Parkinson disease

Other Names: Parkinson's disease; Paralysis agitans; Shaking palsy; Primary parkinsonism

Parkinson disease (PD) is a neurologic disease that affects the movement. The four main symptoms are tremors of the hands, arms, legs, jaw, or head, specially at rest; rigidity, or stiffness; bradykinesia, or slow movement; and postural instability or inability to find balance. Parkinson disease affects several regions of the brain, especially a region known as "substantia nigra" that helps controlling balance and movement. Both men and women can have Parkinson’s disease. However, the disease affects about 50 percent more men than women. Parkinson disease can also affect emotions and thinking ability (cognition). Some affected individuals develop psychiatric conditions such as depression and visual hallucinations. People with Parkinson disease also have an increased risk of developing dementia, which is a decline in intellectual functions including judgment and memory.

Cause

Most cases of Parkinson disease probably result from a complex interaction of environmental and genetic factors. These cases are classified as sporadic and occur in people with no apparent history of the disorder in their family. The cause of these sporadic cases remains unclear.

Approximately 15 percent of people with Parkinson disease have a family history of this disorder. Familial cases of Parkinson disease can be caused by mutations in the LRRK2, PARK7, PINK1, PRKN, or SNCA gene, or by alterations in genes that have not been identified. Mutations in some of these genes may also play a role in cases that appear to be sporadic (not inherited).

Alterations in certain genes, including GBA and UCHL1, do not cause Parkinson disease but appear to modify the risk of developing the condition in some families. Variations in other genes that have not been identified probably also contribute to Parkinson disease risk.

It is not fully understood how genetic changes cause Parkinson disease or influence the risk of developing the disorder. Many Parkinson disease symptoms occur when nerve cells (neurons) in the substantia nigra die or become impaired. Normally, these cells produce a chemical messenger called dopamine, which transmits signals within the brain to produce smooth physical movements. When these dopamine-producing neurons are damaged or die, communication between the brain and muscles weakens. Eventually, the brain becomes unable to control muscle movement.

Some gene mutations appear to disturb the cell machinery that breaks down (degrades) unwanted proteins in dopamine-producing neurons. As a result, undegraded proteins accumulate, leading to the impairment or death of these cells. Other mutations may affect the function of mitochondria, the energy-producing structures within cells. As a byproduct of energy production, mitochondria make unstable molecules called free radicals that can damage cells. Cells normally counteract the effects of free radicals before they cause damage, but mutations can disrupt this process. As a result, free radicals may accumulate and impair or kill dopamine-producing neurons.

Inheritance

Most cases of Parkinson disease occur in people with no apparent family history of the disorder. These sporadic cases may not be inherited, or they may have an inheritance pattern that is unknown.

Among familial cases of Parkinson disease, the inheritance pattern differs depending on the gene that is altered. If the LRRK2 or SNCA gene is involved, the disorder is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

If the PARK7, PINK1, or PRKN gene is involved, Parkinson disease is inherited in an autosomal recessive pattern. This type of inheritance means that two copies of the gene in each cell are altered. Most often, the parents of an individual with autosomal recessive Parkinson disease each carry one copy of the altered gene but do not show signs and symptoms of the disorder.

When genetic alterations modify the risk of developing Parkinson disease, the inheritance pattern is usually unknown.

Symptoms

A number of disorders can cause symptoms similar to those of Parkinson disease. People with symptoms that resemble Parkinson disease but that result from other causes are sometimes said to have parkinsonism. Some of these disorders are listed below.

• Postencephalitic parkinsonism
• Drug-induced parkinsonism
• Toxin-induced parkinsonism
• Arteriosclerotic parkinsonism
• Parkinsonism-dementia complex of Guam
• Post-traumatic parkinsonism
• Essential tremor
• Normal pressure hydrocephalus
• Progressive supranuclear palsy
• Corticobasal degeneration
• Multiple system atrophy
• Dementia with Lewy bodies

Parkinsonian symptoms may also appear in patients with other, clearly distinct neurological disorders such as Wilson disease, Huntington disease, Alzheimer disease, spinocerebellar ataxias, and Creutzfeldt-Jakob disease. Each of these disorders has specific features that help to distinguish them from Parkinson disease.

Diagnosis

There are currently no blood or laboratory tests that have been proven to help diagnose sporadic cases of Parkinson disease. The diagnosis is generally made after careful evaluation of medical history, current symptoms, and exclusion of other conditions.The clinical findings of tremor, rigidity, and bradykinesia are highly suggestive of Parkinson disease. The genetic cause of some forms of Parkinson disease has been identified. In those cases, genetic testing may be utilized to identify affected family members People may be given levodopa, with any resulting improvement in motor impairment helping to confirm the PD diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered final proof that the person had PD. The clinical course of the illness over time may reveal it is not Parkinson's disease, requiring that the clinical presentation be periodically reviewed to confirm accuracy of the diagnosis. Computed tomography (CT) scans of people with PD usually appear normal. MRI has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive T2* and SWI sequences at a magnetic field strength of at least 3T, both of which can demonstrate absence of the characteristic 'swallow tail' imaging pattern in the dorsolateral substantia nigra.In a meta-analysis, absence of this pattern was highly sensitive and specific for the disease.

Diffusion MRI has shown potential in distinguishing between PD and Parkinson plus syndromes, though its diagnostic value is still under investigation. CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and chronic ischemic insults, as well as less frequent entities such as basal ganglia tumors and hydrocephalus.

Treatment

Treatment is usually based on a medication known as levodopa. Other medication includes bromocriptine, pramipexole, ropinirole, amantadine, rasagiline and safinamide. Deep brain stimulation (DBS) a surgical procedure where electrodes are implanted into the brain may be useful for some people.Prognosis varies, and while some people become disabled, others will have only minor movement problems.Studies have shown that people with PD who have cognitive impairment, postural hypotension, and sleep problems may have a more rapid progression of the disease. Deep brain stimulation (DBS) can offer symptomatic relief in later stages of PD and may reduce requirements for L-DOPA treatment and exposure to its side effects. DBS is also used to treat other movement disorders, including essential tremor, which causes involuntary shaking (often in the hands) that worsens during movement, and dystonia, which causes involuntary muscle contractions and slow, repetitive movements or abnormal postures.

DBS involves a device similar to a cardiac pacemaker that sends electrical signals through wire electrodes implanted in the brain. For movement disorders, electrode locations include brain structures important for motor control. Rigidity, tremor, and dopamine-induced dyskinesia in people with PD are treated with stimulation in the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) (FDA approval, 2002). These same sites are stimulated for the treatment of dystonia (granted a special FDA approval called a Humanitarian Device Exemption (HDE), in 2003). DBS in the ventral intermediate nucleus of the thalamus (VIM) is used to treat essential tremor and tremor as a primary symptom of PD (FDA approval, 1997).

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Apomorphine HCL (Brand name: Apokyn®)FDA-approved indication: For the acute, intermittent treatment of hypomobility, "off" episodes ("end-of-dose-wearing-off" and unpredictable :on/off" episodes) associated with advanced Parkinson's disease
• Selegiline HCl (Brand name: Eldepryl) As an adjuvant to levodopa and carbidopa treatment of idiopathic Parkinson's disease (paralysis agitans), postencephalitic Parkinsonism, and symptomatic Parkinsonism.
• Droxidopa (Brand name: Northera)Droxidopa (Northera) was approved for the treatment of orthostatic dizziness, lightheadedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure (Parkinson's disease, multiple system atrophy, and pure autonomic failure), dopamine beta-hydroxylase deficiency, and non-diabetic autonomic neuropathy.