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Parkinson’s Disease

Humza Khizer

Overview

<p><span style="color:#000000">Parkinson&rsquo;s disease (PD) is a neurological disorder in which progressive neurodegeneration is observed. Neurodegeneration is the phenomenon explained by decreasing brain efficiency, resulting in cognitive decline.&nbsp;</span></p>

<p><span style="color:#000000">The neuronal loss observed in Parkinson&rsquo;s disease can be related to motor function. However, non-motor symptoms are also observed in some instances.&nbsp;</span><span style="color:#000000">When the neuronal loss is in the non-dopaminergic area, it gives rise to non-motor symptoms, whereas loss of striatal dopaminergic neurons leads to motor symptoms<sup><a href="#accordion">[1]</a></sup></span><span style="color:#1155cc">.</span></p>

<p>&nbsp;</p>

<p>Parkinson&rsquo;s disease, previously known as &ldquo;shaking palsy&rdquo;, is a chronic disease that alters the way your brain functions physiologically. Parkinson&rsquo;s is not only challenging for the patient but also for the people around them. It&rsquo;s a difficult scenario for the patient&rsquo;s family members and health care practitioners. This is because Parkinson&rsquo;s patients classically present with depression due to the pressures from society for not being able to function properly. Hence, physical and mental health have to be kept in check simultaneously.</p>

<div>
<p>The signs and symptoms of Parkinson&rsquo;s disease (PD) are such a distinct variety that a new term &ldquo;Parkinsonism&rdquo; was coined to categorize them. Parkinsonism is a symptom complex used to describe the motor features of PD, which include resting tremors, bradykinesia, and muscular rigidity.</p>

<p>Bradykinesia refers to the slow movement that develops in PD. Different studies prove that the pathology settles in before the onset of symptoms including sleep disorders, depression, and cognitive alterations.</p>

<p>A major histopathological feature of PD is Lewy Bodies (LB), which are essentially intracellular cytoplasmic aggregates that comprise proteins, lipids, and other constituents. The presence of LB also promotes the production of Ubiquitin, which is a malformed protein generally seen after neurodegeneration has taken place.</p>

<p>Major receptors that are in play in Parkinson&rsquo;s disease are the dopamine receptors namely D1 and D2. D1 is excitatory, whereas D2 is inhibitory. PD patients report a decrease in dopamine, which in turn causes decreased thalamus activity. Additionally, decreased dopamine may lead to increased cholinergic activity.</p>

<p>Reports show that PD affects 1-2 per 1000 people globally. PD prevalence is directly proportional to age and affects 1% of the population who are above 60 years of age. As far as Pakistan&rsquo;s prevalence rate is concerned, it is estimated that 1 million people have Parkinson&rsquo;s disease, and this number is most likely to reach 1,200,000 by 2030<sup><a href="#accordion">[1][2][3]</a></sup>.</p>

<div>&nbsp;</div>
</div>

Signs And Symptoms

<p>There is essentially only one type of Parkinson&rsquo;s disease, however, Parkinsonism can be seen in diseases other than PD. These include:<br />
&nbsp;</p>

<ul>
	<li>Progressive Supranuclear Palsy (PSP)&nbsp;</li>
	<li>Multiple System Atrophy (MSA)</li>
	<li>Corticobasal Degeneration (CBD)</li>
	<li>Vascular Parkinsonism (VaP)<br />
	&nbsp;</li>
</ul>

<p>The classical PD has 5 stages and each stage is descriptive with its exclusive signs and symptoms<sup><a href="#accordion">[4]</a></sup>.<br />
&nbsp;</p>

<h5><strong>Stage I</strong></h5>

<p>Initially, the person has only mild symptoms. Hence, there is no interference with daily activities. The signs and symptoms observed are:<br />
&nbsp;</p>

<ul>
	<li>Tremors in hands, arms, legs, jaw, or head</li>
	<li>Unilateral movement symptoms&nbsp;</li>
	<li>Changes in posture, walking pattern, and facial expressions<br />
	&nbsp;</li>
</ul>

<h5><strong>Stage II</strong></h5>

<p>Stage II has aggravated symptoms compared to stage I and can be distinctively diagnosed by:<br />
&nbsp;</p>

<ul>
	<li>Tremors in hands, arms, legs, jaw, or head</li>
	<li>Rigidity of the muscles</li>
	<li>Bilateral movement&nbsp;</li>
	<li>Walking problems and poor posture<br />
	&nbsp;</li>
</ul>

<h5><strong>Stage III</strong></h5>

<p>Stage III is usually referred to as the mid-stage disease. Stage III has 2 hallmark symptoms that might disturb the normal routine of the patient but at the same time aid in diagnosis. These include:<br />
&nbsp;</p>

<ul>
	<li>Loss of balance</li>
	<li>Slow movements&nbsp;<br />
	&nbsp;</li>
</ul>

<p>Other symptoms that a person is likely to experience at this stage are:</p>

<ul>
	<li>Increased risk of falling because of lack of coordination</li>
	<li>Compromised functioning with activities like changing clothes and dining becoming difficult to manage on their own.<br />
	&nbsp;</li>
</ul>

<h5><strong>Stage IV</strong></h5>

<p>Stage IV is a stage in which a patient is severely disabled and needs immediate intervention. Signs and symptoms include:</p>

<p>&nbsp;</p>

<ul>
	<li>Inability to live independently</li>
	<li>Assistance in walking</li>
	<li>Visible bradykinesia</li>
	<li>Muscular rigidity<br />
	&nbsp;</li>
</ul>

<h5><strong>Stage V</strong></h5>

<p>This is the most severe stage of Parkinson&rsquo;s disease and the patient is dependent on their caregiver(s) and/or assistive technology. Signs and symptoms include:<br />
&nbsp;</p>

<ul>
	<li>Mobility is impossible without 24/7 support</li>
	<li>Unable to walk or stand due to stiffness in the legs&nbsp;</li>
	<li>Being bedridden is also a possibility, especially because movement without support is risky</li>
	<li>Hallucinations and delusions may develop<br />
	&nbsp;</li>
</ul>

<p>According to Braak&rsquo;s hypothesis, the patient would have to deal with non-motor symptoms well before the motor symptoms appear. These include a loss of sense of smell (hyposmia), sleep disorders, and constipation. Hence, currently, this is an area of interest for a majority of researchers.&nbsp;&nbsp;</p>

<div>&nbsp;</div>

Causes

<p>PD results due to loss of neurons. This loss of neurons is exclusive to the substantia nigra part of the brain. Substantia nigra makes dopamine, a chemical compound essential for the control and coordination of the body. Hence, classical symptoms of PD are seen here.<br />
&nbsp;</p>

<p>It is crucial to understand what causes neuronal loss<sup><a href="#accordion">[5]</a></sup>:<br />
&nbsp;</p>

<h5><strong>1. Genetic Causes</strong></h5>

<p>It can be transferred from parents who have the faulty genes that cause PD. Studies show that 15% of patients with PD have a family predisposition and mutated genes include LRRK2, PARK2, PARK7, PINK1, or the SNCA gene.<br />
&nbsp;</p>

<h5><strong>2. Environmental Factors</strong></h5>

<p>This has more to do with how toxic your surroundings are. Researchers have revealed that farmers or people who work closely with pesticides and herbicides usually develop PD.<br />
&nbsp;</p>

<h5><strong>3. Drug-Induced Parkinsonism</strong></h5>

<p>Some medications are also capable of inducing Parkinsonism. These drugs include antipsychotics such as Prochlorperazine.&nbsp;&nbsp;</p>

<div>&nbsp;</div>

<p>A detailed history can be an excellent way to screen patients for Parkinson&rsquo;s disease. The following 12 questions are routinely used for screening<sup><a href="#accordion">[6]</a></sup>:</p>

<p>&nbsp;</p>

<ol>
	<li>Have you gotten progressively slower in your daily routine?</li>
	<li>Has your handwriting gotten smaller over time?</li>
	<li>Is your speech slurred or softer than it was before?</li>
	<li>Can you easily get up from a chair?</li>
	<li>Do your lips, hands, arms&nbsp;and/or legs shake themselves?</li>
	<li>Have you noticed any rigidity?</li>
	<li>Do you have trouble dressing yourself and ask for assistance?</li>
	<li>Do you shuffle your feet and/or take smaller steps when you walk?</li>
	<li>Do you feel that your feet are glued to the floor?</li>
	<li>Has anyone told you that you move an arm in an oscillating fashion while walking?</li>
	<li>Do you have any issues regarding your balance and coordination?</li>
	<li>Have you or others noticed that you have an abnormal posture?<br />
	&nbsp;</li>
</ol>

<p>Moreover, a handwriting assessment is also used to check for micrographia (abnormally small handwriting). This is because studies have proven that micrographia sets in earlier than other symptoms, making this assessment an excellent screening test<sup><a href="#accordion">[7]</a></sup>.</p>

<div>&nbsp;</div>

Diagnosis

<p>Multiple testing modalities can reach the diagnosis. However, it should be noted that not all patients qualify for these assessments. Only patients with relevant history should be sent for such assessments.<br />
&nbsp;</p>

<p>The tests that help in diagnosis include<sup><a href="#accordion">[8]</a></sup>:</p>

<ol>
	<li>Specific single-photon emission computerized tomography (SPECT) imaging technique called dopamine transporter (DAT) scan</li>
	<li>MRI, ultrasound of the brain, and PET scan&nbsp;give the doctors a better idea about the brain parenchyma and any characteristic indications of PD. It would also help in ruling out any other diagnoses.</li>
	<li>Drug response is checked. Patients are given carbidopa and levodopa (drugs that are used to treat PD) to see if there is any improvement in symptoms.&nbsp;</li>
</ol>

<div>&nbsp;</div>

Treatment

<p>PD is a dangerous disease since its progression leads to disability. Hence, it is vital that the disease is diagnosed correctly and appropriate treatment is started as early as possible. The goal of the therapy is to make dopamine readily available, decrease the severity of symptoms and delay, if not stop, the progression as a whole<sup><a href="#accordion">[9]</a></sup>.</p>

<p>&nbsp;</p>

<h5><strong>1. Medical</strong></h5>

<p>These include:</p>

<p>&nbsp;</p>

<ul>
	<li><strong>Carbidopa-Levodopa:&nbsp;</strong>Levodopa is essentially a pre-existent form of dopamine and is readily converted to dopamine in the brain. Carbidopa ensures that the levodopa is not being wasted outside the brain, and is being fully utilized to bring up dopamine levels.&nbsp;A combination of Carbidopa and Levodopa can be given in an inhaled form OR as an infusion if the oral medication ceases to work.</li>
</ul>

<p>&nbsp;</p>

<ul>
	<li><strong>Dopamine Agonists:&nbsp;</strong>While levodopa is actually dopamine itself, dopamine agonists mimic dopamine and have the same effects on the brain. Dopamine agonists do not have the same efficacy as levodopa but can be used to wean the patient off levodopa.</li>
</ul>

<p>&nbsp;</p>

<ul>
	<li><strong>MAO B Inhibitors:&nbsp;</strong>MAO B is an enzyme responsible for lowering the levels of dopamine in your brain. Hence, introducing an inhibitor in the system prevents dopamine from falling below the threshold and causing Parkinsonism.&nbsp;However, it should be noted that the inhibitors like selegiline and rasagiline are not to be taken with antidepressants.</li>
</ul>

<p>&nbsp;</p>

<ul>
	<li><strong>&nbsp;Catechol O-Methyltransferase (COMT) Inhibitors:&nbsp;</strong>COMT inhibitors are another class of drugs that stop COMT from breaking down the dopamine in the body and ensure its availability. Examples include Entacapone and Opicapone.</li>
</ul>

<p>&nbsp;</p>

<h5><strong>2. Surgical</strong></h5>

<p>Thise includes&nbsp;deep brain stimulation. The surgeon uses electrodes that are connected to a generator implanted in your chest close to your collarbone. This system then sends electrical pulses to your brain and may be able to reduce your Parkinson&#39;s disease symptoms.&nbsp;The procedure is meant for someone who either is at an advanced stage of disease or on whom medical therapy does not work anymore.</p>

<div>&nbsp;</div>

<p>Parkinson&rsquo;s at advanced stages can cause severe disabilities. These disabilities create further complications<sup><a href="#accordion">[10].</a></sup><br />
&nbsp;</p>

<h5><strong>1.&nbsp;<a href="https://www.merisehat.pk/disease/dementia" target="_blank">Dementia&nbsp;</a></strong></h5>

<p>Dementia is the loss of cognitive functioning, which includes thinking, remembering, and reasoning. Studies show that almost 50&ndash;80% of people with Parkinson&rsquo;s develop dementia. As a result, dementia causes memory loss, poor judgment, and delusions.<br />
&nbsp;</p>

<h5><strong>2. Urinary And Bowel Disturbances&nbsp;</strong></h5>

<p>Patients with Parkinson&rsquo;s have a constant urge to urinate in addition to leakage when they laugh, cough, or sneeze. Patients dealing with Parkinson&rsquo;s also develop diarrhea and <a href="https://www.merisehat.pk/disease/constipation" target="_blank">constipation</a>.<br />
&nbsp;</p>

<h5><strong>3. Dyskinesia (Involuntary Movement)&nbsp;</strong></h5>

<p>This complication is unique to PD. Levodopa is the drug that is used in the treatment of PD and it may cause uncontrolled movements such as head shaking, twitching, swaying, or fidgeting (dyskinesia).<br />
&nbsp;</p>

<h5><strong>4. Pain&nbsp;</strong></h5>

<p>Several studies have confirmed that 80% of PD patients develop pain. The pain can persist in the patient&rsquo;s shoulders, back, neck, and feet.</p>

<div>&nbsp;</div>

<p>Although PD is usually hard to diagnose at earlier stages, there are risk factors that may warrant immediate attention. They include<sup><a href="#accordion">[9]</a></sup>:<br />
&nbsp;</p>

<ul>
	<li><strong>Age</strong>: People who are 60 and above are more likely to have PD.<br />
	&nbsp;</li>
	<li><strong>Gender:</strong>&nbsp;Men are more prone to get PD compared to women, the ratio being 3:2.<br />
	&nbsp;</li>
	<li><strong>Environment: </strong>Exposure to toxins like pesticides, herbicides, and heavy metals can cause PD.<br />
	&nbsp;</li>
	<li><strong>History:</strong> Almost 15% of patients with PD have a positive family history.</li>
</ul>

<div>&nbsp;</div>

<p>First and foremost, it is necessary to keep away from all kinds of pesticides and heavy metals as their accumulation may predispose to PD. Environmental toxins are the main factor that can easily be prevented.&nbsp;</p>

<p>Next, the usage of NSAIDs has been seen to protect the neurons from being destroyed in the substantia nigra part of the brain. This makes them a reliable option to prevent the situation.</p>

<p>And last but not least, nicotine also has a neuroprotective effect when it comes to PD. Smokers have a decreased activity of monoamine oxidase B, which is an enzyme responsible for the oxidation of dopamine. In other words, nicotine helps increase the availability of dopamine. However, it is important to mention that more research is needed to fully understand the protective role of nicotine on the brain cells and how it can be used as a treatment for Parkinson&#39;s patients.<br />
&nbsp;</p>

<p><strong>Note:</strong> Smoking is hazardous to health. It is the leading cause of mortality, i.e. it has a death rate of 3 million globally<sup><a href="#accordion">[11]</a></sup>. Please consult your healthcare practitioner for ascertaining a safe way to introduce nicotine as a treatment for Parkinson&rsquo;s disease.&nbsp; &nbsp;</p>

<div>&nbsp;</div>

<p>Researchers around the globe are making continuous efforts to come up with a breakthrough treatment that might be able to help Parkinson&rsquo;s patients in an unorthodox fashion. Currently, 2 of the most recent advanced research show promising theories and results:<br />
&nbsp;</p>

<ol>
	<li><strong>Identification Of Neural Growth Factor (NGF):&nbsp; </strong>Theoretically, NGF may revive the neurons that are responsible to keep dopamine levels in check. It might be possible to cure symptoms almost immediately using NGF.<br />
	&nbsp;</li>
	<li><strong>Fetal Cell Transplant:&nbsp;</strong>This is an invasive procedure in which fetal cells are introduced into the patient&rsquo;s nervous system to achieve replacement of the dopamine-producing cells. However, the study needs more time as it has caused severe dyskinesia in some cases because of the excessive amount of dopamine that was being produced<sup><a href="#accordion">[12]</a></sup>.</li>
</ol>

<div>&nbsp;</div>

Key Points

<ul>
	<li>Parkinson&rsquo;s disease (PD) is a neurological disorder in which progressive neurodegeneration is observed.</li>
	<li>It can be related to motor function; however, non-motor symptoms are also observed.</li>
	<li>Neuronal loss in the non-dopaminergic area gives rise to non-motor symptoms, whereas loss of striatal dopaminergic neurons leads to motor symptoms.&nbsp;&nbsp;</li>
	<li>Parkinsonism is a symptom complex used to describe the motor features of PD, which include resting tremor, bradykinesia, and muscular rigidity.</li>
	<li>A major histopathological feature of PD is Lewy Bodies (LB) which are essentially intracellular cytoplasmic aggregates that comprise proteins, lipids, and other constituents.</li>
	<li>Major receptors that are at play in Parkinson&rsquo;s disease are the dopamine receptors namely D1 and D2.</li>
	<li>A decrease in dopamine causes decreased thalamus activity. It could also lead to an increased cholinergic activity.&nbsp;&nbsp;</li>
	<li>Parkinson&#39;s disease (PD) affects 1-2 per 1000 people globally.</li>
	<li>It is estimated that 1 million people have Parkinson&rsquo;s disease in Pakistan, and this number is most likely to go up to 1,200,000 by 2030.</li>
	<li>The classical PD has 5 stages and each stage is descriptive with its exclusive signs and symptoms.</li>
	<li>Stage I is a mild stage whereas Stage II has aggravated symptoms similar to Stage I.</li>
	<li>Stage III is usually referred to as the mid-stage disease and has 2 hallmark symptoms namely loss of balance and slowness in movement.</li>
	<li>Stages IV and V are advanced stages where independent movement and management of day-to-day tasks are severely diminished.</li>
	<li>PD can be due to genetic environmental causes.</li>
	<li>Some medications are also capable of inducing Parkinsonism. These drugs include antipsychotics such as Prochlorperazine.</li>
	<li>Parkinson&rsquo;s can be screened mainly based on history.</li>
	<li>A handwriting assessment is also used to check for micrographia (abnormally small handwriting). This is because studies have proved that micrographia develops earlier than other symptoms which makes it an excellent screening test.</li>
	<li>Tests that might help in the diagnosis of PD are MRI, DAT scan, and a drug trial.</li>
	<li>The treatment options can be categorized as either medical or surgical. The carbidopa-levodopa combination is the first line of drug therapy whereas deep brain stimulation is used as a surgical procedure.</li>
	<li>Complications include dementia, urinary and bowel disturbances, pain, and dyskinesia.</li>
	<li>Risk factors are mainly non-modifiable factors such as male gender and old age. However, modifiable risk factors include working or being surrounded by herbicides and insecticides.</li>
	<li>Use of NSAIDs and&nbsp;maybe nicotine in a fair environment is seen to show benefits in preventing PD.</li>
	<li>New developments to treat PD hail fetal cell transplant and neural growth factor as revolutionary.<br />
	&nbsp;</li>
</ul>

[1] DeMaagd, George, and Ashok Philip. “Parkinson's Disease and Its Management: Part 1: Disease Entity, Risk Factors, Pathophysiology, Clinical Presentation, and Diagnosis.” P & T : a peer-reviewed journal for formulary management vol. 40,8 (2015): 504-32

[2] Tufail M. Clinical features and risk factors of parkinson’s disease in a population of Khyber Pakhtunkhwa, Pakistan: A case-control study. Neurodegenerative Diseases. 2019;19(5-6):211-217. doi:10.1159/000506742

[3] Tysnes, Ole-Bjørn, and Anette Storstein. “Epidemiology of Parkinson's disease.” Journal of neural transmission (Vienna, Austria : 1996) vol. 124,8 (2017): 901-905.

[4] Stages of Parkinson's. Parkinson's Foundation.

[5] Parkinson's Disease. NHS choices.

[6] Parkinson's screening questionnaire. The Michael J. Fox Foundation for Parkinson's Research | Parkinson's Disease.

[7] Chandra, Jay et al. “Screening of Parkinson's Disease Using Geometric Features Extracted from Spiral Drawings.” Brain sciences vol. 11,10 1297. 29 Sep. 2021

[8] Emamzadeh FN, Surguchov A. Parkinson’s disease: Biomarkers, treatment, and risk factors. Frontiers in Neuroscience. 2018;12. doi:10.3389/fnins.2018.00612