Parkinson’s Disease Causes, Clinical Manifestations And Treatment

Parkinson’s disease is the second most common neurodegenerative disease. It is the most common cause of Parkinsonism disease. There is a deficiency of dopamine in the brain of people with Parkinson’s disease. It affects 1% of the population over 65 years of age and 2% of the population over 80 years of age.

Causes

Parkinson’s disease is caused by both genetic and environmental factors. If you have a family history of Parkinson’s disease, the environmental factors precipitate the early onset of disease in these peoples. Administration of MPTP by inhalation or ingestion rapidly produced a severe state of Parkinson’s disease. This state is different from advanced Parkinson’s disease. MPTP is a 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine and it is a toxin. Not all the people who use MPTP will develop Parkinson’s disease but all people will suffer from its toxic side effects. Systemic exposure to the pesticide rotenone can reproduce the features of Parkinson's disease. In some peoples with Parkinson’s disease, genetic factors are dominant. The mutation reported in the α-synuclein gene (synaptic protein) is responsible for the development of Parkinson’s disease. These mutations are reported in very few families. Alpha-synuclein plays a vital role in pathological pathways of Parkinson's disease. Recently eight genetic locus and four genes have also been identified as a causative agent for Parkinson’s disease. The proteins produced by these genes are involved in the recycling and excreting of abnormal proteins. This whole process of removal is controlled by a system called ubiquitin-proteasome system.  When these loci and genes are damaged or disturbed, then the abnormalities due to this damage can cause the death of these proteins. This death is due to decreased production of energy of mitochondria and increased stress.

Clinical Manifestations

There are two main types of clinical manifestations reported in Parkinson’s disease, motor and non-motor symptoms.

Motor Symptoms

The motor symptoms of Parkinson’s disease are,

• Bradykinesia (Slowness of movement)
• postural instability (Late feature)
• Rest tremor (Rhythmic movements within a frequency of 4–6 Hz per cycles/s)
• Extrapyramidal rigidity
• Tremors (In almost 80-85%)
• Postural tremor (Up to 60% of cases)
• Loss of arm swing during walking
• Trunk posture may be flexed
• Difficult communication
• Monotonous speech
• Blinking frequency is reduced
• Micrographia (Writing will become small and legible in micrographia)

Non-motor symptoms

The non-motor symptoms of Parkinson’s disease are,

• Autonomic dysfunction
• Greasy skin (seborrhea)
• Frank incontinence (rare)
• Urogenital difficulties
• Erectile dysfunction
• Urinary urgency
• Postural hypotension
• Depression (40% of cases)
• Dementia (80% of cases)
• Cognitive impairment
• Paranoid ideation
• Fluctuations
• Delusions
• Hallucinations

Treatment

All medicines available for the treatment of Parkinson’s disease are symptomatic. During treatment, age, sex, type and severity of disease and co-morbidities are also considered. The most common drug used in the treatment of Parkinson’s disease is levodopa.

Levodopa

Levodopa is the most effective drug available for the symptomatic treatment of Parkinson’s disease. It is used in combination with the peripheral dopa-decarboxylase inhibitors such as carbidopa or benserazide. Levodopa with carbidopa is known as co-careldopa and levodopa with benserazide is known as co-beneldopa. The dopa-decarboxylase inhibitors are used to decrease the dose of levodopa because they block the conversion of levodopa to dopamine. Levodopa can cross the blood brain barrier and is converted into amino acid decarboxylase and then into dopamine. As a result, it stores nigrostriatal nerve terminals. The dose of levodopa in Parkinson’s disease is 50 mg/day increasing every 3–4 days. The maximum dose of levodopa is 50mg three times in a day. If no effect is produced by 50mg three times in a day, the dose may be increased to 100mg.  It is recommended to take levodopa with food to decrease nausea. In advanced stages, you should take levodopa 30 minutes before meal because at this stage protein interferes with the absorption of levodopa. Levodopa can also be used in form of controlled release medications. But there is no effective benefit of levodopa in controlled preparations is reported. A gel of co-careldopa is available to reduce motor fluctuations. It is directly administered into the small bowel by using a percutaneous route.

Dopamine agonists

Dopamine agonists stimulate dopamine receptors both post- and presynaptically. It is less effective and less potent than levodopa. Apomorphine is the only drug in dopamine agonist that is given by parenteral route. Drugs included are ropinirole, apomorphine, cabergoline, pramipexole, pergolide and pramipexole.

Catechol-O-methyltransferase inhibitors

Catechol-O-methyltransferase inhibitors are also used for the treatment of Parkinson’s disease. Catechol-O-methyltransferase is an enzyme found in the gut, liver, kidney and brain. It is present centrally where the conversion of dopamine to homovanillic acid is inhibited. It is also present peripherally where the degradation of levodopa to 3-O-methyldopa is inhibited. Drugs included are tolcapone and entacapone.

Monoamine oxidase type B inhibitors

Monoamine oxidase type B inhibitors slow down the degradation of dopamine in the striatum. They may also have an antiapoptotic effect. Drugs included are selegiline and rasagiline. Selegiline is used in a single dose of 5-10mg and rasagiline is used in the dose of 1mg daily. These drugs can also be used as adjunctive in the treatment of Parkinson’s disease.

Amantadine

It facilitates the presynaptic release of dopamine and blocking the reuptake of dopamine. It may also act as an anticholinergic and N-methyl-d-aspartate (NMDA) receptor antagonist. It is used in the early stages of Parkinson’s disease. It is used in doses of 100–300 mg.

Anticholinergic drugs

They are effective in treating tremors but they have no effect on Bradykinesia. Drugs used are trihexyphenidyl and orphenadrine.