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Parkinson’s Disease

(Extrapyramidal Syndromes)

 

1. Clinical diagnosis.
   1. Parkinson’s disease is a clinical diagnosis made by observation of the patient.  There is no blood test nor x-ray image that can delineate the diagnosis of Parkinson’s disease.  Some combination of the following would lead to diagnosis of Parkinson’s disease or an extrapyramidal syndrome. 

                                                              i.      Tremor (shaking).

                                                            ii.      Stiffness.

                                                          iii.      Slowness (bradykinesia).

                                                          iv.      Weakness (fatigue).

                                                            v.      Difficulty walking (postural imbalance).

2. Other associated signs and symptoms can include:

                                                              i.      Dysarthria.

                                                            ii.      Drooling.

                                                          iii.      Micrographia.

                                                          iv.      Orthostatic dizziness.

                                                            v.      Loss of sense of smell.

                                                          vi.      Seborrheic dermatitis.

 

2. Primary Parkinson’s disease is not associated with any identifiable cause.  It could be idiopathic (probably degenerative), inherited, or one of the “degenerative plus” syndromes. 

 

3. Secondary Parkinson’s disease is extremely common and can be related to:
   1. Psychotropic medications (major tranquilizers).
   2. Head trauma.
   3. Multi-infarct syndrome (strokes).
   4. Wilson’s disease.
   5. Hyperparathyroidism.
   6. Poisons (carbon monoxide, other chemicals, including some found in the process of illicit drug use).
   7. Hydrocephalus.
   8. Hypoxic brain injury as with cardiac arrest. 
   9. Huntington’s disease.
   10. Hereditary or familial Parkinson’s disease is not common but is sometimes seen.  The inheritance may have variable penetrance and severity of manifestations. 
   11. Secondary Parkinson’s disease often does not respond as well as to drugs as compared to primary or idiopathic Parkinson’s disease.  An exception to this rule is Parkinson’s disease related to psychotropic medications. 

 

4. Initial treatment priorities should be first addressed to general medical conditions pertinent to functioning, overall health, well being, and longevity:
   1. Hypertension.
   2. Diabetes.
   3. Thyroid dysfunction.
   4. Hyperlipidemia.
   5. Vascular disease affecting the brain and heart.
   6. Vitamin deficiencies.
   7. Arthritis.
   8. Others.

 

5. Secondary considerations include assurance of management of other nonspecific complaints such as:
   1. Constipation.
   2. Heartburn.
   3. Anxiety.
   4. Depression.
   5. Sexual dysfunction.

 

6. In sum.  It is important not to be one dimensional in consideration and treatment of Parkinson’s disease.  A neurology specialist needs to work in conjunction with the primary doctor in providing holistic care.

 

7. The specific treatment of Parkinson’s disease involves trying to decrease the aforementioned symptoms of:
   1. Tremor.
   2. Stiffness.
   3. Slowness.
   4. Weakness.
   5. Postural imbalance.

 

8. Medications may include:
   1. Carbidopa/levodopa combination (Sinemet) has been the primary mainstay of treatment for Parkinson’s disease.  This drug combination can help all the above-mentioned five problems to a certain extent, although often some more than others. 
   2.  In relative terms, the carbidopa/levodopa combination will “loosen up” a patient and help them be more athletic, brisk, and comfortable in their movements.

 

9. Worries and observations with regards to use of the Sinemet requires some reassurance, and these include:
   1. The early institution of treatment with Sinemet does not adversely affect the long-term outcome of Parkinson’s disease.
   2. The early and long-term use of Sinemet is not going to adversely affect the brain or cause the brain to deteriorate. 
   3. Sensitivity and benefit from Sinemet can initially be quite striking.  Sometimes the effect can then start to wear off, and increasing doses and more frequent administration of the Sinemet becomes required. 
   4. Unfortunately, the course of Parkinson’s disease tends to be an insidiously worsening or declining process.  Many patients can have very low grade indolent symptoms very responsive to Sinemet for many years.  Some patients can show a more rapid decline and then a resistance to the Sinemet. 
   5. Dyskinesia, dystonia, and akathisia can all be side effects of the use of Sinemet and other dopamine agonists.  These are abnormal involuntary movements, which occur as a consequence of the dopamine stimulation with the Sinemet.  Examples include facial grimacing and “restlessness.” Unfortunately, abnormal movements, dyskinesia, etc. can occur while the Parkinsonian symptoms of tremor, stiffness, etc., seem to be relatively undertreated.  A patient can, relatively speaking, be undermedicated and at the same time be “poisoned” or toxic from the Sinemet.  In any event, there can be a delicate state of balance between the side effects of Sinemet and its benefit. 
   6. Disturbed sleep with abnormally vivid dreams, variable degrees of mania or hypomania, and even outright hallucinations with delirium can occur in some patients as a side effect of the Sinemet or dopamine stimulation.  On occasion these drug-induced hallucinations or hypomania (psychosis) related to Sinemet have to be counteracted with other drugs:

                                                              i.      Amitriptyline and trazodone can be helpful for sleep fragmentation.

                                                            ii.      Severely vivid dreams and hallucinations can be dampened with quetiapine (Seroquel).

                                                          iii.      Mood stabilizers such as lithium and valproic acid (Depakote) can be also useful in counteracting the unwanted “brain stimulation” and restlessness or hallucinations caused by the dopamine stimulation. 

                                                          iv.      Hallucinations, confusion, and psychosis can be limiting factors sometimes preventing treatment with Sinemet even though the patient cannot function without it.

 

10. Other secondary drugs are added to enhance or augment the effect of Sinemet or smooth out the side effects.  These include:
    1. Amantadine (Symmetrel) as a dopamine agonist effect to enhance the Sinemet, although can be associated with side effects of leg swelling and vascular “mottling” of the legs.
    2. MAO-B inhibitors include selegiline (Eldepryl), Zelapar, and rasagiline (Azilect).  These drugs provide primary benefit with regards to symptoms of Parkinson’s disease and also augment the effects of Sinemet.  Although they are MAO-B inhibitors, they are not much prone to the side effects of the “classic” MAO inhibitors used in psychiatry for depression. 
    3. Entacapone (Comtan) either given as an adjunct to Sinemet or in a primary combination with Sinemet in one pill (Stalevo).  Stalevo is a combination of three drugs, carbidopa, levodopa, and entacapone that comes in a wide variety of dosage forms. 
    4. Ropinirole (Requip) and Pramipexole (Mirapex) are the two primary dopamine agonists used in either initial or secondary treatment of Parkinson’s disease. There is no particular advantage to starting the primary dopamine agonist as above as opposed to starting Sinemet.  Theoretical concerns that these primary dopamine agonists are “better” for initial treatment of Parkinson’s disease and lessen chances of dyskinesias or yo-yoing are unfounded.  These primary dopamine agonists should,  therefore, be added as is necessary and clinically indicated to augment or enhance the overall comprehensive drug plan in any given Parkinsonian patient. 

Unfortunate side effects with the dopamine agonists (Requip and Mirapex) can include:

                                                              i.      Fluid retention.

                                                            ii.      Vivid dreams.

                                                          iii.      Agitation.

                                                          iv.      Hallucinations.

                                                            v.      Delirium.

                                                          vi.      Sudden and unexplained sleepiness or “sleep attacks.”

In any event, these dopamine agonists need to be initiated with extreme care and caution and with clinical expertise to help identify potential developing side effects.

e.   Anticholinergics medications such as trihexyphenidyl (Artane) and benztropine (Cogentin) can sometimes help with a resistant tremor.  However, these older treatments can be associated with side effects of dry mouth, constipation, urinary retention, and mental confusion, or delirium.  They are sometimes avoided for these reasons.

f.    Apomorphine injections have been touted to help attenuate dyskinesias and yo‑yoing.  However, this injection is associated with marked nausea and sometimes vomiting and dizziness.  This is not a practical pharmacologic tool. 

g.   Neupro (rotigotine) patch was very helpful, but it is for the time being off the market due to bioavailability issues.

h.   Mental “stimulants” such as Aricept (donepezil), Exelon (rivastigmine), and Namenda (memantine) can be helpful to combat primary and secondary memory loss and confusion.  Theoretically, these drugs should have “negative” effects on the Parkinson’s disease but they do not seem to do so.  However, the main toxicities of these mental “stimulants” include dizziness and nausea, which are often already a problem in this type of patient. 

 

11.  Non-drug treatment can include:  
    1. Ablative cerebral surgery is done when the basal ganglia and other accessory “motor control” centers of the brain are “therapeutically damaged” neurosurgically to palliate symptoms, particularly tremor. 
    2. Deep brain stimulation (DBS) with an adjustable “brain pacemaker” has been shown to help attenuate tremor, decrease “off” time, lessen dyskinesia, and sometimes help troublesome gait freezing.  Deep brain stimulation can sometimes be beneficial with regards to a total “load” of drugs necessary.  Deep brain stimulation would not likely ever eliminate the need for separate and additional drug treatment.  Side effects of deep brain stimulation include surgical complications of cerebral bleeding, brain infection, stroke, depression, and others. 
    3. Stem cell research carries on the possibility of tissue transfer of new functioning cells to a diseased brain.  This has not turned about to be successful in the past even though it sounds like a good idea.  Considering the degenerative character of Parkinson’s disease, the entire brain is affected to a certain extent with the process.  At the very least, the network of “wiring” or synopsis interconnecting brain processes and communication are not replaced or restored even if the area of the basal ganglia has an area of limited tissue refurbishing (transplant). 

 

12.  In conclusion two major problems tend to cause grief as Parkinson’s disease progresses. 

1. “Yo-Yoing” and “On-Off” phenomena are variable intermittent and limited responses to treatment such that the patient waxes and wains with ability to function interrupted by sudden periods of tremor, rigidity, termor, and immobility.  “On/off” phenomenon can include periods of more functional and athletic status alternating with periods of dyskinesia or involuntary movements.  “Yo-Yoing” and “On-Off” phenomena can sometimes be dealt with by more frequent administration of Parkinsonian medications and with addition of other augmenting medications. 
2. Sinemet is more effectively absorbed on an empty stomach either 30 minutes before or 2 hours after meals.  However, nausea with the drugs sometimes requires the Sinemet to be taken with food o requires other drugs to “protect” the stomach.    
3. Another discouraging problem is the development or progression of dementia or mental and cognitive decline with time.  With this cognitive or mental decline a patient with Parkinson’s disease sometimes becomes more sensitive to the adverse affects of the dopamine stimulation (Sinemet).  This becomes an unfortunate “catch 22.”  Confusion and hallucinations with the drugs can be intolerable while on the other hand the patient cannot physically function without the Sinemet.    

 

Fortunately, there are many pharmacologic and therapeutic options with regards to Parkinson’s disease and a long-term comprehensive approach with foresight as to the future cannot provide optimal care.