User:Anthonyhcole/sandbox

|Paragraph 1
Parkinson's disease (PD, also known as idiopathic or primary Parkinson's disease), hypokinetic rigid syndrome, or paralysis agitans), is a degenerative disorder of the central nervous system., mainly affecting the motor system. Many of the motor symptoms of Parkinson's disease PD result from the death loss of pigmented dopamine-generating cells in the substantia nigra, a region of the midbrain. The causes of this cell death are poorly understood. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, and depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems. A progressive reduction in the speed and range of voluntary movement is the only physical sign present in all patients and is responsible for the common early complaints of loss of dexterity, writing difficulties, clumsiness and difficulty walking. Muscular stiffness of the limbs and trunk are also common. Trembling of one limb at rest, although not necessarily present in all cases, is the commonest symptom leading to accurate diagnosis. Dysfunction of the autonomic nervous system is also common, leading to constipation lightheadedness or faintness on standing (orthostatic hypotension), bladder problems and disturbed temperature regulation with excessive sweating. Depression may be an early sign of the disease and frequently develops as a reaction to increasing disability and social isolation. In elderly patients there is an increased risk of cognitive impairment and dementia. Parkinson's disease is more common in older people, with most cases occurring after the age of 50 60; when it is seen in young adults under the age of 45 years, it is called young onset PD.

MS.

I dont agree that paralysis agitans should be replaced. It was always a poor term- there is no paralysis -I would prefer shaking palsy.

AJL

An editor has moved the alternative names from the introduction to the "infobox" (the list of links and facts in the top right corner) [https://en.wikipedia.org/w/index.php?title=Parkinson%27s_disease&diff=prev&oldid=710300350] so is this issue resolved?

AHC

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Reviewers: we try to make the language as simple as possible while avoiding ambiguity or loss of nuance - especially in the first, summary, paragraphs.

"A progressive reduction in the speed and amplitude of voluntary movement...": Can anyone think of a more accessible form of words than "amplitude"?

"In elderly patients there is an increased risk of cognitive impairment and dementia." An alternative to "cognitive impairment"?

AHC

Perhaps we could use term range of movement instead of amplitude.

MK

That sounds good to me, Mark. I have replaced "amplitude" with "range" in the left hand column. If anyone objects, please speak up here.

AHC

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Reviewers: Regarding "Parkinson's disease is more common in older people, with most cases occurring after the age of 50 60; when it is seen in young adults under the age of 45 years, it is called young onset PD":

The article presently cites

[http://www.ncbi.nlm.nih.gov/pubmed/?term=15172778 Samii A, Nutt JG, Ransom BR (2004). "Parkinson's disease". Lancet 363 (9423)]

which says,

"The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset PD, begin between the ages of 20 and 50."

I notice

[http://www.ncbi.nlm.nih.gov/books/NBK1223/#parkinson-overview.Definition Farlow J, Pankratz ND, Wojcieszek J, Foroud T (2004/2014) "Parkinson Disease Overview" GeneReviews]

also states,

"...onset around age 60 years; however, onset can be earlier. Generally, onset before age 20 years is considered to be juvenile-onset Parkinson disease, before age 50 years is considered to be early-onset Parkinson disease, and after age 50 years is considered late-onset Parkinson disease."

Can you point to a recent authoritative source that supports the proposed change? Per Wikipedia's guideline on sources for medical information, ideal sources include literature reviews and systematic reviews published in relevant, reputable journals, recognised standard textbooks by experts in the field, and medical guidelines and position statements from national or international expert bodies.

AHC

The statements in the literature can be confusing, but they do support this statement. For example, the relevant chapter in the 2015 edition of Harrison's Principles of Internal Medicine states, "The mean age of onset is about 60 years. The frequency of PD increases with aging, but cases can be seen in patients in their 20s and even younger."{{cite book|author1=C. Warren Olanow|author2=Anthony H.V. Schapira|author3=Jose A. Obeso|editor1-last=Kasper|editor1-first=Dennis|editor2-last=Fauci|editor2-first=Anthony|editor3-last=Hauser|editor3-first=Stephen|editor4-last=Longo|editor4-first=Dan|editor5-last=Jameson|editor5-first=J. Larry|editor6-last=Loscalzo|editor6-first=Joseph|title=Harrison's Principles of Internal Medicine|publisher=McGraw-Hill|isbn=9780071802154|edition=19|accessdate=23 May 2016|chapter=449: Parkinson's Disease and Other Movement DIsorders}} In a recent review, Goetz and Pal state, "The onset of Parkinson’s disease is rare before the age of 50 years, and a sharp increase in incidence is seen after age 60."{{cite journal|last1=Goetz|first1=CG|last2=Pal|first2=G|title=Initial management of Parkinson's disease.|journal=BMJ (Clinical research ed.)|date=19 December 2014|volume=349|pages=g6258|pmid=25527341|url=http://www.bmj.com.proxy1.library.jhu.edu/content/349/bmj.g6258|accessdate=23 May 2016}} and they cite De Lau and Breteler.{{cite journal|last1=de Lau|first1=LM|last2=Breteler|first2=MM|title=Epidemiology of Parkinson's disease.|journal=The Lancet. Neurology|date=June 2006|volume=5|issue=6|pages=525-35|doi=doi:10.1016/S1474-4422(06)70471-9|pmid=16713924|accessdate=23 May 2016}} The latter is from 2006, but it's directly cited in the 2014 review and it shows that the preponderance of people with PD are over 60.

Regarding "young onset PD", a 2010 systematic review by van Rooden et al noted the lack of standardization of this term, i.e. "{{tq|Additionally, four studies included in the present review allowed insight in the extent to which each variable contributed to the classification of the subtypes.20, 21, 23, 25 Second, in the studies reported in the review by Foltynie et al.2 young age-at-onset, for example, was defined as <40 years, while the mean age-at-onset of the young onset subtypes that were found in the studies included in the present review ranged from 50 to 60 years and already showed clear differences with profiles with an old age-at-onset. Thus, researcher-based cut-off criteria may differ from mean values of clusters that are determined by CA and this may have consequences for the subtypes.}}".{{cite journal|last1=van Rooden|first1=SM|last2=Heiser|first2=WJ|last3=Kok|first3=JN|last4=Verbaan|first4=D|last5=van Hilten|first5=JJ|last6=Marinus|first6=J|title=The identification of Parkinson's disease subtypes using cluster analysis: a systematic review.|journal=Movement disorders : official journal of the Movement Disorder Society|date=15 June 2010|volume=25|issue=8|pages=969-78|pmid=20535823}} I will keep trying, but I don't see a MEDRS for the cutoff at age 45.

SR

I still don't see such a cutoff in MEDRS.

SR

| Paragraph 2
The main motor symptoms are collectively called parkinsonism, or a "parkinsonian syndrome". The disease can be either primary or secondary. Primary Parkinson's disease is referred to as idiopathic (having no known cause), although some atypical Probably fewer than 5% of cases have a clear genetic origin, while secondary parkinsonism is due to known causes like drugs, toxins and cerebrovascular disease. Many risks and protective factors have been investigated: the clearest strongest evidence is for an increased risk of PD in people exposed to certain pesticides and a reduced risk in tobacco smokers (although this may be due to individuals predisposed to PD being less prone to smoking addiction). The pathology of the disease is characterized by believed to be due to the accumulation of abnormal proteins into Lewy bodies in neurons, and insufficient formation and activity of dopamine in certain parts of the midbrain. Where the Lewy bodies are located is often related to the expression and degree of the symptoms of an individual. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used for confirmation in nerve cells, leading to their eventual cell death. The aggregated protein forms microscopic inclusions known as Lewy bodies that can be found in the substantia nigra. Bradykinesia and rigidity result from loss of dopamine containing cells in the substantia nigra. The diagnosis of Parkinson’s disease is based on accurate history taking and a neurological examination. Neuroimaging including CT and MR imaging is useful to exclude other disorders masquerading as Parkinsons disease and dopamine transporter imaging (SPECT scans) can be helpful when the clinical diagnosis is uncertain.

MK

Reviewers: Is there a source for this percentage? I've found several sources that talk in this ball-park, but they vary a bit.

• {{cite journal |vauthors=Klein C, Westenberger A |title=Genetics of Parkinson's disease |journal=Cold Spring Harb Perspect Med |volume=2 |issue=1 |pages=a008888 |year=2012 |pmid=22315721 |pmc=3253033}}

say, "Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%-5% of the sporadic cases."

• [http://onlinelibrary.wiley.com/doi/10.1111/ane.12563/abstract;jsessionid=D4EB4989AAC4D345F7627DFB8B2DD1E3.f02t02 Kalinderi K, Bostantjopoulou S, Fidani L (2016) Acta Neurologica Scandinavica Early view]

claim "Approximately 5–10% of PD patients have monogenic forms of the disease, exhibiting a classical Mendelian type of inheritance, however, the majority PD cases are sporadic, probably caused by a combination of genetic and environmental risk factors." They cite [http://hmg.oxfordjournals.org/content/18/R1/R48.long Lesage and Brice, 2009] for the figure.

• {{cite journal |vauthors=Lesage S, Brice A |title=Role of mendelian genes in "sporadic" Parkinson's disease |journal=Parkinsonism Relat. Disord. |volume=18 Suppl 1 |issue= |pages=S66–70 |year=2012 |pmid=22166458 |doi=10.1016/S1353-8020(11)70022-0 |url=http://hal.upmc.fr/file/index/docid/807470/filename/Review_Brice-complete.pdf}}

say, "...PD with Mendelian inheritance, which represent no more than 10% of the cases..."

AHC

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Editors: Regarding "...the clearest strongest evidence is for an increased risk of PD in people exposed to certain pesticides and a reduced risk in tobacco smokers..."

The two sources cited in the body of the article do not support the claim for pesticides. The second source,

• [https://www.ncbi.nlm.nih.gov/pubmed/22698719 Van Maele-Fabry G1, Hoet P, Vilain F, Lison D. (2012) "Occupational exposure to pesticides and Parkinson's disease: a systematic review and meta-analysis of cohort studies." Environment International 1;46:30-43]

does not address this risk factor's relative strength against other risk factors. The first source,

• [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556649/ Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. (2012) "Meta-Analysis of Early Nonmotor Features and Risk Factors for Parkinson Disease" Ann Neurol. 2012 Dec; 72(6): 893–901],

says, "the strongest associations with later diagnosis of PD were found for having a first-degree or any relative with PD or any relative with tremor; constipation; or lack of smoking history, each at least doubling the risk of PD."

Reviewers: Should we mention constipation and family?

AHC

This is a good paper to include and I think it would be worth mentioning constipation as a risk factor. It is a much more robust risk than pesticides.

AJL

Not family, too? Can someone please propose a change to the current clause, "...the strongest evidence is for a reduced risk in tobacco smokers..."

AHC

How about: "In addition to genetic/family association, constipation and being a non-smoker each have been associated with increased risk of developing PD later in life (e.g., individuals predisposed to PD may be less prone to smoking addiction)." This adheres to the cited reference, and seems more readable.

SR

|Paragraph 3
Treatments, typically the antiparkinson medications L-DOPA and dopamine agonists, improve the early symptoms of the disease. L-dopa, the natural precursor of dopamine, is the most effective treatment but other drugs including dopamine agonists and selective monoamine oxidase inhibitiors are useful adjuvant treatments. As the disease progresses and dopaminergic neurons and a variety of other types of neurons continue to be lost, these dopaminergic drugs eventually become ineffective whilst at the same time produce a complication marked by remain effective for most motor symptoms related to dopamine deficiency but the response can vary from hour to hour (motor fluctuations) and most patients also experience the complication of involuntary writhing movements (choreiform movements termed dyskinesias). Surgery and such as deep brain stimulation, and continuous infusions of dopaminergic drugs such as apomorphine and enteral infusion of a levodopa gel have been used to reduce motor symptoms as a last resort in severe cases where drugs are ineffective. in cases where oral medications have been ineffective in providing smooth control of dopamine-responsive motor symptoms or where severe tremor or dyskinesias cause disability. Research directions include investigations into new animal models of the disease and of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents. Medications to treat non-movement-related symptoms of PD, such as sleep disturbances, bowel and bladder symptoms, drooling of saliva and emotional problems, also exist are available. Diet and some forms of rehabilitation have shown some effectiveness at improving symptoms. Changes in diet can improve the response to l-dopa treatment and physical therapies can improve gait, balance and posture.

Every non-commonplace claim in the introduction should be repeated in the body of the article, and the claim in the body should be supported by a reliable source. This claim appears in the "Palliative care" subsection but the cited source does not support it.

AHC

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Editors: "... as a last resort in severe cases where drugs are ineffective."

"Last resort" is not used in any of the supporting sources.
AHC

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"Research directions include investigations into new animal models of the disease and of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents.":

Perhaps this is not so informative here, it is also quite incomplete.

MK.

The introductory paragraphs are meant to summarise the most important points of the article, and are covered more fully in the body of the article. I have no opinion on the relevance of "research directions" in the introduction. This is possibly something we could leave up to the wider editing community to decide.

AHC

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choreatiform is incorrect this should be choreiform or choreic.

AJL

Each of these variants seems to be in use:

• [http://www.ncbi.nlm.nih.gov/pubmed/?term=choreatiform choreatiform at PubMed] (6 results)
• [http://www.ncbi.nlm.nih.gov/pubmed/?term=choreiform choreiform at PubMed] (427 results)
• [http://www.ncbi.nlm.nih.gov/pubmed/?term=choreic choreic at PubMed] (479 results)
• [https://www.google.com/search?tbm=bks&q=choreatiform+ choreatiform at Google Books] (435 results)
• [https://www.google.com/search?safe=off&tbm=bks&q=choreiform&oq=choreiform&gs_l=serp.3...902163.902385.0.903893.2.2.0.0.0.0.687.687.5-1.1.0....0...1c.1.64.serp..1.0.0.mwxM2n9ehTQ choreiform at Google Books] (44,700 results)
• [https://www.google.com/search?safe=off&tbm=bks&q=choreic&oq=choreic&gs_l=serp.3...84797.87335.0.87540.5.5.0.0.0.0.1222.1222.7-1.1.0....0...1c.1.64.serp..4.0.0.Veuy7jnFDdo choreic at Google Books] (57,500 results)
  

but the latter two are most widely in use.

Reviewers: How about we say:

"...most patients also experience the complication of choreiform dyskinesia (brief, irregular muscle contractions that are not repetitive or rhythmic, but appear to flow from one muscle to the next)" citing [http://www.ninds.nih.gov/disorders/chorea/chorea.htm this NINDS definition]?

AHC

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The following sentence should read : Changes in diet can improve the response to l-dopa treatment and physical therapies can improve gait, balance and posture.

AJL

I've added it as a proposed change to the left hand column.

AHC

|Paragraph 4
In 2013 PD resulted in about 103,000 deaths globally, up from 44,000 deaths in 1990. The disease is named after the English doctor apothecary surgeon James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817. Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson's disease day (on the birthday of James Parkinson, 11 April) and the use of a red tulip as the symbol of the disease. People with parkinsonism who have increased the public's awareness of the condition include actor Michael J. Fox, Olympic cyclist Davis Phinney, England football player Ray Kennedy and professional boxer Muhammad Ali.

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The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and Parkinson plus syndromes or multiple system degeneration. Parkinsonism is defined as the presence of bradykinesia (slowness of initiation of movement and motor decrement on repetitive movement) in combination with one of three other physical signs namely muscular (lead pipe or cogwheel) rigidity, a rest tremor and postural instability.

Step 1. Diagnosis of Parkinsonian Syndrome
1. Bradykinesia
2. At least one of the following

Muscular rigidity

4-6 Hz rest tremor

postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction

AHC

These criteria are now known as the Queen Square Brain Bank Criteria for Parkinson's disease

AJL

| Paragraph 2
Parkinson's disease is the most common form of parkinsonism and is usually defined as "primary" parkinsonism, meaning parkinsonism with no external identifiable cause. In recent years several genes that are directly related to some cases of Parkinson's disease have been discovered. As much as this conflicts with the definition of Parkinson's disease as an idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included under the Parkinson's disease label. The terms "familial Parkinson's disease" and "sporadic Parkinson's disease" can be used to differentiate genetic from truly idiopathic forms of the disease. Usually classified as a movement disorder, PD also gives rise to several non-motor types of symptoms such as sensory deficits, cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features. These identifiable causes may include side effects of drugs, toxins, infections, metabolic derangement and strategic brain lesions such as strokes. Several neurodegenerative disorders may also present with parkinsonism and are sometimes referred to as atypical parkinsonism or Parkinson’s plus syndromes. They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies. There are also cases of parkinsonism where the cause has been identified, including gene mutations.

Could this be incorporated in the earlier addition beginning "These identifiable causes may include..."? I'll do that soon, if there are no objections.

AHC

| Paragraph 3
In terms of pathophysiology, PD is considered Scientists sometimes refer to Parkinson’s disease as a synucleiopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases to distinguish it from other neurodegenarations such as Alzheimer's disease where the brain accumulates tau protein in the form of neurofibrillary tangles, and beta amyloid in the form of plaques. Nevertheless, there is Considerable clinical and pathological overlap exists between tauopathies and synucleinopathies. The most typical symptom of Alzheimer's disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD. In contrast to Parkinson's disease, Alzheimer's disease presents most commonly with memory loss, and the cardinal signs of Parkinson's disease (slowness, stiffness and tremor) do not occur.

"In contrast to Parkinson's disease, Alzheimer's disease presents most commonly with memory loss, and the cardinal signs of Parkinson's disease (slowness, stiffness and tremor) do not occur."

AJL

I've replaced the text in the left column.

AHC

|Paragraph 4
Dementia with Lewy bodies (DLB) is another synucleinopathy that has close pathological similarities with PD, and especially with the subset of PD cases with dementia. However, the relationship between PD and DLB is complex and still has to be clarified. They may represent parts of a continuum with variable distinguishing clinical and pathological features or they may prove to be separate diseases.

| Paragraph 1

The most recognizable symptoms in Parkinson's disease affects movement, producing are impaired initiation and fluency of movements giving rise to motor symptoms. Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory (especially altered sense of smell) and sleep difficulties, are also common. Some of these non-motor symptoms are often may be present at the time of diagnosis and can precede motor symptoms.

| Reviewers: regarding, "The most recognizable symptoms in Parkinson's disease affect the initiation and fluency of movements giving rise to motor symptoms" Might this be clearer: "The most recognizable symptoms in Parkinson's disease affect the are impaired initiation and fluency of movements giving rise to motor symptoms"

AHC

Yes much better

AJL

OK. I've changed that. Do we really need "giving rise to motor symptoms"? Aren't "impaired initiation and fluency" the motor symptoms?

AHC

Last sentence here should read. Some of these non-motor symptoms may be present at the time of diagnosis.

AJL

OK. I've incorporated that proposed change in the left-hand column.

AHC

| Paragraph 2

Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.

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| Paragraph 3

Tremor is the most apparent and well-known symptom. It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses. It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep. A coarse slow tremor of the fingers at rest is the commonest presenting symptom which disappears during voluntary movement of the affected limb and in the deeper stages of sleep. It affects to a greater extent the most distal part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later. Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is pill-rolling, the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement. The term derives from the similarity between the movement in people with PD and the earlier early pharmaceutical technique of manually making pills.

| I would say here 'A coarse slow tremor of the fingers at rest is the commonest presenting symptom which disappears during voluntary movement of the affected limb and in the deeper stages of sleep' to replace lines 1-5

AJL

Done.

AHC

| Paragraph 4

Hypokinesia Bradykinesia (slowness of movement) is another characteristic feature found in every case of PD, and is due to disturbances in motor planning of movement initiation, and associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement. Performance of sequential and simultaneous movement is hindered impaired. Bradykinesia is commonly a very disabling symptom in the early stages of the disease. Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed. Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet. Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject, to the point that some people are barely able to walk yet can still ride a bicycle. Generally people with PD have less difficulty when some sort of external cue is provided. the most handicapping symptom of Parkinson’s disease leading to difficulties with everyday tasks such as dressing, feeding and bathing. It leads to particular difficulty in carrying out two independent motor activities at the same time and can be made worse by emotional stress or intercurrent illnesses. Paradoxically patients with Parkinson's disease can often ride a bicycle or climb stairs more easily than walk on a level. While most physicians may readily notice bradykinesia, formal assessment requires a patient to do repetitive movements with their fingers and feet.

| Hypokinesia means reduction in movement not slowness. Bradykinesia is the term most often used to apply to the disabling deficit seen in Parkinson's.

AEL.

Reviewers: Can anyone think of a source that supports the remaining changes?

AHC

Lees, A.J, Hardy, J, Revesz T Parkinsons disease. Lancet 2009;373; 2055-2066

AJL

Thank you!

AHC

| Paragraph 5

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles. In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity). The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity. Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease. In early stages of Parkinson's disease PD, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities. With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

|

| Paragraph 6

Postural instability is typical in the late later stages of the disease, leading to impaired balance and frequent falls, and secondarily to bone fractures, loss of confidence and reduced mobility. Instability is often absent in the initial stages, especially in younger people, especially prior to the development of bilateral symptoms. Up to 40% may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.

| Editors: Regarding "loss of confidence and reduced mobility"

This is supported by:

• Mark Hallett; Werner Poewe (13 October 2008). [http://books.google.com/books?id=fEezGoZ4h7YC&pg=PA417 Therapeutics of Parkinson's Disease and Other Movement Disorders]. John Wiley & Sons. p. 417. ISBN 978-0-470-71400-3. 

AHC

Editors: regarding "Instability is often absent in the initial stages, especially in younger people, especially prior to the development of bilateral symptoms."

This is supported by

• Hoehn MM, Yahr MD (1967). "Parkinsonism: onset, progression and mortality". Neurology. 17 (5): 427–42. PMID [https://www.ncbi.nlm.nih.gov/pubmed/6067254 6067254]. 

  AHC

| Paragraph 7

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking), speech and swallowing disturbances including voice disorders, mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large. with absent flexed arm swing. Freezing of gait (brief arrests when the feet seem to get stuck to the floor, especially on turning or changing direction)), a slurred monotonous quiet voice, mask-like face expression and handwriting that gets smaller and smaller are other common signs.

| Reviewers: "...are other common signs" is redundant. I'll remove it if no one objects.

AHC

Editors: This proposed change is supported by

• Rajesh Pahwa; Kelly E. Lyons (25 March 2003). [http://books.google.com/books?id=gX5mAIk5F6UC&pg=PA76 Handbook of Parkinson's Disease, Third Edition]. CRC Press. p. 76. ISBN 978-0-203-91216-4. 

AHC

| Paragraph 8

Parkinson's disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.

| Usually ("speech") refers to language and language disorders are not seen in Parkinson's. Hypophonia (reduction in speech volume) is a problem and mentioned later and is not a Neuropsychiatric problem so it doesn’t belong in this section.

AEL.

| Paragraph 9

A person with PD has two to six times the risk of dementia compared to the general population. The prevalence of dementia increases with age and to a lesser degree duration of the disease. Dementia is associated with a reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing nursing home care.

| Reviewers: "The prevalence of dementia increases with age and to a lesser degree duration of the disease.":

Can anyone think of a reliable source that supports this?

AHC

Perhaps PMID [https://www.ncbi.nlm.nih.gov/pubmed/19733364 19733364] or PMID [https://www.ncbi.nlm.nih.gov/pubmed/20522088 20522088], though they are a bit dated?

LeadSongDog come howl! 21:11, 28 April 2016 (UTC)

Actually, PMID [https://www.ncbi.nlm.nih.gov/pubmed/27502301 27502301] ("Parkinson Disease and Dementia") was published in 2016 after your comment, User:LeadSongDog, and supports this claim.

Anthonyhcole (talk · contribs · email) 08:12, 3 July 2017 (UTC)

| Paragraph 10

Behavior and mood alterations are more common in PD without cognitive impairment than in the general population, and are usually present in PD with dementia. The most frequent mood difficulties are depression, apathy, anhedonia and anxiety. Establishing the diagnosis of depression is complicated by symptoms that often occur in Parkinson's including dementia, decreased facial expression, decreased movement, a state of indifference, and quiet speech. Impulse control behaviors such as medication overuse and craving, binge eating, hypersexuality, or pathological gambling can appear in PD and have been related to the medications used to manage the disease. Psychotic symptoms—the fact that the body language of depression may masquerade as PD including a sad expressionless anxious face, a hang dog appearance, slow movement and monotonous speech. Up to 30% of patients with PD may experience symptoms of anxiety, ranging from a generalized anxiety disorder to social phobia, panic disorders and obsessive compulsive disorders. They contribute to impaired quality of life and increased severity of motor symptoms such as on/off fluctuations or freezing episodes. Impulse control disorders including pathological gambling, compulsive sexual behaviour, binge eating, compulsive shopping and reckless generosity can be caused by medication, particularly orally active dopamine agonists. The dopamine dysregulation syndrome - with wanting of medication leading to overusage - is a rare complication of l-dopa use (Giovannoni, et al. 2000). Punding in which complicated repetitive aimless stereotyped behaviours occur for many hours is another iatrogenic disturbance. Formed complex visual hallucinations or delusions—occur in 4% of people with PD, and it is assumed that the main precipitant of psychotic phenomena in Parkinson’s disease is dopaminergic excess secondary to treatment; it therefore becomes more common with increasing age and levodopa intake. approximately 50% of people over a lifetime, and may be a harbinger for dementia. These range from "minor hallucinations" - sense of passage (something quickly passing beside the person) or presence (the perception of something/someone standing just to the side or behind the person) - to full blown vivid, formed visual hallucinations and paranoid ideation. Unlike schizophrenia, auditory hallucinations are uncommon, and are rarely described as voices. It is now believed that this disturbance is an integral part of the disease but anti-Parkinsonian drugs may be a risk factor. A psychosis with delusions and associated delirium is another recognized complication of drug treatment but may also be caused by urinary tract infections, as frequently occurs in the fragile elderly. However, it is clear that this is not the only factor, and underlying brain pathology or changes in other neurotransmitters or their receptors (e.g., acetylcholine, serotonin) are also thought to play a role.

| "...hallucinations or delusions—occur in 4% of people with PD..."

This figure (4%) is definitely incorrect. It is much higher than this. For this section I suggest citing:

• Beaulieu-Boire I, Lang AE (2015). "Behavioral effects of levodopa". Mov. Disord. 30 (1): 90–102. PMID [https://www.ncbi.nlm.nih.gov/pubmed/25491470 25491470]. doi:[https://doi.org/10.1002%2Fmds.26121 10.1002/mds.26121]. 

AEL.

Tony, does that source support all of the proposed changes in this paragraph?

AHC

| Paragraph 11

Sleep problems are a feature of the disease and can be worsened by medications. Symptoms can manifest as daytime drowsiness, (including sudden sleep attacks resembling narcolepsy), disturbances in REM sleep, or insomnia. REM behavior disorder (RBD), in which patients act out dreams, sometimes injuring themselves or their bed partner, may begin many years before the development of motor or cognitive features of PD or DLB. A systematic review shows that sleep attacks occur in 13.0% of patients with Parkinson's disease on dopaminergic medications.

| Reviewers: Can anyone suggest a good source for these changes?

AHC

| Paragraph 12

Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence and altered sexual function. Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health. PD is related to several eye and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision. Changes in perception may include an impaired sense of smell, disturbed vision, sensation of pain and paresthesia (skin tingling and numbness). All of these symptoms can occur years before diagnosis of the disease.

| Reviewers: A brief explanation of this proposed change?

AHC

| Paragraph 1
A number of environmental factors have been associated with an increased risk of Parkinson's including: pesticide exposure, head injuries, and living in the country or farming. Rural environments and the drinking of well water may be risks as they are indirect measures of exposure to pesticides. Implicated agents include insecticides, primarily chlorpyrifos and organochlorines and pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange and ziram. Heavy metals exposure has been proposed to be a risk factor, through possible accumulation in the substantia nigra; however, studies on the issue have been inconclusive.
Exposure to pesticides and a history of head injury have been linked with PD but the risk is modest. People who have never smoked cigarettes have an increased risk of developing PD while never drinking caffeinated beverages moderately increases risk. A high serum uric acid has also been found to reduce the risk of PD.

AHC

The Noyce review referenced earlier covers this.

AJL

Thank you.

• [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556649/ Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. (2012) "Meta-Analysis of Early Nonmotor Features and Risk Factors for Parkinson Disease" Ann Neurol. 2012 Dec; 72(6): 893–901]

AHC

| Paragraph 2
PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease. At least About 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.

| Paragraph 3
Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), and DJ-1 and ATP13A2. In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD. The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. This means that harboring the mutation may not necessarily lead to the disease but puts the individual at an increased risk, often in combination with other risk factors. Mutations in GBA are known to cause Gaucher's disease. Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.

SNCA, LRRK2, VPS35, EIF4G1, DNAJC13, and CHCHD2 are the dominant genes associated with this while parkin, PINK1 and DJ-1 are the recessively inherited genes that need to be mentioned here.

We have reviewed all of this in a recent major review paper that you could cite here and elsewhere (for example the sections on Brain cell death, Diagnosis, Prevention):

• Kalia L, Lang AE. Parkinson’s disease. Lancet 2015 Aug 29;386(9996):896-912. doi: 10.1016/S0140-6736(14)61393-3

AEL.

ATP13A2 is not a typical Parkinson’s disease gene, it is mainly associated with rapid onset dystonia and parkinsonism. Should be removed here.

MK.

Agree this should be removed.

AJL

Done.

Reviewers: We don't yet mention VPS35, EIF4G1, DNAJC13, and CHCHD2. Would someone like to propose language to incorporate them?

AHC

| Paragraph 4
The LRRK2 gene (PARK8) encodes a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain. Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases. There are many mutations described in LRRK2, however unequivocal proof of causation only exists for a few. LRRK2 mutation, especially the commonest (G2019S), may have penetrance as low as 26% in some populations, for example Ashkenazi Jews.

AEL.

I'm not seeing the relevance of this detail for a broad overview article.

AHC

| Paragraph 4
The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD. The main most important pathological characteristic of PD lesion is cell death in the substantia nigra and, more specifically, the ventral (front) part of the pars compacta, affecting up to 70% of the cells by the time death occurs.

This should probably be revised  – its typically stated that there is greater than 50% cell loss at the time of clinical presentation. Usually the cell loss at death would be considerably higher than 70%.

AEL.

Reviewers: A source for greater than 50% at presentation and higher than 70% at death?

AHC

----"The main most important pathological characteristic of PD lesion is cell death..."

Reviewers: Can we find a more accessible term than "lesion"?

AHC

----Reviewers: "...the ventral (front) part ..."

I thought "ventral" meant underside in the brain?

AHC

----Reviewers: Are we talking about 70% of the substantia nigra or of the ventral pars compacta?

AHC

| Paragraph 5
Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of neuromelanin pigmentation in the substantia nigra and locus coeruleus. The histopathology (microscopic anatomy) of the substantia nigra and several Several other brain regions shows show neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.

Generally there is overgrowth of astrocytes (“astrocytosis”); what is the evidence that there is death of astrocytes? To my knowledge this is never highlighted as a pathological feature and should probably be deleted.

AEL.

Editors: On page 273, the cited source,

• {{cite book |author=Dickson DV|chapter=Neuropathology of movement disorders |editor=Tolosa E, Jankovic JJ| title=Parkinson's disease and movement disorders|publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2007 |pages= 271–83|isbn=0-7817-7881-6|url=https://books.google.com.au/books?id=0XijYbEuoQcC}}

says

"Neuronal loss in the substantia nigra is accompanied by astrocytosis and microglial activation."

So the editor who added this appears to have misunderstood the source.

In the left hand column, I've proposed deletion of the entire sentence beginning "Neuronal loss is accompanied..."

AHC

| Paragraph 1
There is speculation of several mechanisms by which the brain cells could be lost. One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies. According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum; with individuals at this stage being may be asymptomatic or may have prodromal non-motor symptoms (such as loss of sense of smell, sleep and some automatic dysfunction). As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step finally the neocortex. These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective (with the abnormal protein sequestered or walled off). Other forms of alpha-synuclein (e.g., oligomers) that are not aggregated in Lewy bodies and Lewy neurites may actually be the toxic forms of the protein. In people with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer's disease, are not common unless the person is demented.

AHC

|Illustration caption
Fluorodeoxyglucose (18F) (FDG) PET scan of a healthy brain. Hotter areas reflect higher glucose uptake. A decreased activity in the basal ganglia can aid in diagnosing Parkinson's disease.

AEL.

Reviewers: Do any of you know where we can get such an image? The copyright owner would have to be willing to relinquish most rights, but they'd be credited on the image's file in [https://commons.wikimedia.org/wiki/Main_Page our media repository], and reusers would have to credit them.

AHC

| Paragraph 2
Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer's disease, multiple cerebral infarction and drug-induced parkinsonism. Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out. Anti-Parkinson's medications are typically less effective at controlling symptoms in these Parkinson plus syndromes. Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself. Genetic forms are usually classified as PD, although the terms familial Parkinson's disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance are sometimes referred to as familial Parkinson's disease or familial parkinsonism.

| Paragraph 3
Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson's Disease Society Queen Square Brain Bank for Neurological Disorders and the U.S. National Institute of Neurological Disorders and Stroke. The PD Society Queen Square Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following supportive features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa. Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates. Very recently, a task force of the International Parkinson and Movement Disorder Society (MDS) has proposed diagnostic criteria for Parkinson’s disease as well as research criteria for the diagnosis of prodromal disease, but these will require validation against the more established criteria.

Andrew, can you please briefly explain these changes?

AHC

The criteria were developed by Bill Gibb and me at the Queen Square Brain Bank in the eighties and they have been very widely used by researchers. The attachment of PD Society to the name was related to funding at the time they were devised but in the last 10 years the criteria have been referred to as UK Brain Bank or better Queen Square Brain Bank. It will important to have the reference in too to balance the Postuma one below and is

Gibb, W.R.G and Lees, A.J. The relevance of the Lewy body to the pathogenesis of Parkinsons disease. J. Neurol. Neurosurg. Psychiat. 1988;51;745-752

----

"Very recently, a task force of the International Parkinson and Movement Disorder Society (MDS) has proposed diagnostic criteria for Parkinson’s disease as well as research criteria for the diagnosis of prodromal disease, but these will require validation against the more established criteria.":

• Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marek K, Litvan I, Lang AE, Halliday G, Goetz CG, Gasser T, Dubois B, Chan P, Bloem BR, Adler CH, Deuschl G.MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015 Oct;30(12):1591-601. doi: 10.1002/mds.26424.
• Berg D, Postuma RB, Adler CH, Bloem BR, Chan P, Dubois B, Gasser T, Goetz CG, Halliday G, Joseph L, Lang AE, Liepelt-Scarfone I, Litvan I, Marek K, Obeso J, Oertel W, Olanow CW, Poewe W, Stern M, Deuschl G.MDS research criteria for prodromal Parkinson's disease. Mov Disord. 2015 Oct;30(12):1600-11. doi: 10.1002/mds.26431.

AEL.

| Paragraph 4
Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal. These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus. A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation. Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fluorodeoxyglucose fluoro-L-dopa (18F) and DTBZ for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD and distinguish it from drug-induced parkinsonism. Reduced dopaminergic activity is, however, also seen in the Parkinson-plus disorders so these are not reliable in distinguishing PD from other neurodegenerative causes of parkinsonism, and therefore of limited use in this clinical situation.

| Paragraph 1
Exercise in middle age reduces may slightly reduce the risk of Parkinson's disease PD later in life. Caffeine also appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee. Although tobacco smoke causes adverse health effects, decreases life expectancy and quality of life, it may reduce the risk of PD by a third when compared to non-smokers. The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant. Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect. However, recently it has been suggested that the negative association with smoking is not protective but is due to an inherent difference in the propensity of patients destined to develop PD to become addicted to nicotine.

• Ritz B, Lee PC, Lassen CF, Arah OA. Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease. Neurology 2014; 83: 1396–402.

AEL.

Reviewers: This is a primary source. Has anyone, independent of the authors, reviewed their results and supported this suggestion?

Belay that. Found:

• Ma, Chaoran; Liu, Yesong; Neumann, Samantha; Gao, Xiang (2017). [https://www.ncbi.nlm.nih.gov/pubmed/28680589 "Nicotine from cigarette smoking and diet and Parkinson disease: a review"]. Translational Neurodegeneration. 6: 18.

| Paragraph 2
Antioxidants, such as vitamins C and D E, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven. The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-increasing effects or no effects. Also, there have been preliminary indications of a possible protective role of estrogens, and anti-inflammatory drugs, certain calcium channel blocking drugs () and higher levels of uric acid ().

You could cite the Kalia and Lang Lancet paper here as a review that covers this material.

AEL.

• {{cite journal |vauthors=Kalia LV, Lang AE |title=Parkinson's disease |journal=Lancet |volume=386 |issue=9996 |pages=896–912 |year=2015 |pmid=25904081 |doi=10.1016/S0140-6736(14)61393-3 |url=}}

AHC

| Paragraph 1
There is no cure for Parkinson's disease PD, but medications, surgery and multidisciplinary management physical treatment can provide relief, from the symptoms and are much more effective than those available for other neurological disorders like Alzheimer’s disease, motor neurone disease, the Parkinson plus syndromes and multiple sclerosis. The main families of drugs useful for treating motor symptoms are levodopa L-DOPA (usually now always combined with a dopa decarboxylase inhibitor or COMT inhibitor which does not cross the blood–brain barrier, dopamine agonists and MAO-B inhibitors. The stage of the disease determines which group is most useful. Two Three stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs requiring pharmacological treatment, then a second stage in which an individual develops associated with the development of motor complications related to levodopa usage, and a third stage when non-dopaminergic symptoms (motor and non-motor) may predominate. Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from improvement of dopaminergic function. The start of levodopa (or L-DOPA) treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias. However, levodopa remains the most effective treatment for PD and should not be delayed in patients whose quality of life is impaired. Indeed, dyskinesias correlate more strongly with duration and severity of the disease than duration of levodopa treatment, so delaying this therapy may not really provide much longer dyskinesia-free time than earlier use (). In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed. When oral medications are not enough to adequately control symptoms, surgery and such as deep brain stimulation, and infusion therapies using pumps subcutaneous waking day apomorphine infusion and enteral dopa pumps can be of use. The third stage presents many challenging problems requiring a variety of treatments for psychiatric symptoms, orthostatic hypotension, bladder dysfunction, etc.. In the final stages of the disease, palliative care is provided to improve quality of life.

The cited source ([https://www.nice.org.uk/guidance/cg35/evidence/full-guideline-194930029 NICE 2006 guidelines, page 141]) supports this change.

AHC

----

"L-DOPA (usually now always combined with a dopa decarboxylase inhibitor or COMT inhibitor which does not cross the blood–brain barrier and sometimes combined with a COMT inhibitor)":

Reviewers: We'll need a source for this.

AHC

----

Reviewers: "Two Three stages are usually distinguished...":

I'm seeing a fair amount of variety in the number and nature of stages authors describe. Can we use "Three stages may be distinguished"?

AHC

----

"However, levodopa remains the most effective treatment for PD and should not be delayed in patients whose quality of life is impaired. Indeed, dyskinesias correlate more strongly with duration and severity of the disease than duration of levodopa treatment, so delaying this therapy may not really provide much longer dyskinesia-free time than earlier use ()."

We'll need a source for this.

AHC

• Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ. Fourteen-year final report of the randomized PDRG-UK trial comparing three initial treatments in PD. Neurology 2008;71(7):474-480.

  AJL

Thank you. We use secondary sources such as reviews, as opposed to primary sources like this trial report. The following 2006 review uses this trial report to make the point, so I'll cite it in the article.

• Zhang, Jinglin; Tan, Louis Chew-Seng (2016). "Revisiting the Medical Management of Parkinson's Disease: Levodopa versus Dopamine Agonist". Current Neuropharmacology. 14 (4): 356–363.

AHC

----

"When medications are not enough to adequately control symptoms, surgery and such as deep brain stimulation, and infusion therapies using pumps can be of use.":

Aren't infusions medications?

AHC

Should read 'when oral medications'

and then remove infusion and put subcutaneous waking day apomorphine infusion and enteral dopa pumps

AJL

Done.

AHC

Insert references for apomorphine the seminal paper is:

• Stibe CM, Lees AJ, Kempster PA, Stern GM. Subcutaneous apomorphine in parkinsonian on-off oscillations. Lancet 1988;1(8582):403-406.

AJL

Thank you. Wikipedia insists we cite secondary sources so I've cited the following review which cites the 1988 Lancet article and makes the point.:

•  Pedrosa, David J.; Timmermann, Lars (2013). "Review: management of Parkinson's disease". Neuropsychiatric Disease and Treatment. 9: 321–340. ISSN 1176-6328. PMC 3592512 Freely accessible. PMID 23487540. doi:10.2147/NDT.S32302.

| Paragraph 2
Levodopa has been the most widely used treatment for over 30 years. L-DOPA is converted into dopamine in the dopaminergic and possibly other (e.g., serotonergic) neurons by dopa decarboxylase. Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.

AHC

| Paragraph 3
Only 5–10% of L-DOPA crosses the blood–brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness vomiting and orthostatic hypotension. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors, which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa (co-careldopa) and benserazide/levodopa (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding. There are controlled release versions of levodopa. in the form intravenous and intestinal infusions that spread out the effect of the medication. These slow-release Older controlled-release levodopa preparations have poor and unreliable absorption and bioavailability and have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations. A newer extended-release levodopa preparation does seem to be more effective in controlling motor fluctuations but in many patients problems persist. Intestinal infusions of levodopa (Duodopa) can result in striking improvements in motor fluctuations compared to oral levodopa due to insufficient uptake caused by gastroparesis. Oral, longer acting formulations are under study currently and other formulations of levodopa (inhaled, transdermal) are under development.

AEL.

Editors: The cited source, reference 54,

• Section 7, "Symptomatic pharmacological therapy in Parkinson’s disease" of UK NHS [https://www.nice.org.uk/guidance/cg35/evidence/full-guideline-194930029 National clinical guideline for diagnosis and management in primary and secondary care] (2006)

doesn't mention dyskinesias or joint stiffness in relation to levodopa metabolised outside the brain. The editor who added that has misread the source.

AHC

----

Reviewers: It would be nice to have a source attributing nausea, vomiting and orthostatic hypotension to peripheral metabolism of levodopa.

AHC

Got it:

• {{Cite book|page=10|url=https://www.worldcat.org/oclc/993068595|title=Levodopa pharmacokinetics -from stomach to brain A study on patients with Parkinson's disease.|last=Maria.|first=Nord,|date=2017|publisher=Linköping University Electronic Press|isbn=9789176855577|location=Linköping|oclc=993068595}}

AHC.

----

"There are controlled release versions of levodopa. in the form intravenous and intestinal infusions...":

Intravenous infusions of levodopa are not used clinically – they are only a research tool.

AEL.

----

"A newer extended-release levodopa preparation does seem to be more effective in controlling motor fluctuations but in many patients problems persist."

• Hauser RA, Hsu A, Kell S, Espay AJ, Sethi K, Stacy M, Ondo W, O'Connell M, Gupta S; IPX066 ADVANCE-PD investigators.  Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial. Lancet Neurol. 2013 Apr;12(4):346-56. doi: 10.1016/S1474-4422(13)70025-5.

AEL.

Reviewers: We should cite someone who has reviewed this (Connolly & Lang, 2014?). We can cite the trial report, too, but we really should show it has been evaluated and contextualised by independent expert authors.

AHC

----

"Intestinal infusions of levodopa (Duodopa) can result in striking improvements in motor fluctuations.":

• Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, Vanagunas A, Othman AA, Widnell KL, Robieson WZ, Pritchett Y, Chatamra K, Benesh J, Lenz RA, Antonini A; LCIG Horizon Study Group. Continuous intrajejunal infusion of levodopa- carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014 Feb;13(2):141-9. doi: 10.1016/S1474-4422(13)70293-X.

AEL.

Reviewers: Has this been discussed in an independent review?

AHC

| Paragraph 4
Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa. It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage. A similarly effective drug Another COMT-inhibitor, entacapone, has not been shown to cause significant alterations of liver function but is less efficacious than tolcapone. Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.

AEL.

Editors: The following source,

• {{cite journal |vauthors=Marsala SZ, Gioulis M, Ceravolo R, Tinazzi M |title=A systematic review of catechol-0-methyltransferase inhibitors: efficacy and safety in clinical practice |journal=Clin Neuropharmacol |volume=35 |issue=4 |pages=185–90 |year=2012 |pmid=22805229 |doi=10.1097/WNF.0b013e31825c034a |url=}}

confirms this. Quote: "Tolcapone is undoubtedly the most effective drug, although in clinical practice sporadic cases of hepatotoxicity have limited its use in patients unresponsive to entacapone. ... Entacapone is generally well tolerated, and no significant adverse events are reported."

AHC

| Paragraph 5
Levodopa preparations frequently lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication. When this occurs a person with PD can change from phases with good response to medication and few symptoms ("on" state), to phases with no response to medication and significant motor symptoms ("off" state). For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice. A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now, since it can bring dangerous side effects such as neuroleptic malignant syndrome. Most people with PD will eventually need levodopa and later develop motor side effects.

This approach is being used much less now. There is no good evidence that there is important advantage in delaying levodopa except in young patients where dyskinesia can become problematic. Rather than citing reference numeral 54 repeatedly (somewhat outdated and in some cases clearly wrong) I would suggest citing a large review that we wrote for JAMA (evidence-based studies were emphasized in all of the sections of this paper):

• {{cite journal |vauthors=Connolly BS, Lang AE |title=Pharmacological treatment of Parkinson disease: a review |journal=JAMA |volume=311 |issue=16 |pages=1670–83 |year=2014 |pmid=24756517 |doi=10.1001/jama.2014.3654 |url=}}

AEL.

| Paragraph 6
Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa. These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications. Like levodopa, these can improve all of the dopaminergic motor symptoms but they are generally less effective than levodopa.When used in late PD they are useful at reducing the off periods. Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride and rotigotine. The most commonly used oral dopamine agonists are pramipexole and ropinirole. Rotigotine is used as a transdermal patch.

• {{cite journal |vauthors=Waters C |title=The development of the rotigotine transdermal patch: a historical perspective |journal=Neurol Clin |volume=31 |issue=3 Suppl |pages=S37–50 |year=2013 |pmid=23931953 |doi=10.1016/j.ncl.2013.04.012 |url=}}

Quote: "In conclusion, the preclinical and clinical development of the rotigotine transdermal system has established this system as an effective method for providing continuous delivery of a dopamine agonist across the skin, and may have clinical advantages compared with other agents."

AHC

| Paragraph 7
Dopamine agonists can produce significant, although usually mild, side effects including orthostatic hypotension, drowsiness, hallucinations, insomnia, nausea and constipation. Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug. Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They tend to be more expensive than levodopa. Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset. Thus dopamine agonists are the may be preferred as initial treatment for earlier in younger onset patients, as opposed to levodopa in for later onset. However, recent studies have emphasized little advantage to so-called "levodopa sparing" approaches (e.g., dopamine agonists, MAO-B inhibitors) in early disease. Agonists have been related to impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa, particularly pathological gambling, and discontinuing dopamine agonists may be associated with "dopamine agonist withdrawal syndrome", with symptoms similar to withdrawal from narcotics, and apathy.

AEL.

Editors: The source cited for this is [https://www.nice.org.uk/guidance/cg35/evidence/full-guideline-194930029 page 63 of the NICE 2006 guideline]. It says:

"However, agonists generate significant dopaminergic adverse events. The latter do not lead to drug withdrawal, which suggests that they are mild and that tolerance develops. These conclusions apply to the relatively young people included in these studies. Further work on the efficacy and safety of dopamine agonists in older people is required."

So Wikipedia's assertion that side effects are usually mild misinterprets the source.

AHC

----

"However, recent studies have emphasized little advantage to so-called "levodopa sparing" approaches (e.g., dopamine agonists, MAO-B inhibitors) in early disease":

• PD Med Collaborative Group, Gray R, Ives N, Rick C, Patel S, Gray A, Jenkinson C, McIntosh E, Wheatley K, Williams A, Clarke CE.Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet. 2014 Sep 27;384(9949):1196-205. doi: 10.1016/S0140-6736(14)60683-8.

AEL.

Reviewers: Per our medical sources guideline, we prefer to cite secondary sources. I don't have access to the following. Does it support this change?

• {{cite journal |vauthors=Rascol O |title=Parkinson disease: Can a new trial end controversy over when to use levodopa? |journal=Nat Rev Neurol |volume=10 |issue=9 |pages=488–9 |year=2014 |pmid=25134709 |doi=10.1038/nrneurol.2014.147 |url=}}

AHC

----

"...and discontinuing dopamine agonists may be associated with "dopamine agonist withdrawal syndrome":

• Pondal M, Marras C, Miyasaki J, Moro E, Armstrong MJ, Strafella AP, Shah BB, Fox S, Prashanth LK, Phielipp N, Lang AE. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry. 2013 Feb;84(2):130-5. doi: 10.1136/jnnp-2012-302684

AEL.

Reviewers: Where possible, we prefer to cite topic overviews, rather than individual studies. Would this source be adequate support for the claim?

• {{cite journal |vauthors=Nirenberg MJ |title=Dopamine agonist withdrawal syndrome: implications for patient care |journal=Drugs Aging |volume=30 |issue=8 |pages=587–92 |year=2013 |pmid=23686524 |doi=10.1007/s40266-013-0090-z |url=}}

AHC

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"...with symptoms similar to withdrawal from narcotics, and apathy" 

• Thobois S, Lhommée E, Klinger H, Ardouin C, Schmitt E, Bichon A, Kistner A, Castrioto A, Xie J, Fraix V, Pelissier P, Chabardes S, Mertens P, Quesada JL, Bosson JL, Pollak P, Broussolle E, Krack P. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain. 2013 May;136(Pt 5):1568-77. doi: 10.1093/brain/awt067.

AEL.

----

"Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset.":

I missed this report! Believe this statement is not appropriate in this setting.

MS.

Editors: The source cited for this is

• {{cite journal |vauthors=Samii A, Nutt JG, Ransom BR |title=Parkinson's disease |journal=Lancet |volume=363 |issue=9423 |pages=1783–93 |year=2004 |pmid=15172778 |doi=10.1016/S0140-6736(04)16305-8 |url=}}

It does not comment on the prevalence of dyskinesias due to dopamine agonists in younger people.

AHC

| Paragraph 9
MAO-B inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They These agents inhibit the enzyme, monoamine oxidase B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased L-DOPA in the striatum. Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early disease, but produce more adverse effects and are clearly less effective than levodopa. There are few studies of their drug effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods. An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven. There remains a question whether these MAO-B inhibitors may slow the progression of the disease. This effect has not been proven and is likely very modest if it exists at all.

AEL.

Reviewers and editors: The source ([https://www.nice.org.uk/guidance/cg35/evidence/full-guideline-194930029 the NICE guideline]) says on p. 71,

"The trial evidence supports the ability of MAOB inhibitors in PD to improve motor symptoms, improve activities of daily living and delay the need for levodopa. ... This is at the expense of more dopaminergic adverse events and, as a result, more withdrawals from treatment".

But it's a very old source. (It's being re-written now, for publication in 2017(?) I think.)

Given the age of the source and the relatively thin evidence they based the claim on, the simple act of challenging the claim should be sufficient to see it removed. But if you know of a recent source that compares the adverse event profiles of levodopa and MAO-B inhibitors, it would be nice to have.

AHC

| Paragraph 10
Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, because they are old drugs the evidence from modern clinical trials supporting them lacks quality, so they are not rarely first choice treatments. Amatadine is now most often used to control dyskinesias in many patients. In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems. Examples are the use of clozapine and quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness. A 2010 meta-analysis found that non-steroidal anti-inflammatory drugs (apart from aspirin), have been associated with at least a 15 percent (higher in long-term and regular users) reduction of incidence of the development of Parkinson's disease.

AEL.

Tony, is this covered in a review?

AHC

| Paragraph 11
Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa introduction of L-DOPA in 1969 the number of operations declined. Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient no longer sufficiently controls symptoms due to motor fluctuations, and increasingly in patients with less advanced disease. Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus, and depend on the main clinical symptoms involved. Deep brain stimulation of the subthalamic nucleus is the most commonly used surgical treatment, developed in the 1980s by Alim-Louis Benabid and others. It involves the implantation of a medical device called a neurostimulator which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD with motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems. Other, less common, surgical therapies involve intentional formation of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy involves surgical destruction (a lesion) of the globus pallidus to control dyskinesia, and thalamotomy lesions a region in the thalamus to control tremor. A new technique of lesioning brain areas such as the thalamus without opening the skull uses the technique of focused ultrasound and another uses gamma irradiation (gamma-knife). A major advantage of DBS procedures over these and older lesioning techniques is that they can be applied much more safely to both sides of the brain (bilateral procedures), and is more reversible by switching the device on and off. New developments in DBS include manufacturing closed loop systems in which deep brain electrodes simultaneously pick up local field potentials to respond with the appropriate electrical signal.

• Sheupbach et al. N Engl J Med. 2013 Feb 14;368(7):610-22. doi: 10.1056/NEJMoa1205158. Neurostimulation for Parkinson's disease with early motor complications.

MK.

This study doesn't seem to support the quoted text. The existing source,

• The National Collaborating Centre for Chronic Conditions, ed. (2006). "Surgery for Parkinson’s disease".Parkinson's Disease. London: Royal College of Physicians. pp. 101–11

though old, seems adequate for the claim.

Ah. Sorry. I'm misreading. The old source doesn't say that surgery is used increasingly in patients with less advanced disease and I'm not seeing it in Sheupbach et al. either. Can you think of a review, position statement or guideline that supports that claim?

AHC

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"New developments in DBS include manufacturing closed loop systems in which deep brain electrodes simultaneously pick up local field potentials to respond with the appropriate electrical signal.":

• Advances in functional neurosurgery for Parkinson's disease. Metman LV, Slavin KV. Mov Disord. 2015 Sep 15;30(11):1461-70. doi: 10.1002/mds.26338. Epub 2015 Aug 14. Review.

MK.

I realise it's sometimes just not possible, but is there any way we can say this so it's understandable by the intelligent lay reader?

AHC

| Paragraph 13
Palliative care is specialized medical care for people with serious illnesses, including Parkinson’s parkinsonism. The goal of this speciality is to improve quality of life for both the person suffering from Parkinson’s PD and the family by providing relief from the symptoms, pain, and stress of illnesses. As Parkinson’s PD is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature.

| Paragraph 14
Along with offering emotional support to both the patient and family, palliative care serves an important role in addressing goals of care. People with Parkinson’s parkinsonism may have many difficult decisions to make as the disease progresses such as wishes for feeding tube, non-invasive ventilator, and tracheostomy; wishes for or against cardiopulmonary resuscitation; and when to use hospice care. Palliative care team members can help answer questions and guide people with Parkinson’s on provide guidance around these complex and emotional topics to help them make the best decision based on their own values.

| Paragraph 15
Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period than normal). A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction. As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.

• Fasano et al. : Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. [http://www.ncbi.nlm.nih.gov/pubmed/25987282 Gastrointestinal dysfunction in Parkinson's disease.] Lancet Neurol. 2015 Jun;14(6):625-39. doi: 10.1016/S1474-4422(15)00007-1.

  AEL.

| Paragraph 16
Levodopa L-DOPA and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access. When they are taken together, this results in a reduced effectiveness of the drug. Therefore, when levodopa is introduced when L-DOPA is used, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended may reduce medication efficacy in some patients. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To If dietary protein is determined to reduce levodopa efficacy, strategies to minimize interaction with proteins, levodopa should be taken 30 include ingestion of levodopa 60 minutes before meals or two hours after meals. At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening. Food in the stomach and constipation both slow stomach emptying which delays or reduces L-DOPA access to the upper small intestine where it is absorbed, resulting in poorer responses to individual doses.

Reviewers: A source for this? Does Fasano et al. 2015 support this?

• Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF. [http://www.ncbi.nlm.nih.gov/pubmed/25987282 Gastrointestinal dysfunction in Parkinson's disease.] Lancet Neurol. 2015 Jun;14(6):625-39. doi: 10.1016/S1474-4422(15)00007-1.

AHC

| Paragraph 17
Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias. Its usefulness in PD is an open research topic, although recent studies have shown no effect by rTMS. Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins, or food additives or orally ingested and intravenous glutathione improve symptoms. There is no evidence to substantiate that acupuncture and practice of Qigong, or T'ai chi, have any effect on the course of the disease or symptoms. Further research on the viability of Tai chi for balance or motor skills are necessary. Fava beans and velvet beans the cowhage (Mucuna pruriens) are natural sources of levodopa and are eaten used by many people with PD. While they have shown some effectiveness in clinical trials, their intake is not free of risks, particularly since the quantities of levodopa received in these formulations are quite variable. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.

Would ask other authors to comment on whether this should be stated.

MS.

From Wikipedia's perspective, it's appropriate to mention prominent fringe treatments and the strength (or weakness) of the evidence supporting their use.

AHC

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You need a source for Mucuna bean use;

Katzenschlager R Evans A Manson A et al Mucuna pruriens in Parkinsons disease a double blind clinical and pharmacological study. Journal of Neurology, Neurosurgery and Psychiatry 2004 75 1672-1677

AJL

| Paragraph 1
PD invariably progresses with time. A severity rating method known as the Unified Parkinson's Disease Rating Scale (UPDRS) is the most commonly used metric for clinical study. A modified version known as the MDS-UPDRS is also sometimes incresaingly being used. An older scaling method known as the Hoehn and Yahr scale (originally published in 1967), and a similar scale known as the Modified Hoehn and Yahr scale, have also been commonly used. The Hoehn and Yahr scale defines five basic stages of progression; it emphasizes gait and posture instability levodopa response, although ratings for the status of on and off medication can be applied.

| Paragraph 2
Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later in linear fashion. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden are bedbound and dependent on others for everyday activities like dressing feeding and bathing after ten years. However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability because of the undesired effects of levodopa after years of use quality of life considerably and probably life expectancy by reducing early deaths. In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years. However, it is hard to predict what course the disease will take for a given individual. Age is the best predictor of disease progression. The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.

Reviewers: The cited source for the original claim is

• {{cite journal |vauthors=Poewe W |title=The natural history of Parkinson's disease |journal=J. Neurol. |volume=253 Suppl 7 |issue= |pages=VII2–6 |year=2006 |pmid=17131223 |doi=10.1007/s00415-006-7002-7 |url=}}

I'm awaiting access to that. Can anyone provide a source that supports a linear course?

I've got that 2006 article now and it says:

:"progression of motor impairment is likely non-linear in PD with steeper declines earlier vs. later in the disease. This was originally suggested by Fearnley and Lees (1991) who reported an exponential decline of neuronal cell counts in the SN of PD brains over time and is supported by clinical observations of faster rates of progression of UPDRS motor scores in the first vs. the 10th year of disease or plateaning of OFF-period motor scores with disease durations of 9 years and above as observed in cross-sectional studies. These observations highlight the need for early intervention when attempting to modify disease progression in PD"

"Likely". So, at the very least, we should make the claim less categorical. Given the age of the source and the "likely", in the absence of a stronger, more recent source, I think simply challenging the claim should be enough to warrant its removal.

To change the language to "in linear fashion" we'll need a good source supporting that.

AHC

| Paragraph 3
Since current therapies improve many of the motor symptoms, disability at present is mainly related to non-motor features of the disease as well as the non-dopaminergic motor features. Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms. As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage. Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline. All of these symptoms, especially cognitive decline, greatly increase disability.

| Paragraph 1
PD is the second most common neurodegenerative disorder after Alzheimer's disease and affects approximately seven million people globally and one million people in the United States. The proportion in a population at a given time is about 0.3% in industrialized countries. PD is more common in the elderly and rates rises from 1% in those over 60 years of age to 4% of the population over 80. The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset PD, begin between the ages of 20 and 50. There is also some evidence that the incidence of the disease reduces in the ninth decade of life. PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed. Some Most, but not all, studies have proposed show that it is more common in men than women, but others failed to detect any differences between the two sexes. The number of new cases per year of PD is between 8 and 18 per 100,000 person–years.

• Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2014 Nov;29(13):1583-90

AEL.

| Paragraph 2
Many risk factors and protective factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease, however none have been conclusively related to PD by empirical. When epidemiological studies have been carried out in order to test the relationship between a given factor and PD, they have often been flawed and their results have in some cases been contradictory. The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.

AHC

| Paragraph 1
11 April, the birthday of James Parkinson, has been designated as Parkinson's disease day. A red tulip was chosen by international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip cultivar, registered in 1981 by a Dutch horticulturalist. Advocacy organizations include the National Parkinson Foundation, which has provided more than $180 million in care, research and support services since 1982, Parkinson's Disease Foundation, which has distributed nearly $110 million for research and nearly $47 million for education and advocacy programs since its founding in 1957 by William Black; the American Parkinson Disease Association, founded in 1961; Parkinson’s UK, which has been helping people with Parkinson’s in the UK for over 40 years; and the European Parkinson's Disease Association, founded in 1992.

DB.

| Paragraph 2
Actor Michael J. Fox has PD and has greatly increased the public awareness of the disease. After diagnosis, Fox embraced his Parkinson's in television roles, sometimes acting without medication, in order to further illustrate the effects of the condition. He has written two autobiographies in which his fight against the disease plays a major role, and appeared before the United States Congress without medication to illustrate the effects of the disease. The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease. Fox received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson's disease.

"Parkinson's is a common disease, so lots of notable people have it.  Please only add people here who have played a MAJOR role in supporting research or public understanding of the disease.  All others can be listed at the main article about people diagnosed with Parkinson's disease."

Who should be included, and how, can probably be easily resolved in a conversation with the editors.

AHC

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"... sometimes acting without medication to illustrate the effects of the condition.":

This needs to be checked carefully. As I understood it, he was criticized for doing that when in fact people misinterpreted his dyskinesia (due to his medication) for the primary symptoms of the disease and claimed that he had withheld his medication to get sympathy. This clearly indicated a lack of understanding on the part of the congressional members who criticized him. (At least that is my understanding what took place but perhaps I am wrong).

AEL.

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"The Michael J. Fox Foundation aims to develop a cure for Parkinson's disease.":

I would add something about how much they have raised for research emphasizing that this has been an extremely effective organization.

AEL.

| Paragraph 3
Muhammad Ali showed signs of Parkinson's when he was 38, but was not diagnosed until he was 42, and has been called the "world's most famous Parkinson's patient". Whether he has PD or a parkinsonism related to boxing is unresolved. Ray Kennedy the Arsenal and Liverpool football player developed PD towards the end of his professional football career at the age of 35. Retrospective examination of television footage confirmed that he had physical signs in one arm while he was still playing football at a high level(Lees 1992).

We cannot really resolve the dx of lewy body parkinsonism in anyone prior to autopsy. Does it help any reader to think about parkinsonism and boxing? Muhammad was certainly not demented when I ran the Ali Center, and that was 20 years after diagnosis.

MS.

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Do we include a link to Robin Williams? Others?

DB.

| Paragraph 1
There is little prospect of dramatic new PD treatments expected in a short time frame the next 5 years. Currently active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents.

AHC

| Paragraph 2
PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The appearance of parkinsonian symptoms in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans. Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb. Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed. Using the The neurotoxin 6-hydroxydopamine, also known as 6-OHDA, it creates a model of Parkinson’s disease PD in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra or the striatum.

| Paragraph 3
Gene therapy typically involves the use of a non-infectious virus (i.e., a viral vector such as the adeno-associated virus) to shuttle genetic material into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage proteins that could affect symptoms of PD in a variety of ways including increasing dopamine production, stimulating the sprouting or regeneration of remaining dopamine cells by trophic factors, or causing neurons to change their transmitter function in hopes of normalizing basal ganglia network activity. In 2010 there were four clinical trials using gene therapy in PD. There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown. One of these reported positive results in 2011, but the company filed for bankruptcy in March 2012. More recently, gene therapy for the trophic factor neurturin, injected into both the striatum and substantia nigra, failed to show benefit in a well-designed randomized controlled clinical trial

• Warren Olanow C, Bartus RT, Baumann TL, Factor S, Boulis N, Stacy M, Turner DA, Marks W, Larson P, Starr PA, Jankovic J, Simpson R, Watts R, Guthrie B, Poston K, Henderson JM, Stern M, Baltuch G, Goetz CG, Herzog C, Kordower JH, Alterman R, Lozano AM, Lang AE.Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. Ann Neurol. 2015 Aug;78(2):248-57. doi: 10.1002/ana.24436.

AEL.

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Tony, can you think of a source (if Warren Olanow doesn't) that supports the earlier addition beginning with "...proteins that could affect symptoms..."?

AHC

| Paragraph 4
Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments. However, none of them have been conclusively demonstrated to reduce degeneration. Agents currently under investigation include anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF). Preclinical research also targets alpha-synuclein. A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), has entered clinical trials in humans. Both active and passive methods of immunizing against alpha-synuclein are being actively pursued.

Me – look up Kalia recent MDJ paper and edit.

AEL.

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"Several molecules have been proposed as potential treatments.":

Suggest adding the following reference in which we reviewed this area in considerable detail very recently so it is the most up to date reference on the topic:

• {{cite journal |vauthors=Kalia LV, Kalia SK, Lang AE |title=Disease-modifying strategies for Parkinson's disease |journal=Mov. Disord. |volume=30 |issue=11 |pages=1442–50 |year=2015 |pmid=26208210 |doi=10.1002/mds.26354 |url=}}

AEL.

Presently we cite

• {{cite journal |vauthors=Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G |title=Missing pieces in the Parkinson's disease puzzle |journal=Nat. Med. |volume=16 |issue=6 |pages=653–61 |year=2010 |pmid=20495568 |doi=10.1038/nm.2165 |url=}}

AHC

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"Both active and passive methods of immunizing against alpha-synuclein are being actively pursued."

Reviewers: Is there a one or two sentence layman's explanation for "active and passive methods"?

AHC

| Paragraph 5
Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra striatum in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost. Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term fail to provide adequate benefit in the majority of patients, particularly in these trials, although individual patients (often younger and with milder disease) have shown marked prolonged improvement. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias development of graft-induced dyskinesias that did not require levodopa or other dopaminergic medications to be maintained. Stem cell transplants are a recent research target, because stem cells are easy to manipulate and stem cells transplanted into the brains of rodents and monkeys have been found to survive and reduce behavioral abnormalities. Nevertheless, use of fetal stem cells is controversial. It has been proposed that effective treatments may be developed in a less controversial way by use of induced pluripotent stem cells taken from adults. It remains uncertain whether early 'physiological' replacement of the damaged nigrostriatal dopamine pathway will correct all the symptoms and signs of Parkinson’s disease.

Only one group has injected them into the substantia nigra; all other studies that use the striatum.

AEL.

----

"Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term fail to provide adequate benefit in the majority of patients, particularly in these trials..."

Reviewers: I don't understand "particularly in these trials". What trials?

The article presently cites

• {{cite journal |vauthors=Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, Hirsch EC, Farrer M, Schapira AH, Halliday G |title=Missing pieces in the Parkinson's disease puzzle |journal=Nat. Med. |volume=16 |issue=6 |pages=653–61 |year=2010 |pmid=20495568 |doi=10.1038/nm.2165 |url=}}

AHC

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"although individual patients (often younger and with milder disease) have shown marked prolonged improvement."

Reviewers: Can we have a source that supports this?

AHC

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"It remains uncertain whether early 'physiological' replacement of the damaged nigrostriatal dopamine pathway will correct all the symptoms and signs of Parkinson’s disease.":

• Olanow CW, Kordower JH, Lang AE, Obeso JA. Dopaminergic transplantation for Parkinson's disease: current status and future prospects. Ann Neurol. 2009 Nov;66(5):591-6. doi: 10.1002/ana.21778.

AEL.