Please read:

An urgent appeal from

Wikipedia founder Jimmy Wales

Parkinson's disease
From Wikipedia, the free encyclopedia
Jump to: navigation, search
"Parkinson's" redirects here. For other uses, see Parkinson's (disambiguation).
Parkinson's
Classification and external resources

Illustration of Parkinson's disease by William Richard Gowers

from A Manual of Diseases of the Nervous System in 1886
ICD-10 G20., F02.3
ICD-9 332
DiseasesDB 9651
MedlinePlus 000755
neuro/304 neuro/635 in young
eMedicine
pmr/99 rehab

Parkinson's disease (also known as Parkinson's, Parkinson disease, or PD) is a

degenerative disorder of the central nervous system that impairs motor skills, cognitive
processes, and other functions. The most obvious symptoms are motor-related, including
tremor, rigidity, slowness of movement, and postural instability. Among non-motor
symptoms are autonomic dysfunction and sensory and sleep difficulties. Cognitive and
neurobehavioral problems, including dementia, are common in the advanced stages of the
disease. PD usually appears around the age of 60, although there are young-onset cases.

PD is also called "primary parkinsonism" or "idiopathic PD" (meaning having no known

cause), although some cases have a genetic origin. Many risk and protective factors have
been investigated, showing an increased risk of PD in those exposed to pesticides; and a
reduced risk in smokers. Symptoms result from insufficient formation and action of
dopamine produced in the dopaminergic neurons of the midbrain (specifically the
substantia nigra). Pathologically the disease is characterized by the accumulation of
alpha-synuclein protein forming inclusions called Lewy bodies. Such pathology can only
be demonstrated at autopsy so diagnosis is mainly clinical (based on symptoms). Some
tests such as neuroimaging techniques can also aid in diagnosis.

Current treatments are effective at managing the early motor symptoms of the disease,
through the use of levodopa, dopamine agonists and MAO-B inhibitors. As the disease
advances, however, the continued use of medications leads to a second stage in which the
patient develops motor complications called dyskinesias. Medications to treat other
symptoms of PD also exist. Diet and some forms of rehabilitation have shown some
effectiveness at mitigating symptoms, and surgery and deep brain stimulation may be
used to reduce motor symptoms in the most extreme cases.

The disease is named after English apothecary James Parkinson, who gave the first
detailed description of it in "An Essay on the Shaking Palsy" (1817). PD is a costly
disease to society. Several major organizations promote research and improvement of
quality of life of those with the disease and their families. Research directions include a
search of new animal models of the disease, and investigations of the potential usefulness
of gene therapy, stem cells transplants and neuroprotective agents. Advocacy actions
include April 11, birthday of James Parkinson, as the world's Parkinson's disease day, and
the use of a red tulip as the symbol of the disease. People with PD who have greatly
affected public awareness include Michael J. Fox and Muhammad Ali.

Contents
[hide]

• 1 Classification
• 2 Signs and symptoms
o 2.1 Motor
o 2.2 Neuropsychiatric
o 2.3 Other
• 3 Causes
o 3.1 Genetic
• 4 Pathophysiology
o 4.1 Physiology
o 4.2 Pathology
• 5 Diagnosis
• 6 Management
 o 6.1 Levodopa
o 6.2 Dopamine agonists
o 6.3 MAO-B inhibitors
o 6.4 Other drugs
o 6.5 Surgery and deep brain stimulation
o 6.6 Rehabilitation
o 6.7 Diet
o 6.8 Alternative treatments
• 7 Prognosis
• 8 Epidemiology
o 8.1 Risk and protective factors
• 9 History
o 9.1 Early descriptions
o 9.2 19th century
o 9.3 20th century
• 10 Research directions
o 10.1 Animal models
o 10.2 Gene therapy
o 10.3 Neuroprotective treatments
o 10.4 Neural transplantation
• 11 Society and culture
o 11.1 Cost
o 11.2 Advocacy
o 11.3 Notable cases
• 12 References

• 13 External links

[edit] Classification

Positive Alpha-Synuclein staining of a Lewy body in a patient with Parkinson's disease.

Presence of Lewy bodies in the brains of those with PD has led to the classification of the
disease as a synucleinopathy.

The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at
rest, stiffness, slowing of movement and postural instability. Parkinsonisms can be
divided into four subtypes according to their origin: primary or idiopathic, secondary or
acquired, hereditary parkinsonism, and parkinson plus syndromes or multiple system
degeneration.[1] Parkinson's disease is the most common form of parkinsonism, and is
usually defined as "idiopathic" parkinsonism, meaning parkinsonism with no identifiable
cause.[2][3]

PD is usually classified as a movement disorder, although it also gives rise to several

non-motor types of symptoms such as cognitive difficulties or sleep problems. Parkinson-
plus diseases are primary parkinsonisms which present additional features.[2] They
include multiple system atrophy, progressive supranuclear palsy, corticobasal
degeneration and dementia with Lewy bodies.[2]

In terms of pathophysiology, PD is considered a synucleinopathy 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.[4] 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 PD patients' brains at autopsy.[4] Dementia with
Lewy bodies is another synucleinopathy that has many similarities with PD. Thus the two
diseases, especially PD with dementia, may be considered parts of the same continuum.[5]
However the relationship between the two diseases is complex and still has to be
clarified.[5]

[edit] Signs and symptoms

Main article: Signs and symptoms of Parkinson's disease

Parkinson's disease affects movement, producing motor symptoms.[1] Non-motor

symptoms, which include autonomic dysfunction, cognitive and neurobehavioral
problems, and sensory and sleep difficulties, are also common.[1]

[edit] Motor

Further information: Parkinsonian gait

Parkinson's disease patient showing a flexed walking posture pictured in 1892. Photo
appeared in Nouvelle Iconographie de la Salpètrière, vol. 5.
Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of
movement, and postural instability.[1] Tremor is the most apparent and well-known
symptom.[1] It is most commonly a rest tremor: maximal when the limb is at rest and
disappearing with voluntary movement and sleep.[1] 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.[1] Though around 30% of individuals with PD do not have
tremor at disease onset, most develop it as the disease progresses.[1] Rigidity is due to
joint stiffness and increased muscle tone, which combined with a resting tremor produce
a ratchety, "cogwheel rigidity" when the limb is passively moved.[1] Rigidity may be
associated with joint pain, such pain being a frequent initial manifestation of the disease.
[1]
Bradykinesia (slowness of movement) is the most characteristic clinical feature of PD,
and is associated with difficulties with the planning, initiation and execution of a
movement.[1] The performance of sequential and simultaneous movements is also
hindered.[1] Bradykinesia is the most disabling symptom in the early stages of the disease.
[2]
In the late stages postural instability is typical, which leads to impaired balance and
frequent falls.[1] Instability is often absent in the initial stages, especially in younger
patients.[2]

Other motor symptoms include gait and posture disturbances such as decreased arm
swing, a forward-flexed posture and the use of small steps when walking; speech and
swallowing disturbances; and other symptoms such as a mask-like face expression or
small handwriting are examples of the range of common motor problems that can appear.
[1]

[edit] Neuropsychiatric

Parkinson's disease causes neuropsychiatric disturbances, which include mainly

cognition, mood and behavior problems, and can be as disabling as motor symptoms.[1]

A high proportion of people with PD will have mild cognitive impairment as the disease
advances although cognitive disturbances can also occur in the initial stages of the
disease in some cases.[6][1] The most common cognitive deficits in non-demented patients
are executive dysfunction. The executive system is responsible for planning, cognitive
flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting
inappropriate actions, and selecting relevant sensory information. PD patients may have
problems with these cognitive processes. Fluctuations in attention and slowed cognitive
speed are among other cognitive difficulties. Memory is also affected, specifically in
recalling learned information. Nevertheless improvement appears when recall is aided by
cues. Visuospatial skills difficulties are also part of the disease, which are for example
seen when the individual is asked to perform tests of facial recognition and perception of
the orientation of drawed lines.[6]

Deficits tend to aggravate with time, in many cases developing into dementia. A person
with PD has a sixfold increased risk of suffering dementia,[1] and the overall rate in
people with the disease is around 30%.[6] Moreover, prevalence of dementia increases in
relation to disease duration, going up to 80%.[6] Dementia has been associated with a
reduced quality of life in people with PD and their caregivers, increased mortality and a
higher probability of attending a nursing home.[6]
Cognitive problems and dementia are usually accompanied by behavior and mood
alterations, although these kind of changes are also more common in those without
cognitive impairment than in the general population. Most frequent mood difficulties
include depression, apathy and anxiety.[1] Impulse control behaviors such as craving,
binge eating, hypersexuality, pathological gambling, or other, can also appear in PD, and
have been related the medications for the disease.[1][7] Psychotic symptoms are common in
later PD. Symptoms of psychosis are either hallucinations, or delusions.[8]

[edit] Other

In addition to cognitive and motor symptoms PD can impair other body functions. Sleep
problems can be worsened by medications, but they are a core feature of the disease.[1]
They can manifest as daytime somnolence, disturbances in REM sleep or insomnia.[1] The
autonomic system is altered which can lead for example to orthostatic hypotension, oily
skin and seborrheic dermatitis, excessive sweating, urinary incontinence and altered
sexual function.[1] Constipation and gastric dysmotility can be severe enough to endanger
comfort and health.[9] PD is also related to different ophthalmological abnormalities such
as decreased blink rate and alteration in the tear film, leading to irritation of the eye
surface, abnormalities in ocular pursuit and saccadic movements and limitations in the
upward gaze.[1] Changes in perception include reduced sense of smell and sensation of
pain and paresthesias.[1]

[edit] Causes
Most people with Parkinson's disease are described as having idiopathic Parkinson's
disease (having no specific known cause). A small proportion of cases are known to
originate as genetic factors.

[edit] Genetic

PD traditionally has been considered a non-genetic disorder, however around 15% of

individuals with PD have a first-degree relative who also has the disease.[2] At least 5% of
the patients are now known to have forms of the disease that occur due to a single gene
mutation.[10] Other genes act as risk factors for sporadic cases of the disease.

A number of specific genetic mutations causing PD have been discovered. Genes

conclusively identified are alpha-synuclein (SNCA), ubiquitin carboxy-terminal
hydrolase L1 (UCH-L1), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or
dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[10][11] With the
exception of LRRK2 they account for a small minority of cases of PD.[11] In most cases,
people with these mutations will develop PD. The most extensively studied PD-related
genes are SNCA and LRRK2.

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the
main component of Lewy bodies.[10] Missense mutations (mutation in which a single
nucleotide is changed) of the gene, and duplications and triplications of the locus
containing it have been found in different groups with familial PD.[10] Missense mutations
are very rare.[10] On the other hand, multiplications of the SNCA locus account for around
2% of familial cases.[10] Multiplications have also been found in asymptomatic carriers
leading to the conclusion that penetrance is incomplete or age-dependent.[10]
The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin
comes from a Basque word for tremor since such gene was first identified in families
from England and the north of Spain.[11] LRRK is the most common cause known of
familial and sporadic PD, with mutations in this gene in up to 10% of the patients with a
family history of the disease and 3% of sporadic cases.[10][11] Although more than 40
different mutations of the gene have been found, one of them (G2019S) appears in 5% of
the familial cases and 2% of the sporadic ones in Europe.[10] Nevertheless prevalence of
this mutation varies greatly with ethnicity; it is rare in Asia but very common in cases in
northern Africa and among Ashkenazi Jews.[10] The penetrance of the G2019S mutation
ranges between 28% at age 60 and 75% at age 80 with sex having no effect.[10]

Other mutations in at least three of the causative genes of the familial forms of the
disease have been found to be a risk factor for the so-called sporadic PD. The three are
SNCA, LRRK2 and GBA.[10] Genome-wide association studies, which search for mutated
alleles with low penetrance in sporadic cases, have yielded few positive results although
the number of such studies has been scarce and their size small.[10]

[edit] Pathophysiology
The basal ganglia are a group of brain structures innervated by the dopaminergic system
and considered the most seriously affected brain area in PD.[12] The symptoms of
Parkinson's disease result from the greatly reduced activity of dopamine-secreting cells
due to cell death in the pars compacta region of the substantia nigra.[12] The characteristic
pathological finding in PD is Lewy bodies.

[edit] Physiology

Connections of the basal ganglia in the normal state.

Connections of the basal ganglia in Parkinson's disease, resulting from decreased activity
of the pars compacta region of the substantia nigra. Larger and smaller arrows refer to
pathways with increased and decreased activity, respectively, in Parkinson's disease.
Model of the circuits of the basal ganglia in the normal state (left) and PD (right).
Substantia nigra is seen at bottom right. Pictures show 2 coronal slices that have been
superimposed to include the involved basal ganglia structures. + and - signs at the point
of the arrows indicate respectively whether the pathway is excitatory or inhibitory in
effect. Green arrows refer to excitatory glutamatergic pathways, red arrows refer to
inhibitory GABAergic pathways and turquoise arrows refer to dopaminergic pathways
that are excitatory on the direct pathway and inhibitory on the indirect pathway. Dis-
inhibitory pathways are in effect excitatory on the feedback to the cortex, while dis-dis-
inhibitory pathways are inhibitory.

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 orbitofrontal
circuits, with names indicating the main projection area of each circuit.[12] All of them are
affected in PD, and their disruption likely explains much of the symptomatology of the
disease since these circuits are involved in a wide variety of functions including
movement, attention or learning.[12] Scientifically, the motor circuit has been examined
the most intensively.[12]

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.[12] This model divides the efferent neurons from the striatum into
two different projection systems, known as the direct and indirect pathways.[12] The direct
pathway connects the putamen directly with the globus pallidus pars interna (GPi) -
substantia nigra pars reticulata (SNr), and facilitates movement by reducing the output of
the basal ganglia.[12] The indirect pathway consists of three links, first a projection from
the putamen to GPe; second a projection from GPe to the subthalamic nucleus (STN);
and third a projection from STN to SNr. The indirect pathway, as opposed to the direct,
inhibits movement by increasing activity in the basal ganglia.[12] According to this model,
dopamine reduction in PD produces functional consequences related to motor symptoms
of the disease. The most important consequence is increased activity in the indirect
pathway, leading to excessive inhibition of movement and thus to hypokinetic symptoms.
[12]
On the other hand it is believed levodopa administrations leads to a reduction of the
basal ganglia output, which if excessively marked, produces dyskinesias.[12] Similarly it
has been demonstrated that lesion or blockade of the STN or GPi lead to a reduced
hyperactivity of the basal ganglia and to an improvement of symptoms.[12] Evidence
partially conflicting with the model has led to the inclusion of the interaction between
further connections and neurotransmitters with the aim of better reflecting the complexity
of the basal ganglia in healthy subjects, their disruption in PD, and the effect produced by
the treatments for the disease.[12] Some of these enhancements are included in the image
above.

[edit] Pathology

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 stem damage may be the first
identifiable stage of PD neuropathology.[13]

The main pathological characteristic of PD is cell death in the substantia nigra and more
specifically the ventral part of the pars compacta, affecting up to 70% of the cells by
death time.[11] The mechanisms by which the brain cells in Parkinson's are lost are varied.
[14]
One mechanism consists of an abnormal accumulation of the protein alpha-synuclein
bound to ubiquitin in the damaged cells. This protein accumulation forms inclusions
called Lewy bodies.[11] 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, individuals at this stage being asymptomatic. As the
disease evolves, Lewy bodies later attain the substantia nigra, areas of the midbrain and
basal [[forebrain] and finally reach areas of the neocortex.[11] Other cell-death
mechanisms include proteosomal and lysosomal system dysfunction, and reduced
mitochondrial activity.[14] Iron accumulation in the substantia nigra is also typically
observed in conjunction with the protein inclusions. It may be related to oxidative stress,
protein aggregation and neuronal death, although mechanisms are not fully understood.[15]

[edit] Diagnosis
PET scan of a healthy brain. A decreased dopamine activity in the basal ganglia, using an
appropriate neurotracer, can aid in diagnosing Parkinson's disease.

Typically the diagnosis is based on medical history and neurological examination.[1] The
physician interviews and observes the patient in search of the cardinal motor symptoms,
while also attending to other possible symptoms that would exclude the diagnosis of PD.
[1]
Reduction of motor impairment in response to administration of levodopa is considered
a strong sign pointing to PD.[1] There is no definitive test for diagnosis, but finding Lewy
bodies during autopsy has traditionally been considered the gold standard.[1] Common
presentations of the disease are usually easily diagnosed. On the other hand diagnosis can
be difficult when the symptomatology array is not typical of PD since parkinsonisms can
occur due to a range of pathologies, with only slight clinical differences between them
and PD.[1] This difficulty is especially strong in the early stages when symtoms are not as
marked.[1]

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
come from the UK Parkinson’s Disease Society Brain Bank and the US National Institute
of Neurological Disorders and Stroke.[1] The PD Society Brain Bank criteria require the
person to suffer from slowness of movement (bradykinesia) plus either rigidity, resting
tremor, or postural instability. Other possible causes for these symptoms need to be ruled
out. Finally the person would have to have three or more of the following features during
onset or evolution: unilateral onset, rest tremor, progression, asymmetry of motor
symptoms, response to levodopa during at least 5 years, clinical course of at least ten
years, and appearance of dyskinesias induced by the intake of excessive levodopa.[1]
Accuracy of diagnostic criteria evaluated at autopsy is between 75 and 90%, with
specialists such as neurologists having the highest rates.[1]

Differential diagnosis requires distinguishing PD from other kind of tremors and also
other causes of parkinsonism.[16] Other tremors include postural and action tremors or
intention tremor.[16] Other causes that can secondarily produce a parkinsonian syndrome
are Alzheimer's disease, multiple cerebral infarction, and drug-induced parkinsonism.[16]
Parkinson plus syndromes such as progressive supranuclear palsy and multiple system
atrophy also must be ruled out.[1] Anti-Parkinson's medications are typically less effective
controlling symptoms in Parkinson-plus diseases.[1] Faster progression rates, early
cognitive dysfunction or postural instability, minimal tremor or excessive symmetry at
onset may also indicate a Parkinson plus disease rather than PD itself.[17] Genetic forms
are usually classified as PD, although the terms familial Parkinson’s disease and familial
parkinsonism are also used for disease entities with an autosomal dominant or recessive
pattern of inheritance.[2]

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

[edit] Management
Main article: Treatments of Parkinson's Disease

At present, 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, dopamine agonists and
MAO-B inhibitors.[19] The most commonly used treatment approach varies depending on
the disease stage. Two phases are usually distinguished: an initial phase in which the
individual with PD has already developed some disability for which he needs
pharmacological treatment, and a second stage in which the patient develops motor
complications related to levodopa usage.[19] Treatment in the initial state aims to attain an
optimal tradeoff between good management of symptoms and side-effects resulting from
enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed
by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope
of causing the onset of dyskinesias to be retarded.[19] In the second stage the aim is to
reduce symptoms while controlling fluctuations between on and off periods. Sudden
withdrawals from medication, and overuse by some patients, also have to be controlled.
[19]
When medications are not enough to control symptoms surgery and deep brain
stimulation can be of use.[20]

[edit] Levodopa

Stalevo, a commercial preparation combining entacapone, levodopa and carbidopa for

treatment of Parkinson's disease
Circuits of the basal ganglia in treatment of Parkinson's disease. Model of the effect of
medication on motor symptoms: levodopa, dopamine agonists and MAO-B inhibitors
stimulate excitatory signals from the thalamus to the cortex by effects on the striatum,
compensating for decreased dopaminergic signals from substantia nigra (seen at bottom
right).

Levodopa (or L-DOPA) has been the most widely used treatment for over 30 years.[19] L-
DOPA is transformed into dopamine in the dopaminergic neurons by dopa-
decarboxylase.[19] Since motor symptoms are produced by a lack of dopamine in the
substantia nigra the administration of L-DOPA temporarily diminishes the motor
symptomatology.[19]

Only 5-10% of L-DOPA crosses the blood-brain barrier. The remaining is often
metabolised to dopamine elsewhere, causing a wide variety of side effects including
nausea, dyskinesias and stiffness.[19] Carbidopa and benserazide are peripheral dopa
decarboxylase inhibitors.[19] They help to prevent the metabolism of L-DOPA before it
reaches the dopaminergic neurons and therefore reduce side effects. They are generally
given as combination preparations with levodopa.[19] Existing preparations are
carbidopa/levodopa (co-careldopa, trade names Sinemet, Parcopa, Atamet) and
benserazide/levodopa (co-beneldopa, trade name Madopar). Levodopa has also been
related to a dopamine dysregulation syndrome, which is a compulsive overuse of the
medication, and punding.[7]

There are controlled release versions of Sinemet and Madopar that spread out the effect
of the levodopa. Duodopa is a combination of levodopa and carbidopa. Slow-release
levodopa preparations have not shown an increased control of motor symptoms or motor
complications when compared to immediate release preparations.[19]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the
effects of levodopa.[19] It has been used to complement levodopa. However, due to its
possible side effects such as liver failure, it's limited in its availability.[19] A similar drug,
entacapone has not been shown to cause significant alterations of liver function and
maintains adequate inhibition of COMT over time.[19] Entacapone is available for
treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo).[19]

Levodopa results in a reduction in the endogenous formation of L-DOPA, and eventually

becomes counterproductive. 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.[19] When this occurs PD
patients change fastly from stages with good response to medication and few symptoms
("on" state) to phases with no response to medication and important motor symptoms
("off" state).[19] For this reason levodopa doses are kept as low as possible while
maintaining functionality.[19] Delaying the initiation of dopatherapy, using instead
alternatives for some time, is also common practice.[19] A former strategy to reduce motor
complications was to withdraw patients from L-DOPA for some time. It is discouraged
now since it can bring dangerous side effects such as neuroleptic malignant syndrome.[19]
Most people will eventually need levodopa and later develop motor complications.[19]

[edit] Dopamine agonists

Dopamine agonists in the brain have a similar effect to levodopa since they bind to
dopaminergic post-synaptic receptors.[19] Dopamine agonists were initially used for
patients experiencing on-off fluctuations and dyskinesias as a complementary therapy to
levodopa but they are now mainly used on their own as an initial therapy for motor
symptoms with the aim of delaying motor complications.[19][21] When used in late PD they
are useful at reducing the off periods.[19] Dopamine agonists include bromocriptine,
pergolide, pramipexole, ropinirole , piribedil, cabergoline, apomorphine, and lisuride.

Agonists produce significant, although mild, side effects including somnolence,

hallucinations, insomnia, nausea, and constipation.[19] Sometimes side effects appear even
at a the minimal clinically efficacious dose, leading the physician to search for a different
agonist or kind of drug.[19] When compared with levodopa, while they delay motor
complications they control worse symptoms.[19] Nevertheless they are usually effective
enough to manage symptoms in the initial years.[2] They are also more expensive.[2]
Dyskinesias with dopamine agonists are rare in younger patients, but along other side
effects more common in older patients.[2] All this has led to agonists being the preferential
initial treatment for the former as opposed to levodopa in the latter.[2] Agonists at higher
doses have also been related to a wide variety of impulse control disorders.[7]

Apomorphine, which is a non-orally administered dopamine agonist, may be used to

reduce off periods and dyskinesia in late PD.[19] It is administered by intermitent
injections or continuous subcutaneous infusions.[19] Since secondary effects such as
confusion and hallucinations are not rare it has been recommended that patients under
apomorphine treatment should be closely monitored.[19]

[edit] MAO-B inhibitors

MAO-B inhibitors (Selegiline and rasagiline) increase the level of dopamine in the basal
ganglia by blocking its metabolization. They inhibit monoamine oxidase-B (MAO-B)
which breaks down dopamine secreted by the dopaminergic neurons. Therefore reducing
MAO-B results in higher quantities of L-DOPA in the striatum.[19] Similarly to dopamine
agonists, MAO-B inhibitors improve motor symptoms and delay the need of taking
levodopa when used as monotherapy in the first stages of the disease but produce more
adverse effects and are less effective than levodopa. Evidence on their efficacy in the
advanced stage is reduced although it points towards them being useful to reduce
fluctuations between on and off periods.[19] Although an initial study had as result that
selegiline in combination with levodopa increased the risk of death this has been later
disproven.[19]

[edit] Other drugs

There is some indication that other drugs such as amantadine and anticholinergics may be
useful as treatment of motor symptoms, but since quality of evidence on efficacy is
reduced they are not first choice treatments.[19] In addition to motor, PD is accompanied
by an ample range of different symptoms. Different compounds are used to improve
some of these problems.[22] Examples are the use of clozapine for psychosis,
cholinesterase inhibitors for dementia and modafinil for day somnolence.[22][23]

[edit] Surgery and deep brain stimulation

Illustration showing an electrode placed deep seated in the brain

Treating motor symptomatology with surgery was once a common practice, but after the
discovery of levodopa, number of surgeries was reduced.[24] Studies in the past few
decades have led to great improvements in surgical techniques, and surgery is again being
used in people with advanced PD for whom drug therapy is no longer sufficient.[24] Deep
brain stimulation (DBS) is presently the most used surgical mean of treatment but other
surgical therapies consisting in producing lesions in specific subcortical areas are also
effective.[24] DBS involves the implantation of a medical device called a brain pacemaker,
which sends electrical impulses to specific parts of the brain. Target areas for DBS or
lesions include the thalamus, the globus pallidus (the lesion technique being called
pallidotomy) or the subthalamic nucleus.[24] DBS is recommended to PD patients without
important neuropsychiatric problems who suffer motor fluctuations and tremor badly
controlled by medication, or to those who are intolerant to medication.[20]

[edit] Rehabilitation

There is partial evidence that speech or mobility problems can improve with
rehabilitation although studies are scarce and of low quality.[25][26] Regular physical
exercise and/or therapy can be beneficial to maintain and improve mobility, flexibility,
strength, gait speed, and quality of life.[26] Exercise may also improve constipation.[9] One
of the most widely practiced treatment for speech disorders associated with Parkinson's
disease is the Lee Silverman Voice Treatment (LSVT), which focuses on increasing
vocal loudness and has an intensive approach of one month.[25][27] Speech therapy and
specifically LSVT may improve voice and speech function.[25] Occupational therapy (OT)
aims to promote health and quality of life by helping people with the disease to
participate in as many activities of their daily living as possible.[25] 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.[25][28]

[edit] Diet

Muscles and nerves that control the digestive process may be affected by PD, therefore, it
is common to experience constipation and gastroparesis (food remaining in the stomach
for a longer period of time than normal).[9] A balanced diet is recommended to help
improve digestion. Diet should include high-fiber foods and plenty of water.[9] Levodopa
and proteins use the same transportation system in the intestine and the blood-brain
barrier, competing between them for access.[9] When taken together the consequences of
such competition is a reduced effectiveness of the drug.[9] Therefore when levodopa is
introduced excessive proteins are discouraged, while in advanced stages additional intake
of low-protein products such as bread or pasta is recommended for similar reasons.[9] To
minimize interaction with proteins levodopa is recommended to be taken 30 minutes
before meals.[9] At the same time, regimens for PD restrict proteins during breakfast and
lunch and are usually taken at dinner.[9] As the disease advances dysphagia may appear.
In such cases specific measures include the use of thickening agents for liquid intake,
special postures when eating and gastrostomy in the worst cases.[9]

[edit] Alternative treatments

Different nutrients have been proposed as possible treatments; however there is no

evidence that vitamin or food additives improve symptoms.[29] There is not enough
evidence to suggest that acupuncture, and practice of qigong or tai chi have any effect on
symptoms.[30][31][32] Fava and velvet beans are natural sources of L-DOPA and are taken by
many people with PD. While they have shown some effectiveness,[33] their intake is not
free of risks. Life threatening adverse reactions have been described, such as the
neuroleptic malignant syndrome.[34][35]

[edit] Prognosis
See also: Hoehn and Yahr scale and Unified Parkinson's Disease Rating Scale

Disability-adjusted life year for Parkinson Disease per 100,000 inhabitants in 2004.
no data less than 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 more than 80

PD progresses with time. If not treated, motor symptoms have an aggressive advance at
the beginning of the disease with a slower advance later: those untreated are expected to
lose independent ambulation after 8 years and be bedridden after 10 years.[36] However it
is not common to find untreated people nowadays and medication has improved the
prognosis of motor symptoms, while at the same time it is also a new source of disability
due to the undesired effects of L-DOPA after years of use.[36] Different studies of the
history of the disease on people taking L-DOPA have found that the mean progression of
symptoms to a stage of high dependency of subjects may take around 15 years.[36]
However it is hard to predict what course the disease will take for an individual.[36] Age is
the best predictor of disease progression.[14] Rate of motor decline is greater in those with
less impairment at diagnosis while cognitive impairment is more frequent in those who
are over 70 years of age at symptoms onset.[14]

Since current therapies improve motor symptoms, disability at present is mainly related
to non-motor features of the disease.[14] Nevertheless the relationship between disease
progression and disability is not linear. At first disability is related to motor symptoms
and specially motor complications, which appear in up to 50% of the patients after 5
years of L-DOPA usage.[36] As the disease advances disability is more related to motor
symptoms that have a bad response to medication such as swallowing and speech
difficulties and gait and balance problems.[36] Finally after ten years most people with the
disease have autonomic disturbances, sleep problems, mood alterations and cognitive
decline.[36] All of them, but specially the latter, greatly increase disability.[14][36]

The average life expectancy of a person with PD is lower than for people who do not
have the disease.[36] Mortality ratios are around twice of those unaffected.[36] Cognitive
decline and dementia, old age at onset, a more advanced disease, and presence of
swallowing problems are all mortality risk factors. Conversely a cause of death twice as
common in individuals with PD than in the healthy population is aspiration pneumonia.[36]
On the other hand a disease mainly characterized by tremor as opposed to rigidity
predicts an improved survival.[36]

[edit] Epidemiology
Two main measures are used in epidemiological studies: incidence and prevalence.
Incidence is the number of new cases per unit of person–time at risk (usually number of
new cases per thousand person–years); while prevalence is the total number of cases of
the disease in the population at a given time. PD is the most common neurodegenerative
disorder after Alzheimer's disease.[37] The prevalence is estimated at being 0.3% in the
whole population in industrialized countries, rising to 1% in those over 60 years of age
and to 4% of the population over 80.[37] Mean age of onset is around 60 years, although 5-
10% of cases are considered of young onset as begin between the age of 20 and 50.[2] PD
might be less prevalent in those of African and Asian ancestry, although results are
controversial.[37] Some studies have also proposed that it is more common in men than
women while others did not found any differences between the two groups.[37] Studies on
incidence report that it is between 8 and 18 per 100,000 person-years.[37]

Many risk and protective factors have been proposed in accordance to possible
mechanisms of the disease, however none have been conclusively related to PD. While
epidemiological studies have been carried out trying to prove or disprove the relationship
between a given factor and PD, they have commonly been biased, and results of have
been contradictory.[37] Most replicated relationships are an increased risk of PD in those
exposed to pesticides; and a reduced risk in smokers.[37]

[edit] Risk and protective factors

U.S. Army Huey helicopter spraying Agent Orange over Vietnamese agricultural land.
Agent Orange has been associated to PD.

MPTP injections produce a range of symptoms similar to PD as well as a selective

damage to the dopaminergic neurons in the substantia nigra. This has led to theorizing
that exposure to some environmental toxins may increase the risk of having PD.[37]
Toxins that have been consistently related to the disease are certain pesticides and
herbicides, with exposure doubling the risk.[37] Conversely indirect measures of exposure,
such as living in rural environments, have also been found to increase the risk of PD.
Limited evidence suggests that exposure to agent orange and other herbicides used during
the Vietnam War is associated with an increased chance of developing Parkinson's
disease.[38] In 2010 the department of veterans affairs of the United States issued a
regulation which presumed an association between exposure to agent orange and other
herbicides and PD in veterans. Vietnam veterans with PD are eligible for several benefits
from the department.[39] Heavy metals exposure has also been proposed to be a risk factor,
being its hypothetical mechanism their accumulation in the substantia nigra, however
studies on the issue have been inconclusive.[37]

A protective effect of tobacco has been consistently found. The basis for such effect is
not known but possibilities include an effect of nicotine as dopamine stimulant.[37]
Caffeine consumption also protects from PD.[40] Antioxidants, such as vitamin C and D,
have been proposed to protect against the disease but results of studies have been
contradictory and their positive effect is not proven. Regarding fat and fatty acids, the
results have also been contradictory, with both protective, risk enhancing or no effects.[37]
Finally there have also been some preliminary indications of a possible protective role of
estrogens and anti-inflammatory drugs.[37]

[edit] History

First page of Parkinson's classical essay on the Shaking palsy

The disease was not formally recognized and its symptoms were not documented until
1817 in An Essay on the Shaking Palsy[41] by the British apothecary James Parkinson. PD
was then known as paralysis agitans (shaking palsy in English), the term "Parkinson's
disease" being coined by Jean-Martin Charcot.[42]

[edit] Early descriptions

There are early sources which talk about symptoms that are coherent with PD.[43] An
Egyptian papyrus from the 12th century B.C talks about a king drooling with age and the
Bible has references to tremor.[42][43] An early ayurvedic medical treatise dating back to
the 10th century B.C describes a disease that evolves with tremor, lack of movement,
drooling and other symptoms of PD. Moreover, this disease was treated with remedies
derived from the mucuna family, which is rich in L-DOPA.[43] Galen writes on a disease
which most surely is PD when he describes tremors that occur only at rest, postural
changes and paralysis.[43]

After Galen there are no references known to be related to PD until the 17th century.[43] In
this and the following century different authors write about some of the elements of the
disease, preceding the description by Parkinson. Franciscus Sylvius separated as Galen
tremor at rest from other tremors, and Johannes Baptiste Sagar and Hieronymus David
Gaubius talk about festination.[43][44] John Hunter provided an excellent description of the
disease, and it is even thought that gave Parkinson the idea of collecting and describing
patients with "paralisis agitans".[43][45] Finally, Auguste François Chomel in his pathology
treatise, which is contemporary to Parkinson's essay, has many descriptions on abnormal
movements and rigidity typical of PD.[43]

[edit] 19th century

Jean-Martin Charcot (pictured) made important contributions to the understanding of the
disease and proposed its current name honoring James Parkinson.

In 1817 James Parkinson, aged 62, publishes his essay, reporting 6 cases of paralysis
agitans.[42] "An Essay on the Shaking Palsy" describes the patients' resting tremor,
abnormal posture and gait, paralysis and diminished muscle strength.[46] The accuracy of
the description of the disease course is remarkable.[42] He also acknowledges the
contributions of many of the previous authors to the understanding of PD.[42] Although
the article has been later considered the first seminal work on the disease, it received very
little attention for more than forty years.[46] Nevertheless early neurologists who made
further additions to the knowledge of the disease include Trousseau, Charcot, Gowers,
Kinnier Wilson and Erb.[42] Moreover Charcot studies between 1868 and 1881 were a
landmark in the understanding of the disease.[42] Among other advances he made the
distinction between rigidity, weakness and bradykinesia.[42] He also led the disease to be
re-named on behalf of James Parkinson.[42]

[edit] 20th century

First speculations of the anatomical substrate of PD were made 80 years after Parkinson's
essay, when Brissaud proposed that it had its origin in the subthalamus or the cerebral
peduncle and might be caused by an ischemic lesion.[42] In 1912 Frederic Lewy described
a pathologic finding in affected brains, later named "Lewy bodies".[42] It was Konstantin
Tretiakoff who in 1919 discovered that the substantia nigra was the main cerebral
structure affected, but it was not widely accepted until further studies by Hassler in 1938.
[42]
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 his role on
PD. He later won a Nobel Prize for his work.[47]

While levodopa was first synthesized in 1911 by Funk, it received little attention until the
mid 20th century.[47] It entered clinical practice in 1967, and the first large study reporting
improvements in patients with Parkinson's disease resulting from treatment with
levodopa was published in 1968. Levodopa use was a major revolution in the
management of PD which still lasts.[47][48] Surgery for tremor was initiated in 1939 and
was improved for over 20 years, but the arrival of levodopa reduced its use dramatically.
[49]
By the late 1980s deep brain stimulation emerged as a possible treatment and it was
approved by the FDA in 1997.[50]

[edit] Research directions

See also: Parkinson's disease clinical research

There are no new PD treatments expected in the short time, however several lines of
research are active for new treatments.[51] Such research directions include the search of
new animal models of the disease, and the potential usefulness of gene therapy, stem cells
transplants and neuroprotective agents.[14]

[edit] Animal models

The tragedy of a group of drug addicts in California in the early 1980s who consumed a
contaminated and illicitly produced batch of the synthetic opiate MPPP brought to light
MPTP as a cause of parkinsonian symptoms.[52] Other predominant toxin-based models
employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[53]
Models based on toxins are most commonly used in primates. Transgenic rodent models
also exist.[54]

[edit] Gene therapy

Gene therapy is currently under investigation.[14][55] It involves the use of a non-infectious

virus to shuttle a gene into a part of the brain. The gene used leads to the production of an
enzyme which helps to manage PD symptoms or protects the brain from further damage.
[14]
As of 2010 there are four clinical trials using gene therapy in PD.[14] There have not
been important adverse effects in these trials although the clinical usefulness of gene
therapy is still unknown.[14]

[edit] Neuroprotective treatments

While several chemical compounds such as GNDF (chemical structure pictured) have
been proposed as neuroprotectors in PD, none has proven its efficacy.

Investigations on neuroprotection are at the forefront of PD research. Several molecules

have been proposed as potential treatments.[14] However none of them has been
conclusively demonstrated to reduce degeneration.[14] Agents currently under
investigation include anti-apoptotics (TCH346, CEP-1347), antiglutamatergics,
monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10,
creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[14]
Preclinical research also targets alpha-synuclein.[51]

[edit] Neural transplantation

Since early in the eighties fetal, porcine, carotid or retinal tissues have been used in cell
transplants for PD patients.[14] Although there was initial evidence of mesencephalic
dopamine-producing cell transplants being beneficial, the best constructed studies up to
date indicate that cell transplants have no effect.[14] An additional significant problem was
the excess release of dopamine by the transplanted tissue, leading to dystonias.[56] Stem
cells transplants are a main research recent target: they are easy to manipulate and when
transplanted into the brains of rodents and monkeys cells survive and improve behavioral
abnormalities of the animals.[14][57] Nevertheless use of fetal stem cells is controversial.[14]
Some have proposed that such controversy may be overcome with the use of induced
pluripotent stem cells from adults.[14]

[edit] Society and culture

Muhammad Ali is considered one of the most famous people with PD. Picture is of the
boxer in 2006, 26 years after his diagnosis.

[edit] Cost

Costs of PD to society are high.[58] Nevertheless it is hard to calculate the exact expenses
due to methodological difficulties of its research and differences between countries.[58]
Annual cost in the United Kingdom is estimated to be between 449 million pounds and
3.3 billions, while the cost by individual and year in the US is probably around $10,000
and the total burden around 23 billions.[58] Highest direct costs come from inpatient care
and nursing homes, while among the lowest are medications.[58] Indirect costs are also
important and include looses from reduced productivity and caregiver burden.[58] In
addition to economic costs PD also reduces quality of life of those with the disease and
their caregivers.[58]

[edit] Advocacy

April 11, birthday of James Parkinson, is the world's Parkinson's disease day.[42][59] A
design of a red tulip was chosen by many worldwide organizations as the symbol of the
disease in 2005. It represents James Parkinson Tulip' cultivar, which was registered in
1981 by a Dutch horticulturalist.[59] Advocacy organizations on the disease include the
Parkinson's Disease Foundation, which has provided more than $85 million for research
and $30 million for education and advocacy programs since its foundation in 1957 by
William Black, President of Chock full o'Nuts coffee company;[60][61] the American
Parkinson Disease Association, founded in 1961;[62] and the European Parkinson's
Disease Association, founded in 1992.[63]

[edit] Notable cases

Among the many famous people with PD, one which has greatly increased the public
awareness of the disease has been actor Michael J. Fox. Fox was diagnosed in 1991,
when he was 30 and kept secret to the public his condition for seven years.[64] His first
book, Lucky Man focused on how after seven years of unacceptance of the disease he set
up the Michael J. Fox Foundation, stopped drinking and began to be an advocate of those
with PD.[65] His second book Always Looking Up: The Adventures Of An Incurable
Optimist describes his life between 1999 and 2009, with much of the book centered on
how Fox began to advocate for stem cell research.[65] The Michael J. Fox Foundation
aims to develop a cure for Parkinson's disease. It is the major Parkinson's fundraiser in
the US with 140 million dollars in research between 2001 and 2008.[65] In 2010, the Fox
foundation launched the first large-scale clinical study on evolution biomarkers of the
disease with a cost of 40 million dollars in 5 years.[66] Michael J. Fox also appeared in the
United States Congress without medication to illustrate the effects of the disease.[65] His
work led him to be named one of the 100 people "whose power, talent or moral example
is transforming the world" in 2007 by the Time magazine,[64] and he received an honorary
doctorate in medicine from Karolinska Institutet for his contributions to research in
Parkinson's disease.[67] Another foundation that supports Parkinson's research was
established by professional cyclist Davis Phinney.[68] The Davis Phinney Foundation
strives to improve the lives of those living with Parkinson's disease by providing them
with information and tools.[69] Muhammad Ali has been called the "world's most famous
Parkinson's patient".[70] He was 42 at diagnosis although he already showed signs of
parkinsonism when he was 38.[71] Nevertheless whether he truly has PD or a parkinsonian
syndrome due to boxing is still an open question.[71][72]

[edit] References
1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai Jankovic J (April 2008).
"Parkinson's disease: clinical features and diagnosis". J. Neurol. Neurosurg.
Psychiatr. 79 (4): 368–76. doi:10.1136/jnnp.2007.131045. PMID 18344392.
http://jnnp.bmj.com/content/79/4/368.full.
2. ^ a b c d e f g h i j k l Samii A, Nutt JG, Ransom BR (May 2004). "Parkinson's disease".
Lancet 363 (9423): 1783–93. doi:10.1016/S0140-6736(04)16305-8. PMID 15172778.
 • Parkinson's Disease at the Open Directory Project
• Parkinson's Disease: Hope Through Research (National Institute of Neurological
Disorders and Stroke)
• GeneReview/NIH/UW entry on LRRK2-Related Parkinson Disease
• European Parkinson's Disease Association

[show]
v•d•e
Mental and behavioral disorders (F · 290–319)

[hide]

Neurological/symptomatic

Mild cognitive impairment · Alzheimer's disease · Multi-infarct dementia ·

Pick's disease · Creutzfeldt–Jakob disease · Huntington's disease · Parkinson's
Dementia
disease · AIDS dementia complex · Frontotemporal dementia · Sundowning,
Wandering

Other Delirium · Post-concussion syndrome · Organic brain syndrome

[show]

Psychoactive substances, substance abuse, drug abuse and substance-related

disorders

[show]

Schizophrenia, schizotypal and delusional

[show]

Mood (affective)

[show]

Neurotic, stress-related and somatoform

Agoraphobia · Social anxiety/Social phobia (Anthropophobia) ·

Phobia
Specific phobia (Claustrophobia) · Specific social phobia
Anxiety
disorder
Panic disorder/Panic attack · Generalized anxiety disorder · OCD ·
Other
stress (Acute stress reaction, PTSD)

Adjustment Adjustment disorder with depressed mood

disorder

Somatization disorder · Body dysmorphic disorder · Hypochondriasis ·

Somatofor Nosophobia · Da Costa's syndrome · Psychalgia · Conversion disorder
m disorder (Ganser syndrome, Globus pharyngis) · Neurasthenia · Mass Psychogenic
Illness

Dissociative Dissociative identity disorder · Psychogenic amnesia · Fugue state ·

disorder Depersonalization disorder

[show]

Physiological/physical behavioral

Eating
Anorexia nervosa · Bulimia nervosa · Rumination syndrome · NOS
disorder

Nonorganic
(Nonorganic hypersomnia, Nonorganic insomnia) · Parasomnia (REM
sleep
behavior disorder, Night terror, Nightmare)
disorders

sexual desire (Hypoactive sexual desire disorder, Hypersexuality) · sexual

Sexual
arousal (Female sexual arousal disorder) · Erectile dysfunction · orgasm
dysfunction
(Anorgasmia, Premature ejaculation) · pain (Vaginismus, Dyspareunia)

Postnatal Postpartum depression · Postnatal psychosis

[show]

Adult personality and behavior

Sexual
and
Sexual maturation disorder · Ego-dystonic sexual orientation · Sexual relationship
gender
disorder · Paraphilia (Voyeurism, Fetishism)
identit
y

Personality disorder · Impulse control disorder (Kleptomania, Trichotillomania,

Other Pyromania) · Body-focused repetitive behavior · Factitious disorder (Munchausen
syndrome)

[show]

Mental disorders diagnosed in childhood

Mental
X-Linked mental retardation (Lujan-Fryns syndrome)
retardation

Psychological Specific · Pervasive

development
(developmental
disorder)

ADHD · Conduct disorder (ODD) · emotional disorder (Separation

Emotional and anxiety disorder) · social functioning (Selective mutism, RAD, DAD) ·
behavioral Tic disorder (Tourette syndrome) · Speech (Stuttering, Cluttering) ·
Movement disorder (Stereotypic)

[show]

Symptoms and uncategorized

M: PSO/PSI mepr dsrd (o, p, m, p, a, proc,

d, s), sysi/epon, drug(N5A/5B/5C/6A/6B/6D
spvo )
[show]
v•d•e
Pathology of the nervous system, primarily CNS (G04–G47, 323–349)

Brain Encephalitis (Viral encephalitis, Herpesviral encephalitis) · Cavernous sinus thrombosis · Brain a

Spinal
Myelitis: Poliomyelitis · Demyelinating disease (Transverse myelitis) · Tropical spastic parapares
cord

Encephalomyelitis (Acute disseminated)

Both/either
Meningoencephalitis

Basal ganglia disease: Parkinsonism (PD, Postencephalitic, NMS) · PKAN · T

Striatonigral degeneration · Hemiballismus · HD · OA
Extrapyramidal
and
Dyskinesia: Dystonia (Status dystonicus, Spasmodic torticollis, Meige's, Blep
movement
(Choreoathetosis) · Myoclonus (Myoclonic epilepsy) · Akathesia
disorders
Tremor (Essential tremor, Intention tremor) · Restless legs · Stiff person
Degenerative
Tauopathy: Alzheimer's (Early-onset) · Frontotemporal dementia/Frontotempo
degeneration (Pick's, Dementia with Lewy bodies)
Dementia
Multi-infarct dementia

Mitochondrial
Leigh's
disease

autoimmune (Multiple sclerosis, Neuromyelitis optica, Schilder's disease) · hereditary (Adren

DemyelinatingAlexander, Canavan, Krabbe, ML, PMD, VWM, MFC, CAMFAK syndrome) · Central pontin
Marchiafava-Bignami disease · Alpers' disease
 Seizure/epilepsyFocal · Generalised · Status epilepticus · Myoclonic epilepsy

Headache Migraine (Familial hemiplegic) · Cluster · Tension

TIA (Amaurosis fugax, Transient global amnesia)

Episodic/
Cerebrovascular Stroke (MCA, ACA, PCA, Foville's, Millard-Gubler, Lateral medullary, Web
paroxysmal
stroke)

Insomnia · Hypersomnia · Sleep apnea (Obstructive, Ondine's curse) · Narcol

Sleep disorders Kleine-Levin · Circadian rhythm sleep disorder (Advanced sleep phase syndr
phase syndrome, Non-24-hour sleep-wake syndrome, Jet lag)

Intracranial hypertension (Hydrocephalus/NPH, Idiopathic intracranial hypertension) · Cerebr

CSF
Intracranial hypotension

Other Brain herniation · Reye's · Hepatic encephalopathy · Toxic encephalopathy

SA Friedreich's ataxia · Ataxia telangiectasia

UMN only: PLS · PP · HSP

Degenerative
LMN only: PMA · PBP (Fazio-Londe, Infantile progressive bulbar palsy) · SMA (SMN-li
MND
disease, SMAX2, DSMA1)

both: ALS

M: anat(s,m,p,4,e,b,d,c,a,f,l,g)/phys/devp/cel noco(m,d,e,h,v,s)/cong/tumr,sysi/epon,inj proc,drug(N1A/2A

CNS l r
[show]
v•d•e
Antiparkinson agents (N04)

DA
precursors/prodrug Etilevodopa • Droxidopa • Levodopa • Melevodopa
s

DA receptor Aplindore • Apomorphine • Bromocriptine • Cabergoline • Ciladopa • Dihydroergocrypt

agonists Pardoprunox • Pergolide • Piribedil • Pramipexole • Ropinirole • Rotigotine

MAO-B inhibitors Ladostigil • Lazabemide • Mofegiline • Pargyline • Rasagiline • Selegiline

COMT inhibitors Entacapone • Tolcapone

AAAD inhibitors Benserazide • Carbidopa • Methyldopa

 M: anat(s,m,p,4,e,b,d,c,a,f,l,g)/phys/devp/cel noco(m,d,e,h,v,s)/cong/tumr,sysi/epon,inj proc,drug(N1A/2A
CNS l r