Definition and Classification

PD is the most prevalent type (approximately 80%) of Parkinsonism, a clinical syndrome pathologically characterized by lesions of the basal ganglia, predominantly in the substantia nigra, that produce abnormalities in motor activities.

Parkinsonism is a clinical entity rather than an etiologic diagnosis; it is associated with variety of pathological process that damages the extra pyramidal system. The causes of Parkinsonism are as follows:

Primary or idiopathic

Parkinson's disease (PD)

Secondary Parkinsonism

Toxin

• MPTP intoxication
• Methanol
• Carbon monoxide intoxication
• Cyanide
• Carbon disulfide intoxication
• Disulfiram
• Manganese intoxication

Infectious

• Postencephalitic
• Creutzfeldt-Jakob disease
• AIDS
• Subacute sclerosing panencephalitis
• Fungal infections
• Intracytoplasmic hyaline inclusion disease

Vascular

• Binswanger's disease
• Multi-infarct

Metabolic

• Chronic hepatocerebral degeneration
• Hypocalcemic Parkinsonism

Hydrocephalus

• Noncommunicating hydrocephalus
• Normal pressure hydrocephalus

Drug-induced

• Lithium
• Diltiazem, flunarizine, cinnarizine
• Dopamine receptor blockers (neuroleptics)
• Dopamine depleters (tetrabenazine, reserpine)

Hypoxia

Trauma

Psychogenic

Tumor

Hemiatrophy-hemiparkinsonism

Syringomesencephalia

Paraneoplastic Parkinsonism

Parkinson's-Plus Syndromes

Dementia syndrome

• Pick's disease
• Alzheimer's disease
• Cortical diffuse Lewy body disease

Multiple system atrophy syndromes

• Shy-Drager syndrome
• Motor neuron disease-Parkinson
• Striatonigral degeneration
• Sporadic olivopontocerebellar atrophy

Progressive supranuclear palsy

Progressive pallidal atrophy

Cortical-basal ganglionic degeneration

Eighty percent of cases of Parkinsonism are PD patients.(1) PD was first described by James Parkinson in 1817 and later named as Paralysis agitans by Marshall Hall in 1841.(2) It is a progressive neurological disorder, the symptoms of which can be easily memorized with the nemonic PART

Postural reflex impairment
Akinesia/Bradykinesia
Rigidity (cogwheel)
Tremor (resting)

Resting tremor is the pathognomic sign of PD; it presents early in the disease and may remain present even very late in the disease.(2) Resting tremor occurs in varying degrees in other forms of Parkinsonism.

Epidemiology

PD usually occurs between the ages of 40 & 70 years, with peak age of onset in the sixth decade. It is rare before the age of 30 (only four out of 380 case were seen in one series).(2) Juvenile Parkinsonism has age of onset before 20 years of life, has a different pattern of nigral degeneration and is often hereditary.(3)

There are approximately one million patients with PD in North America; about 1% of the population over the age of 65 years are afflicted.(2) Both incidence and prevalence increase with age.(3)

When to Start Treatment/Goals of Treatment

Initiation of treatment (especially pharmacotheraphy) is a very important decision in the management of PD.(4) Almost always it is highly individualized and both patient and physician play a major role in therapeutic decision If the symptoms of disease do not affect the patient's life, treatment is usually not helpful. It is recommended that early stage disease may be left untreated until it limits motor functions.

Treatment

Early treatment should involve physical therapy with stress on posture and gait. Visualization techniques to improve gait can be particularly useful. Treatment of PD can be divided into three components:

Symptomatic:

For improvement of sign and symptoms.

Protective:

To interfere with the pathophysiological mechanism of disease.

Surgical/Restorative:

To implant new neurons or to stimulate growth and functions of the remaining neuron.

Classification and doses of drugs

Levodopa

• Carbidopa/Levodopa (Mixture of dopamine agonist and decarboxylase inhibitors)
  Start: 1/2 of 25/100 tablet, bid, after meal; increase by ½ tablet/d, q 4-7 days.
• Carbidopa/Levodopa (controlled-release)
  Start: 25/100 tablet or 50/100 tablet bid.

Direct Dopamine Agonists

• Pramipexole (Mirapex®)
  Start: 0.125 mg/d, tid; gradually increase, but no more frequently than every 5 to 7 days.
  Max. therapeutic range is 1.5-4.5 mg/d.
• Ropinirole (Requip®)
  Start: 0.25 mg/d, tid; increase weekly by 0.25 mg/d, tid, to max. of 8 mg/d, tid.
• Pergolide (Permax®)
  Start 0.05 mg/d for 2 days; increase 0.10 or 0.15 mg/d for 12 days; increase 0.25mg/d to 3mg/d, tid.
• Bromocriptine (Parlodel®)
  Start: ½ of 2.5 mg tablet with meals, bid; increase 2.5 mg/d q 14-28 days to 5-15 mg/d.

Catechol-O-methyltransferase (COMT) Inhibitors (Used in combination with carbidopa)

• Tolcapone (Tasmar®)
  Start: 100 mg or 200 mg, tid, q 6 h.
• Entacapone (Comtan®) Investigational drug.
  Start: 200 mg with each dose of levodopa

Anticholinergics

• Procyclidine (Kemadrin®)
  Start: 2.5 mg, tid, after meals; increase to 5 mg, tid or qid.
• Trihexyphenidyl (Artane®)
  Start: 1 mg with meal on first day; increase 2 mg/d for 3-5 days to 6 mg/d, tid, at mealtimes.
• Benztropine (Cogentin®)
  Start: 0.5-1 mg/d at bedtime; can increase to 4-6 mg/d in divided doses.

Others

• Selegiline (Eldepryl®) (MAO-B inhibitor)
  Start: 5 mg at breakfast and lunch; 5 mg/d may be effective in some patients.
• Amantadine (Symmetrel®) (antiviral agent)
  Alone or in combination with other anti-Parkinson's drugs: 100-200 mg/d.
  50 mg/d in older persons and those with renal impairment.
• Vitamin E
• Hormone Replacement Therapy (HRT)

Selection of Levodopa or other anti-parkinsonian drug

Almost all patients, who take levodopa on a long-term basis, develop complications. With levodopa, younger patients in particular show response fluctuations, so other anti-parkinsonian drugs should first be considered.

It is appropriate to start with levodopa if patient symptoms interfere with his or her activities. For mild symptoms, there are other choices to begin with:

• Do not start symptomatic medications until it seems appropriate to start levodopa therapy
• Possibly start with neuroprotective drugs, e.g., selegline (this is controversial - vide infra)
• Begin treatment with anticholinergic, amantadine, or a dopamine agonist agent.

Future drugs

Ethyl Ester of levodopa

It achieves greater striatal levels and lasts longer if injected subcutaneously in experimental animals. It may be potent rescue agent to overcome "off" time in PD patients.(5)

Remacemide

This is a new, nondopaminergic glutamate receptor antagonist, an anticonvulsant, and neuroprotective agent. It has been shown to improve the motor symptoms of MPTP-induced Parkinsonism animal models.

This drug is under study for its efficacy and safety in the treatment of PD.

Immunophilins

Immunophilins are protein receptors for immunosuppressant drugs such as cyclosporin. Immunophilins, such as FKBP-12, bend to calcineurin and regulate intracellular calcium. They are also involved as chaperones in the regulation of the heat shock protein 90 (hsp 90) system. They are being actively studied for the treatment of PD.(24),(25)

Non-Pharmacological Management of PD

First and most important is the psychological support, from the onset of symptomatology and throughout the course of PD.(22) The best care of PD patients is basically a team effort that should involve:

• Family and primary care physician
• Neurologist or geriatrician
• Family members
• Physical, occupational and speech therapist.(6)

The following problems need careful consideration:

Patient Education:

Patients and family members should be provided with the latest and reliable information about the course and the prognosis of the disease, which is often helpful in relieving the fear and anxiety associated with the disease.

Environmental Modifications:

These include an elevated bed to allow the patient to rise easily, a chair with armrests and a firm seat, a urinal or commode near the bed, raised toilet seat and a grab bar. Utensils with large handles, easy hold cups and nonskid plates. Specific spoons to control tremor are available.

Driving:

This is very important aspect of the PD patient's life, so they need careful consideration in assessing their driving capability, e.g., mental status, judgment and reaction speed.

Psychotherapy:

Especially when depression occurs, psychological counseling may be useful. Antidepressants can be helpful.

Occupational Therapy:

To help the patient manage the activities of daily living.

Speech Therapy:

Breathing control exercises; patients practice augmentation of voice loudness and variation in pitch. Loud reading and singing. Swallowing difficulties may need assessment and dietary modifications.

Physical Therapy:

Simple exercises, such as swimming, walking and bicycling, should be encouraged. As the disease advances, prescribed exercises likely to improve postural instability, stooped posture and shuffling gait should be instituted. Strength training needs to be continued throughout life. Visualization techniques to teach the patient to step over objects may improve gait.

A recent report suggests that a special exercise program can improve mobility in patients with early and mid-stage PD.(23)

Dental Care:

Daily flossing and tooth brushing with fluoride or tartar-control toothpaste are recommended.

Family Counseling:

All available information should be provided to the family members and caregivers so they understand the PD and its complications. Caregiver support groups can be helpful.

Non-Pharmacologic Treatment of Associated Disorders

Constipation:

Can be improved by the use of adequate water and high dietary fiber, stool softeners and regular exercise.

Nutritional Disturbances:

Diet should be well balanced and dietary consultation is often helpful.

Particular attention should be given to the following:

• Dietary protein reduces the absorption of levodopa, so the timing of meal and medications should be different. High protein diets are inappropriate.
• Supplemental iron may also interfere with the action of carbidopa/levodopa, so the two should not be given at the same time.
• Medications should be taken on an empty stomach.
• Weight loss is common and may be related to increased energy expenditure (tremor), depression or difficulty in eating and swallowing.

Swallowing Problem and Sialorrhea:

Can be best-evaluated and treated by speech therapist.

Sexuality:

Decreased sexuality in PD patients is partly due to aging and disease itself. Other contributory factors are: autonomic disturbances, depression and fatigue.

Counseling to improve self-esteem, exercise and adequate diet are helpful. Those patients who are on levodopa may have feelings of well-being and short-lived increase in sexuality

Dopamine agonist therapy occasionally causes hypersexuality.

Both family and physician should anticipate these problems. When impotence occurs it should be treated as in association with any other disease.

Seborrheic Dermatitis:

Its severity is partially reduced by levodopa. It can be treated with over-the-counter medications such as:

• Selenium containing shampoos or lotions.
• Pyrithione zinc containing shampoos, lotions, and creams.
• Neutral or bland acne soap.

Hip Fractures:

PD patients have an increase in hip fractures. This is due in part to gait abnormalities, balance problems and abnormal posture leading to increased falls. Osteoporosis should be evaluated using DEXA bone density and treated when present. Hip protection should be considered when the patient is having repeated falls -- a wheeled walker is often protective against falls and improve gait.

Complications of PD and Their Treatment

Levodopa Dose-Related Motor Fluctuations:

Early sign of fluctuations are:

• Internal tremor as an end-of-dose pattern.
• Early morning akinesia
• Fidgetiness or restlessness
• Loss of refreshing effect of sleep
• It is suggested that reduced dopamine storage is partly responsible for the fluctuating level of levodopa.(7)

Stimulation of D1 (excitatory) receptors is associated with dyskinesia, while D2 (inhibitory) do the opposite. Therefore, dopamine agonists are likely to produce less dyskinesia than levodopa.(8)

Motor abnormalities and their treatment are as follows:

Motor abnormalities	Treatment
Drug failure	Domperidone (not available in USA) Cisapride
Peak-dose dyskinesia/dystonia	Decrease each dose of levodopa Dopamine agonist Add anticholinergic
"On-off"	Dopamine agonist Clozapine Liquid levodopa
"Off"-period dystonia	COMT inhibitors Controlled-release levodopa Dietary adjustments Dopamine agonist
"Wearing-off"	COMT inhibitors Controlled-release levodopa Increase dose frequency of levodopa Dopamine agonist
Beginning-of-Dose Deterioration	No treatment
Freezing	Levodopa® Norepinephrine<® Auditory, visual, and proprioceptive cues
Restless legs	Controlled-release levodopa Carbamazepine

Orthostatic Hypotension:

It may be due to disease itself or to anti-parkinsonian medications(9) (most likely direct dopaminergic agonist):

1. If minimal, no treatment
2. Elevate head of bed
3. Drink a large glass of water in morning
4. Adequate salt intake
5. Do not limit late evening fluid intake
6. Compression stockings (need to be put on while in bed)
7. Bedside urinal and walker
8. Florinef^®
9. Midodrine^® (new alpha 1-adrenoreceptor agonist)

Gastrointestinal Side Effects:

Nausea:

• Most commonly due to all dopaminergic drugs; taking medication with food is helpful.
• Carbidopa can be used as supplement.

Constipation:

Can be treated by:

1. High fiber diet
2. Increase fluid intake
3. Bran, psyllium, and docusates
4. Cisapride (propulsid)
5. Anticholinergic and narcotic containing drugs should be avoided.

Psychiatric and Behavioral Disorders:

Psychiatric/Behavioral Disorder	Treatment
Psychosis and hallucinations	Reduce dosage of levodopa Stop or reduce: Dopamine agonist Adjunctive medications   (e.g., anticholinergics & amantadine)   Olanzapine   Clozapine
Depression	Antidepressant If apathy is major feature, use stimulating antidepressant. If sleep disturbance is major feature, use sedating antidepressant.
Sleep Disorders	Caffeine Increase activity
Sleep fragmentation	Sedating antidepressant Benzodiazepine (short-acting) Controlled-release carbidopa/levodopa
Vivid dreams/nocturnal vocalizations	Decrease dopaminergic medication near bedtime

Surgery

Pallidotomy:

Indicated for: Drug induced dyskinesia, dystonia ("off" or "on"), "on-off" phenomenon and motor fluctuations.

Target sites are:

• Antereodorsal part of pallidum 1950s. (Tremor and rigidity reported to recur in 25% of patients after pallidotomy compared to 11% after thalamotomy.)
• Posterolateral part of pallidum 1992 (associated with more side effects).
• Stereotactic ventral pallidotomy 1995 (less surgical time, fewer side effects).

Thalamotomy:

Indicated for: tremor, rigidity and drug induced dyskinesia.

Bilateral thalamotomy associated with more side effects than unilateral or subthalotomy.

Deep-Brain Stimulation (DBS) (Thalamus):

Recommended as alternative to thalamotomy for tremor.(10)

Chronic stimulation may also improve rigidity, unilateral pain and dyskinesia (this needs more studies).

More recently, DBS has been implanted in GPi (Globus Pallidus interna) and GPe (Globus Pallidus externa) and has reportedly improved the cardinal motor symptom, especially tremor. Other sites have yet to be explored that can provide useful results by electrical stimulation.

Advantages:

• Does not create any irreversible lesion.
• Mostly provides functional improvement in:
  • Patients who had an earlier contralateral thalamotomy
  • Elderly
  • Patients who have had bilateral tremor
  • Patients who have a speech disorder.

Disadvantages:

• Stimulatory device may need replacement because of fracture or infection
• Battery also requires replacement after several years.

Transplantation of Dopamine-Producing Cells

A criterion of patient selection for transplantation is not yet established, however advanced PD patients are usually recommended.(11) Two types of donor tissue are used for transplantation:

• Chromaffin cells of adrenal medulla
• Fetal nigral neurons of the ventral mesencephalon.

At present there is little human data supporting this approach. A few patients with MPTP-induced Parkinsonism have claimed to have had dramatic improvement.

Coming Approaches of Neural Transplantation

By the use of new approaches, the following therapeutic agents can be directly delivered in to the central nervous system:

• Ex vivo and in vivo gene therapy
• Polymer encapsulated cells
• Implantation of immortalized cells engineered to produce a specific protein.

A potentially exciting approach is electromagnetic brain stimulation. In some individuals this produces dramatic improvement.

Summary

Parkinson's disease is a common aging associated disease which produces profound deficits in functional status. While Sinemet^® remains the mainstay of treatment, numerous new pharmacological agents are available that allow fine tuning of the treatment. The interdisciplinary team members, especially physical therapists, are key to optimum management of Parkinson's disease. There has been increased use of surgical techniques over the last few years. Brain transplantation and immunophilins represent major possibilities for the future treatment of Parkinson's disease.