Management of Parkinson's disease

The main families of drugs useful for treating motor symptoms are levodopa, dopamine agonists, and MAO-B inhibitors. 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. Controlled, slow-release versions of Sinemet and Madopar 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. Dopamine agonists Dopamine agonists in the brain have a similar effect to levodopa since they bind to dopaminergic postsynaptic receptors. When used in late PD, they are useful at reducing the off periods. They are also more expensive. Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, modafinil for day somnolence, and atomoxetine for executive dysfunction. However, this form of treatment is also not considered a first-choice treatment but is usually used to treat a specific symptom of PD or when typical treatment for PD is insufficient. These specific symptoms include Gastrointestinal Dysfunction, eye twitching, and Sialorrhea also known as excessive salivating or drooling. There have been several studies that have established efficacy of BoNT, particularly for Sialorrhea and Gastrointestinal Dysfunction. A preliminary study indicates taking donepezil (Aricept) may help prevent falls in people with Parkinson's. Donepezil boosts the 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. 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." ==Diet==

Muscles and nerves that control the digestive process may be affected by PD, so it is common to experience constipation and gastroparesis (food remaining in the stomach for a longer period of time than normal). 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. ==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. Target areas for DBS or lesions include the thalamus, the globus pallidus (the lesion technique being called pallidotomy), or the subthalamic nucleus. 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 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 contraindications 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. ==Rehabilitation==

Studies of rehabilitation in Parkinson's disease are scarce and are of low quality. Partial evidence indicates speech or mobility problems can improve with rehabilitation. 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. 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 with or without physiotherapy 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, and meditation techniques. Common changes in gait associated with the disease such as hypokinesia (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. 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 (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 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 and 10-Meter Walking Test ) in people with Parkinson's disease. Newer data has provided another benefit of exercise for patients with Parkinson's disease. The external and internal stressors provided by engaging in exercise induce production of brain neurotrophic factors. This finding is significant because it provides evidence that exercise contributes to neuroplasticity which is especially beneficial in a neurodegenerative disease such as Parkinson's disease. Another study reported that regular aerobic exercise increases brain derived neurotrophic factor in patients with either Parkinson's, multiple sclerosis, or people who have had a stroke. 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. 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). Occupational therapy 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. 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. 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 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, 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 temporarily improves levodopa-induced dyskinesias. Its full usefulness in PD is an open research field. Different nutrients have been proposed as possible treatments; however, no evidence shows vitamins or food additives improve symptoms. Not enough evidence exists to suggest that acupuncture, and practice of qigong or tai 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. Faecal transplants may have a beneficial impact on symptoms. ==History==

, who made important contributions to the understanding of the disease, including the proposal of anticholinergics as treatments for tremor The positive albeit modest effects of anticholinergic alkaloids 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 with paralysis instead of tremor as result. Anticholinergics and surgery were the only treatments 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. 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==

No new PD treatments are expected in the short term, but several lines of research are active for new treatments. 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'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. The use of somatic-cell gene transfer to alter gene expression in brain neurochemical systems is a novel alternative conventional treatment. It involves the use of a noninfectious 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. 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 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 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 0.5–1.0 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 dose as monotherapy 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, porcine, carotid or retinal tissues have been used in cell transplants for PD patients. An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias. However, it is important to note, that several defining featurs of Parkinson's disease (e.g., postural instability, bradykinesia, and resting tremors) are attributable to the degeneration of midbrain dopaminergic neurons. This degeneration disrupts neurotransmitter balance, enhances inhibitory signaling within the motor pathways, and ultimately contributes to impaired motor function. To help manage this condition, stem cell transplants has emerged as 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.. Using an animal model of Parkinson's disease, one study examined the replacement of lost midbrain dopamine neurons by transplanting induced pluripotent stem (iPSC) derived neurons into rats with parkinsonian symptoms. After transplantation, these transplanted cells had the capacity to survive, grow neural projections, and develop into functioning dopamine producing neurons over the course of several weeks. Correspondingly, the rats who were treated in the study showed improvements in behavioral outcomes, including a reduction in abnormal motor movements. In another study, the transplantation of Mouse iPSC-derived GABAergic progenitors was also shown to improve motor function and restored GABAergic signaling, which is crucial for the regulation of motor control. Despite these findings, the 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. ==References==