Parkinson's+Disease

=Parkinson's Disease=

What it is
Parkinson's disease is a disorder that affects nerve cells, or neurons, in a part of the brain that controls muscle movement. In Parkinson's, neurons that make a chemical called dopamine die or do not work properly. Dopamine normally sends signals that help coordinate your movements.

Parkinson's usually begins around age 60, but it can start earlier. It is more common in men than in women.

Pathology
The symptoms of Parkinson's disease result from the loss of pigmented dopaminergic cells in the pars compacta  region of the substantia nigra  (literally "black substance"). These neurons project to the striatum  and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway  and excitation of the indirect pathway. The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder. The lack of dopamine  results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex , thus leading to hy pokinesia. There are four major dopamine pathways in the brain; the nigrostriatal pathway, referred to above, mediates movement and is the most conspicuously affected in early Parkinson's disease. The other pathways are the mesocortical, the mesolimbic, and the tuberoinfundibular. These pathways are associated with, respectively: volition and emotional responsiveness; desire, initiative, and reward; and sensory processes and maternal behavior. Disruption of dopamine along the non-striatal pathways likely explains much of the neuropsychiatric pathology associated with Parkinson's disease.

**Causes**
//Idiopathic Parkinson's disease (degenerative or paralysis agitans)// - most common variety with no obvious cause //Drug induced Parkinsonism -// therapeutic drugs (DA antagonists - metoclopramide, butyrophenones, phenothiazines; DA depleters - reserpine) - toxic substances (manganese dust, carbon disulphide after CO poisoning) - MPTP (kills DA-producing neurons) //Parkinsonism associated with other neurological disease// - Shy-Drager syndrome, progressive supranuclear palsy, repeated episodes of head trauma

Symptoms
//Tremor at rest:// trembling of hands, arms, legs, jaw and face //Rigidity:// stiffness of the arms, legs and trunk (leadpipe and cogwheel) //Bradykinesia: s//lowness of movement (mask-like face, monotonous speech, micrographia, bent posture, slow gait, loss of arm swing) - Poor balance and coordination As symptoms get worse, people with the disease may have trouble walking, talking or doing simple tasks. They may also have problems such as depression, sleep problems or trouble chewing, swallowing (excessive drooling) or speaking.

How to Treat
The available drugs aim to redress the balance between the dopaminergic deficiency and relative cholinergic excess in the brain by either increasing dopamine or acting as dopamine agonists or anticholinergics. Start with a low dose taken with the evening meal and increase gradually to improve mobility while minimising adverse effects.

//Levodopa:// - Improves bradykinesia and rigidity more consistently than tremor. - First line treatment for most people, especially the elderly and people with cognitive impairment.

//Bromocriptine, cabergoline, pergolide:// - Improve bradykinesia and rigidity, but are less effective than levodopa. - May cause confusion and hallucinations more commonly than levodopa.

//Amantadine:// - May improve bradykinesia, tremor and rigidity; believed to increase release of endogenous dopamine, with some anticholinergic effects and action on NMDA receptors. - Main place in therapy is in suppressing dyskinesias induced by levodopa.

//Apomorphine:// - Useful in people severely disabled by motor fluctuations refractory to conventional treatment. May allow a reduction in levodopa dosage. - Start treatment in hospital under specialist supervision. Administer by SC injection or continuous infusion with portable pump. - Is highly emetogenic and requires pretreatment with domperidone to reduce nausea.

//Entacapone:// - May be used as an adjunct to levodopa in patients with motor fluctuations. It increases duration of motor improvement ('on' time), but also increases levodopa-induced dyskinesias and GI adverse effects.

//Anticholinergics:// - Improve tremor, with minimal effectiveness for akinesia/hypokinesia. - Good for patients with sialarrhoea (persistent salivation) and/or urge incontinence.

Other advice
- antipsychotics may make PD worse (use non-drug tricks): atypicals preferred - benzodiazepines (especially short-acting) may be useful)

-** include: end of dose slowing, peak dose dyskinesias, motor blocks and freezing, early morning dystonias, on-off phenomenon - most can be treated by: - increasing the frequency of the dose while keeping the overall dose steady (dividing doses) - using slow-release preparations (may need kick-start dose in the morning) - using DA agonists (have long half-lives) - adding MAO-B inhibitor to increase half-life
 * Motor Problems:

//consider when: -// patient < 60 - unilateral tremor and rigidity - unresponsive to drug therapy
 * Surgery:**

Additional Resources
[|MedlinePlus] [|AMH - Parkinson's Disease] //AP400// [|Parkinson's Disease]
 * Lecture Notes:**