Archive for September 13th, 2016

The Pronk Pops Show 754, September 13, 2016, Story 1: Name That Malady — Parkinson’s Disease? Multiple sclerosis (MS)? A.L.S. ( Amyotrophic Lateral Sclerosis) or sometimes called Lou Gehrig’s disease? Power Palpitations? — Clue: Blue Sung Glasses! — Videos — Story 2: Clinton Will Power Through — Big Lie Media Lying and Spinning Away For Hillary–Send In The Clowns — There Here — Videos

Posted on September 13, 2016. Filed under: 2016 Presidential Campaign, 2016 Presidential Candidates, Addiction, American History, Blogroll, Breaking News, Bribery, Cartoons, College, Communications, Congress, Constitutional Law, Corruption, Countries, Crime, Culture, Diet, Disasters, Diseases, Donald J. Trump, Donald J. Trump, Donald Trump, Donald Trump, Drugs, Education, Elections, Empires, Employment, Exercise, Food, Foreign Policy, Government, Government Spending, Health, Health Care, High Crimes, Hillary Clinton, Hillary Clinton, Hillary Clinton, History, Homicide, House of Representatives, Human, Human Behavior, Illegal Immigration, Illegal Immigration, Immigration, Impeachment, Iran Nuclear Weapons Deal, Law, Legal Immigration, Life, Lying, Media, Medicare, Movies, Music, News, Philosophy, Photos, Politics, Polls, Progressives, Radio, Raymond Thomas Pronk, Resources, Scandals, Security, Senate, Unemployment, United States Constitution, United States of America, Videos, Violence, War, Wealth, Wisdom | Tags: , , , , , , , , , , , , , , , |

Project_1

The Pronk Pops Show Podcasts

Pronk Pops Show 754: September 13, 2016 

Pronk Pops Show 753: September 12, 2016 

Pronk Pops Show 752: September 9, 2016 

Pronk Pops Show 751: September 8, 2016 

Pronk Pops Show 750: September 7, 2016 

Pronk Pops Show 749: September 2, 2016 

Pronk Pops Show 748: September 1, 2016

Pronk Pops Show 747: August 31, 2016 

Pronk Pops Show 746: August 30, 2016 

Pronk Pops Show 745: August 29, 2016 

Pronk Pops Show 744: August 26, 2016 

Pronk Pops Show 743: August 25, 2016

Pronk Pops Show 742: August 24, 2016 

Pronk Pops Show 741: August 23, 2016 

Pronk Pops Show 740: August 22, 2016

Pronk Pops Show 739: August 18, 2016

Pronk Pops Show 738: August 17, 2016

Pronk Pops Show 737: August 16, 2016

Pronk Pops Show 736: August 15, 2016

Pronk Pops Show 735: August 12, 2016

Pronk Pops Show 734: August 11, 2016

Pronk Pops Show 733: August 9, 2016

Pronk Pops Show 732: August 8, 2016

Pronk Pops Show 731: August 4, 2016

Pronk Pops Show 730: August 3, 2016

Pronk Pops Show 729: August 1, 2016

Pronk Pops Show 728: July 29, 2016

Pronk Pops Show 727: July 28, 2016

Pronk Pops Show 726: July 27, 2016

Pronk Pops Show 725: July 26, 2016

Pronk Pops Show 724: July 25, 2016

Pronk Pops Show 723: July 22, 2016

Pronk Pops Show 722: July 21, 2016

Pronk Pops Show 721: July 20, 2016

Pronk Pops Show 720: July 19, 2016

Pronk Pops Show 719: July 18, 2016

Pronk Pops Show 718: July 15, 2016

Pronk Pops Show 717: July 14, 2016

Pronk Pops Show 716: July 13, 2016

Pronk Pops Show 715: July 12, 2016

Pronk Pops Show 714: July 7, 2016

Pronk Pops Show 713: July 6, 2016

Pronk Pops Show 712: July 5, 2016

Pronk Pops Show 711: July 1, 2016

Pronk Pops Show 710: June 30, 2016

Pronk Pops Show 709: June 29, 2016

Pronk Pops Show 708: June 28, 2016

Pronk Pops Show 707: June 27, 2016

Pronk Pops Show 706: June 24, 2016

Pronk Pops Show 705: June 23, 2016

Pronk Pops Show 704: June 22, 2016

Pronk Pops Show 703: June 21, 2016

Pronk Pops Show 702: June 20, 2016

Pronk Pops Show 701: June 17, 2016

Pronk Pops Show 700: June 16, 2016

Pronk Pops Show 699: June 15, 2016

Pronk Pops Show 698: June 14, 2016

Pronk Pops Show 697: June 13, 2016

Pronk Pops Show 696: June 10, 2016

Pronk Pops Show 695: June 9, 2016

Pronk Pops Show 694: June 8, 2016

Pronk Pops Show 693: June 6, 2016

Pronk Pops Show 692: June 3, 2016

Pronk Pops Show 691: June 2, 2016

Pronk Pops Show 690: June 1, 2016

Story 1: Name That Malady —  Parkinson’s Disease? Multiple sclerosis (MS)? A.L.S. ( Amyotrophic Lateral Sclerosis) or sometimes called Lou Gehrig’s disease? Power Palpitations? — Clue: Blue Sung Glasses! — Videos 

mal·a·dy
ˈmalədē/
noun
  1. a disease or ailment.
    “an incurable malady”
    synonyms: illness, sickness, disease, infection, ailment, disorder, complaint, indisposition, affliction,infirmity, syndrome;

    informalbug, virus
    “every time we visit Jerry, he has a new malady”

“Power tends to corrupt, and absolute power corrupts absolutely. .”

~John Emerich Edward Dalberg-Acton, 1st Baron Acton

Image result for cartoons hillary clinton health problems medical condition~

Hillary's dramatic collapse in New York on Sunday  is prompting new examination of her health ¿ as well as how her aides have closely guarded information

Image result for cartoons hillary clinton health problems medical condition

 

Image result for cartoons hillary clinton falling down

Image result for cartoons hillary clinton falling down

 

Image result for cartoons hillary clinton health problems medical condition

Image result for cartoons hillary clinton health problems medical condition

Image result for Hillary for President CartoonsImage result for cartoons hillary clinton health problems medical condition

 

Kids Singing About Disease

Name That Tune – Best ever

Hillary Clinton Pneumonia Diagnosis: 3 Facts

Irrefutable Proof: Hillary Clinton Has a Seizure Disorder!

Pneumonia diagnosis fuels questions about Clinton’s health

What is Parkinson’s disease?

Hillary Clinton’s Health Crisis | Mike Cernovich and Stefan Molyneux

A Field Guide to spotting Hillary Clinton’s Parkinson’s Disease Signs

Hillary’s fall: Which official excuse is the truth?

Z1 F133 protective prism blue Seizure filter lens Vox Day Theodore Beale Drew Pinsky Ted Noel

What to Do for Someone Having a Seizure | Epilepsy

Sunglasses Reveal Hillary’s Shady Health Lies

Multiple Sclerosis

The Connection Between Multiple Sclerosis and Vision

ALS (Lou Gehrig’s Disease) – Health Matters

What is A.L.S. or Lou Gehrig’s Disease ?

Bill Clinton weighs in on Hillary’s health

Dr. Drew: Hillary Has “Brain Damage”

Judy Collins Send in the Clowns

Isn’t it rich?
Are we a pair?
Me here at last on the ground,
You in mid-air..
Where are the clowns?

Isn’t it bliss?
Don’t you approve?
One who keeps tearing around,
One who can’t move…
Where are the clowns?
Send in the clowns.

Just when I’d stopped opening doors,
Finally knowing the one that I wanted was yours.
Making my entrance again with my usual flair
Sure of my lines…
No one is there.

Don’t you love farce?
My fault, I fear.
I thought that you’d want what I want…
Sorry, my dear!
And where are the clowns
Send in the clowns
Don’t bother, they’re here.

Isn’t it rich?
Isn’t it queer?
Losing my timing this late in my career.
And where are the clowns?
There ought to be clowns…
Well, maybe next year.

 

Three blood clots, a concussion, deep vein thrombosis: Hillary’s shielded medical history is no longer just for conspiracy theorists as her ‘penchant for privacy’ gets serious scrutiny

  • Clinton suffered her first blood clot in 1998 while she was First Lady and experienced a second incident in 2009
  • She suffered a concussion after falling in her home in 2013 near the end of her tenure as secretary of state
  • Her doctors say she has deep vein thrombosis, which can lead to clotting in leg veins
  • She suffered a blood clot in her brain in December 2011 and takes blood thinners to treat her condition
  • She has been diagnosed with hypothyroidism
  • Broke her elbow, as spokesman warned it would crimp her texting 
  • Clinton collapsed when she left a 9/11 ceremony early on Sunday. Her office finally revealed she has pneumonia
  • Campaign spokesman Brian Fallon says Clinton plans to release more medical records this week as criticism mounts

Hillary Clinton’s medical history – and her tendency to keep personal and medical information far from view – is coming in for new scrutiny following revelations that the candidate got diagnosed with pneumonia Friday in advance of her stumble in New York.

Clinton’s stumble, caught on camera Sunday after she had to leave Sept. 11th anniversary memorial services after about an hour and a half, was the latest in a line of health spats that have made it into the news during her career.

‘Antibiotics can take care of pneumonia. What’s the cure for an unhealthy penchant for privacy that repeatedly creates unnecessary problems?’ asked President Obama’s former message guru David Axelrod in a tweet Monday – a message promptly retweeted by Trump‘s campaign manager Kellyanne Conway.

Below is a compilation of Clinton’s ailments and health incidents that have entered the public record:

Clinton’s medical history – and her tendency to keep personal and medical information far from view – is coming in for new scrutiny following revelations that the candidate got diagnosed with pneumonia Friday

Hillary's dramatic collapse in New York on Sunday  is prompting new examination of her health ¿ as well as how her aides have closely guarded information

Hillary’s dramatic collapse in New York on Sunday  is prompting new examination of her health – as well as how her aides have closely guarded information

1998 Blood Clot

Clinton’s first known blood clot occurred in 1998, while she was still first lady.

Clinton experienced symptoms while attending a fundraiser for Sen. Charles Schumer of New York, who would soon become her Senate home-state colleague. Her right foot swelled up to the point where she couldn’t put on her shoe.

Clinton got quietly taken to the National Naval Medical Center in Bethesda for treatment at the time. She was found to have ‘a big clot’ blood clot behind her knee, Clinton wrote in her memoir, ‘Living History.’

She called it ‘the most significant health scare I’ve ever had,’ the Washington Post noted.

According to her physician, Mt. Kisco physician, Lisa Bardack, Clinton was advised at the time to take Lovenox, described as a short-acting blood thinner, when she took flights. The meds were discontinued when she went on Coumadin.

 

2009 Blood Clot 

 Clinton had a second blood clot incident in 2009. The episode was described by her doctor in a 2015 letter.

The doctor didn’t provide a detailed description of the event. Rather, she wrote that Clinton’s ‘past medical history is notable for a deep vein thrombosis in 1998, 2009 and a concussion in 2012.

Clinton takes a daily blood thinning medication for her deep vein thrombosis.

Clinton, a frequent flier whose staff catalogued her pursuit of the overall mileage record as secretary of state, may have exacerbated the problem through her extensive air travel.

Frequent jet travel can exacerbate blood clots, which is why some people make sure to walk around the cabin on long flights

Frequent jet travel can exacerbate blood clots, which is why some people make sure to walk around the cabin on long flights

2009 Elbow Fracture 

 Clinton had to work from home for a while after she fractured her elbow during a fall in 2009, CNN recounted. She fell at the State Department on the way to the White House, and went to George Washington University hospital for treatment.

She underwent a two-hour surgical procedure.

‘She is working from home. She is already taking some calls, and I’m sure starting to learn the limits of movement – how well you can text with one arm in a sling,’ quipped then spokesman P.J. Crowley at the time, in an early reference to Clinton’s communications habits.

Clinton was pictured wearing a sling emblazoned with the seal of the State Department when she returned to work. She also was photographed providing left-handed hand shake with a visiting Palestinian dignitary owing to her condition. She has showed no visible signs of lingering problems related to the injury.

HARD KNOCKS: Clinton got a fractured elbow in 2009, but still managed to negotiate with Hondouran leaders, and, according to her spokesman, text with one hand

HARD KNOCKS: Clinton got a fractured elbow in 2009, but still managed to negotiate with Hondouran leaders, and, according to her spokesman, text with one hand

2012 Blood Clot and Concussion 

Clinton got a bad stomach bug and fainted at her home in Washington in 2012, an event that led her to get a concussion. Information about what exactly had happened emerged only slowly over time.

As her doctor put it, ‘In December 2012, Mrs. Clinton suffered a stomach virus after traveling, became dehydrated, fainted and sustained a concussion.’

The then-secretary of state wasn’t seen in public between Dec. 7th and when she left the hospital in New York January 2, 2013.

Clinton experienced ‘double vision for a period of time and benefited from wearing glasses with a Fresnel Prism,’ a special corrective lens, her doctor wrote in a letter voluntarily released to the media in 2015 as part of Clinton’s presidential campaign. Her concussion ‘resolved within two months,’ Bardack wrote.

In 2014, Bill Clinton revealed that the injury ‘required six months of very serious work to get over.’ The former president called it a ‘terrible concussion’

Clinton was diagnosed with a blood clot in the brain, transverse sinus venous thrombosis, and began anticoagulation therapy, her doctor wrote.

Clinton had to work from home and postpone planned testimony before a House Benghazi committee.

Clinton leaves New York Presbyterian Hospital with husband Bill and daughter Chelsea on January 2, 2013. The secretary of state, had not been seen in public since Dec. 7

Clinton leaves New York Presbyterian Hospital with husband Bill and daughter Chelsea on January 2, 2013. The secretary of state, had not been seen in public since Dec. 7

Hypothyroidism

Clinton also suffers from Hypothyroidismrefers to an under-active thyroid gland, resulting in a lack of important hormones.

Clinton’s doctor identified the condition in her 2015 letter, but did not state for how long Clinton has suffered from the condition. She takes a medication called Armour Thyroid.

Allergies

Clinton suffers from ‘seasonal allergies,’ according to her physician. It isn’t known for how long she has suffered from allergies, although Clinton herself has cited her allergies when she has developed a cough – including on-stage during public events.

Her doctor states that Clinton is taking antihistamines, which treat the effects of allergies.

2016 Collapse and Pneumonia Diagnosis

Clinton had to leave a Sept. 11th service in New York early after spending 90 minutes at the ceremony. Her staff first cited heat and exhaustion, then ultimately revealed that Clinton had been diagnosed in pneumonia on Friday.

Clinton campaign spokesman Brian Fallon did not reveal what type of pneumonia Clinton has during a Monday interview on MSNBC, but said Clinton would be putting out more medical information.

‘She was put on antibiotics and advised to rest and modify her schedule,’ said Bardack in a statement released at the end of the day. While attending the event, ‘she became overheated and dehydrated. I have just examined her and she is now re-hydrated and recovering nicely.’

Hours after Clinton was taken away from the Sept. 11th ceremony, her office released a doctor’s statement. ‘Secretary Clinton has been experiencing a cough related to allergies. On Friday, during follow-up evaluation of her prolonged cough, she was diagnosed with pneumonia. She was put on antibiotics, and advised to rest and modify her schedule. While at this morning’s event, she became overheated and dehydrated. I have just examined her and she is now rehydrated and recovering nicely,’ Clinton’s doctor, Lisa Bardack, said in a written statement Sunday.’

‘There’s no other undisclosed condition. The pneumonia is the extent of it,’ Clinton campaign spokesman Brian Fallon told MSNBC.

Fallon also acknowledged: ‘I think in retrospect we could have handled it better in terms of providing more information more quickly.’

Campaign manager Robby Mook, speaking of the 90 minute delay before the press was told Clinton’s status after she left the New York event, said Monday: ‘We wish that that had been a lot shorter and that’s on us.’

Clinton herself tweeted Monday: ‘Thanks to everyone who’s reached out with well wishes! I’m feeling fine and getting better,’ signing the missive with the letter ‘H.’

Clinton had to shake with her left hand following her 2009 injury. She is pictured here with Palestinian Authority Salam Fayyad 

Clinton had to shake with her left hand following her 2009 injury. She is pictured here with Palestinian Authority Salam Fayyad

Clinton campaigned in New York in June along with aide Huma Abedin. She was diagnosed with pneumonia Friday, according to her office

Clinton campaigned in New York in June along with aide Huma Abedin. She was diagnosed with pneumonia Friday, according to her office

Clinton is 68 and would be 69 when she assumed office, second to Ronald Reagan in age taking office. Donald Trump is 70, and has released few details about his medical background.

‘She participates in a healthy lifestyle and has had a full medical evaluation, which reveals no evidence of additional medical issues or cardiovascular disease. Her cancer screening evaluations are all negative. She is in excellent physical condition and fit to serve as President of the United States,’ her doctor wrote.

The letter released by Clinton's physician details her 2012 concussion and double vision

The letter released by Clinton’s physician details her 2012 concussion and double vision

Clinton was a 'healthy-appearing female' during her last examination, according to Dr. Lisa Bardack

Clinton was a ‘healthy-appearing female’ during her last examination, according to Dr. Lisa Bardack

http://www.dailymail.co.uk/news/article-3786187/Three-blood-clots-concussion-deep-vein-thrombosis-Hillary-Clinton-s-shielded-medical-history-isn-t-just-conspiracy-theorists-penchant-privacy-gets-scrutiny.html#ixzz4KAAhLLNB

 

Parkinson’s disease

From Wikipedia, the free encyclopedia
“Parkinson’s” redirects here. For other uses, see Parkinson’s (disambiguation).
Parkinson’s disease
idiopathic or primary parkinsonism, hypokinetic rigid syndrome, paralysis agitans
Two sketches (one from the front and one from the right side) of a man, with an expressionless face. He is stooped forward and is presumably having difficulty walking.

Illustration of Parkinson’s disease by William Richard Gowers, which was first published in A Manual of Diseases of the Nervous System (1886)
Classification and external resources
Specialty Neurology
ICD10 G20, F02.3
ICD9-CM 332
OMIM 168600556500
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304neuro/635 in young
pmr/99 rehab
MeSH D010300
GeneReviews

Parkinson’s disease (PD) is a long term disorder of the central nervous system that mainly affects the motor system.[1] The symptoms generally come on slowly over time. Early in the disease, the most obvious are shaking, rigidity, slowness of movement, and difficulty with walking.[1]Thinking and behavioral problems may also occur.Dementia becomes common in the advanced stages of the disease. Depression and anxiety are also common occurring in more than a third of people with PD.[2] Other symptoms include sensory, sleep, and emotional problems.[1][2] The main motor symptoms are collectively called “parkinsonism“, or a “parkinsonian syndrome”.[3][4]

The cause of Parkinson’s disease is generally unknown, but believed to involve both genetic and environmental factors. Those with a family member affected are more likely to get the disease themselves[4] There is also an increased risk in people exposed to certain pesticides and among those who have had prior head injuries while there is a reduced risk in tobacco smokers and those who drink coffee or tea.[4][5] The motor symptoms of the disease result from the death of cells in the substantia nigra, a region of the midbrain. This results in not enough dopamine in these areas.[1] The reason for this cell death is poorly understood but involves the build-up ofproteins into Lewy bodies in the neurons.[4] Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used to rule out other diseases.[1]

There is no cure for Parkinson’s disease.[1] Initial treatments is typically with the antiparkinson medicationlevodopa, with dopamine agonists being used once levodopa becomes less effective. As the disease progresses and neurons continue to be lost, these medications become less effective while at the same time they produce acomplication marked by involuntary writhing movements.[2] Diet and some forms of rehabilitation have shown some effectiveness at improving symptoms.[6][7]Surgery to place the microelectrodes for deep brain stimulation has been used to reduce motor symptoms in severe cases where drugs are ineffective.[1] Evidence for treatments for the non-movement-related symptoms of PD, such as sleep disturbances and emotional problems, is less strong.[4]

In 2013 PD was present in 53 million people and resulted in about 103,000 deaths globally.[8][9] Parkinson’s disease typically occurs in people over the age of 60, of which about one percent are affected.[1][10] Males are more often affected than females.[4] When it is seen in people before the age of 40 or 50, it is called young onset PD.[11] The average life expectancy following diagnosis is between 7 and 14 years.[2] The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy, in 1817.[12][13] Public awareness campaigns include World Parkinson’s Day (on the birthday of James Parkinson, 11 April) and the use of a red tulip as the symbol of the disease.[14] People with parkinsonism who have increased the public’s awareness of the condition include actor Michael J. Fox, Olympic cyclist Davis Phinney, and late professional boxer Muhammad Ali.[15][16][17]

Classification

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:

  1. primary or idiopathic
  2. secondary or acquired
  3. hereditary parkinsonism, and
  4. Parkinson plus syndromes or multiple system degeneration.[18]

Parkinson’s disease is the most common form of parkinsonism and is usually defined as “primary” parkinsonism, meaning parkinsonism with no external identifiable cause.[19][20] 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.[21]

Usually classified as a movement disorder, PD also gives rise to several non-motor types of symptoms such as sensory deficits,[22] cognitive difficulties, and sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features.[19] They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies.[19][23]

In terms of pathophysiology, PD is considered 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 such as Alzheimer’s disease where the brain accumulates tau protein in the form of neurofibrillary tangles.[24] Nevertheless, there is clinical and pathological overlap 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.[24]

Dementia with Lewy bodies (DLB) is another synucleinopathy that has 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.[25] They may represent parts of a continuum or they may be separate diseases.[25]

Signs and symptoms

Black and white picture of a male with PD stooping forward as he walks. He is viewed from the left side and there is a chair behind him.

A man with Parkinson’s disease displaying a flexed walking posture pictured in 1892.[26]

French signature reads "Catherine Metzger 13 Octobre 1869"

Handwriting of a person affected by PD[27]

Parkinson’s disease affects movement, producing motor symptoms.[18] Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common. Some of these non-motor symptoms are often present at the time of diagnosis and can precede motor symptoms.[18]

Motor

Further information: Parkinsonian gait

Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.[18]

Tremor is the most apparent and well-known symptom.[18] 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.[18] It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep.[18] 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.[18] 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.[18][28]The term derives from the similarity between the movement of people with PD and the earlier pharmaceutical technique of manually making pills.[28]

Hypokinesia (slowness of movement) is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.[18] Performance of sequential and simultaneous movement is hindered.[18] Bradykinesia is commonly a very disabling symptom in the early stages of the disease.[19] Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed.[18] Clinical evaluation is based on similar tasks such as alternating movements between both hands or both feet.[19] 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.[18] Generally people with PD have less difficulty when some sort of external cue is provided.[18][29]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.[18] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).[18][19][30][31] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[32]Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[18] In early stages of Parkinson’s disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[33] With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls,[34] and secondarily to bone fractures.[18] Instability is often absent in the initial stages, especially in younger people.[19] Up to 40% may experience falls and around 10% may have falls weekly, with the number of falls being related to the severity of PD.[18]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking),[18] speech and swallowing disturbances including voice disorders,[35]mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large.[18]

Neuropsychiatric

Parkinson’s disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.[18]

Cognitive disturbances can occur in the early stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.[18][36] The most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, working memory, and selecting relevant sensory information.[36][37] Fluctuations in attention, impaired perception and estimation of time, slowed cognitive processing speed are among other cognitive difficulties.[36][37] Memory is affected, specifically in recalling learned information.[36] Nevertheless, improvement appears when recall is aided by cues.[36] Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.[36][37]

A person with PD has two to six times the risk of dementia compared to the general population.[18][36] The prevalence of dementia increases with duration of the disease.[36] Dementia is associated with a reducedquality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing nursing home care.[36]

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 and anxiety.[18] 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.[38]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.[18][39]Psychotic symptoms—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.[40][41]

Other

In addition to cognitive and motor symptoms, PD can impair other body functions.

Sleep problems are a feature of the disease and can be worsened by medications.[18] Symptoms can manifest as daytime drowsiness, disturbances in REM sleep, or insomnia.[18] A systematic review shows that sleep attacks occur in 13.0% of patients with Parkinson’s disease on dopaminergic medications.[42]

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.[18]Constipationand gastric dysmotility can be severe enough to cause discomfort and even endanger health.[6] 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.[18][43] Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness).[18] All of these symptoms can occur years before diagnosis of the disease.[18]

Causes

Parkinson’s disease in most people is idiopathic (having no specific known cause). However, a small proportion of cases can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationships have been proven.

Environmental factors

U.S. Army helicopter spraying Agent Orange over Vietnamese agricultural land during the Vietnam war

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.[44][45] Rural environments and the drinking of well water may be risks as they are indirect measures of exposure to pesticides.[46][47]

Implicated agents include insecticides, primarily chlorpyrifos and organochlorines[48] and pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange andziram.[46][47][49][50]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.[46]

Genetics

Parkin crystal structure

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.[19] At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.[51]

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), DJ-1 and ATP13A2.[21][51] 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.[21] 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. Mutations in GBA are known to cause Gaucher’s disease.[51]Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[52]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[51]Missense mutations of the gene (in which a singlenucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD.[51] Missense mutations are rare.[51] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[51] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[51]

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.[21]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.[21][51] There are many mutations described in LRRK2, however unequivocal proof of causation only exists for a few.[51]

Several Parkinson-related genes are involved in the function of lysosomes, organelles that digest cellular waste products. It has been suggested that some forms of Parkinson may be caused by lysosome dysfunctions that reduce the ability of cells to break down alpha-synuclein.[53]

Pathology

Several brain cells stained in blue. The largest one, a neurone, with an approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears.

A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson’s disease. The brown colour is positive immunohistochemistrystaining for alpha-synuclein.

Anatomical

The basal ganglia, a group of brain structures innervated by the dopaminergic system, are the most seriously affected brain areas in PD.[54] The main pathologicalcharacteristic of PD 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.[21]

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.[55] The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows 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.[55]

Pathophysiology

Composite of three images, one in top row (referred to in caption as A), two in second row (referred to as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". The fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one sagittal and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem.

A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson’s disease, as proposed by Braak and colleagues
B. Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brain stemdamage may be the first identifiable stage of PD neuropathology[56]

The primary symptoms of Parkinson’s disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of thesubstantia nigra.[54]

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor, oculo-motor, associative, limbic and orbitofrontalcircuits, with names indicating the main projection area of each circuit.[54] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.[54] Scientifically, the motor circuit has been examined the most intensively.[54]

A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.[54] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus, the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[54] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.[54]

Brain cell death

There is speculation of several mechanisms by which the brain cells could be lost.[57] One mechanism consists of an abnormal accumulation of the protein alpha-synucleinbound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies.[21][58] 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 asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step theneocortex.[21] 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.[57][58] 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.[55]

Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.[57] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[59]

Diagnosis

Sagittal PET scan at the level of the striatum. Hottest areas are the cortical grey matter and the striatum.

Fludeoxyglucose (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.

A physician will diagnose Parkinson’s disease from the medical history and a neurological examination.[18] There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. People may be given levodopa and resulting relief of motor impairment tends to confirm the diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the person had Parkinson’s disease. The progress of the illness over time may reveal it is not Parkinson’s disease, and some authorities recommend that the diagnosis should be periodically reviewed.[18][60]

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer’s disease, multiple cerebral infarction and drug-induced parkinsonism.[60]Parkinson plus syndromessuch as progressive supranuclear palsy and multiple system atrophy must be ruled out.[18] Anti-Parkinson’s medications are typically less effective at controlling symptoms in Parkinson plus syndromes.[18] 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.[61] 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.[19]

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 Brain Bank and the U.S. National Institute of Neurological Disorders and Stroke.[18] The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes of these symptoms need to be ruled out. Finally, three or more of the following 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.[18]Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.[18]

Computed tomography (CT) and conventional magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.[62] 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.[62] 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.[62] Dopaminergic function in the basal ganglia can be measured with different PET and SPECTradiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fluorodeoxyglucose (18F)[62] and DTBZ[63] for PET. A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.[62]

Prevention

Exercise in middle age reduces the risk of Parkinson’s disease later in life.[7]Caffeine also appears protective with a greater decrease in risk occurring with a larger intake of caffeinated beverages such as coffee.[64]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.[46] The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.[46][65] Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.[66]

Antioxidants, such as vitamins C and D, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven.[46] The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-increasing effects or no effects.[46] Also, there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.[46]

Management

Pharmacological treatment of Parkinson’s disease

There is no cure for Parkinson’s disease, but medications, surgery, and multidisciplinary management can provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor which does not cross the blood–brain barrier), dopamine agonists and MAO-B inhibitors.[67] The stage of the disease determines which group is most useful. Two stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs pharmacological treatment, then a second stage in which an individual develops motor complications related to levodopa usage.[67] 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.[67] 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.[67] When medications are not enough to control symptoms, surgery, and deep brain stimulation can be of use.[68] In the final stages of the disease, palliative care is provided to improve quality of life.[69]

Levodopa

Levodopa has been the most widely used treatment for over 30 years.[67] L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase.[67] Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.[67]

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.[67]Carbidopaand benserazide are peripheral dopa decarboxylase inhibitors,[67] which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasingbioavailability. They are generally given as combination preparations with levodopa.[67] 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.[39] 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 levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.[67][70]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.[67] It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.[67] A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function.[67] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[67]

Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.[67] 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).[67] For this reason, levodopa doses are kept as low as possible while maintaining functionality.[67] Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice.[67] 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.[67] Most people with PD will eventually need levodopa and later develop motor side effects.[67]

Dopamine agonists

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.[67] 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.[67][71] When used in late PD they are useful at reducing the off periods.[67] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea, and constipation.[67] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[67] Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.[67]Nevertheless, they are usually effective enough to manage symptoms in the initial years.[19] They tend to be more expensive than levodopa.[19] 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.[19] Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset.[19] 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.[39]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[67] It is administered by intermittent injections or continuous subcutaneous infusions.[67] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[67] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) and are useful for people in the initial stages and possibly to control off states in those in the advanced state.[70]

MAO-B inhibitors

MAO-B inhibitors (safinamide, selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They inhibit 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.[67] 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 less effective than levodopa. There are few studies of their effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods.[67] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.[67]

Other drugs

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments.[67] 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.[72] Examples are the use of quetiapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.[72][73] 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.[74]

Surgery

Placement of an electrode into the brain. The head is stabilised in a frame forstereotactic surgery.

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined.[75] 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.[75] 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.[75]Deep brain stimulation (DBS) 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.[68] Other, less common, surgical therapies involve intentional formation of lesions to suppress overactivity of specific subcortical areas. For example, pallidotomy involves surgical destruction of the globus pallidus to control dyskinesia.[75]

Rehabilitation

Exercise programs are recommended in people with Parkinson’s disease.[7] There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[76][77] Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[77] When an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.[78] In terms of improving flexibility and range of motion for people experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques.[79] As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on but are not limited to improving gait speed, the base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).[80] Strengthening exercises have shown improvements in strength and motor function for people with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson’s disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that people with PD should perform exercises 45 minutes to one hour after medications when they are at their best.[81] Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson’s disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.[82] Exercise may improve constipation.[6]

One of the most widely practiced treatments for speech disorders associated with Parkinson’s disease is the Lee Silverman voice treatment (LSVT).[76][83] Speech therapy and specifically LSVT may improve speech.[76]Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[76] There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.[76][84]

Palliative care

Palliative care is specialized medical care for people with serious illnesses, including Parkinson’s. The goal of this speciality is to improve quality of life for both the person suffering from Parkinson’s and the family by providing relief from the symptoms, pain, and stress of illnesses.[85] As Parkinson’s is not a curable disease, all treatments are focused on slowing decline and improving quality of life, and are therefore palliative in nature.[86]

Palliative care should be involved earlier, rather than later in the disease course.[87][88] Palliative care specialists can help with physical symptoms, emotional factors such as loss of function and jobs, depression, fear, and existential concerns.[87][88][89]

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 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.[86] Palliative care team members can help answer questions and guide people with Parkinson’s on these complex and emotional topics to help them make the best decision based on their own values.[88][90]

Other treatments

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).[6] 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.[6] 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.[6]

Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, thereby competing for access.[6] When they are taken together, this results in a reduced effectiveness of the drug.[6] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.[6] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[6] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[6]

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[91] Its usefulness in PD is an open research topic,[92] although recent studies have shown no effect by rTMS.[93]Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[94] 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.[95][96][97]Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. While they have shown some effectiveness in clinical trials,[98] their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.[99][100]

Prognosis

Global burden of Parkinson’s disease, measured in disability-adjusted life years per 100,000 inhabitants in 2004

  no data
  < 5
  5–12.5
  12.5–20
  20–27.5
  27.5–35
  35–42.5
  42.5–50
  50–57.5
  57.5–65
  65–72.5
  72.5–80
  > 80

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 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.

Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years.[101] 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.[101] In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.[101] However, it is hard to predict what course the disease will take for a given individual.[101] Age is the best predictor of disease progression.[57] 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.[57]

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.[57] Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.[101] 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.[101] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.[101] All of these symptoms, especially cognitive decline, greatly increase disability.[57][101]

The life expectancy of people with PD is reduced.[101]Mortality ratios are around twice those of unaffected people.[101] Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand, a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival.[101] Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population.[101]

In 2013 PD resulted in about 103,000 deaths globally, up from 44,000 deaths in 1990.[8] The death rate increased from an average of 1.5 to 1.8 per 100,000 during that time.[8]

Epidemiology

Deaths from Parkinson disease per million persons in 2012

  0-1
  2-4
  5-6
  7-8
  9-10
  11-12
  13-17
  18-36
  37-62
  63-109

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.[34][46] 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.[46] 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.[19] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[46] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.[46] The number of new cases per year of PD is between 8 and 18 per 100,000 person–years.[46]

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 evidence. 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.[46] The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.[46]

History

Jean-Martin Charcot, who made important contributions to the understanding of the disease and proposed its current name honoring James Parkinson

Several early sources, including an Egyptianpapyrus, an Ayurvedic medical treatise, the Bible, and Galen‘s writings, describe symptoms resembling those of PD.[102] After Galen there are no references unambiguously related to PD until the 17th century.[102] In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius,Gaubius, Hunter and Chomel.[102][103][104]

In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans.[14]An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.[12][105] Early neurologists who made further additions to the knowledge of the disease include Trousseau, Gowers, Kinnier Wilson and Erb, and most notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a landmark in the understanding of the disease.[14] Among other advances, he made the distinction between rigidity, weakness and bradykinesia.[14] He also championed the renaming of the disease in honor of James Parkinson.[14]

In 1912 Frederic Lewy described microscopic particles in affected brains, later named “Lewy bodies“.[14] In 1919 Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938.[14] The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and Oleh Hornykiewicz on its role on PD.[106] In 1997, alpha-synuclein was found to be the main component of Lewy bodies by Spillantini, Trojanowski, Goedert and others.[58]

Anticholinergics and surgery (lesioning of the corticospinal pathway or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically.[103][107]Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century.[106] It entered clinical practice in 1967 and brought about a revolution in the management of PD.[106][108] By the late 1980s deep brain stimulation introduced by Alim-Louis Benabid and colleagues at Grenoble, France, emerged as a possible treatment.[109]

Society and culture

Cost

“Parkinson’s awareness” logo with red tulip symbol.

The costs of PD to society are high, but precise calculations are difficult due to methodological issues in research and differences between countries.[110] The annual cost in the UK is estimated to be between 449 million and 3.3 billion pounds, while the cost per patient per year in the U.S. is probably around $10,000 and the total burden around 23 billion dollars.[110] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medication is substantially lower.[110] Indirect costs are high, due to reduced productivity and the burden on caregivers.[110] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.[110]

Advocacy

11 April, the birthday of James Parkinson, has been designated as World Parkinson’s Day.[14] 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.[111] Advocacy organizations include the National Parkinson Foundation, which has provided more than $180 million in care, research and support services since 1982,[112]Parkinson’s Disease Foundation, which has distributed more than $115 million for research and nearly $50 million for education and advocacy programs since its founding in 1957 by William Black;[113][114] the American Parkinson Disease Association, founded in 1961;[115] and the European Parkinson’s Disease Association, founded in 1992.[116]

Notable cases

Muhammad Ali at theWorld Economic Forum inDavos, at the age of 64. He had shown signs of parkinsonism from the age of 38 until his death.

Actor Michael J. Fox has PD and has greatly increased the public awareness of the disease.[15] 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,[117] and appeared before the United States Congress without medication to illustrate the effects of the disease.[117]The Michael J. Fox Foundation aims to develop a cure for Parkinson’s disease.[117] Fox received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson’s disease.[118]

Professional cyclist and Olympic medalist Davis Phinney, who was diagnosed with young onset Parkinson’s at age 40, started the Davis Phinney Foundation in 2004 to support Parkinson’s research, focusing on quality of life for people with the disease.[16][119][120]

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”.[17] Whether he had PD or a parkinsonismrelated to boxing is unresolved.[121][122]

Research

There is little prospect of significant new PD treatments in the near future.[123] 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.[57]

Animal models

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 opiateMPPP 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.[124] Other predominant toxin-based models employ the insecticide rotenone, the herbicideparaquat and the fungicide maneb.[125] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[126] Using the neurotoxin 6-hydroxydopamine, also known as 6-OHDA, it creates a model of Parkinson’s disease in rats by targeting and destroying dopaminergic neurons in the nigrostriatal pathway when injected into the substantia nigra.[127]

Gene therapy

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 anenzyme that helps to manage PD symptoms or protects the brain from further damage.[57][128] In 2010 there were four clinical trials using gene therapy in PD.[57] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.[57] One of these reported positive results in 2011,[129] but the company filed for bankruptcy in March 2012.[130]

Neuroprotective treatments

Several chemical compounds such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, but their effectiveness has not been proven.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[57] However, none of them have been conclusively demonstrated to reduce degeneration.[57] 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).[57] Preclinical research also targets alpha-synuclein.[123] A vaccine that primes the human immune system to destroy alpha-synuclein, PD01A (developed by Austrian company, Affiris), has entered clinical trials in humans.[131]

Neural transplantation

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 in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[57] Although there was initial evidence ofmesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term benefit.[57] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias.[132]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.[57][133]Nevertheless, use of fetal stem cells is controversial.[57] 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.[57]

https://en.wikipedia.org/wiki/Parkinson%27s_disease

Multiple sclerosis

From Wikipedia, the free encyclopedia
Multiple sclerosis
disseminated sclerosis, encephalomyelitis disseminata
MS Demyelinisation CD68 10xv2.jpg

Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100
Classification and external resources
Specialty Neurology
ICD10 G35
ICD9-CM 340
OMIM 126200
DiseasesDB 8412
MedlinePlus 000737
eMedicine neuro/228oph/179emerg/321pmr/82radio/461
Patient UK Multiple sclerosis
MeSH D009103
GeneReviews

Multiple sclerosis (MS) is a demyelinating disease in which the insulating covers of nerve cells in the brain and spinal cord are damaged.[1] This damage disrupts the ability of parts of the nervous system to communicate, resulting in a range of signs and symptoms, including physical, mental, and sometimes psychiatric problems.[2][3][4] Specific symptoms can include double vision, blindness in one eye, muscle weakness, trouble with sensation, or trouble with coordination.[1] MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing forms) or building up over time (progressive forms).[5] Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially as the disease advances.[5]

While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells.[6] Proposed causes for this include genetics and environmental factors such as being triggered by a viral infection.[3][7] MS is usually diagnosed based on the presenting signs and symptoms and the results of supporting medical tests.[8]

There is no known cure for multiple sclerosis.[1] Treatments attempt to improve function after an attack and prevent new attacks.[3] Medications used to treat MS, while modestly effective, can have side effects and be poorly tolerated. Physical therapy can help with people’s ability to function.[1] Many people pursue alternative treatments, despite a lack of evidence.[9] The long-term outcome is difficult to predict, with good outcomes more often seen in women, those who develop the disease early in life, those with a relapsing course, and those who initially experienced few attacks.[10]Life expectancy is on average 5 to 10 years lower than that of an unaffected population.[2]

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system.[11] In 2013, about 2.3 million people were affected globally with rates varying widely in different regions and among different populations.[12][13] That year about 20,000 people died from MS, up from 12,000 in 1990.[14] The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.[15] MS was first described in 1868 by Jean-Martin Charcot.[16] The name multiple sclerosis refers to the numerous scars (sclerae—better known as plaques or lesions) that develop on the white matter of the brain and spinal cord.[16] A number of new treatments and diagnostic methods are under development.[17]

Signs and symptoms

Main symptoms of multiple sclerosis

A person with MS can have almost any neurological symptom or sign, with autonomic, visual, motor, and sensory problems being the most common.[2] The specific symptoms are determined by the locations of the lesions within the nervous system, and may include loss of sensitivity or changes in sensation such as tingling, pins and needles or numbness, muscle weakness, very pronounced reflexes, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia);problems with speech or swallowing, visual problems (nystagmus, optic neuritis or double vision), feeling tired, acute or chronic pain, and bladder and bowel difficulties, among others.[2] Difficulties thinking and emotional problems such as depression or unstable mood are also common.[2]Uhthoff’s phenomenon, a worsening of symptoms due to exposure to higher than usual temperatures, and Lhermitte’s sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS.[2] The main measure of disability and severity is the expanded disability status scale (EDSS), with other measures such as the multiple sclerosis functional composite being increasingly used in research.[18][19][20]

The condition begins in 85% of cases as a clinically isolated syndrome (CIS) over a number of days with 45% having motor or sensory problems, 20% having optic neuritis, and 10% having symptoms related to brainstem dysfunction, while the remaining 25% have more than one of the previous difficulties.[8] The course of symptoms occurs in two main patterns initially: either as episodes of sudden worsening that last a few days to months (called relapses, exacerbations, bouts, attacks, or flare-ups) followed by improvement (85% of cases) or as a gradual worsening over time without periods of recovery (10-15% of cases).[15] A combination of these two patterns may also occur[5] or people may start in a relapsing and remitting course that then becomes progressive later on.[15] Relapses are usually not predictable, occurring without warning.[2] Exacerbations rarely occur more frequently than twice per year.[2] Some relapses, however, are preceded by common triggers and they occur more frequently during spring and summer.[21] Similarly, viral infections such as the common cold, influenza, or gastroenteritis increase their risk.[2]Stress may also trigger an attack.[22] Women with MS who become pregnant experience fewer relapses; however, during the first months after delivery the risk increases.[2] Overall, pregnancy does not seem to influence long-term disability.[2] Many events have been found not to affect relapse rates including vaccination, breast feeding,[2] physical trauma,[23] and Uhthoff’s phenomenon.[21]

Causes

The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents.[2]Theories try to combine the data into likely explanations, but none has proved definitive. While there are a number of environmental risk factors and although some are partly modifiable, further research is needed to determine whether their elimination can prevent MS.[24]

Geography

MS is more common in people who live farther from the equator, although exceptions exist.[2][25] These exceptions include ethnic groups that are at low risk far from the equator such as the Samis, Amerindians, Canadian Hutterites, New Zealand Māori,[26] and Canada’s Inuit,[15] as well as groups that have a relatively high risk close to the equator such as Sardinians,[15] inland Sicilians,[27]Palestinians and Parsis.[26] The cause of this geographical pattern is not clear.[15] While the north-south gradient of incidence is decreasing,[25] as of 2010 it is still present.[15]

MS is more common in regions with northern European populations[2] and the geographic variation may simply reflect the global distribution of these high-risk populations.[15] Decreased sunlight exposure resulting in decreased vitamin D production has also been put forward as an explanation.[28][29][30] A relationship between season of birth and MS lends support to this idea, with fewer people born in the northern hemisphere in November as compared to May being affected later in life.[31] Environmental factors may play a role during childhood, with several studies finding that people who move to a different region of the world before the age of 15 acquire the new region’s risk to MS. If migration takes place after age 15, however, the person retains the risk of his home country.[2][24] There is some evidence that the effect of moving may still apply to people older than 15.[2]

Genetics

HLA region of Chromosome 6. Changes in this area increase the probability of getting MS.

MS is not considered a hereditary disease; however, a number of genetic variations have been shown to increase the risk.[32] Some of these genes appear to have higher levels of expression in microglial cells than expected by chance.[33] The probability of developing the disease is higher in relatives of an affected person, with a greater risk among those more closely related.[3] In identical twins both are affected about 30% of the time, while around 5% for non-identical twins and 2.5% of siblings are affected with a lower percentage of half-siblings.[2][3][34] If both parents are affected the risk in their children is 10 times that of the general population.[15] MS is also more common in some ethnic groups than others.[35]

Specific genes that have been linked with MS include differences in the human leukocyte antigen (HLA) system—a group of genes on chromosome6 that serves as the major histocompatibility complex (MHC).[2] That changes in the HLA region are related to susceptibility has been known since the 1980s,[36] and additionally this same region has been implicated in the development of other autoimmune diseases such as diabetes type I and systemic lupus erythematosus.[36] The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6.[2] Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11.[2] Overall, it has been estimated that HLA changes account for between 20 and 60% of the genetic predisposition.[36] Modern genetic methods (genome-wide association studies) have discovered at least twelve other genes outside the HLA locus that modestly increase the probability of MS.[36]

Infectious agents

Many microbes have been proposed as triggers of MS, but none have been confirmed.[3] Moving at an early age from one location in the world to another alters a person’s subsequent risk of MS.[7] An explanation for this could be that some kind of infection, produced by a widespread microbe rather than a rare one, is related to the disease.[7]Proposed mechanisms include the hygiene hypothesis and the prevalence hypothesis. The hygiene hypothesis proposes that exposure to certain infectious agents early in life is protective, the disease being a response to a late encounter with such agents.[2] The prevalence hypothesis proposes that the disease is due to an infectious agent more common in regions where MS is common and where in most individuals it causes an ongoing infection without symptoms. Only in a few cases and after many years does it cause demyelination.[7][37] The hygiene hypothesis has received more support than the prevalence hypothesis.[7]

Evidence for a virus as a cause include: the presence of oligoclonal bands in the brain and cerebrospinal fluid of most people with MS, the association of several viruses with human demyelination encephalomyelitis, and the occurrence of demyelination in animals caused by some viral infection.[38]Human herpes viruses are a candidate group of viruses. Individuals having never been infected by the Epstein–Barr virus are at a reduced risk of getting MS, whereas those infected as young adults are at a greater risk than those having had it at a younger age.[2][7] Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing,[7] others believe that there is no contradiction, since it is a first encounter with the causative virus relatively late in life that is the trigger for the disease.[2] Other diseases that may be related include measles, mumps and rubella.[2]

Other

Smoking has been shown to be an independent risk factor for MS.[28]Stress may be a risk factor although the evidence to support this is weak.[24] Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached.[24]Vaccinations were studied as causal factors; however, most studies show no association.[24] Several other possible risk factors, such as diet andhormone intake, have been looked at; however, evidence on their relation with the disease is “sparse and unpersuasive”.[28]Gout occurs less than would be expected and lower levels of uric acid have been found in people with MS. This has led to the theory that uric acid is protective, although its exact importance remains unknown.[39]

Pathophysiology

Multiple sclerosis

The three main characteristics of MS are the formation of lesions in the central nervous system (also called plaques), inflammation, and the destruction of myelin sheaths of neurons. These features interact in a complex and not yet fully understood manner to produce the breakdown of nerve tissue and in turn the signs and symptoms of the disease.[2] Additionally, MS is believed to be an immune-mediated disorder that develops from an interaction of the individual’s genetics and as yet unidentified environmental causes.[3] Damage is believed to be caused, at least in part, by attack on the nervous system by a person’s own immune system.[2]

Lesions

Demyelination in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be appreciated (Original scale 1:100)

The name multiple sclerosis refers to the scars (sclerae – better known as plaques or lesions) that form in the nervous system. These lesions most commonly affect the white matter in the optic nerve, brain stem, basal ganglia, and spinal cord, or white matter tracts close to the lateral ventricles.[2] The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.[3]

To be specific, MS involves the loss of oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electrical signals (action potentials).[2] This results in a thinning or complete loss of myelin and, as the disease advances, the breakdown of the axons of neurons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[3] A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes are unable to completely rebuild the cell’s myelin sheath.[40] Repeated attacks lead to successively less effective remyelinations, until a scar-like plaque is built up around the damaged axons.[40] These scars are the origin of the symptoms and during an attack magnetic resonance imaging (MRI) often shows more than ten new plaques.[2] This could indicate that there are a number of lesions below which the brain is capable of repairing itself without producing noticeable consequences.[2] Another process involved in the creation of lesions is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons.[2] A number of lesion patterns have been described.[41]

Inflammation

Apart from demyelination, the other sign of the disease is inflammation. Fitting with an immunological explanation, the inflammatory process is caused by T cells, a kind oflymphocyte that plays an important role in the body’s defenses.[3] T cells gain entry into the brain via disruptions in the blood–brain barrier. The T cells recognize myelin as foreign and attack it, explaining why these cells are also called “autoreactive lymphocytes”.[2]

The attack of myelin starts inflammatory processes, which triggers other immune cells and the release of soluble factors like cytokines and antibodies. Further breakdown of the blood–brain barrier in turn causes a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.[3] Inflammation can potentially reduce transmission of information between neurons in at least three ways.[2] The soluble factors released might stop neurotransmission by intact neurons. These factors could lead to or enhance the loss of myelin, or they may cause the axon to break down completely.[2]

Blood–brain barrier

The blood–brain barrier is a part of the capillary system that prevents the entry of T cells into the central nervous system. It may become permeable to these types of cells secondary to an infection by a virus or bacteria. After it repairs itself, typically once the infection has cleared, T cells may remain trapped inside the brain.[3]Gadolinium cannot cross a normal BBB and, therefore, Gadolinium-enhanced MRI is used to show BBB breakdowns.[42]

Diagnosis

Animation showing dissemination of brain lesions in time and space as demonstrated by monthly MRI studies along a year

Multiple sclerosis as seen on MRI

Multiple sclerosis is typically diagnosed based on the presenting signs and symptoms, in combination with supporting medical imaging and laboratory testing.[8] It can be difficult to confirm, especially early on, since the signs and symptoms may be similar to those of other medical problems.[2][43] The McDonald criteria, which focus on clinical, laboratory, and radiologic evidence of lesions at different times and in different areas, is the most commonly used method of diagnosis[13] with the Schumacher and Poser criteria being of mostly historical significance.[44] While the above criteria allow for a non-invasive diagnosis, some state that the only definitive proof is an autopsy or biopsy where lesions typical of MS are detected.[2][45][46]

Clinical data alone may be sufficient for a diagnosis of MS if an individual has had separate episodes of neurological symptoms characteristic of the disease.[45] In those who seek medical attention after only one attack, other testing is needed for the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine may show areas of demyelination (lesions or plaques). Gadolinium can be administeredintravenously as a contrast agent to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.[45][47] Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation in the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.[45][48] The nervous system in MS may respond less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined usingvisual– and sensory-evoked potentials.[49]

Clinical course

Progression of MS subtypes

Several phenotypes (commonly named types), or patterns of progression, have been described. Phenotypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for treatment decisions. In 1996, the United States National Multiple Sclerosis Society described four clinical courses.[5] This set of courses was later reviewed by an international panel in 2013, adding clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) as phenotypes, but leaving the main structure untouched.[50]

  1. relapsing-remitting (RRMS)
  2. secondary progressive (SPMS)
  3. primary progressive (PPMS)
  4. progressive relapsing (PRMS). This entity was removed in the 2013 review.[50]

The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits that occur during attacks may either resolve or leave problems, the latter in about 40% of attacks and being more common the longer a person has had the disease.[2][8] This describes the initial course of 80% of individuals with MS.[2] When deficits always resolve between attacks, this is sometimes referred to as benign MS,[51]although people will still build up some degree of disability in the long term.[2] On the other hand, the term malignant multiple sclerosis is used to describe people with MS having reached significant level of disability in a short period.[52] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a person has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis.[2][53] 30 to 70% of persons experiencing CIS later develop MS.[53]

Nerve axon with myelin sheath

Secondary progressive MS occurs in around 65% of those with initial relapsing-remitting MS, who eventually have progressive neurologic decline between acute attacks without any definite periods of remission.[2][5] Occasional relapses and minor remissions may appear.[5] The most common length of time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.[54]

The primary progressive subtype occurs in approximately 10–20% of individuals, with no remission after the initial symptoms.[8][55] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[5] The usual age of onset for the primary progressive subtype is later than of the relapsing-remitting subtype. It is similar to the age that secondary progressive usually begins in relapsing-remitting MS, around 40 years of age.[2]

Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also have clear superimposed attacks. This is the least common of all subtypes.[5]

Unusual types of MS have been described; these include Devic’s disease, Balo concentric sclerosis, Schilder’s diffuse sclerosis, and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases.[56] Multiple sclerosis behaves differently in children, taking more time to reach the progressive stage.[2] Nevertheless, they still reach it at a lower average age than adults usually do.[2]

Management

Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some people, despite the shortage of supporting evidence.

Acute attacks

During symptomatic attacks, administration of high doses of intravenouscorticosteroids, such as methylprednisolone, is the usual therapy,[2] with oral corticosteroids seeming to have a similar efficacy and safety profile.[57] Although, in general, effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[58] The consequences of severe attacks that do not respond to corticosteroids might be treatable by plasmapheresis.[2]

Disease-modifying treatments

Relapsing remitting multiple sclerosis

As of 2016, nine disease-modifying treatments have been approved by regulatory agencies for relapsing-remitting multiple sclerosis (RRMS) including: interferon beta-1a, interferon beta-1b, glatiramer acetate,mitoxantrone, natalizumab, fingolimod,[59]teriflunomide,[60]dimethyl fumarate[61] and alemtuzumab.[62] Their cost effectiveness as of 2012 is unclear.[63] In May 2016 the FDA approved daclizumab for the treatment of relapsing multiple sclerosis in adults, with requirements for postmarketing studies and submission of a formal risk evaluation and mitigation strategy.[64][65]

In RRMS they are modestly effective at decreasing the number of attacks.[59] The interferons and glatiramer acetate are first-line treatments[8] and are roughly equivalent, reducing relapses by approximately 30%.[66]Early-initiated long-term therapy is safe and improves outcomes.[67][68] Natalizumab reduces the relapse rate more than first-line agents; however, due to issues of adverse effects is a second-line agent reserved for those who do not respond to other treatments[8] or with severe disease.[66] Mitoxantrone, whose use is limited by severe adverse effects, is a third-line option for those who do not respond to other medications.[8]Treatment of clinically isolated syndrome (CIS) with interferons decreases the chance of progressing to clinical MS.[2][69] Efficacy of interferons and glatiramer acetate in children has been estimated to be roughly equivalent to that of adults.[70] The role of some newer agents such as fingolimod, teriflunomide, and dimethyl fumarate, as of 2011, is not yet entirely clear.[71]

Progressive multiple sclerosis

No treatment has been shown to change the course of primary progressive MS[8] and as of 2011 only one medication, mitoxantrone, has been approved for secondary progressive MS.[72] In this population tentative evidence supports mitoxantrone moderately slowing the progression of the disease and decreasing rates of relapses over two years.[73][74]

Adverse effects

Irritation zone after injection of glatiramer acetate.

The disease-modifying treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferons (up to 90% with subcutaneous injections and 33% with intramuscular injections).[75] Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known aslipoatrophy, may develop.[75] Interferons may produce flu-like symptoms;[76] some people taking glatiramer experience a post-injection reaction with flushing, chest tightness, heart palpitations, and anxiety, which usually lasts less than thirty minutes.[77] More dangerous but much less common are liver damage from interferons,[78]systolic dysfunction(12%), infertility, and acute myeloid leukemia (0.8%) from mitoxantrone,[73][79] and progressive multifocal leukoencephalopathy occurring with natalizumab (occurring in 1 in 600 people treated).[8][80]

Fingolimod may give rise to hypertension and slowed heart rate, macular edema, elevated liver enzymes or a reduction in lymphocyte levels.[71] Tentative evidence supports the short-term safety of teriflunomide, with common side effects including: headaches, fatigue, nausea, hair loss, and limb pain.[59] There have also been reports of liver failure and PML with its use and it is dangerous for fetal development.[71] Most common side effects of dimethyl fumarate are flushing and gastrointestinal problems.[61][71] While dimethyl fumarate may lead to a reduction in the white blood cell count there were no reported cases of opportunistic infections during trials.[81][82]

Associated symptoms

Both medications and neurorehabilitation have been shown to improve some symptoms, though neither changes the course of the disease.[83] Some symptoms have a good response to medication, such as an unstable bladder and spasticity, while others are little changed.[2] For neurologic problems, a multidisciplinary approach is important for improving quality of life; however, it is difficult to specify a ‘core team’ as many health services may be needed at different points in time.[2] Multidisciplinary rehabilitation programs increase activity and participation of people with MS but do not influence impairment level.[84] There is limited evidence for the overall efficacy of individual therapeutic disciplines,[85][86] though there is good evidence that specific approaches, such as exercise,[87][88] and psychology therapies, in particular cognitive behavioral approaches are effective.[89]

Alternative treatments

Over 50% of people with MS may use complementary and alternative medicine, although percentages vary depending on how alternative medicine is defined.[9] The evidence for the effectiveness for such treatments in most cases is weak or absent.[9][90] Treatments of unproven benefit used by people with MS include dietary supplementation and regimens,[9][91][92] vitamin D,[93]relaxation techniques such as yoga,[9]herbal medicine (including medical cannabis),[9][94]hyperbaric oxygen therapy,[95]self-infection with hookworms, reflexology, and acupuncture.[9][96] Regarding the characteristics of users, they are more frequently women, have had MS for a longer time, tend to be more disabled and have lower levels of satisfaction with conventional healthcare.[9]

Prognosis

Disability-adjusted life year for multiple sclerosis per 100,000 inhabitants in 2004

  no data
  <13
  13–16
  16–19
  19–22
  22–25
  25–28
  28–31
  31–34
  34–37
  37–40
  40–43
  >43

The expected future course of the disease depends on the subtype of the disease; the individual’s sex, age, and initial symptoms; and the degree of disability the person has.[10] Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.[10][97]

The average life expectancy is 30 years from the start of the disease, which is 5 to 10 years less than that of unaffected people.[2] Almost 40% of people with MS reach the seventh decade of life.[97] Nevertheless, two-thirds of the deaths are directly related to the consequences of the disease.[2]Suicide is more common, while infections and other complications are especially dangerous for the more disabled.[2] Although most people lose the ability to walk before death, 90% are capable of independent walking at 10 years from onset, and 75% at 15 years.[98][needs update?]

Epidemiology

Deaths from multiple sclerosis per million persons in 2012

  0-0
  1-1
  2-2
  3-5
  6-12
  13-25

MS is the most common autoimmune disorder of the central nervous system.[11] As of 2010, the number of people with MS was 2–2.5 million (approximately 30 per 100,000) globally, with rates varying widely in different regions.[13][15] It is estimated to have resulted in 18,000 deaths that year.[99] In Africa rates are less than 0.5 per 100,000, while they are 2.8 per 100,000 in South East Asia, 8.3 per 100,000 in the Americas, and 80 per 100,000 in Europe.[13] Rates surpass 200 per 100,000 in certain populations of Northern European descent.[15] The number of new cases that develop per year is about 2.5 per 100,000.[13]

Rates of MS appear to be increasing; this, however, may be explained simply by better diagnosis.[15] Studies on populational and geographical patterns have been common[37] and have led to a number of theories about the cause.[7][24][28]

MS usually appears in adults in their late twenties or early thirties but it can rarely start in childhood and after 50 years of age.[13][15] The primary progressive subtype is more common in people in their fifties.[55] Similar to many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[2][25] As of 2008, globally it is about two times more common in women than in men.[13] In children, it is even more common in females than males,[2] while in people over fifty, it affects males and females almost equally.[55]

History

Medical discovery

Detail of Carswell’s drawing of MS lesions in the brain stem and spinal cord (1838)

Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease.[100] Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”.[2] Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.[101][102]

The French neurologistJean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.[100] Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques.

Diagnosis

The first attempt to establish a set of diagnostic criteria was also due to Charcot in 1868. He published what now is known as the “Charcot Triad”, consisting in nystagmus,intention tremor, and telegraphic speech (scanning speech)[103] Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”.[16]

Diagnosis was based in Charcot triad and clinical observation until Schumacher made the first attempt to standardize criteria in 1965 by introducing some fundamental requirements: Dissemination of the lesions in time (DIT) and space (DIS), and that “signs and symptoms cannot be explained better by another disease process”.[103] Both requirements were later inherited by Poser criteria and McDonald criteria, whose 2010 version is currently in use.

During the 20th century theories about the cause and pathogenesis were developed and effective treatments began to appear in the 1990s.[2]

Historical cases

Photographic study of locomotion of a MS female patient with walking difficulties created in 1887 byMuybridge

There are several historical accounts of people who probably had MS and lived before or shortly after the disease was described by Charcot.

A young woman called Halldora who lived in Iceland around 1200 suddenly lost her vision and mobility but, after praying to the saints, recovered them seven days after. Saint Lidwina of Schiedam (1380–1433), a Dutchnun, may be one of the first clearly identifiable people with MS. From the age of 16 until her death at 53, she had intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS.[104] Both cases have led to the proposal of a “Viking gene” hypothesis for the dissemination of the disease.[105]

Augustus Frederick d’Este (1794–1848), son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly had MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.[106][107] Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle.[107] His diary was published in 1919 as The Journal of a Disappointed Man.[108]

Research

For the journal formerly known as Multiple Sclerosis, see Multiple Sclerosis Journal.

Medications

Chemical structure of alemtuzumab

There is ongoing research looking for more effective, convenient, and tolerable treatments for relapsing-remitting MS; creation of therapies for the progressive subtypes;neuroprotection strategies; and effective symptomatic treatments.[17]

During the 2000s and 2010s, there has been approval of several oral drugs that are expected to gain in popularity and frequency of use.[109] Several more oral drugs are under investigation, including ozanimod and laquinimod. Laquinimod was announced in August 2012 and is in a third phase III trial after mixed results in the previous ones.[110]Similarly, studies aimed to improve the efficacy and ease of use of already existing therapies are occurring. This includes the use of new preparations such as the PEGylatedversion of interferon-β-1a, which it is hoped may be given at less frequent doses with similar effects.[111][112] Request for approval of peginterferon beta-1a is expected during 2013.[112]

Monoclonal antibodies have also raised high levels of interest. Alemtuzumab, daclizumab, and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumabhave all shown some benefit and are under study as potential treatments.[82] Their use has also been accompanied by the appearance of potentially dangerous adverse effects, the most important of which being opportunistic infections.[109] Related to these investigations is the development of a test for JC virus antibodies, which might help to determine who is at greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.[109] While monoclonal antibodies will probably have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated with them.[109]

Another research strategy is to evaluate the combined effectiveness of two or more drugs.[113] The main rationale for using a number of medications in MS is that the involved treatments target different mechanisms and, therefore, their use is not necessarily exclusive.[113]Synergies, in which one drug improves the effect of another are also possible, but there can also be drawbacks such as the blocking of the action of the other or worsened side-effects.[113] There have been several trials of combined therapy, yet none have shown positive enough results to be considered as a useful treatment for MS.[113]

Research on neuroprotection and regenerative treatments, such as stem cell therapy, while of high importance, are in the early stages.[114] Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS.[109]

Disease biomarkers

MRI brain scan produced using aGradient-echo phase sequenceshowing an iron deposit in a white matter lesion (inside green box in the middle of the image; enhanced and marked by red arrow top-left corner)[115]

While diagnostic criteria are not expected to change in the near future, work to develop biomarkers that help with diagnosis and prediction of disease progression is ongoing.[109] New diagnostic methods that are being investigated include work with anti-myelin antibodies, and studies with serum and cerebrospinal fluid, but none of them has yielded reliably positive results.[116]

At the current time, there are no laboratory investigations that can predict prognosis. Several promising approaches have been proposed including: interleukin-6, nitric oxideand nitric oxide synthase, osteopontin, and fetuin-A.[116] Since disease progression is the result of degeneration of neurons, the roles of proteins showing loss of nerve tissue such as neurofilaments, tau, and N-acetylaspartate are under investigation.[116] Other effects include looking for biomarkers that distinguish between those who will and will not respond to medications.[116]

Improvement in neuroimaging techniques such as positron emission tomography (PET) or magnetic resonance imaging (MRI) carry a promise for better diagnosis and prognosis predictions, although the effect of such improvements in daily medical practice may take several decades.[109] Regarding MRI, there are several techniques that have already shown some usefulness in research settings and could be introduced into clinical practice, such as double-inversion recovery sequences, magnetization transfer, diffusion tensor, and functional magnetic resonance imaging.[117] These techniques are more specific for the disease than existing ones, but still lack some standardization of acquisition protocols and the creation of normative values.[117] There are other techniques under development that include contrast agents capable of measuring levels of peripheralmacrophages, inflammation, or neuronal dysfunction,[117] and techniques that measure iron deposition that could serve to determine the role of this feature in MS, or that of cerebral perfusion.[117] Similarly, new PET radiotracers might serve as markers of altered processes such as brain inflammation, cortical pathology, apoptosis, or remylienation.[118] Antibiodies against the Kir4.1 potassium channel may be related to MS.[119]

Chronic cerebrospinal venous insufficiency

In 2008, vascular surgeon Paolo Zamboni suggested that MS involves narrowing of the veins draining the brain, which he referred to as chronic cerebrospinal venous insufficiency (CCSVI). He found CCSVI in all patients with MS in his study, performed a surgical procedure, later called in the media the “liberation procedure” to correct it, and claimed that 73% of participants improved.[120] This theory received significant attention in the media and among those with MS, especially in Canada.[121] Concerns have been raised with Zamboni’s research as it was neither blinded nor controlled, and its assumptions about the underlying cause of the disease are not backed by known data.[122] Also, further studies have either not found a similar relationship or found one that is much less strong,[123] raising serious objections to the hypothesis.[124] The “liberation procedure” has been criticized for resulting in serious complications and deaths with unproven benefits.[122] It is, thus, as of 2013 not recommended for the treatment of MS.[125] Additional research investigating the CCSVI hypothesis are under way.[126]

See also

https://en.wikipedia.org/wiki/Multiple_sclerosis

Amyotrophic lateral sclerosis

From Wikipedia, the free encyclopedia
  (Redirected from Lou Gehrig Disease)
“ALS” redirects here. For other uses, see ALS (disambiguation).
“Motor neurone disease” redirects here. For the broader group of diseases, see Motor neuron disease.
Amyotrophic lateral sclerosis
Lou Gehrig’s disease, Charcot disease
ALS Coronal.jpg

An MRI with increased signal in the posterior part of the internal capsule which can be tracked to themotor cortex consistent with the diagnosis of ALS.
Classification and external resources
Specialty Neurology
ICD10 G12.2
ICD9-CM 335.20
OMIM 105400
DiseasesDB 29148
MedlinePlus 000688
eMedicine neuro/14emerg/24pmr/10
Patient UK Amyotrophic lateral sclerosis
MeSH D000690
GeneReviews
Orphanet 803

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease and motor neurone disease (MND), is a specific disorder that involves the death of neurons that control voluntary muscles.[1][2][3][4] Some also use motor neuron disease for a group of five conditions of which ALS is the most common.[5] ALS is characterized by stiff muscles, muscle twitching, and gradually worsening weakness due to muscles decreasing in size.[6] This results in difficulty in speaking,swallowing, and eventually breathing.[3][6]

The cause is not known in 90% to 95% of cases.[1] About 5–10% of cases are inherited from a person’s parents.[7] About half of these genetic cases are due to one of two specific genes. The diagnosis is based on a person’s signs and symptoms with testing done to rule out other potential causes.[1]

No cure for ALS is known.[1] A medication called riluzole may extend life by about two to three months.[8]Non-invasive ventilation may result in both improved quality and length of life.[9] The disease usually starts around the age of 60 and in inherited cases around the age of 50.[7] The average survival from onset to death is three to four years.[10] About 10% survive longer than 10 years.[1] Most die from respiratory failure. In much of the world, rates of ALS are unknown.[7] In Europe and the United States the disease affects about two people per 100,000 per year.[7][11]

Descriptions of the disease date back to at least 1824 by Charles Bell.[12] In 1869, the connection between the symptoms and the underlying neurological problems was first described by Jean-Martin Charcot, who in 1874 began using the term amyotrophic lateral sclerosis.[12] It became well known in the United States in the 20th century when in 1939 it affected the baseball player Lou Gehrig,[2] and later worldwide when physicist Stephen Hawking, diagnosed in 1963 and expected to die within two years, became famous.[13] In 2014 videos of the ice bucket challenge went viral on the Internet and increased public awareness.[14]

Signs and symptoms

The disorder causes muscle weakness and atrophy throughout the body due to the degeneration of the upper and lower motor neurons. Individuals affected by the disorder may ultimately lose the ability to initiate and control all voluntary movement, although bladder and bowel function and the muscles responsible for eye movement are usually spared until the final stages of the disorder.[15]

Cognitive function is generally spared for most people, although some (about 5%) also develop frontotemporal dementia.[16] A higher proportion of people (30–50%) also have more subtle cognitive changes which may go unnoticed, but are revealed by detailed neuropsychological testing. Sometimes, ALS coexists in individuals who also experience dementia, degenerative muscle disorder, and degenerative bone disorder as part of a syndrome called multisystem proteinopathy.[17]Sensory nerves and the autonomic nervous system are generally unaffected, meaning the majority of people with ALS maintain hearing, sight, touch, smell, andtaste.[18]

Initial symptoms

The start of ALS may be so subtle that the symptoms are overlooked.[19] The earliest symptoms of ALS are muscle weakness and/or muscle atrophy. Other presenting symptoms include trouble swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech. The parts of the body affected by early symptoms of ALS depend on which motor neurons in the body are damaged first.[citation needed]

About 75% of people contracting the disorder first experience weakness or atrophy in an arm or leg and this is known as “limb-onset” ALS. Awkwardness when walking or running or even tripping over or stumbling may be experienced and often this is marked by walking with a “dropped foot” which drags gently on the ground. Or if arm-onset, difficulty with tasks requiring manual dexterity such as buttoning a shirt, writing, or turning a key in a lock may be experienced. Occasionally, the symptoms remain confined to one limb for a long period of time or for the duration of the illness; this is known as monomelic amyotrophy.[citation needed]

About 25% of cases begin as progressive bulbar palsy termed “bulbar-onset” ALS. Initial symptoms will mainly be of difficulty speaking clearly or swallowing. Speech may become slurred, nasal in character, or quieter. There may be difficulty in swallowing and loss of tongue mobility. A smaller proportion of people experience “respiratory-onset” ALS, where the intercostal muscles that support breathing are affected first. A small proportion of people may also present with what appears to be frontotemporal dementia, but later progresses to include more typical ALS symptoms.[citation needed]

Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski’s sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations) although twitching is not a diagnostic symptom and more of a side effect so twitching would either occur after or accompany weakness and atrophy. Around 15–45% of people experience pseudobulbar affect, a neurological disorder also known as “emotional lability”, which consists of uncontrollable laughter, crying, or smiling, attributable to degeneration of bulbar upper motor neurons, resulting in exaggeration of motor expressions of emotion.[citation needed] For ALS to be diagnosed, symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes must be present.[citation needed]

Progression

Although the order and rate of symptoms varies from person to person, most people eventually are not able to walk or use their hands and arms. They also lose the ability to speak and swallow food, while most end up on a portable ventilator, called bilevel positive airway pressure. The rate of progression can be measured using an outcome measure called the “ALS Functional Rating Scale Revised (ALSFRS-R)”, a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability). Though the degree of variability is high and a small percentage of people have a much slower disorder, on average, patients lose about 0.9 FRS points per month. A survey-based study amongst clinicians showed that they rated a 20% change in the slope of the ALSFRS-R as being clinically meaningful.[20] Regardless of the part of the body first affected by the disorder, muscle weakness and atrophy spread to other parts of the body as the disorder progresses. In limb-onset ALS, symptoms usually spread from the affected limb to the opposite limb before affecting a new body region, whereas in bulbar-onset ALS, symptoms typically spread to the arms before the legs.[citation needed]

Disorder progression tends to be slower in patients who are younger than 40 at onset,[21][22] are mildly obese,[23] have disorder restricted primarily to one limb, and those with primarily upper motor neuron symptoms.[24] Conversely, progression is faster and prognosis poorer in people with bulbar-onset disorder, respiratory-onset disorder, and frontotemporal dementia.[24]

The CX3CR1allelic variants have also been shown to have an effect on the disorder’s progression and life expectancy.[25]

Late stages

Although respiratory support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Most people with ALS die within three to five years from the onset of symptoms. In one study, the median survival time from onset to death was around 39 months, and only 4% survived longer than 10 years.[26] Newer data point to around 10% of people surviving beyond 10 years.[1] Guitarist Jason Becker has lived since 1989 with the disorder, while physicist Stephen Hawking has survived for more than 50 years, but they are considered unusual cases.[27]

Difficulty in chewing and swallowing makes eating very difficult and increases the risk of choking or of aspirating food into the lungs. In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken, measures of lung functionsuch as vital capacity and inspiratory pressure diminish. In respiratory-onset ALS, this may occur before significant limb weakness is apparent. Most people with ALS die of respiratory failure or pneumonia.[7]

In late stages, the oculomotor nerve that controls the movements of the eye can be affected as can the extraocular muscles (EOMs). The eye movements remain unaffected largely until the later stages due to differences in the extraocular muscles compared to the skeletal muscles that are initially and readily affected. In the disease’s final stages, a person’s condition may resemble locked-in syndrome.[28]

Causes

Genetics

About 5–10% of cases are directly inherited from a person’s parents.[7] Overall, first-degree relatives of an individual with ALS have a 1% risk of developing ALS.[29][30]

A defect on chromosome 21, which codes for superoxide dismutase, is associated with about 20% of familial cases of ALS, or about 2% of ALS cases overall.[31][32][33] This mutation is believed to be transmitted in anautosomal dominant manner, and has over a hundred different forms of mutation. The most common ALS-causing mutation is a mutant SOD1 gene, seen in North America; this is characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A-SOD1, is more slowly progressive than typical ALS, and people with this form of the disorder survive for an average of 11 years.[34]

In 2011, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9orf72, which is associated with ALS combined with frontotemporal dementia ALS-FTD,[35] and accounts for some 6% of cases of ALS among white Europeans.[36]

The UBQLN2 gene encodes production of the protein ubiquilin 2 in the cell, which is a member of the ubiquilin family and controls the degradation of ubiquitinated proteins. Mutations in UBQLN2 interfere with protein degradation, leading to neurodegeneration and causing dominantly inherited, chromosome X-linked ALS and ALS/dementia.[37]

To date, a number of genetic mutations have been associated with various types of ALS. The currently known associations are:

Type OMIM Gene Locus Inheritance Remarks
ALS1 105400 SOD1 21q22.1 autosomal dominant (?),autosomal recessive (?) The most common form of familial ALS
ALS2 205100 ALS2 2q33.1 autosomal recessive (?) Juvenile-onset
ALS3 606640 (?) 18q21 (?)
ALS4 602433 SETX 9q34.13 autosomal dominant (?)
ALS5 602099 SPG11 15q21.1 autosomal recessive (?) Juvenile onset
ALS6 608030 FUS 16p11.2 (?)
ALS7 608031 (?) 20p13 (?)
ALS8 608627 VAPB 20q13.3 autosomal dominant (?)
ALS9 611895 ANG 14q11.2 (?)
ALS10 612069 TARDBP 1p36.2 autosomal dominant (?) ALS with or without frontotemporal dementia
ALS11 612577 FIG4 6q21 (?)
ALS12 613435 OPTN 10p13 (?)
ALS13 183090 ATXN2 12q24.12 autosomal dominant (?) Spinocerebellar ataxia 2
ALS14 613954 VCP 9p13.3 (?) Recent new study shows strong link in ALS mechanism[38][39]
ALS15 300857 UBQLN2 Xp11.21 X-linked dominant (?) Described in one family[37]
ALS16 614373 SIGMAR1 9p13.3 autosomal recessive (?) Juvenile onset, very rare, described only in one family[40]
ALS17 614696 CHMP2B 3p11.2 autosomal dominant (?) Very rare, reported only in a handful of people
ALS18 614808 PFN1 17p13.2 (?) Very rare, described only in a handful of Chinese families[41]
ALS19 615515 ERBB4 2q34 autosomal dominant (?) Very rare, as of late 2013 described only in four people[42]
ALS20 615426 HNRNPA1 12q13.13 (?) Very rare, as of late 2013 described only in two people[43]
ALS21 606070 MATR3 5q31.2 autosomal dominant (?) Very rare. Formerly known as “distal myopathy type 2” (MPD2) and “vocal cord and pharyngeal dysfunction with distal myopathy” (VCPDM)
ALS22 616208 TUBA4A 2q35 autosomal dominant (?) “Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia”
FTDALS1 105550 C9orf72 9p21.2 autosomal dominant (?) “Frontotemporal dementia and/or amyotrophic lateral sclerosis type 1”. Accounts for around 6% of ALS cases among white Europeans[citation needed]
FTDALS2 615911 CHCHD10 22q11.23 autosomal dominant (?) “Frontotemporal dementia and/or amyotrophic lateral sclerosis type 2”
FTDALS3 616437 SQSTM1 5q35.3 autosomal dominant (?) “Frontotemporal dementia and/or amyotrophic lateral sclerosis type 3”
FTDALS4 616439 TBK1 12q14.2 autosomal dominant (?) “Frontotemporal dementia and/or amyotrophic lateral sclerosis type 4”

SOD1

In 1993, scientists discovered that mutations in the gene (SOD1) that produces the CuZnsuperoxide dismutase (SOD1) enzyme were associated with around 20% of familial ALS. This enzyme is a powerfulantioxidant that protects the body from damage caused by superoxide, a toxic free radical generated in the mitochondria. Free radicals are highly reactive molecules produced by cells during normal metabolism. Free radicals can accumulate and cause damage to DNA and proteins within cells. To date, over 110 different mutations in SOD1 have been linked with the disorder, some of which (such as H46R) have a very long clinical course, while others, such as A4V, are exceptionally aggressive. When the defenses against oxidative stress fail, programmed cell death (apoptosis) is upregulated.

A defect in SOD1 could be a loss or gain of function. A loss of SOD1 function could lead to an accumulation of free radicals. A gain of SOD1 function could be toxic in other ways.[44][45]

Aggregate accumulation of mutant SOD1 is suspected to play a role in disrupting cellular functions by damaging mitochondria, proteasomes, protein folding chaperones, or other proteins.[46] Any such disruption, if proven, would lend significant credibility to the theory that aggregates are involved in mutant SOD1 toxicity. Critics have noted that in humans, SOD1 mutations cause only 2% or so of overall cases and the etiological mechanisms may be distinct from those responsible for the sporadic form of the disease. To date, the ALS-SOD1 mice remain the best model of the disease for preclinical studies, but it is hoped that more useful models will be developed.

Head injury

While moderate to severe traumatic brain injury is a risk for ALS, it is unclear if mild traumatic brain injury increases rates.[47][48]

In 1994 the National Institute for Occupational Safety and Health (NIOSH) reported a nonsignificant increase in nervous system disorders due to four cases of ALS among NFL football players. It was unclear if this was due to chance or not.[49] Another study from 2012 also found a possible increase in ALS in NFL football players.[50] An older study did not find an increased risk among high school football players.[47] A 2007 review found an increased risk among soccer players.[48] ALS may also occur more often among the US military veterans however the reason is unknown.[51] This may be due to head injury.[52]

Other factors

Where no family history of the disease is present – i.e., in around 90% of cases – no cause is known for ALS. Possible associations for which evidence is inconclusive include military service, frequent drug use, and participation in contact sports.[medical citation needed]

Studies also have focused on the role of glutamate in motor neuron degeneration. Glutamate is one of the neurotransmitters in the brain. Scientists have found, compared with healthy people, people with ALS have higher levels of glutamate in their serum and spinal fluid.[32]Riluzole is currently the only FDA-approved drug for ALS and targets glutamate transporters. It only has a modest effect on survival, however, suggesting that excess glutamate is not the sole cause of the disease.

Certain studies suggested a link between sporadic ALS, specifically in athletes, and a diet enriched with branched-chain amino acids, a common dietary supplement among athletes, which cause cell hyperexcitability resembling that usually observed in people with ALS. The proposed underlying mechanism is that cell hyperexcitability results in increased calcium absorption by the cell, and thus brings about cell death of neuronal cells, which have particularly low calcium buffering capabilities.[53]

Some evidence supports superoxide dismutase 1 (SOD1) protein misfolding propagates between molecules in a similar fashion to prions.[54] Similarly, it has been proposed that incorporation of the cyanobacterial toxin β-methylamino-l-alanine (BMAA) leads to another prion-like protein misfolding propagation.[55][56]

Another very common factor associated with ALS is a lesion to the motor system in areas such as the frontotemporal lobes.[57] Lesions in these areas often show signs of early deficit, which can be used to predict the loss of motor function, and result in the spread of ALS.[57] The mechanisms of ALS are present long before any signs or symptoms become apparent.[58] Before any muscular atrophy becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.[58]

Other potential risk factors including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated, but are without consistent findings.[59][60] There is a tentative association with exposure to a number of pesticides including the organochlorine insecticidesaldrin, dieldrin, DDT, and toxaphene.[61][62][63]

Pathophysiology

The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-richinclusions in their cell bodies and axons. This may be partly due to defects in protein degradation.[37] These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1,TAR DNA binding protein (TDP-43, or TARDBP), and/or FUS.[64]

Diagnosis

MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the diagnosis of ALS.

No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive.[1] Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the person and a series of tests to rule out other diseases.[1] Physicians obtain the person’s fullmedical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are worsening.[1]

Differential diagnosis

Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions.[1] One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles.[1] Certain EMG findings can support the diagnosis of ALS.[1] Another common test measures nerve conduction velocity (NCV).[1] Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. While a magnetic resonance imaging (MRI) is often normal in people with early stage ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, aherniated disk in the neck, syringomyelia, or cervical spondylosis.[1]

Based on the person’s symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases, as well as routine laboratory tests.[1] In some cases, for example, if a physician suspects the person may have a myopathy rather than ALS, a muscle biopsy may be performed.[1]

Viralinfectious diseases such as human immunodeficiency virus (HIV), human T-cell leukaemia virus (HTLV), Lyme disease,[65]syphilis[66] and tick-borne encephalitis[67] can in some cases cause ALS-like symptoms.[1]Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered.[1]

ALS must be differentiated from the “ALS mimic syndromes” which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants.[68] Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, people should always obtain a specialist neurological opinion, so alternative diagnoses are clinically ruled out. Benign fasciculation syndrome is another condition that mimics many of the symptoms of ALS, but is accompanied by normal EMG readings and no major disablement.[citation needed]

However, most cases of ALS are readily diagnosed and the error rate of diagnosis in large ALS clinics is less than 10%.[69][70] In one study, 190 patients who met the MND/ALS diagnostic criteria, complemented with laboratory research in compliance with both research protocols and regular monitoring. Thirty of these patients (16%) had their diagnosis completely changed during the clinical observation development period.[71] In the same study, three patients had a false negative diagnosis, myasthenia gravis (MG), an autoimmune disease. MG can mimic ALS and other neurological disorders leading to a delay in diagnosis and treatment. MG is eminently treatable; ALS is not.[72] Myasthenic syndrome, also known as Lambert-Eaton syndrome, can mimic ALS and its initial presentation can be similar to that of MG.[73][74]

Management

Management of ALS attempts to relieve symptoms and extend life expectancy. This supportive care is best provided by multidisciplinary teams of health care professionals working with the person and their caregivers to keep them as mobile and comfortable as possible.[citation needed]

Medications

Riluzole (Rilutek) has been found to modestly improve survival.[75] It lengthens survival by several months, and may have a greater survival benefit for those with a bulbar onset. It also extends the time before a person needs ventilation support. People taking it must be monitored for liver damage (occurring in about 10% of people taking the drug).[76] It is approved by Food and Drug Administration (US) and recommended by the National Institute for Clinical Excellence (UK). Riluzole does not reverse damage already done to motor neurons.[77]

Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. Drugs also are available to help patients with pain, depression, sleep disturbances, dysphagia, and constipation. Baclofen and diazepam are often prescribed to control the spasticity caused by ALS, and trihexyphenidyl or amitriptyline may be prescribed when people with ALS begin having trouble swallowing their saliva.[15]

Breathing support

When the muscles that assist in breathing weaken, use of ventilatory assistance (intermittent positive pressure ventilation, bilevel positive airway pressure (BiPAP), or biphasic cuirass ventilation (BCV) may be used to aid breathing. Such devices artificially inflate the person’s lungs from various external sources that are applied directly to the face or body. When muscles are no longer able to maintain oxygen and carbon dioxide levels, these devices may be used full-time. BCV has the added advantage of being able to assist in clearing secretions by using high-frequency oscillations followed by several positive expiratory breaths.[78] People may eventually consider forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. To be effective, this may require a tube that passes from the nose or mouth to the windpipe (trachea) and for long-term use, an operation such as a tracheotomy, in which a plastic breathing tube is inserted directly in the person’s windpipe through an opening in the neck.[citation needed]

Persons and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the person’s quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support and have deep discussions on quality of life. Some persons under long-term tracheotomy intermittent positive pressure ventilation with deflated cuffs or cuffless tracheotomy tubes (leak ventilation) are able to speak, provided their bulbar muscles are strong enough, though in all cases speech will be lost as the disease progresses. This technique preserves speech in some persons with long-term mechanical ventilation. Other persons may be able to use a speaking valve such as a Passey-Muir speaking valve with the assistance and guidance of a speech-language pathologist.[citation needed]

External ventilation machines that use the ventilation mode of BiPAP are frequently used to support breathing, initially at night, and later during the daytime, as well. The use of BPAP (more often referred to as noninvasive ventilation, NIV) is only a temporary remedy, however, and long before BPAP stops being effective, persons should decide whether to have a tracheotomy and long-term mechanical ventilation. At this point, some persons choose palliative hospice care.[citation needed]

Therapy

A man with ALS communicates with his wife by pointing to letters and words with a head mounted laser pointer.

Using low tech to communicate. A man with ALS communicates by pointing to letters and words using an head mounted laser pointer.

Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical and occupational therapists can set goals and promote benefits for individuals with ALS by delaying loss of strength, maintaining endurance, limiting pain, preventing complications, and promoting functional independence.[79]

Occupational therapy and special equipment such as assistive technology can also enhance patients’ independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as performing activities of daily living, walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range of motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical and occupational therapists can recommend exercises that provide these benefits without overworking muscles. They can suggest devices such as ramps, braces, walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help patients remain mobile. Occupational therapists can provide or recommend equipment and adaptations to enable people to retain as much safety and independence in activities of daily living as possible.[citation needed]

People with ALS who have difficulty speaking may benefit from working with a speech-language pathologist. These health professionals can teach patients adaptive strategies such as techniques to help them speak louder and more clearly. As ALS progresses, speech-language pathologists can recommend the use of augmentative and alternative communication such as voice amplifiers, speech-generating devices (or voice output communication devices) and/or low tech communication techniques such as head mounted laser pointers, alphabet boards or yes/no signals.[citation needed]

Nutrition

Patients and caregivers can learn from dieticians how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber and fluid, and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. Occupational therapists can assist with recommendations for adaptive equipment to ease the physical task of self-feeding. Speech-language pathologists make food choice recommendations that are more conducive to their unique deficits and abilities. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube is not painful and does not prevent patients from eating food orally if they wish.[citation needed]

Researchers have stated, “ALS patients have a chronically deficient intake of energy and recommended augmentation of energy intake”[80] and have a severe loss of appetite.[81] Both animal[82] and human research[80][unreliable medical source?][83][unreliable medical source?] suggest that ALS patients should be encouraged to consume as many calories as possible and not to restrict their caloric intake. As of 2012, “a lack of robust evidence for interventions” remained for the management of weight loss.[84]

End of life care

Social workers and home care and hospice nurses help people with ALS, their families, and caregivers with the medical, emotional, and financial challenges of coping, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Home nurses are available not only to provide medical care, but also to teach caregivers about tasks such as maintaining respirators, giving feedings, and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.[citation needed]

Epidemiology

In much of the world, rates of ALS are unknown.[7] In Europe, the disease affects about 2.2 people per 100,000 per year.[7] In the United States, more than 5,600 are diagnosed every year, and up to 30,000 Americans are currently affected. ALS is responsible for two deaths per 100,000 people per year.[85]

ALS is classified as a rare disease, designated by the FDA as an “orphan” disease (affecting fewer than 200,000 people in the United States), but is the most common motor neuron disease. People of all races and ethnic backgrounds are affected. One or two of 100,000 people develop ALS each year.[86] Amyotrophic lateral sclerosis affects around 30,000 Americans.[87] ALS cases are estimated at 1.2–4.0 per 100,000 individuals in Caucasian populations with a lower rate in other ethnic populations.[88]Filipinos are second to Caucasians in terms of ALS prevalence with 1.1-2.8 per 100,000 individuals.[87]

Reports have been made of several “clusters” including three American football players from the San Francisco 49ers, more than 50 association football players in Italy,[89] three association football-playing friends in the south of England,[90] and conjugal (husband and wife) cases in the south of France.[91][92][93][94][95] Although many authors consider ALS to be caused by a combination of genetic and environmental risk factors, so far the latter have not been firmly identified, other than a higher risk with increasing age.

History

Descriptions of the disease date back to at least 1824 by Charles Bell.[12]

English scientist Augustus Waller described the appearance of shriveled nerve fibers in 1850. In 1869, the connection between the symptoms and the underlying neurological problems were first described by Jean-Martin Charcot, who introduced the term amyotrophic lateral sclerosis in his 1874 paper.[12] In 1881, the article was translated into English and published in a three-volume edition of Lectures on the Diseases of the Nervous System.

ALS became a cause célèbre in the United States in 1939 when baseball legend Lou Gehrig‘s career, and two years later, his life, were ended by the disease.[96]

In the 1950s, an epidemic occurred among the Chamorro people on Guam which bore similarities to many conditions, including ALS.[97]

By 1991, researchers had linked chromosome 21 to familial ALS (FALS). In 1993, the SOD1 gene on chromosome 21 was found to play a role in some cases of FALS. In 1996, riluzole became the first FDA-approved drug for ALS.[citation needed]

In 1998, the El Escorial criteria were developed as the standard for classifying ALS patient in clinical research. The next year, the revised ALS Functional Rating Scale was published and soon becomes a gold standard for rating the declines in ALS patient in clinical research. Noncoding repeat expansions in C9ORF72 were found to be a major cause of ALS and frontotemporal dementia in 2011.[citation needed]

Name

Amyotrophic comes from the Greek word amyotrophia: a- means “no”, myo refers to “muscle”, and trophia means “nourishment”; amyotrophia therefore means “no muscle nourishment,” which describes the characteristic atrophy of the sufferer’s disused muscle tissue. Lateral identifies the areas in a person’s spinal cord where affected portions of the nerve cells are located. Degeneration in this area leads to scarring or hardening (“sclerosis“).

In the United Kingdom, India,[98] Australia[99] and some other Commonwealth countries the term motor neurone disease (MND) is commonly used.[4]

Society and culture

In August 2014, a challenge went viral online which was commonly known as the “ALS Ice Bucket Challenge“.[100] Contestants fill a bucket full of ice and water, then state who nominated them to do the challenge, and nominate three other individuals of their choice to take part in it. The contestants then dump the buckets of ice and water onto themselves. However, it can be done in a different order. The contestants then donate at least US $10 (or a similar amount in their local currency) to ALS research at the ALS Association, or Motor Neurone Disease Association in the UK. Any contestants who refuse to have the ice and water dumped on them are expected to donate at least US$100 to ALS research. As of July 2015, the Ice Bucket Challenge had raised $115 million for the ALS Association.[101] Many celebrities have taken part in the challenge.[102] The Ice Bucket Challenge was credited with helping to raise funds that contributed to the discovery that the gene NEK1 may potentially contribute to the development for ALS.[103][104]

ALS is the central topic of the 2014 movie You’re Not You, directed by George C. Wolfe, with Hilary Swank, Emmy Rossum and Josh Duhamel playing the main characters.[105]

American football

After this 2012 report was released, some NFL players involved in the legal settlement with the NFL complained that the NFL, which initially agreed to pay $765 million, was not doing enough to help players. The judge in the case concurred, and the NFL then agreed to pay an unlimited amount of damages for players found to have ALS, Parkinson’s disease, Alzheimer’s disease and dementia.[106]

Research

A number of clinical trials are underway globally for ALS; a comprehensive listing of trials in the US can be found at ClinicalTrials.gov. A large genetic study, called project MinE, initiated by two people with ALS is going on currently. It is a crowdfunded research project with many countries involved to discover more genes.[107] A division of the US Centers for Disease Control and Prevention maintains a registry of Americans with ALS.[108]

https://en.wikipedia.org/wiki/Amyotrophic_lateral_sclerosis

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