Parkinson’s disease is the second most common neurodegenerative disease in the world after Alzheimer’s, which ranks first. Although it has a significant disease burden, medical management still focuses only on minimizing the neuronal damage and providing symptomatic relief as no cure has been discovered yet.
Does that mean there is zero hope for the patients? Of course not. There are a handful of proven ways to alleviate the symptoms effectively. There is a multitude of research going on for more potent therapies as well.
Join us as we probe into the disease’s historical aspects, symptoms, currently used therapies, and how the latest research might shape our management plans for the disease.
Table of Contents
Historical Aspects
Even though the ancient Chinese, Indian, and Western medical systems have described several diseases with tremors and physical disability as major clinical features, Parkinson’s Disease (PD) as we know it today, came into being after James Parkinson, an English physician, published an essay named ‘An Essay on the Shaking Palsy’ in 1817.
Substantia nigra in the basal ganglia was found to be the site of brain damage around 1920, and the chemical changes in PD patients’ brains were discovered in the 1960s. The miracle drug, Levodopa, which is still used as the primary therapeutic agent, came into play in the same decade.
At present, 10 million people are estimated to be living with PD worldwide. The direct and indirect cost of Parkinson’s is estimated to be around $52 billion per year in the US alone. Also, the 200th anniversary of the discovery of the disease was several years ago.
What is Parkinson’s Disease?
Parkinson’s disease is a movement disorder caused by the gradual loss of neurons in the substantia nigra, which is a component of basal ganglia. This degenerative phenomenon leads to reduced production of a substance called dopamine, a neurotransmitter. This neurotransmitter is responsible for the communication between the substantia nigra and the corpus striatum through the nigrostriatal pathway, among several other things. This is essential in coordinating muscle activity in our day-to-day life.
Deficiency of dopamine leads the neurons in the striatum to act without regulation. As a result, the individual becomes incapable of controlling his or her own movements leading to the symptoms of PD. Although this mechanism gives rise to the initial symptoms of the disease, as the disease progresses, other parts of the brain also get degenerated, leading to more serious motor complications.
Genetic and environmental factors are believed to cause the disease, even though the exact reason why the nerves start dying is not known.
Symptoms and Signs
The patient might complain of vague symptoms like aches and pains early in the disease. Symptoms characteristic of the disease appear later as the disease progresses.
A PD patient’s characteristic clinical picture includes an expressionless face, bent posture, stiff and shuffling gait, and “pill-rolling” tremor. This characteristic coarse tremor, which causes the person’s thumb to move forward and backward rhythmically, is almost always caused by PD. It occurs at rest, improves with activity, and disappears with sleep.
On examination, the rigidity (cogwheel and lead pipe types) is seen predominantly in the flexor muscles of the neck, limbs, and trunk, resulting in typical “flexed posture.” Also, the slow movements, which is known as bradykinesia, affects the muscles of facial expression, mastication, speech, and muscles of the trunk and limbs, leading to dysarthria (difficulty of speech), dysphagia (difficulty in swallowing), and slow and deliberate walking with little associated arm swinging.
All these symptoms progressively affect every aspect of the patient’s life, from handwriting to rising from a chair, and can even cause depression, dementia, and drug-induced confusion in later stages.
What are the Treatments Available?
Bloodletting from the neck, followed by vesicatories to induce blistering of the skin, was Parkinson’s recommendation in his initial essay. Jean-Martin Charcot and William Gowers were responsible for much of the advancement in understanding the disease, which led to subsequent therapeutic advances. (in other words, they are the reason why the PD patients today do not get themselves cut in the neck)
Currently, the pharmacological treatment aims to increase the usable dopamine in the brain by giving exogenous dopamine or reducing dopamine breakdown. The major therapeutic goal is to improve the patient’s quality of life by controlling symptoms for as long as possible while minimizing potential side effects. Treatments should be started as early as possible after the diagnosis.
Giving dopamine in its original form is dangerous as it can have toxic effects when present in blood in excess amounts. Therefore, Levodopa, a precursor of dopamine that can cross the blood-brain barrier, is administered. To reduce the conversion of Levodopa to dopamine before it gets into the brain, a peripheral dopa-decarboxylase inhibitor like carbidopa or benserazide is added. This combination is currently considered the most effective form of therapy.
Dopamine agonists, which act directly on the dopamine receptors, may be useful in the early phases of the disease but may not be sufficient to treat more advanced disease stages. Examples for this category include bromocriptine and ropinirole.
Other than that, drugs like entacapone and selegiline are also used as adjuncts. They inhibit the enzymes COMT (Catechol-O-methyltransferase) and MAO (Monoamine Oxidase), respectively, the enzymes involved in degrading dopamine.
Other Symptomatic Therapies
Some of the other symptoms of the disease, which may be more troublesome than the motor symptoms, also need careful management. Most common medications used to relieve them include;
- Domperidone, which is a peripheral dopamine antagonist, to treat nausea
- Polyethylene Glycol, which is an osmotic laxative, to relieve constipation
- Modafinil, which is a wakefulness-promoting agent, to treat daytime sleepiness, and
- Sildenafil, a phosphodiesterase inhibitor, to alleviate erectile dysfunction, among other drugs
Non-drugs treatment options also go hand in hand with medical management as far as the quality of life of a patient is concerned. With proper professional support, these methods also have convincingly relieved symptoms that are not improved enough by taking medicines alone. Some of the strongest evidence-based practices include sports and exercises, occupational therapy, speech therapy, and psychological support. Although they do not modify or reverse the disease process, early interventions can definitely serve a great deal to the patients.
Surgical Management Options for PD
Deep brain stimulation (DBS) is currently the most common surgical treatment for Parkinson’s disease. This treatment is typically indicated for bradykinesia, rigidity, and tremor in patients who no longer respond to medication in a predictable manner or for the patients who suffer medication-induced dyskinesias.
DBS is usually conducted by neurosurgeons who specialize in functional neurosurgery. It is done by implanting one or more electrodes that transmit small electrical stimulation to the insides of the brain. These electrical pulses are generated by a small generator implanted in the chest, just like a pacemaker. Its efficacy is dependent on several factors like proper patient selection, precise placement of electrodes, and adjustments of the pulse generator. Although DBS is not a cure or a disease reversing therapy, it can greatly improve the quality of life of the patients by efficiently improving motor symptoms.
Other than DBS, procedures like radiofrequency ablation, radiosurgery, and focused ultrasound are also utilized for selected tremor symptoms.
What Does the Future Hold?
Current management guidelines and recent advancements mainly target the motor symptoms of PD; however, altering the course of the disease and treating the neurodegenerative and cognitive aspects of the disease is the target of future disease-modifying treatments. However, understanding the underlying pathophysiology is the most important factor that drives the future advancement of therapies.
We will look at three major areas of research that have shown the potential to produce fruitful results in the future.
Stem Cell Therapies
Usually, at the point of diagnosis of PD, half of the cells are already damaged or lost. Therefore, the situation demands therapies that can reverse the disease process rather than nurturing and protecting the remaining dopamine secreting cells.
In this domain, many studies were carried out for a potential breakthrough. The 1980s saw the first cell transplant trial for PD. It was done using human fetal tissue. The result was, however, a mixed bag. Some patients immediately manifested improvement, and some took many months to improve; at the same time, a considerable number of patients showed no significant improvement and a few patients, unfortunately, went on to develop adverse events like dyskinesia. Also, the human fetal tissue used for this transplant was a scarce resource.
This pushed researchers even more towards searching for potential therapies with stem cells. Stem cells are the most basic cells from which all of us are originated. They are also responsible for repairing tissues and organs following damage. The high replication capacity they possess and their ability to secrete growth factors are the most important factors that make them suitable for degenerative diseases like PD.
Stem cells, therefore, hold huge potential as a good lead to develop effective therapies. Several methods have been tried out or currently under trial, including;
- giving stem cells from outside the brain (e.g., bone marrow)
- transplanting stem cells into the brain, and
- administering lab-made dopamine-producing brain cells generated from induced pluripotent stem cells.
Although none of these leads have reached the state of approved therapeutic measures, all these exciting and promising trials continue to keep the hopes ignited for the patients despite the number of questions scientists will have to answer before they become therapeutic options.
Gene Therapies
Gene therapy is an area of active research for over 45 years for diseases like cystic fibrosis, some cancers, some viral infections, and PD. Although the research was ongoing for such a long time, only a few trials have gone beyond the experimental stage to conduct clinical trials.
This therapy attempts to replace a faulty gene or add a new gene in order to cure the disease or improve the body’s ability to fight disease. This is usually done by incorporating a recombinant DNA into a virus, which is expected to get inside the desired cell type while giving different genetic instructions to the cells. In the context of PD, the aim would be to instruct the brain cells to secrete dopamine, the deficiency of which is the primary cause for the symptoms.
AXO-Lenti-PD, developed by Oxford BioMedica (later by Axovant Sciences), delivers the three key genes (TH, CH1, and AADC) required for endogenous dopamine synthesis in a single lentiviral vector with the aim of restoring endogenous, tonic dopamine secretion. Currently, the study is in a phase 2 trial.
Many of the other major trials have resulted, for the most part, in a mixed picture. Also, the performance of gene therapy on a large scale cannot be portrayed exactly by phase 1 or 2 trials. Therefore, it will take many years to come to the market, but if they continue to produce good results as they have in the trials, we may have a way to turn back the clock for many debilitated PD patients.
Growth Factors
Rita Levi Montalcini and Stanley Cohen won the Nobel prize for physiology and medicine in the year 1986 for the extraction of the first growth factor, Nerve Growth Factor (NGF). Other growth factors important in the treatment of PD include; GDNF (glial cell line-derived neurotrophic factor), its close cousin neurturin, BDNF (brain-derived neurotrophic factor), CDNF (cerebral dopamine neurotrophic factor), and MANF (mesencephalic astrocyte-derived neurotrophic factor).
Growth factors are usually large proteins (generally considered as a subset of cytokines) that support the growth and repair of bodily tissues. They can be secreted by a remote tissue, the adjacent cells, or the cells of concern themselves.
If there is a way to deposit the relevant growth factors in the substantia nigra, we might have a good shot at reversing the disease by promoting the cells’ growth. But the complexity of the structure of these signaling proteins and the deep-seated location of subthalamic nuclei in the brain pose a great challenge for us to do just that.
The proposed and tested delivery modes that have delivered varying labels of success include surgery and gene therapy. As both of these approaches require quite complex brain surgery, the researchers are in constant pursuit of a more effective and one-off way to successfully deliver growth factors. Exercises and drugs that stimulate the secretion of growth factors have been tested in this regard.
Conclusion
Even though several very efficient medical and surgical measures for the treatment of motor symptoms of PD are in practice, this progressive and debilitating disease continues to cause suffering to patients worldwide. Further research is essential to uncover the specifics of the underlying disease process, which will enable the discovery of better treatment options, which might take a holistic approach towards the disease rather than trying to alleviate single motor symptoms. Disease-modifying or disease-reversing treatments remain the ultimate goal even though the newer technologies, imaging modalities, drugs, and other therapeutic techniques continue to improve certain aspects of this disease.
References
https://www.parkinsons.org.uk
https://academic.oup.com/ageing/article/47/2/209/4791137
https://www.news-medical.net/health/What-is-Parkinsons-Disease.aspx https://www.ncbi.nlm.nih.gov/books/NBK293718/
https://emedicine.medscape.com/article/1831191-overview