Management of Parkinson's disease

Treatment for Parkinson's Disease (PD), due to its chronic nature, 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. 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 are yet on the market with specific approval to treat Parkinson's.

Pharmacologic
The main families of drugs useful for treating motor symptoms are Levodopa, dopamine agonists 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 for which he needs pharmacological treatment, and a second stage in which the patient develops motor complications related to levodopa usage. Treatment in the initial state aims to attain an optimal tradeoff between good management of symptoms and side-effects resulting from enhancement of dopaminergic function. The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of causing the onset of dyskinesias to be retarded. 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 have to be controlled. When medications are not enough to control symptoms, surgical techniques such as deep brain stimulation can relieve the associated movement disorders.

Levodopa


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

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. Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors. 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 (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.

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.

Tolcapone inhibits the catechol-O-methyltransferase COMT 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's limited in its availability. A similar drug, entacapone 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).

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. Most people will 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 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. 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, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, and lisuride.

Agonists produce significant, although mild, side effects including somnolence, hallucinations, insomnia, nausea, and constipation. 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. 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, which is a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD. Since secondary effects such as confusion and hallucinations are not rare it has been recommended that patients under apomorphine treatment should be closely monitored. 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).

A study performed by the Cochrane review enrolled 5247 patients with early PD and evaluated the efficacy of dopamine agonists compared to levodopa. The results show that patients who took dopamine agonists were less likely to develop dyskinesia (p<0.00001), dystonia (p=0.0002), and motor fluctuations (p=0.002) although were more likely to discontinue therapy due to negative side effects such as nausea, edema, constipation, etc.

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. 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 had as result that 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 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. In addition to motor PD is accompanied by an ample range of different symptoms. Different compounds are used to improve some of these problems. Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia and modafinil for day somnolence.

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. 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 (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.

Surgical
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 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.

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

Neuroablative Lesion Surgery
Neuroablative Lesion surgery (NAS) locates and destroys, by heat, the parts of the brain that are associated with producing Parkinsonian neurological 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, in order 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 that suffer from rigidity and akinesia.

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.. This method has been generally replaced by deep brain surgery.

Deep Brain Stimulation
Deep brain stimulation (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 each individual at their particular stage of disease. DBS employs three hardware components: a neurostimulator, 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 electrodes 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 entire three component system is sometimes referred to as a brain pacemaker, as the system operates on many of the same principles as medical cardiac pacing.

The pre-operative targeting of proper implantation sites can be accomplished via the indirect and direct methods.

The indirect method utilizes computer tomography, magnetic resonance imaging, or ventriculography to locate the anterior and posterior commissures and then employs pre-determined coordinates and distances from the intercommissural line in order to define the target area. Subsequent histologically defined atlas maps can also be used to verify the target area (Nolte, 2012). The direct method provides visualization and targeting of deep nuclei by applying stereotactic pre-operative MRI, which unlike the indirect method, takes into account the anatomic variation of the nuclei’s size, position, and functional segregation amongst individuals (Nolte, 2012)

Electrophysial functional mapping (EFM), a tool utilized in both methods in order to verify the target nuclei, has come under scrutiny due to its associated risks of hemorrhages, dysarthria or tetanic contractions. Recently, Susceptibility Weighted Imaging (SWI), a type of MRI has shown incredible resolving power in its ability to distinguish these deep brain nuclei and is being used in DBS in order to reduce the over-use of EFM (Abosch, 2010).

DBS is recommended to PD patients without important neuropsychiatric contraindications who suffer 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, therefore, it is common to experience constipation and gastroparesis (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 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 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 may appear. In such cases specific measures include the use of thickening agents for liquid intake, special postures when eating and gastrostomy in the worst cases.

Rehabilitation
There is partial evidence that speech or mobility problems can improve with rehabilitation although studies are scarce and of low quality. Regular physical exercise and/or therapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life. Exercise may also improve constipation. Exercise interventions have been shown to benefit patients with Parkinson’s disease in regards to physical functioning, health-related quality of life, 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. There are five proposed mechanisms by which exercise enhances neuroplasticity. 1) intensive activity maximizes synaptic plasticity; 2) complex activities promote greater structural adaptation; 3) activities that are rewardingincrease dopamine levels and therefore promote learning/relearning; 4) dopaminergic neurones are highly responsive to exercise and inactivity (“use it or lose it”); 5) where exercise is introduced at an early stage of the disease, progression can be slowed. 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. Speech therapy and specifically LSVT may improve voice and speech function. 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. 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.

Palliative care
Palliative care 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 ulcers by management of pressure areas of inactive patients; facilitating the patient's end of life decisions for the patient as well as involved friends and relatives.

Other treatments
Repetitive transcranial magnetic stimulation improves temporarilly levodopa induced dyskinesias. Its full usefulness in PD is an open research field. Different nutrients have been proposed as possible treatments; however there is no evidence that vitamin or food additives improve symptoms. There is not enough evidence to suggest that acupuncture, and practice of qigong or t'ai chi have any effect on symptoms. Fava and velvet 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. It has been suggested that faecal transplants may have a beneficial impact on symptoms.

History
The positive albeit modest effects of anticholinergic alkaloids obtained from the plant of the belladona were described during 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 with paralysis instead of tremor as result. Anticholinergics and surgery were the only treaments until the arrival of levodopa, which reduced their use dramatically.

Levodopa was first synthesized in 1911 by Casimir Funk, 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 emerged as a possible treatment, and it was approved for clinical use by the FDA in 1997.

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

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

Gene therapy
Present treatments of Parkinson disease provide satisfactory disease control for most early stages patients. However, present gold standard treatment of Parkinson disease using Levodopa, is associated with motor complications, and does not prevent disease progression. More effective and long term treatment of Parkinson disease are urgently needed to control the progression of the disease. In vivo gene therapy is a new approach for treatment of Parkinson disease. 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 non-infectious virus to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme which helps to manage PD symptoms or protects the brain from further damage.

One of the gene therapy based approach involves gene delivery of neurturin and gilial-cell-derived nuerotrophic factor (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 the open-label trials have shown 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 Parkinson disease 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 circuity are affected. This strategy used andeno-associated viral vectoe (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 Parkinson Disease.

Neuroprotective treatments
Investigations on neuroprotection are at the forefront of PD research. Currently, there are no proven neuroprotective agents or treatments available for Parkinson Disease (Medscape). 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. 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 anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF). Preclinical research also targets alpha-synuclein.

Selegiline
Selegiline is in a group of medications called monoamine oxidase type B (MAO-B) 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 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.

Rasagiline
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.

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