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In the management of Parkinson's disease, due to the chronic nature of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
(PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms. While many medications treat Parkinson's, none actually reverses the effects of the disease. Furthermore, the gold-standard treatment varies with the disease state. People with Parkinson's, therefore, often must take a variety of medications to manage the disease's symptoms. Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of PD. However, none is yet on the market with specific approval to treat Parkinson's.


Medication

The main families of drugs useful for treating motor symptoms are
levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
,
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
s, and MAO-B inhibitors. 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 which requires pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Guidance wa
reviewed in 2011
and no changes were made.
According to NICE
as of July 2014 a revised guidance was under development with anticipated publication in 2017.
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 delaying the onset of dyskinesias. In the second stage, the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication, and overuse by some patients, also must be controlled. When medications are not enough to control symptoms, surgical techniques such as
deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleu ...
can relieve the associated movement disorders.


Levodopa

Levodopa (or
L-DOPA -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
) has been the most widely used treatment for over 30 years. L-DOPA is transformed into
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
in the
dopaminergic neurons Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first ident ...
by dopa-decarboxylase. Since motor symptoms are produced by a lack of dopamine in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
, the administration of L-DOPA temporarily diminishes the motor symptoms. Only 5–10% of L-DOPA crosses the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of ...
. The remainder is often metabolised to dopamine elsewhere, causing a wide variety of side effects including
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
dyskinesia Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of t ...
s, and stiffness.
Carbidopa Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–bra ...
and
benserazide Benserazide (also called Serazide or Ro 4-4602) is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is on the World Health Organization's List of E ...
are peripheral
dopa decarboxylase inhibitor An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, Extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme ar ...
s. They inhibit the metabolism of L-DOPA in the periphery, thereby increasing levodopa delivery to the central nervous system. They are generally given as combination preparations with levodopa. Existing preparations are
carbidopa/levodopa Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. It is primarily used to manage the symptoms of Parkinson's disease, but it does not slow down the disease or stop it ...
(co-careldopa, trade names Sinemet, Pharmacopa, Atamet) and benserazide/levodopa (co-beneldopa, trade name Madopar). Levodopa has also been related to a
dopamine dysregulation syndrome Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dop ...
, which is a compulsive overuse of the medication, and punding. Controlled,
slow-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...
versions of Sinemet and Madopar spread out the effect of the levodopa.
Duodopa Carbidopa/levodopa, also known as levocarb and co-careldopa, is the combination of the two medications carbidopa and levodopa. It is primarily used to manage the symptoms of Parkinson's disease, but it does not slow down the disease or stop it ...
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.
Tolcapone Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-''O''-methyltransferase (COMT). It has demonstrat ...
inhibits the catechol-O-methyltransferase (
COMT Catechol-''O''-methyltransferase (COMT; ) is one of several enzymes that degrade catecholamines (neurotransmitters such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structu ...
) enzyme, which degrades dopamine and levadopa, thereby prolonging the therapeutic effects of levodopa. It, alongside inhibitors of peripheral dopa decarboxylase, have been used to complement levodopa. However, due to its possible side effects such as liver failure, it is limited in its availability. A similar drug,
entacapone Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a l ...
, has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time. Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (
Stalevo Carbidopa/levodopa/entacapone, sold under the brand name Stalevo among others, is a dopaminergic fixed-dose combination medication that contains carbidopa, levodopa, and entacapone for the treatment of Parkinson's disease. It is marketed by Swis ...
). 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. When this occurs, PD patients change rapidly 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). For this reason, levodopa doses are kept as low as possible while maintaining functionality. Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice. 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 Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fas ...
. Most people eventually need levodopa and later develop motor complications. The on-off phenomenon is an almost invariable consequence of sustained levodopa treatment in patients with Parkinson's disease. Phases of immobility and incapacity associated with depression alternate with jubilant thaws. Both pharmacokinetic and pharmacodynamic factors are involved in its pathogenesis, but evidence is presented to indicate the importance of levodopa handling has been underestimated and progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Redistribution of levodopa dosage which may mean smaller, more frequent doses, or larger less frequent increments, may be helpful in controlling oscillations in some patients. Dietary protein restriction and the use of
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
and
bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic maligna ...
may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous
apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagon ...
, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intraduodenal administration of levodopa. In animal models it was shown that the intake of
adenosine receptor antagonist An adenosine receptor antagonist is a drug which acts as an antagonist of one or more of the adenosine receptors. The best known are xanthines and their derivatives (natural: caffeine, theophylline, and theobromine; and synthetic: PSB-1901), but th ...
s together with levodopa can amplify its therapeutic effects.


Dopamine agonists

Dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
s in the brain have a similar effect to levodopa since they bind to dopaminergic postsynaptic receptors. 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. When used in late PD, they are useful at reducing the off periods. Dopamine agonists include
bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic maligna ...
,
pergolide Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced do ...
,
pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
,
ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. I ...
,
piribedil Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties. ...
,
cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an er ...
,
apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagon ...
, and
lisuride Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth. Side effects of lis ...
. Agonists produce significant, although mild, side effects including
somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
,
hallucination A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
s,
insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
, and
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
. Sometimes, side effects appear even at the minimal clinically efficacious dose, leading the physician to search for a different agonist or kind of drug. When compared with levodopa, while they delay motor complications, they control worse symptoms. Nevertheless, they are usually effective enough to manage symptoms in the initial years. They are also more expensive. Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects, more common in older patients. All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter. Agonists at higher doses have also been related to a wide variety of impulse-control disorders.
Apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antagon ...
, which is a dopamine agonist not orally administered, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare, patients under apomorphine treatment should be closely monitored. Apomorphine can be administered by subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial "apomorphine challenge" in hospital to test its effectiveness and brief patient and
primary caregiver A caregiver or carer is a paid or unpaid member of a person's social network who helps them with activities of daily living. Since they have no specific professional training, they are often described as informal caregivers. Caregivers most commo ...
(often a spouse or partner), the latter of whom takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules. Apomorphine is also available in a more acute dose as an
autoinjector An autoinjector (or auto-injector) is a medical device designed to deliver a dose of a particular drug. The injectors were initially designed to overcome the hesitation associated with self-administration of the needle-based drug delivery device ...
pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require
domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the le ...
(an antiemetic). In a study evaluating the efficacy of dopamine agonists compared to levodopa, the results showed patients who took dopamine agonists were less likely to develop dyskinesia, dystonia, and motor fluctuations, although were more likely to discontinue therapy due to negative side effects such as nausea, edema, constipation, etc.


MAO-B inhibitors

Monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espe ...
s (
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
and
rasagiline Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The racemic form of the drug was invented by ...
) 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. 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. Although an initial study indicated selegiline in combination with levodopa increased the risk of death, this has been later disproven. Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be
stomatitis Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration. In its widest meaning, stomatitis can have a multitude of different cau ...
. Unlike other nonselective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.


Other drugs

Some evidence indicates other drugs such as
amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...
and
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system ...
s may be useful as treatment of motor symptoms in early and late PD, but since the quality of evidence on efficacy is reduced, they are not first-choice treatments. In addition to motor symptoms, PD is accompanied by a range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of
clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...
for psychosis,
cholinesterase inhibitors Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the syn ...
for dementia,
modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...
for day
somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...
, and
atomoxetine Atomoxetine, sold under the brand name Strattera, among others, is a medication used to treat attention deficit hyperactivity disorder (ADHD). It may be used alone or along with psychostimulants. It is also used as a cognitive enhancer to impro ...
for executive dysfunction. A preliminary study indicates taking
donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...
(Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts the levels of the neurotransmitter
acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
, and is currently an approved therapy for the cognitive symptoms of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
. In the study, participants taking donepezil experienced falls half as often as those taking a placebo, and those who previously fell the most showed the most improvement. The introduction of
clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...
(Clozaril) represents a breakthrough in the treatment of psychotic symptoms of PD. Prior to its introduction, treatment of psychotic symptoms relied on reduction of dopamine therapy or treatment with first generation antipsychotics, all of which worsened motor function. Other
atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
s useful in treatment include
quetiapine Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its ...
(Seroquel),
ziprasidone Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation ...
(Geodon),
aripiprazole Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
(Abilify), and
paliperidone Paliperidone, sold under the trade name Invega among others, is an atypical antipsychotic. It is mainly used to treat schizophrenia and schizoaffective disorder. It is marketed by Janssen Pharmaceuticals. An extended release formulation is a ...
(Invega). Clozapine is believed to have the highest efficacy and lowest risk of extrapyramidal side effect.


Getting medication on time

Parkinson's patients who do not get the correct medicine at the right time when they are in hospital, (frequently they are in hospital due to unrelated illnesses) sometimes cannot talk or walk. The health of a majority deteriorated due to unsatisfactory medication management when they are in hospital. Parkinson's UK believes the NHS could save up to £10m a year and improve the care of Parkinson's patients if mandatory training is introduced for all hospital staff. Parkinson UK found: *"Nearly two thirds of people who have Parkinson's don't always get their medication on time in hospital." *"More than three quarters of people with Parkinson's that we asked reported that their health deteriorated as a result of poor medication management in hospital." *"Only 21% of respondents told us they got their medication on time without having to remind hospital staff."


Surgery

Treating PD with surgery was once a common practice, but after the discovery of levodopa, surgery was restricted to only a few cases. 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. Less than 10% of those with PD qualify as suitable candidates for a surgical response. The three different mechanisms of surgical response for PD are: ablative surgery, (the irreversible burning or freezing of brain tissue), stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery. Target areas for DBS or lesions include the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
, the
globus pallidus The globus pallidus (GP), also known as paleostriatum or dorsal pallidum, is a subcortical structure of the brain. It consists of two adjacent segments, one external, known in rodents simply as the globus pallidus, and one internal, known in rod ...
(the lesion technique being called
pallidotomy Pallidotomy is a neurosurgical procedure. It is used to treat Parkinson's disease and some other conditions, often as an alternative to deep brain stimulation. It involves placing a tiny electrical probe in the globus pallidus, one of the basal g ...
), or the
subthalamic nucleus The subthalamic nucleus (STN) is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. In terms of anatomy, it is the major part of the subthalamus. As suggested by its name, the ...
.


Neuroablative lesion surgery

Neuroablative lesion surgery locates and destroys, by heat, the parts of the brain associated with producing Parkinsonian
neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal ...
symptoms. The procedures generally involve a thalamotomy and/or pallidotomy. A thalamotomy is the destruction of a part of the thalamus, in particular the ventralis intermedius, to suppress tremor in 80-90% of patients. If rigidity and akinesia are apparent, the subthalamis nucleus is then the site of ablation. A pallidotomy involves the destruction of the globus pallidus, in particular the globus pallidus interna, in patients with Parkinson's who have rigidity and akinesia. Because it is difficult to accurately measure the amount of tissue to be destroyed,
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
s not uncommonly persist through multiple courses of surgery, since tissue is irreversibly damaged and removed and testing smaller areas of tissue is safer to prevent serious complications, such as a
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
or
paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
.. This method has been generally replaced by deep brain surgery.


Deep brain stimulation

Deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleu ...
(DBS) is presently the most used method of surgical treatment because it does not destroy brain tissue, it is reversible, and it can be tailored to individuals at their particular stage of disease. DBS employs three hardware components: a
neurostimulator Neurostimulation is the purposeful modulation of the nervous system's activity using invasive (e.g. microelectrodes) or non-invasive means (e.g. transcranial magnetic stimulation or transcranial electric stimulation, tES, such as tDCS or transcr ...
, also called an implanted pulse generator (IPG), which generates electrical impulses used to modulate neural activity, a lead wire which directs the impulses to a number of metallic
electrode An electrode is an electrical conductor used to make contact with a nonmetallic part of a circuit (e.g. a semiconductor, an electrolyte, a vacuum or air). Electrodes are essential parts of batteries that can consist of a variety of materials de ...
s towards the tip of the lead near the stimulation target, and an extension wire that connects the lead to the IPG. The IPG, which is battery-powered and encased in titanium, is traditionally implanted under the collarbone, and is connected by the subcutaneous extension to the lead, which extends from outside the skull under the scalp down into the brain to the target of stimulation. The IPG, or the entire three-component system, are sometimes referred to as a brain pacemaker, due to the precedence and renown of
cardiac pacemakers 350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical conduction system of the heart. The muscle contraction, contraction of cardiac muscle (heart muscle) in all animals is initiated by electrical ...
and similarities in the components of both types of systems. The preoperative targeting of proper implantation sites can be accomplished by the indirect and direct methods. The indirect method uses computer tomography, magnetic resonance imaging, or ventriculography to locate the anterior and posterior commissures and then employs predetermined coordinates and distances from the intercommissural line to define the target area. Subsequent histologically defined atlas maps can also be used to verify the target area. The direct method provides visualization and targeting of deep nuclei by applying stereotactic preoperative MRI, which unlike the indirect method, takes into account the anatomic variation of the nuclei's size, position, and functional segregation amongst individuals. Electrophysial functional mapping, a tool used in both methods to verify the target nuclei, has come under scrutiny due to its associated risks of hemorrhages,
dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...
or tetanic contractions. Recently, susceptibility-weighted imaging, a type of MRI, has shown incredible power in its ability to distinguish these deep brain nuclei and is being used in DBS to reduce the overuse of EFM. DBS is recommended to PD patients without important neuropsychiatric
contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
s who have motor fluctuations and tremor badly controlled by medication, or to those who are intolerant to medication. DBS is effective in suppressing symptoms of PD, especially tremor. A recent clinical study led to recommendations on identifying which Parkinson's patients are most likely to benefit from DBS.


Diet

Muscles and nerves that control the digestive process may be affected by PD, so it is common to experience
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
and
gastroparesis Gastroparesis (gastro- from Ancient Greek γαστήρ – gaster, "stomach"; and -paresis, πάρεσις – "partial paralysis"), also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) ...
(food remaining in the stomach for a longer period of time than normal). A balanced diet is recommended to help improve digestion. Diet should include high-
fiber Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...
foods and plenty of water. Levodopa and proteins use the same transportation system in the intestine and the blood–brain barrier, competing between them for access. When taken together, the consequences of such competition is a reduced effectiveness of the drug. Therefore, when levodopa is introduced, excessive
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
are discouraged, while in advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons. To minimize interaction with proteins, levodopa is recommended to be taken 30 minutes before meals. At the same time, regimens for PD restrict proteins during breakfast and lunch and are usually taken at dinner. As the disease advances,
dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right. It may be a sensation that suggests difficulty in the passag ...
may appear. In such cases, specific measures include the use of
thickening agent A thickening agent or thickener is a substance which can increase the viscosity of a liquid without substantially changing its other properties. Edible thickeners are commonly used to thicken sauces, soups, and puddings without altering their t ...
s for liquid intake, special postures when eating, and
gastrostomy Gastrostomy is the creation of an artificial external opening into the stomach for nutritional support or gastric decompression. Typically this would include an incision in the patient's epigastrium as part of a formal operation. It can be perfor ...
in the worst cases.


Rehabilitation

Studies of rehabilitation in
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
are scarce and are of low quality. Partial evidence indicates speech or mobility problems can improve with rehabilitation. Regular
physical exercise Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
and/or
therapy A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...
can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Exercise may also improve
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
. Exercise interventions have been shown to benefit patients with Parkinson's disease in regards to physical functioning, health-related quality of life, and balance and fall risk. In a review of 14 studies examining the effects of exercise on persons with Parkinson's disease, no adverse events or side effects occurred following any of the exercise interventions. Five proposed mechanisms by which exercise enhances neuroplasticity are known. Intensive activity maximizes synaptic plasticity; complex activities promote greater structural adaptation; activities that are rewarding increase dopamine levels and therefore promote learning/relearning; dopaminergic neurones are highly responsive to exercise and inactivity ("use it or lose it"); and where exercise is introduced at an early stage of the disease, progression can be slowed. One of the most widely practiced treatments 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. Speech therapy and specifically LSVT may improve voice and speech function.
Occupational therapy Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...
(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. Few studies have been conducted on the effectiveness of OT and their quality is poor, although some indication shows it may improve motor skills and quality of life for the duration of the therapy. For monitoring patients with Parkinson's disease, research teams are examining whether virtual house calls can replace visits to clinical facilities. In a trial of such video visits, patients preferred the remote specialist after 1 year. The home care was considered convenient but requires access to and familiarity with Internet-enabled technologies.


Exercise

Regular
physical exercise Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
with or without
physiotherapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...
can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Parkinson's Disease often causes sedentary behaviours resulting in lower quality of life in the long-term. In terms of improving flexibility and range of motion for patients 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 Diaphragmatic breathing, abdominal breathing, belly breathing, or deep breathing, is breathing that is done by contracting the diaphragm, a muscle located horizontally between the thoracic cavity and abdominal cavity. Air enters the lungs as the ...
, and
meditation Meditation is a practice in which an individual uses a technique – such as mindfulness, or focusing the mind on a particular object, thought, or activity – to train attention and awareness, and achieve a mentally clear and emotionally cal ...
techniques. Common changes in gait associated with the disease such as
hypokinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sym ...
(slowness of movement), shuffling and decreased arm swing are addressed by a variety of strategies to improve functional mobility and safety. Goals with respect to gait during rehabilitation programs include improving gait speed, 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 varying environments (surfaces, inputs, open vs. closed). Strengthening exercises have led to improvements in strength and motor functions in patients with primary muscular weakness and weakness related to inactivity in cases of mild to moderate Parkinson's disease. Patients perform exercises when at their best, 45 minutes to one hour after medication. An 8-week resistance training study geared towards the lower legs found that patients with Parkinson's Disease gained abdominal strength, and improved in their stride length, walking velocity and postural angles. Also, due to the forward flexed posture and respiratory dysfunctions in advanced Parkinson's disease, deep diaphragmatic breathing exercises are beneficial for improving chest wall mobility and vital capacity. Exercise may correct constipation. Exercise training on a vibratory platform, also called
whole body vibration Whole body vibration is a generic term used when vibrations (mechanical oscillations) of any frequency are transferred to the human body. Humans are exposed to vibration through a contact surface that is in a mechanical vibrating state. Humans are ...
(WBV) training, has been recently introduced as a training tool complementing standard physical rehabilitation programs for people with Parkinson's disease. Compared to no intervention, single sessions of WBV have resulted in improved motor ability, as reflected by Unified Parkinson's Disease Rating Scale (UPDRS)
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
and rigidity scores. However, longer-term (3–5 weeks) WBV programs have not led to improved UPDRS motor scores compared to conventional exercises. Furthermore, multiple sessions of WBV have failed to enhance mobility measures (i.e., the
Timed Up and Go Test timed (time daemon (computing), daemon) is an Daemon (computing), operating system program that maintains the system time in synchronization with time servers using the Time Synchronization Protocol (TSP) developed by Riccardo Gusella and Stefa ...
an
10-Meter Walking Test
in people with Parkinson's disease. A recent review deemed that the evidence of the effects of WBV training on sensorimotor and functional performance remains inconclusive.


Psychological treatments

Psychological treatment is based on cognitive-behavioral interventions.
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) is a psycho-social intervention that aims to reduce symptoms of various mental health conditions, primarily depression and anxiety disorders. CBT focuses on challenging and changing cognitive distortions (suc ...
is confirmed as efficient for treatment of parkinsonian pain, insomnia, anxiety, depression, and impulse control disorders. Treating Parkinson's disease engages a multidisciplinary approach, and includes a psychologist, because motor symptoms can be worsened by psychosocial factors like anxiety, phobia, and panic attacks. Psychological treatment is tailored to each individual, based on clinical recommendations, especially if they have severe motor disability or cognitive problems.


Gait training

Patients with Parkinson's disease have an altered gait. There is a reduced gait speed and step length, increased axial rigidity, and impaired rhythmicity. These gait problems worsen as the disease continues. This is a major disease burden that markedly affects independence and quality of life. Since it is proven that tremor-dominant and akinetic rigid types of Parkinson's disease have various different visuomotor deficiencies, like problems in visual perception and motor coordination, that can influence their gait training, it is recommended for them to receive neuropsychological assessment before physical therapy. Task-specific gait training may also lead to long-term gait improvement for patients with Parkinson's disease. Previous research studies have utilized body weight support systems during gait training, where individuals are suspended from an overhead harness with straps around the pelvic girdle as they walk on a treadmill. This form of gait training has been shown to improve long-term walking speed and a shuffling gait following a one-month intervention period. Studies are also looking at the effect of tai chi on gait performance, and balance in people with Parkinson's Disease. The first study concluded that tai chi was ineffective since there was no improvement on gait performance and no improvement on the Part III score of the Unified Parkinson's Disease Rating Scale (UPDRS). The second study found that patients taking tai chi improved on their UPDRS score, Timed Up and Go test, six-minute walk and backwards walking. It did not however, show any improvements on their forward walking or their one leg stance test.


Speech and occupational therapy

One of the most widely practiced treatments for speech disorders associated with Parkinson's disease is the Lee Silverman voice treatment (LSVT). Speech therapy and specifically LSVT may improve speech. People with Parkinson's disease can develop dysarthria which is characterized by reduced speech intelligibility. Prosodically based treatments may help.
Occupational therapy Occupational therapy (OT) is a global healthcare profession. It involves the use of assessment and intervention to develop, recover, or maintain the meaningful activities, or ''occupations'', of individuals, groups, or communities. The field of ...
aims to promote health and quality of life by helping people with the disease to participate in as much of their daily routine as possible. There is indication that occupational therapy may improve motor skills and quality of life for the duration of the therapy.


Rhythmic auditory stimulation

Rhythmic auditory stimulation (RAS) is a neurological rehabilitation technique consisting in compensating the loss of motor regulation through an external sensory stimulation, mediated by the sound. This technique relies on the strong interaction between auditory and motor neural system. By synchronizing his footsteps on the emitted sound (that can be "metronome-like" cues or complex music) the patient can improves his gait speed and his stride length.


Telemedicine

A 2017 one-year randomized controlled trial found that providing remote neurologic care to individuals with Parkinson's Disease in their own homes was feasible and as effective as in-person care. While it can be more difficult for remote caregivers to establish trust while providing remote care, that assessment of video visits in a patient's home found that, after four virtual visits over one year, individuals with Parkinson's Disease preferred their connection with the remote specialist to their local clinician. Benefits of telemedicine include convenience and cost-effectiveness, as the virtual in-home visits have been found to reduce travel costs and time for patients relative to in-office visits. Some studies have found that the technology supports personalized connections similar to the house calls of the past. Five randomized controlled trials indicated that quality of life was similar or improved for those receiving telemedicine care. Challenges related to telemedicine in treatment of individuals with Parkinson's Disease are related to the technological requirements, as patients and their friends or families must have access to and familiarity with Internet-based technologies. In part because of these technological requirements, studies in the United States have tended to include few participants from ethnic minorities and disproportionately include more highly educated populations. One solution proposed to reduce social and economic barriers to access to remote care is to establish satellite teleneurology clinics in underserved regions. Physicians cite barriers with inability to perform a full neurologic exam in addition to technology and reimbursement issues. New telemedicine technologies being used or evaluated in the context of telemedicine include proprietary wearables, self-sensing and adjusting closed loop systems, robotic technologies, smart devices to detect movements, programs to improve medication adherence, smart home integration, and artificial intelligence or machine learning-based systems.


Palliative care

Palliative care Palliative care (derived from the Latin root , or 'to cloak') is an interdisciplinary medical caregiving approach aimed at optimizing quality of life and mitigating suffering among people with serious, complex, and often terminal illnesses. Wit ...
is often required in the final stages of the disease, often when dopaminergic treatments have become ineffective. The aim of palliative care is to achieve the maximum quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative are caring for patients at home while adequate care can be given there, reducing or withdrawing dopaminergic drug intake to reduce drug side effects and complications, preventing
pressure ulcer Pressure ulcers, also known as pressure sores, bed sores or pressure injuries, are localised damage to the skin and/or underlying tissue that usually occur over a bony prominence as a result of usually long-term pressure, or pressure in combi ...
s by management of pressure areas of inactive patients, and facilitating the patient's end-of-life decisions for the patient, as well as involved friends and relatives.


Other treatments

Repetitive transcranial magnetic stimulation Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation in which a changing magnetic field is used to induce an electric current at a specific area of the brain through electromagnetic induction. An electric pulse gener ...
temporarily improves levodopa-induced dyskinesias. Its full usefulness in PD is an open research field. Different
nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excret ...
s have been proposed as possible treatments; however, no evidence shows
vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an Nutrient#Essential nutrients, essential micronutrient that an organism needs in small quantities for the proper functioning of its ...
s or
food additive Food additives are substances added to food to preserve flavor or enhance taste, appearance, or other sensory qualities. Some additives have been used for centuries as part of an effort to preserve food, for example vinegar (pickling), salt (salt ...
s improve symptoms. Not enough evidence exists to suggest that
acupuncture Acupuncture is a form of alternative medicine and a component of traditional Chinese medicine (TCM) in which thin needles are inserted into the body. Acupuncture is a pseudoscience; the theories and practices of TCM are not based on scientifi ...
, and practice of ''
qigong ''Qigong'' (), ''qi gong'', ''chi kung'', ''chi 'ung'', or ''chi gung'' () is a system of coordinated body-posture and movement, breathing, and meditation used for the purposes of health, spirituality, and martial-arts training. With roots in ...
'' or ''
t'ai chi Tai chi (), short for Tai chi ch'üan ( zh, s=太极拳, t=太極拳, first=t, p=Tàijíquán, labels=no), sometimes called " shadowboxing", is an internal Chinese martial art practiced for defense training, health benefits and meditation. ...
'' have any effect on symptoms.
Fava ''Vicia faba'', commonly known as the broad bean, fava bean, or faba bean, is a species of vetch, a flowering plant in the pea and bean family Fabaceae. It is widely cultivated as a crop for human consumption, and also as a cover crop. Varieti ...
and
velvet Weave details visible on a purple-colored velvet fabric Velvet is a type of woven tufted fabric in which the cut threads are evenly distributed, with a short pile, giving it a distinctive soft feel. By extension, the word ''velvety'' means ...
beans are natural sources of L-DOPA and are taken by many people with PD. While they have shown some effectiveness, their intake is not free of risks. Life-threatening adverse reactions have been described, such as the
neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare but life-threatening reaction that can occur in response to neuroleptic or antipsychotic medication. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fas ...
.
Faecal transplants Fecal microbiota transplant (FMT), also known as a stool transplant, is the process of transferring fecal bacteria and other microbes from a healthy individual into another individual. FMT is an effective treatment for ''Clostridioides diffici ...
may have a beneficial impact on symptoms.


History

The positive albeit modest effects of
anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous system ...
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
s obtained from the plant of the belladonna were described during the 19th century by Charcot, Erb, and others. Modern surgery for tremor, consisting of the lesioning of some of the basal ganglia structures was first tried in 1939, and was improved over the following 20 years. Before this date, surgery consisted in lesioning the
corticospinal pathway The pyramidal tracts include both the corticobulbar tract and the corticospinal tract. These are aggregations of efferent nerve fibers from the upper motor neurons that travel from the cerebral cortex and terminate either in the brainstem (''cort ...
with
paralysis Paralysis (also known as plegia) is a loss of motor function in one or more muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory damage. In the United States, roughly 1 in 50 ...
instead of tremor as result. Anticholinergics and surgery were the only treatments until the arrival of levodopa, which reduced their use dramatically.
Levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...
was first synthesized in 1911 by
Casimir Funk Kazimierz Funk (; February 23, 1884 – November 19, 1967), commonly anglicized as Casimir Funk, was a Polish-American biochemist generally credited with being among the first to formulate (in 1912) the concept of vitamins, which he called "vita ...
, but it received little attention until the mid-20th century. It entered clinical practice in 1967, and the first large study reporting improvements in people with Parkinson's disease resulting from treatment with levodopa was published in 1968. Levodopa brought about a revolution in the management of PD. By the late 1980s
deep brain stimulation Deep brain stimulation (DBS) is a neurosurgical procedure involving the placement of a medical device called a neurostimulator, which sends electrical impulses, through implanted electrodes, to specific targets in the brain (the brain nucleu ...
emerged as a possible treatment, and it was approved for clinical use by the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
in 1997.


Research directions

No new PD treatments are expected in the short term, but several lines of research are active for new treatments. Such research directions include the search of new
animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...
s of the disease, and the potential usefulness of gene therapy,
stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
s transplants, and
neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
agents.


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 An opiate, in classical pharmacology, is a substance derived from opium. In more modern usage, the term ''opioid'' is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonis ...
MPPP Desmethylprodine or 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP, Ro 2-0718) is an opioid analgesic drug developed in the 1940s by researchers at Hoffmann-La Roche. Desmethylprodine has been labeled by the DEA as a Schedule I drug in the U ...
brought to light
MPTP MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a prodrug to the neurotoxin MPP+, which causes permanent symptoms of Parkinson's disease by destroying dopaminergic neurons in the substantia nigra of the brain. It has been used to study d ...
as a cause of parkinsonian symptoms. Other predominant toxin-based models employ the insecticide
rotenone Rotenone is an odorless, colorless, crystalline isoflavone used as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the seeds and stems of several plants, such as the jicama vine plant, and the roots of several member ...
, the herbicide
paraquat Paraquat (trivial name; ), or ''N'',''N''′-dimethyl-4,4′-bipyridinium dichloride (systematic name), also known as methyl viologen, is an organic compound with the chemical formula C6H7N)2l2. It is classified as a viologen, a family of redox ...
, and the fungicide
maneb Maneb is a fungicide and a polymeric complex of manganese with the ethylene bis(dithiocarbamate) anionic ligand.Arno H. Reidies "Manganese Compounds" Ullmann's Encyclopedia of Chemical Technology 2007; Wiley-VCH, Weinheim. Applications It can be ...
. Models based on toxins are most commonly used in
primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians (monkeys and apes, the latter including huma ...
s.
Transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...
models also exist.


Gene therapy

Present treatments of Parkinson's disease provide satisfactory disease control for most early-stage patients. However, present gold-standard treatment of PD using levodopa is associated with motor complications, and does not prevent disease progression. More effective and long-term treatment of PD are urgently needed to control its progression. ''In vivo'' gene therapy is a new approach for treatment of PD. The use of somatic-cell gene transfer to alter gene expression in brain neurochemical systems is a novel alternative conventional treatment. Gene therapy is currently under investigation. It involves the use of a noninfectious
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
to shuttle a gene into a part of the brain. The gene used leads to the production of an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
which helps to manage PD symptoms or protects the brain from further damage. One of the gene therapy based approach involves gene delivery of
neurturin Neurturin (NRTN) is a protein that is encoded in humans by the ''NRTN'' gene. Neurturin belongs to the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, which regulate the survival and function of neurons. Neur ...
and
glial cell line-derived neurotrophic factor Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particula ...
(GDNF) to the putamen in patients with advanced Parkinson's disease. GDNF protects dopamine neurons ''in vitro'' and animal models of parkinsonism; neurturin is a structural and functional analogue of GDNF that protected dopamine neuron in animal model of the disease. Despite open-label trials showing benefits of continuous infusion of GDNF, the results were not confirmed in double-blind studies. This may be due to the distribution factor; the trophic factor was not distributed sufficiently throughout the target place. Another gene therapy of PD involved insertion of the glutamic acid decarboxylase (GAD) into the subthalamic nucleus. GAD enzyme controls GABA productions. In Parkinson's disease, the activity of both GABA efferents to the subthalamic nucleus and its target within the basal ganglia circuitry are affected. This strategy used adeno-associated viral vector (AAV2) to deliver GAD to the subthalamic nucleus. The trial was done to compare the effect of bilateral delivery of AAV2-GAD into the subthalamic nucleus with bilateral sham surgery in patients with advanced Parkinson's disease. The study showed the first success of randomised, double-blind gene therapy trial for a neurodegenerative disease and justified the continued development of AAV2-GAD for treatment of PD.


Neuroprotective treatments

Investigations on
neuroprotection Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...
are at the forefront of PD research. Currently, no proven neuroprotective agents or treatments are available for PD. While still theoretical, neuroprotective therapy is based on the idea that certain
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s that produce
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and are susceptible to premature degeneration and cell death can be protected by the introduction of neuroprotective
pharmaceuticals A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and rel ...
. This protection can occur before any symptoms manifest based on genetic risk, and also during early- or late-stage PD when other treatments have ceased their impact due to the progression of the disease. Accordingly, neuroprotective therapy seeks to delay the introduction of levodopa. Several molecules have been proposed as potential treatments. However, none of them has been conclusively demonstrated to reduce degeneration. Agents currently under investigation include antiapoptotics ( omigapil, CEP-1347), antiglutamatergics,
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The first ...
inhibitors (
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It is provided in the form of a capsule or ...
,
rasagiline Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The racemic form of the drug was invented by ...
), promitochondrials (
coenzyme Q10 Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...
,
creatine Creatine ( or ) is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various modifications (tautomers) in solution. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate ( ...
),
calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s (
isradipine Isradipine (tradenames DynaCirc, Prescal) is a calcium channel blocker of the dihydropyridine class. It is usually prescribed for the treatment of high blood pressure in order to reduce the risk of stroke and heart attack. It was patented in 197 ...
) and
growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s (
GDNF Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particula ...
). Preclinical research also targets
alpha-synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...
.


Selegiline

Selegiline is in a group of medications called monoamine oxidase type B (
MAO-B Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. ...
) inhibitors. Selegiline is used to help control the symptoms of Parkinson's disease in people who are taking levodopa and carbidopa combination (Sinemet). Selegiline may help people with PD by stopping the effects of levodopa/carbidopa from wearing off, and increasing the length of time levodopa/carbidopa continues to control symptoms.


Rasagiline

In response to potentially toxic
amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s caused by selegiline, another promising treatment is in MAO B
propargyl In organic chemistry, the propargyl group is a functional group of 2-propynyl with the structure . It is an alkyl group derived from propyne (). The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framework n ...
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
inhibitor
rasagiline Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The racemic form of the drug was invented by ...
(N-propargyl-1-R-aminoindan, Azilect((R))). The oral
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
of rasagiline is 35%, it reaches T(max) after 0.5–1.0 hours and its half-life is 1.5–3.5 hours. Rasagiline undergoes extensive hepatic
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
primarily by
cytochrome Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bin ...
P450 type 1A2 (CYP1A2).
Rasagiline Rasagiline (Azilect, Azipron) is an irreversible inhibitor of monoamine oxidase-B used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advanced cases. The racemic form of the drug was invented by ...
is initiated at 1-mg once-daily dose as
monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...
in early PD patients and at 0.5–1.0 mg once-daily as adjunctive to levodopa in advanced PD patients.


Neural transplantation

Since early in the 1980s
fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...
,
porcine The pig (''Sus domesticus''), often called swine, hog, or domestic pig when distinguishing from other members of the genus '' Sus'', is an omnivorous, domesticated, even-toed, hoofed mammal. It is variously considered a subspecies of ''Sus s ...
,
carotid In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
l tissues have been used in cell transplants for PD patients. Although there was initial evidence of
mesencephalic The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...
dopamine-producing cell transplants being beneficial, the best constructed studies up to date indicate that cell transplants have no effect. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
s.
Stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...
transplants are a main research recent target: they are easy to manipulate and when transplanted into the brains of
rodent Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are na ...
s and
monkey Monkey is a common name that may refer to most mammals of the infraorder Simiiformes, also known as the simians. Traditionally, all animals in the group now known as simians are counted as monkeys except the apes, which constitutes an incomple ...
s, cells survive and improve behavioral abnormalities of the animals. Nevertheless, use of fetal stem cells is
controversial Controversy is a state of prolonged public dispute or debate, usually concerning a matter of conflicting opinion or point of view. The word was coined from the Latin ''controversia'', as a composite of ''controversus'' – "turned in an opposite ...
. Some have proposed that such controversy may be overcome with the use of
induced pluripotent stem cell Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in ...
s from adults.


References


External links


Parkinson's Medication Chart
at th
Parkinson's Disease Foundation

PDtrials

Find What Treatments Are Possible
{{DEFAULTSORT:Treatments Of Parkinson's Disease Parkinson's disease