[Conductor71]

Viral Parkinsonism may be considered secondary as a movement disorder following infection by the influenza, H1N1 virus, Bird Flu, streptococcus, and Epstein Barr virus (causes the common mononucleosis) and Encephalitis Lethargica. I am beginning to believe that the encephalopathy is the key in the ignition switch for quite a few of us. The infections end up with a manifest Parkinson's- all cardinal signs present, and there is a lot here we can sink our teeth into:

-In many cases, patients respond to levodopa
-In many cases, patients fully recover with a round of steroids
-Others stabilize and stay static while others progress.
-Upon MRI, the basal ganglia shows lesions
-the inflammatory immune response results in aggregation of alpha-syuclein
-this virus and immune response triggers the cascade event now considered the prevailing disease model. The activity and inflammation persists long after infection is gone.
-anti brain anti bodies are present in most cases.

I am going to take a closer look at lethargica because it offers some features hitting closer to home for us:

-in this illness that occurs post or with viral infection, the parkinsonism can be indistinguishable from what we call idiopathic pd: including dystonia, excellent response to levodopa, and dyskinesia.

-it can occur up to 20 years after the initial infection, most appear within 5-10 years.

-there is a case with a man who lived with an encephalic brain for 71 years! He experienced his trigger illness at age 3 and presented with a progressive Parkinsonism at age 40!

Lest anyone still be on the fence on the auto immune connection with PD here is a an interesting assessment of lethargica and an alpha-synuclein little kick in the butt:

http://onlinelibrary.wiley.com/doi/1...21664/abstract
Contemporary encephalitis lethargica presenting with agitated catatonia, stereotypy, and dystonia-parkinsonism


Both patients suffered concurrent hyperkinetic and Parkinsonian features resulting in therapeutic challenges. Bradykinetic features responded to dopamine replacement therapy and both patients also had adverse affects to dopamine antagonists (oculogyric crises plus neuroleptic malignant syndrome). Investigation was unremarkable other than the presence of CSF lymphocytosis and oligoclonal bands. Despite prolonged in-patient stays and intensive care management, both patients have made complete recoveries. We believe these cases support the hypothesis that this syndrome is an inflammatory encephalitis that specifically effects dopamine neurotransmission.


Monoclonal antibodies against Epstein-Barr virus cross-react with alpha-synuclein in human brain.Date: 2000

Using antibodies generated against the latent membrane protein 1 of Epstein-Barr virus, intense immunoreactivity of Lewy bodies (in PD and dementia with Lewy bodies) and glial cytoplasmic inclusions (in multiple system atrophy) was demonstrated. ELISA and Western blotting techniques confirmed that this immunolabeling was due to cross-reactivity of the antiviral antibody with alpha-synuclein, a neuronal protein implicated in the pathogenesis of PD. This example of cross-reactivity between Epstein-Barr virus and alpha-synuclein may bear implications for further elucidating infectious or autoimmune mechanisms in PD.

Who is to say that one of us did not present with an encephalopathy? I did not have an MRI until 3 years with my first neuro. One is not always symptomatic with it and as we saw you can live with it a very long time.

This really does substantiate that diagnosis we have means both nothing and everything. Nothing in the sense that it is junk and we have to fumble around putting pieces together ourselves. It means everything because we have been marked; it means no disability insurance, no private insurance , no long term care insurance. It means you quickly become marked by your employer as a liability. It means your life has fundamentally shifted out of your control; and the person who has done this to you knows less about what is going on than you likely do. I'd say if they can't be bothered to test us or for anti bodies or give us an MRI just to rule out encephalitis and recovery with a round of steroids, than they have no business ruining my life with the label "idiopathic parkinson disease". Give me the safer, vague label of "Parkinsonism" any day. Medical science is capable of far more.

Laura

[Conductor71]

Rick started this all rolling for me. Check out his stupendous blog

[girija]

Originally Posted by Conductor71

Rick started this all rolling for me. Check out his stupendous blog

Hi Laura,
Thanks for bringing up this topic again. It is nice to see these new reports showing up in the literature while, we (forum) have been postulating these ideas for at east 5 years. As you know, I have been trying to secure funds to validate this hypothesis for a while and unable to convince any granting agency about it. I finally gave up on submitting grant applications on this topic and hoped that someone would bring it out someday.
I cannot tell you how frustrating it is to see a ray of hope to the understanding ofr this dreadful disease and not being able to follow up on that.

Sorry for my rants and raves, I just had to vent it out.

Here is a part of my grant proposal if anyone interested.........

Rationale and Hypothesis:
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the substantia nigra (SN) of the brain. Several factors such as, genetic predisposition, exposure to pesticides and viral/bacterial infections as well as neuroinflammation are known to contribute to the development of PD. However, how these factors contribute to highly localized and specific elimination of neurons in PD is not clear. Several studies suggest that the neuronal death is atleast in part due to alterations in alpha-synuclein, a major component of Lewy bodies, aggregated forms of alpha-synuclein and lipids inside the dopaminergic neurons [1-4]. Based on published literature (summarized below), we offer a novel hypothesis where the progression of PD is due to the activation of autoreactive cells that are specific for alpha-syn due to molecular mimicry. These auto reactive CD4 T cells specifically target neurons of the SN region expressing modified/altered forms of alpha-syn.

The activation of microglia and recruitment of CD4 T cell subsets to an immune privileged site such as the brain during the course of PD are intriguing and are reminiscent of autoimmune disorders [15,16]. Furthermore, recent publication of infection of mice with H1N1 strain of Flu leading to PD-like symptoms suggested that autoimmune responses might be triggered due to molecular mimicry. Furthermore, the failure of transplanted neuronal cells to survive for long term in humans and experimental animals with PD suggests that autoreactive CD4 T cells and their recall responses may be responsible for the continued destruction of neuronal cells.

[Conductor71]

Girija,

Sorry to bring up such a sore spot. I know you and Rick have contributed so much to the viral theory and as both patient and scientist you live in both worlds, so that is twice the frustration at all this. What concerns me is that if you have disease wherein an organ is attacking itself, the first thing that comes to my mind is "auto immune dysfunction" and I am far from being a scientist. Why is that something so basic go overlooked by so many? We have the second most common neurodegenerative disorder, I would have thought establishing it as either immune related or not would be the first mode of attack in research. Yeesh.


Here is a key abstract that hopefully will open some minnds:


Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis.

Monahan AJ, Warren M, Carvey PM.

Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA. Angela_Monahan@rush.edu
Abstract

Despite decades of research and the development of a large group of animal models, our understanding of the mechanisms responsible for the progressive loss of dopamine neurons in Parkinson's disease (PD) is unknown. So-called neuroprotective studies demonstrate that a vast group of molecules readily attenuate the dopamine (DA) neuron loss produced by DA neurotoxin insult. Despite these successes, these neuroprotective strategies have been surprisingly ineffective in patients. This may reflect the fact that the initial pathogenic event and the subsequent disease progression is a consequence of different mechanisms. As we began to think about this disconnect, we discovered that animals exposed to DA neurotoxins exhibited blood-brain barrier (BBB) dysfunction. If the BBB in PD patients is disrupted, then the barrier that normally segregates peripheral vascular factors from brain parenchyma is no longer present. Immune cells could then enter brain and produce a self-perpetuating (progressive) degenerative process. In this review, we propose that peripheral immunity contributes to the degenerative process of PD and may be responsible for the progressive nature of the disease. This hypothesis is supported by a broad and diverse literature that is just beginning to come together to suggest that PD is, in part, an autoimmune disease. In order to understand this hypothesis, the reader must question the conventional wisdom that the BBB is intact in PD, the brain is an immune privileged area, and that pathogenic insult and disease progression may reflect different mechanisms.

[olsen]

Girija, I am certain you thought of this, but did you submit your proposal to MJFF? Did you happen to send it to Andrew Grove? Keep thinking he might want to back a scientific undertaking or at least help with finding the financing. Any of the national PD organizations? madelyn

[olsen]

http://www.nyas.org/Publications/Ebr...0-be821ec5b088

Neuroscience and Immunology
Intersection Yields Clues for the Etiology of Psychiatric and Neurodegenerative Diseases
OverviewMediaSpeakers Speakers: Katerina Akassoglou (Gladstone Institute & UCSF), Andrew Miller (Emory University School of Medicine), Malú Tansey (Emory University School of Medicine), Shi Du Yan (Columbia University), and Raz Yirmiya (Hebrew University)

Organizers: Seongeun (Julia) Cho (U.S. Food and Drug Administration), Ken Jones (Lundbeck Research USA), Lars Pedersen (H. Lundbeck A/S, Denmark), and Jennifer Henry (The New York Academy of Sciences)

Presented by the Biochemical Pharmacology Discussion Group and the New York Chapter of the American Chemical Society
Posted November 19, 2010

Overview
Two ... growing disciplines, neuroscience and immunology, each have made substantial scientific achievements...the two rarely find a common language and purpose necessary to support scientific breakthroughs. A growing number of reports ...may finally change this status quo...

This symposium,... held at the New York Academy of Sciences on October 26, 2010, provided an introduction to the interdisciplinary field of neuroimmunology and presents a compelling case for the role of specific inflammatory cytokines in sickness behavior and in clinical depression. Additional topics included how cytokines mediate the stress response at molecular, cellular, and systems levels; the molecular mechanisms of cellular stress in Alzheimer's disease; and pro-inflammatory signaling's role in amyloid-beta peptide-mediated neuronal dysfunction and memory impairment. Research was presented that identified the neurotoxic mechanisms and transduction pathways that are associated with TNFα signaling... modulating glial reactivity and inflammatory cytokines as a possible therapeutic strategy ..., and they unveiled recent discoveries on specific receptors for fibrinogen that advance our understanding of its role as a clotting factor, a regulator of inflammation, and many functions in between.

Andrew Miller from Emory University School of Medicine provided an introduction to the interdisciplinary field of neuroimmunology ... He provided an outline of inflammation as a common mechanism of diseases ...Raz Yirmiya from Hebrew University then elaborated on how cytokines, such as interleukin 1 (IL-1) mediate the stress response at molecular, cellular, and systems levels. He discussed studies ...demonstrate that inflammatory cytokines in the brain mediate the detrimental effects of chronic stress, infections, and autoimmune and neurodegenerative diseases on memory functioning and mood. ...

Shi Du Yan from Columbia University then discussed the molecular mechanisms of cellular stress in Alzheimer's disease and considered how pro-inflammatory signaling plays a role in amyloid-beta peptide-mediated neuronal dysfunction and memory impairment... detail was provided concerning RAGE, a receptor for advanced glycation end-products. ... RAGE inhibitors hold great potential for significant therapeutic advances against Alzheimer's disease in the near future.
Malú Tansey from Emory University School of Medicine [discussed]...neurotoxic mechanisms and transduction pathways associated with tumor necrosis factor (TNF) signaling... [including]potential therapeutic strategies ...that involve altering glial reactivity and adjusting inflammatory cytokines.
Katerina Akassoglou from Gladstone Institute & UCSF discussed studies in animal models that have demonstrated that extravascular fibrinogen can contribute to inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, and myocardial infarction. ... These studies have demonstrated that fibrinogen is not merely a marker of BBB (blood–brain barrier) disruption, but also a mediator of neuroinflammation, both of which have known links to neurological disease initiation.

(Girjia, Laura and Rick, thought you guys would appreciate the info and the names of the researchers should you wish to delve further into the theoies noted in the above. madelyn)

[@chilles]

I have always suspected a viral component associated with my diagnosis of “Idiopathic PD”. The saga begins in 1967 when I was hospitalized with Epstein-Barr Mononucleosis. Fast forward to 1996 when I developed a severe respiratory viral infection. The cough was so intense that I fractured 7 ribs. During the course of this disease, my liver enzymes elevated significantly. A diagnosis of toxic hepatitis possibly caused by Dicloxiclllin was determined. This was never confirmed. Out of work four months, I never did fully recover. You know the rest of the story. Insidious onset of fatigue, depression, bradykinetic, gait imbalance, and slumping posture ensued. In 2001 a pill rolling tremor developed leading to a diagnosis of “Idiopathic PD” by two prominent Movement Disorder Specialists. When asked if the previous exposure to the virus was a factor they replied “it was doubtful”

I am intrigued by the information that you have collected, and would like to further pursue this avenue. The inflammatory immune response triggering the cascade event fits my disease model. Thank you for including the references and articles in your postings.

Gary