Parkinson's disease overview

# Overview
Parkinson's disease is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech.
Parkinson's disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
PD is the most common cause of parkinsonism, a group of similar symptoms. PD is also called "primary parkinsonism" or "idiopathic PD" (having no known cause). While most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders.

# Historical Perspective
the first person who documented and recognized Parkinsons disease was a British physician, James Parkinson in 1817 who named it paralysis agitans. The first underlying pathology of Parkinson disease was described by a German pathologist Frederick Lewy in 1912. He described that there are cytoplasmic inclusions in some brain areas of PD patients. in 1967 the drug L-dopa was introduced to the market as a treatment of Parkinson s disease.

# Pathophysiology
The underlying pathophysiology of Parkinson disease is dopamine depletion. Reduced number of dopaminergic neurons lead to increased inhibition of thalamus and as a result, decrease excitation of brain cortex, causing bradykinesia.
pathologic hallmark of PD is lewy bodies which are round cytoplasmic eosinophilic inclusions.
This disease can have so many triggers ( Protein misfolding, Defective proteolysis, Mitochondrial dysfunction, Oxidative stress, Iron metabolism and Immunologic and inflammatory mechanisms) but the main etiology of neuronal degeneration is either apoptosis or necrosis.

# Causes
although most of the cases of Parkinson disease are sporadic and idiopathic, there are some underlying cause for this disease including:
Genetics, drugs, oxidative stress, iron metabolism, immunologic and inflammatory mechanisms and protein misfolding.

# Differentiating Parkinson disease from Other Diseases
Differential diagnosis for Parkinson disease includes: Essential tremor, scans without evidence of dopaminergic deficit (SWEDD), dementia with Lewy bodies, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy and idiopathic, familial basal ganglia calcification and Secondary parkinsonism

# Epidemiology and Demographics
The incidence of parkinson disease is 8 to 18.6 per 100,000 person-years.
The prevalence of Parkinson disease is about 0.3% in 40 years old people and older. According to this prevalence currently we have 7.5 million people affected by this disease.
The prevalence of PD can rise with age. In 40 to 49 years old people the prevalence is 41 per 100,000 and in 80 years old and older people its 1900 per 100,000 people.
Some studies suggest that men have a higher risk of developing Parkinson disease than women.
In the study of Stephen K. Van Den Eeden and colleges it was suggested that the incidence of PD from higher to lower is in Hispanic, non-Hispanic whites and blacks.

# Risk Factors
Common risk factors in the development of Parkinson disease are:
Family history, Depression, exposure to pesticides, high consumption of dairy diet, Vitamin D deficiency, history of brain trauma, history of migraine with aura, history of anemia, using of well water, excess intake of iron and manganese, Obesity, exposure to hydrocarbons solvents and low muscle strength.

# Natural History, Complications, and Prognosis
The most common initiating symptoms in PD are slowness of movement (bradykinesia), shaking hands while they are at rest (resting tremor) and muscle stiffness (rigidity).These symptoms usually starts unilaterally and the severity of them remains higher in the side of onset.
Complications that can develop as a result of Parkinson disease includes:
Tremor, rigidity, Bradykinesia, Gait problems, Cognitive dysfunction and dementia, Psychosis and hallucinations, mood disorders including depression, anxiety, and apathy/abulia, sleep disturbances, Fatigue, Olfactory dysfunctio, pain, Autonomic dysfunction including orthostatic hypotension, constipation, dysphagia, urinary and sexual problems. In one of the studies regarding PD prognosis, it was seen that the percent of dead or severely disabled patients is 25 percent within 5 years, 67 percent within 5 to 9 years and 80 percent within 10 to 14 years of disease onset. It was also shown that disability will occurs mostly in 3 to 7 years of disease onset.

# Diagnosis

## History and Symptoms
Common symptoms of Parkinson disease includes: Tremor, rigidity, bradykinesia, Cognitive dysfunction and dementia, psychosis and hallucinations, mood disorders including depression, anxiety, and apathy/abulia, sleep disturbances, fatigue, olfactory dysfunction, pain and autonomic dysfunction.

## Physical Examination
In the appearance of PD patients we can notice that the blinking rate of spontaneous blinking is lower than normal but voluntary blinking is similar to general population. The other finding in PD patient is that their spontaneous facial expressions are less frequent and less varied in comparison to normal people (hypomimia)
In physical examination the have Cogwheel rigidity, Resting tremor, Gait problems, Bradykinesia, Olfactory dysfunction and Orthostatic hypotension.

## Laboratory Findings
There are no diagnostic lab findings associated with Parkinson's disease

## CT scan
On brain CT scan, Parkinson disease is characterized by cortical and subcortical atrophy.

## MRI
MRI findings in Parkinson disease are: reduction in T2 relaxation time and reduced iron content in putamen and GPe.
We can also use MRI to differentiate PD from other conditions. for example in the midbrain, thinning of anteroposterior diameter and enlargement of third ventricle in suggestive of supranuclear palsy. Also we can see atrophy of brainstem and cerebellum in multiple system atrophy.

## Other Imaging Findings
PET scan: In PET scan we can see that the uptake of -flurodopa tracer in reduce in the caudate and putamen in PD patients.
DaTscan: This technique can help us differentiate healthy individuals or patients with essential tremor from diseases with nigrostriatal degeneration (PD, MSA, PSP, and cortical degeneration).
Sonography: In sonography of PD patients brain we can see hyperechogenicity of the STN.

## Other Diagnostic Studies
Response to dopaminergic therapy: One of the useful methods in diagnosing PD is patient response to dopaminergic therapy. Levodopa and apomorphine challenge tests in proven to be useful in distinguishing PD from other parkinsonian syndromes.
Autonomic testing: Autonomic testing including cardiac sympathetic denervation, urodynamic testing, anal or urethral EMG, sympathetic skin responses, quantitative sudomotor axon reflex test, tilt table test and heart rate variability during forced respirations are also useful in diagnosing PD.
Olfactory testing: Olfactory testing is a useful test since olfactory dysfunction in common in PD but not in other parkinsonian syndromes and essential tremor.

# Treatment

## Medical Therapy
The mainstay of therapy for motor symptoms of Parkinson disease are: Levodopa, dopamine agonists, monoamine oxidase (MAO) B inhibitors, anticholinergic agents, amantadine, catechol-O-methyl transferase (COMT) inhibitors, estrogen and other drugs such as Exenatide, uric acid, isradipine, nilotinib and GDNF infusion.
Treatment choices for some of the nonmotor symptoms of PD are:
psychosis: quetiapine, clozapine and pimavanserin.
Dementia: Cholinesterase inhibitors such as rivastigmine and donepezil.
Fatigue: Amantadine, methylphenidate and pemoline.
Depression: Amitriptyline, desipramine, citalopram ,paroxetine, venlafaxine, ropinirole and pramipexole.
Constipation: Increasing probiotics and fibers, lubiprostone and polyethylene glycol.
Sialorrhea: chewing gum and hard candy but in severe cases, botulinum toxin injection into salivary glands .
Sexual dysfunction: sildenafil (for male)
Ortostatic hypotention: Fludrocortisone, Sympathomimetic agents such as ephedrine, pseudoephedrine, methylphenidate and dextroamphetamine.

## Surgery
Deep brain stimulation: Deep brain stimulation in the most common surgical treatment of Parkinson disease and is shown to be effective in improving motor function in these patient especially when its done bilaterally.
Thalamotomy and pallidotomy: Unilateral pallidotomy can reduce dyskinesia, on and off fluctuations, tremor, rigidity, bradykinesia and gait problems but it is not as effective as DBS.
Subthalamotomy: unilateral subthalamotomy is useful in managing PD symptoms.

## Primary Prevention
Effective measures for the primary prevention of multiple sclerosis include staying away from modifiable risk factors of the Parkinson disease:
Depression, exposure to pesticides, high consumption of dairy diet, Vitamin D deficiency, history of brain trauma, history of anemia, using of well water, excess intake of iron and manganese, Obesity, exposure to hydrocarbons solvents and low muscle strength.

## Secondary Prevention
There is no established method for secondary prevention of Parkinson disease.