9) grow normally under standard conditions (- Mn2+) but are much more sensitive to manganese (+ Mn2+) than wild-type (WT) cells.

In the meantime, researchers in Europe published studies about a family that had an early-onset form of a type of Parkinson’s disease caused by mutations in the PARK9 gene. “When I read about this study, I wondered what the closest yeast gene was to the human PARK9 gene and it turned out to be YOR291W,” explains Gitler. “It was one of the genes that could rescue alpha-synuclein toxicity from our yeast screen. That was the big Eureka! and completely unexpected. It suggested that Parkinson’s disease genes could interact with each other in previously unexpected ways.”

Because of its similarity to the human PARK9 gene, Gitler and colleagues renamed the yeast gene to YPK9 (which stands for Yeast PARK9). Researchers at Purdue University and The University of Alabama teamed up with Gitler and his colleagues to show that the PARK9 gene could also protect neurons from alpha-synuclein’s toxic effects.

Next, the team set out to find the function of YPK9. Study co-first author, postdoctoral fellow Alessandra Chesi, PhD, discovered that YPK9 encodes a metal transporter protein. “Its sequence looks like other proteins that we know transport metals,” says Chesi.

She deleted the YPK9 gene from yeast and the cells were fine. Then she exposed YPK9-deficient yeast cells to an excess of different metals — zinc, copper, manganese, iron, etc. — to determine which metal it might transport. Of all the metals Chesi tested, she found that in the presence of manganese, the YPK9-deficient yeast did not grow as well. They were hypersensitive to manganese.

“This was astonishing, because it was known for years that welders and miners that inhale manganese get a Parkinson’s-like disease called manganese poisoning,” says Chesi. “The specific neurons that are lost in the miners are from the globus pallidus, a brain motor center. The European parkinsonism patients with the PARK9 mutation also lose neurons in this region.”

Gitler then found that the protein made by YPK9, the yeast gene equivalent of PARK9, is localized to the vacuole membrane in the yeast cell. Vacuoles are inner cell components that wall off toxic substances for later disposal. “Our hypothesis is that the vacuole, a bag in the cell that captures toxins, is sitting there and taking in manganese and sequestering it for detoxification, keeping it away from other cell organelles,” explains Gitler. “But, having a mutation in the PARK9 gene causes problems for this process in yeast and possibly in humans”.

 

Related Articles

Guilarte TR. Manganese and Parkinson’s disease: a critical review and new findings. Environ Health Perspect 2010;118 (8): 1071-80.

Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet.2009; 41 (3): 308-15.

Aschner M, Erikson KM, Herrero Hernández E, Tjalkens R. Manganese and its role in Parkinson’s disease: from transport to neuropathology. Neuromolecular Med 2009; 11 (4): 252-66.

 

Copper Folds Protein Into Precursors Of Parkinson’s Plaques

Researchers at North Carolina State University have figured out how copper induces misfolding in the protein associated with Parkinson’s disease, leading to creation of the fibrillar plaques which characterize the disease. This finding has implications for both the study of Parkinson’s progression, as well as for future treatments.

The protein in question, alpha-synuclein, is the major component of fibrillar plaques found in Parkinson’s patients. Researchers had already discovered that certain metals, including copper, could increase the rate of misfolding by binding with the protein, but were unsure of the mechanism by which this binding took place.

“We knew that the copper was interacting with a certain section of the protein, but we didn’t have a model for what was happening on the atomic level,” says Frisco Rose, Ph.D. candidate in physics and lead author of the paper describing the research. “Think of a huge swing set, with kids all swinging and holding hands – that’s the protein. Copper is a kid who wants a swing. There are a number of ways that copper could grab a swing, or bind to the protein, and each of those ways would affect all of the other kids on the swing set differently. We wanted to find the specific binding process that leads to misfolding.”

Rose and NC State colleagues Dr. Miroslav Hodak, research assistant professor of physics, and Dr. Jerzy Bernholc, Drexel Professor of Physics and Director of the Center for High Performance Simulation, developed a series of computer simulations designed to ferret out the most likely binding scenario.

According to Hodak, “We simulated the interactions of hundreds of thousands of atoms, which required multiple hundred thousand CPU-hour runs to study the onset of misfolding and the dynamics of the partially misfolded structures.”

The number of calculations was so large that Hodak and Bernholc had to devise a new method to make it possible for a computer to process them. Only supercomputers like Jaguar, Oak Ridge National Laboratory’s most powerful supercomputer – the most powerful in the United States, in fact – were up to the task. But the simulations finally revealed the binding configuration most likely to result in misfolding.

Their results appeared in the June 14 edition of Nature Scientific Reports.

The researchers hope that their finding will advance our understanding of Parkinson’s, one of the most common – and devastating – neurological diseases. “Understanding the molecular mechanism of Parkinson’s disease should help researchers in developing drugs that treat the disease rather than merely alleviate symptoms,” Bernholc says.
Reference

Rose F, Hodak M, Bernholc J. Mechanism of copper(II)-induced misfolding of Parkinson’s disease protein. Scientific Reports 2011; 1, doi:10.1038/srep00011.