Management of Parkinson's disease: Difference between revisions

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Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.
Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.


===Rehabilitation===
==Physical exercise==
There is partial evidence that speech or mobility problems can improve with rehabilitation although studies are scarce and of low quality.<ref name="Nice-rehab">{{cite book |chapter= Other key interventions|editor=The National Collaborating Centre for Chronic Conditions| title=[http://guidance.nice.org.uk/CG35/Guidance/pdf/English Parkinson's Disease]| publisher=Royal College of Physicians|location=London| year=2006| isbn= 1-86016-283-5|pages= 135–146}}</ref><ref name="pmid18181210">{{cite journal |author=Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL |title=The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis |journal=Movement Disorders |volume=23 |issue=5 |pages=631–40 |year=2008 |month=April |pmid=18181210 |doi=10.1002/mds.21922}}</ref> Regular [[physical exercise]] and/or [[Physical therapy|therapy]] can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.<ref name="pmid18181210"/> Exercise may also improve constipation.<ref name="pmid19691125"/> One of the most widely practiced [[Speech therapy|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.<ref name="Nice-rehab"/><ref name="pmid17117354">{{cite journal |author=Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG |title=The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders |journal=Seminars in Speech and Language |volume=27 |issue=4 |pages=283–99 |year=2006 |month=November |pmid=17117354 |doi=10.1055/s-2006-955118}}</ref> Speech therapy and specifically LSVT may improve voice and speech function.<ref name="Nice-rehab"/> [[Occupational therapy]] (OT) aims to promote health and quality of life by helping people with the disease to participate in as many [[Daily living skills|activities of their daily living]] as possible.<ref name="Nice-rehab"/> 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.<ref name="Nice-rehab"/><ref name="pmid17636709">{{cite journal |author=Dixon L, Duncan D, Johnson P, ''et al.'' |title=Occupational therapy for patients with Parkinson's disease |journal=Cochrane Database Syst Rev |volume= |issue=3 |pages=CD002813 |year=2007 |pmid=17636709 |doi=10.1002/14651858.CD002813.pub2 |url=}}</ref>
Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion. Research shows that exercises may change the brain, which makes an impact on Parkinson’s disease symptom.<ref>http://www.pdf.org/en/fall09_exercise_parkinsons</ref>


==Researching New Treatments==
==Researching New Treatments==

Revision as of 15:39, 5 January 2011

As Parkinson's disease is a chronic disorder, Treatment of Parkinson's Disease requires broad-based management including patient and family education, support group services, general wellness maintenance, exercise, and nutrition. At present, there is no cure for PD, but medications or surgery can provide relief from the symptoms.

While many medications treat Parkinson's, none actually reverse the effects of the disease or cure it. People with Parkinson's therefore often must take a variety of medications to manage the disease's symptoms.[1] The Parkinson's Disease Foundation (PDF) has a chart on its website that provides details about Parkinson's medications.

Several medications currently in development seek to better address motor fluctuations and nonmotor symptoms of Parkinson's Disease. However, none are yet on the market with specific approval to treat Parkinson's.[2]

Pharmacologic treatment

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.[3] L-DOPA is transformed into dopamine in the dopaminergic neurons by dopa-decarboxylase.[3] Since motor symptoms are produced by a lack of dopamine in the substantia nigra the administration of L-DOPA temporarily diminishes the motor symptomatology.[3]

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.[3] Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors.[3] 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.[3] 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.[4]

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.[3]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.[3] It has been used to complement levodopa. However, due to its possible side effects such as liver failure, it's limited in its availability.[3] A similar drug, entacapone has not been shown to cause significant alterations of liver function and maintains adequate inhibition of COMT over time.[3] Entacapone is available for treatment alone (COMTan) or combined with carbidopa and levodopa (Stalevo).[3]

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.[3] 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).[3] For this reason levodopa doses are kept as low as possible while maintaining functionality.[3] Delaying the initiation of dopatherapy, using instead alternatives for some time, is also common practice.[3] 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.[3] Most people will eventually need levodopa and later develop motor complications.[3]

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 that the importance of levodopa handling has been underestimated and that progressive reduction in the storage capacity of surviving nigrostriatal dopamine terminals is not a critical factor. Re-distribution 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, the use of selegiline hydrochloride and bromocriptine may also temporarily improve motor fluctuations. New approaches to management include the use of subcutaneous apomorphine, controlled-release preparations of levodopa with a peripheral dopa decarboxylase inhibitor and the continuous intra-duodenal administration of levodopa.

Dopamine agonists

Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic post-synaptic receptors.[3] 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.[3][5] When used in late PD they are useful at reducing the off periods.[3] 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.[3] 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.[3] When compared with levodopa, while they delay motor complications they control worse symptoms.[3] Nevertheless they are usually effective enough to manage symptoms in the initial years.[6] They are also more expensive.[6] Dyskinesias with dopamine agonists are rare in younger patients, but along other side effects more common in older patients.[6] All this has led to agonists being the preferential initial treatment for the former as opposed to levodopa in the latter.[6] Agonists at higher doses have also been related to a wide variety of impulse control disorders.[4]

Apomorphine, which is a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[3] Since secondary effects such as confusion and hallucinations are not rare it has been recommended that patients under apomorphine treatment should be closely monitored.[3] Apomorphine can be administered via 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 (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 pen for emergency doses such as after a fall or first thing in the morning. Nausea and vomiting are common, and may require domperidone (an antiemetic).

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.[3] 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.[3] Although an initial study had as result that selegiline in combination with levodopa increased the risk of death this has been later disproven.[3]

Metabolites of selegiline include L-amphetamine and L-methamphetamine (not to be confused with the more notorious and potent dextrorotary isomers). This might result in side effects such as insomnia. Another side effect of the combination can be stomatitis. Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.

Other drugs

There is some indication that other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms in early and late PD, but since quality of evidence on efficacy is reduced they are not first choice treatments.[3] In addition to motor PD is accompanied by an ample range of different symptoms. Different compounds are used to improve some of these problems.[7] Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia and modafinil for day somnolence.[7][8]

A preliminary study indicates that taking the drug donepezil (Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts levels of the neurotransmitter acetylcholine, and is currently an approved therapy for the cognitive symptoms of Alzheimer's disease.[9] 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.[10]

The introduction of clozapine (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 antipsychotics useful in treatment include quetiapine (Seroquel), ziprasidone (Geodon), aripiprazole (Abilify), and paliperidone (Invega). Clozapine is believed to have the highest efficacy and lowest risk of extrapyramidal side effect.[8]

Surgical interventions

Illustration showing an electrode placed deep seated in the brain

Treating PD with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases.[11] 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.[11]

Less than 10% of PD sufferers qualify as suitable candidates for a surgical response. There are three different mechanisms of surgical response for PD: ablative surgery, (the irreversible burning or freezing of brain tissue) stimulation surgery or deep brain stimulation (DBS), and transplantation or restorative surgery. [12]

Target areas for DBS or lesions include the thalamus, the globus pallidus (the lesion technique being called pallidotomy) or the subthalamic nucleus.[11]

Ablation

Ablative surgery locates and destroys the part of the brain that is associated with the neurological symptoms.

Because it is difficult to accurately measure the amount of tissue to be destroyed, it is not uncommon for tremors to persist through multiple courses of surgery since tissue is irreversibly damaged and removed and it is safer to test smaller areas of tissue to prevent serious complications, such as a stroke or paralysis.[citation needed]

Deep Brain Stimulation

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.[11] DBS consists of 3 components: a battery-powered, titanium-encased neurostimulator that interrupts neural activity via electrical impulses, a lead wire that directs the impulse, and an extension wire that connects the lead to the neurostimulator, also called an implanted pulse generator. DBS involves the implantation of an electrode called a brain pacemaker deep in the brain, which sends electrical impulses to specific parts of the brain. The electrode is connected to a battery pack that implanted under the collarbone via a subcutaneous wire.

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.[13]

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. [14]

Other

Currently under investigation is gene therapy. This involves using a harmless virus to shuttle a gene into a part of the brain called the subthalamic nucleus (STN). The gene used leads to the production of an enzyme called glutamic acid decarboxylase (GAD), which catalyses the production of a neurotransmitter called GABA. GABA acts as a direct inhibitor on the overactive cells in the STN.

GDNF infusion involves, by surgical means, the infusion of GDNF (glial-derived neurotrophic factor) into the basal ganglia using implanted catheters. Via a series of biochemical reactions, GDNF stimulates the formation of L-dopa. GDNF therapy is still in development.

In the future, implantation of cells genetically engineered to produce dopamine or stem cells that transform into dopamine-producing cells may become available. Even these, however, will not constitute cures because they do not address the considerable loss of activity of the dopaminergic neurons.

Nutrients

Nutrients have been used in clinical studies and are widely used by people with Parkinson's disease in order to partially treat Parkinson's disease or slow down its deterioration. The L-dopa precursor L-tyrosine was shown to relieve an average of 70% of symptoms.[15] Ferrous iron, the essential cofactor for L-dopa biosynthesis was shown to relieve between 10% and 60% of symptoms in 110 out of 110 patients.[16] [17]

More limited efficacy has been obtained with the use of THFA, NADH, and pyridoxine—coenzymes and coenzyme precursors involved in dopamine biosynthesis. They now constitute largely experimental methods and former treatments rather than common medical practice. Vitamin C and vitamin E in large doses are commonly used by patients in order to theoretically lessen the cell damage that occurs in Parkinson's disease. This is because the enzymes superoxide dismutase and catalase require these vitamins in order to nullify the superoxide anion, a toxin commonly produced in damaged cells. However, in the randomized controlled trial, DATATOP of patients with early PD, no beneficial effect for vitamin E compared to placebo was seen[18]

Coenzyme Q10 has more recently been used for similar reasons. MitoQ is a newly developed synthetic substance that is similar in structure and function to coenzyme Q10. However, proof of benefit has not been demonstrated yet.

Rehabilitation

There is partial evidence that speech or mobility problems can improve with rehabilitation although studies are scarce and of low quality.[19][20] Regular physical exercise and/or therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[20] Exercise may also improve constipation.[21] 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.[19][22] Speech therapy and specifically LSVT may improve voice and speech function.[19] 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.[19] 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.[19][23]

Researching New Treatments

Many of the treatments described above need further testing in clinical trials before they become available to patients with Parkinson's. However, the lack of participation in trials by people with Parkinson's delays the development of these treatments and their delivery to the Parkinson's community.[24]

To address this problem, a number of Parkinson's organizations have collaborated on PDtrials, an initiative dedicated to increasing education and awareness about clinical research. Central to this initiative is the www.pdtrials.org website that provides information and education about Parkinson's disease clinical research, and provides a portal for people with Parkinson's to search for specific clinical trials using criteria such as location, trial type, and symptom.

Due to the pervasive nature of PD, typical medical measures are occasionally ignored in favor of more experimental and controversial methods of treatment. A study, as of April, 2009, is underway to showcase any benefit of low-level electromagnetic fields to the cells health. Related, a study of repetitive magnetic brain stimulation has also been introduced, where a device creates a short-lasting magnetic field which induces an electric current (50 Hz) in the brain. These are called transcranial magnetic stimulations (TMS), and hope to change the electrical activity on a cellular level.

Neuroprotective Therapy

While still theoretical, neuroprotective therapy is based on the idea that certain neurons that produces dopamine and are susceptible to premature degeneration and cell death can be protected by the introduction of neuroprotective pharmaceuticals. 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. While the introduction of levodopa, a dopamine precursor, was a great medical leap in PD treatment, motor complications of chronic levodopa therapy have emerged as a major limitation in an otherwise effective therapy. [25].

Accordingly, neuroprotective therapy seeks to delay the introduction of levodopa. Selegiline is used to help control the symptoms of Parkinson's disease in people whom are taking levodopa and carbidopa combination (Sinemet). Selegiline may help people with Parkinson's disease by... stopping the effects of levodopa/carbidopa from wearing off, and increasing the length of time that levodopa/carbidopa will continue to control symptoms. Selegiline is in a group of medications called monoamine oxidase type B (MAO-B) inhibitors. [26]

In response to potentially toxic amphetamine metabolites caused by selegiline, another promising treatment is in MAO B propargyl amine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect((R))). The oral bioavailability of rasagiline is 35%, it reaches T(max) after 0.5-1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5-1 mg once-daily as adjunctive to levodopa in advanced PD patients. [27]

References

  1. ^ http://www.pdf.org/en/meds_treatments
  2. ^ http://www.pdf.org/fall08_medications
  3. ^ 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 Cite error: The named reference Nice-pharma was invoked but never defined (see the help page).
  4. ^ a b Ceravolo R, Frosini D, Rossi C, Bonuccelli U (2009). "Impulse control disorders in Parkinson's disease: definition, epidemiology, risk factors, neurobiology and management". Parkinsonism Relat. Disord. 15 Suppl 4: S111–5. doi:10.1016/S1353-8020(09)70847-8. PMID 20123548. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Goldenberg MM (2008). "Medical management of Parkinson's disease". P & T. 33 (10): 590–606. PMC 2730785. PMID 19750042. {{cite journal}}: Unknown parameter |month= ignored (help)
  6. ^ a b c d Samii A, Nutt JG, Ransom BR (2004). "Parkinson's disease". Lancet. 363 (9423): 1783–93. doi:10.1016/S0140-6736(04)16305-8. PMID 15172778. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ a b The National Collaborating Centre for Chronic Conditions, ed. (2006). "Non-motor features of Parkinson's disease". Parkinson's Disease. London: Royal College of Physicians. pp. 113–133. ISBN 1-86016-283-5. {{cite book}}: External link in |title= (help)
  8. ^ a b Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, Pandurangi AK (2009). "Pharmacological management of psychosis in elderly patients with parkinsonism". Am. J. Med. 122 (7): 614–22. doi:10.1016/j.amjmed.2009.01.025. PMID 19559160. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Donepezil (Aricept®) Reduces Falls in People with Parkinson’s. Parkinson's Disease Foundation Science News. 11 November, 2010.
  10. ^ Chung, KA. (October 2010). "Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease". Neurology. 75 (10): 1263–1269. {{cite journal}}: External link in |title= (help)
  11. ^ a b c d The National Collaborating Centre for Chronic Conditions, ed. (2006). "Surgery for Parkinson's disease". Parkinson's Disease. London: Royal College of Physicians. pp. 101–111. ISBN 1-86016-283-5. {{cite book}}: External link in |title= (help)
  12. ^ Parkinson's disease surgery neurology Channel. Retrieved on 2010-02-02
  13. ^ Bronstein JM, Tagliati M, Alterman RL; et al. (2010). "Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues". Arch Neurol. doi:10.1001/archneurol.2010.260. PMID 20937936. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Bronstein, J.; Tagliati, M.; Alterman, R. L.; Lozano, A. M.; Volkmann, J.; Stefani, A.; Horak, F. B.; Okun, M. S.; Foote, K. D. (October 11, 2010). "Deep Brain Stimulation for Parkinson Disease: An Expert Consensus and Review of Key Issues". Arch Neurol. 67 (10). doi:10.1001/archneurol.2010.260. {{cite journal}}: External link in |title= (help)
  15. ^ (unknown) (1986). "(unknown)". Comptes rendus academie des sciences. 302: 435. {{cite journal}}: Cite uses generic title (help)
  16. ^ W. Birkmayer and J. G. D. Birkmayer (1986). "Iron, a new aid in the treatment of Parkinson patients". Journal of Neural Transmission. 67 (3–4): 287–292. doi:10.1007/BF01243354.
  17. ^ (unknown) (1989). "Early diagnosis and preventive therapy in Parkinson's disease". (unknown): 323.
  18. ^ The Parkinson Study Group, (1993). "Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group". N Engl J Med. 328 (3): 176–83. doi:10.1056/NEJM199301213280305. PMID 8417384.{{cite journal}}: CS1 maint: extra punctuation (link)
  19. ^ a b c d e The National Collaborating Centre for Chronic Conditions, ed. (2006). "Other key interventions". Parkinson's Disease. London: Royal College of Physicians. pp. 135–146. ISBN 1-86016-283-5. {{cite book}}: External link in |title= (help)
  20. ^ a b Goodwin VA, Richards SH, Taylor RS, Taylor AH, Campbell JL (2008). "The effectiveness of exercise interventions for people with Parkinson's disease: a systematic review and meta-analysis". Movement Disorders. 23 (5): 631–40. doi:10.1002/mds.21922. PMID 18181210. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  21. ^ Cite error: The named reference pmid19691125 was invoked but never defined (see the help page).
  22. ^ Fox CM, Ramig LO, Ciucci MR, Sapir S, McFarland DH, Farley BG (2006). "The science and practice of LSVT/LOUD: neural plasticity-principled approach to treating individuals with Parkinson disease and other neurological disorders". Seminars in Speech and Language. 27 (4): 283–99. doi:10.1055/s-2006-955118. PMID 17117354. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  23. ^ Dixon L, Duncan D, Johnson P; et al. (2007). "Occupational therapy for patients with Parkinson's disease". Cochrane Database Syst Rev (3): CD002813. doi:10.1002/14651858.CD002813.pub2. PMID 17636709. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ http://www.pdtrials.org/en/about_PDtrials_what
  25. ^ Neuroprotective therapy in Parkinson's disease and motor complications National Center for Biotechnology Information. Retrieved on 2010-02-02
  26. ^ Selegiline Information MedLine Plus. Retrieved on 2010-02-02
  27. ^ Treat Parkinson Disease Effectively Retrieved on 2010-02-02

External links

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