1. SELECTED GERIATRIC NEUROLOGIC DISEASE Module 1 Parkinson’s disease
Bill Lyons, M.D.
UNMC Geriatrics
Asst. Professor
Welcome to the modules on selected neurologic diseases in the geriatric population. Over the next many slides we will attempt to review the most important aspects of this important subject. We hope that you will have as much fun learning from this material as we had making it.

2. OVERVIEW Parkinson’s disease Other movement disorders Stroke and TIA
Our process will be for you to complete a series of three modules and questions on the following three neurologic topics: (1) Parkinson’s disease, (2) Other movement disorders, and (3) Stroke and Transient Ischemic Attack. These modules will utilize PowerPoint with voice overlay. Each will be followed by 1-3 case-based questions, followed by discussion to explain the right and wrong answers. Following the questions and answers, you will have the option to continue with the next module, or to take a break at that time. The computerized system will keep track of how far you have gone in the modules so that, in the future, you may pick up where you left off.

3. Objectives
Re: Parkinson’s disease, upon completion the learner will be able to;
List the diagnostic characteristics
Describe the key pathologic features
Describe evaluation and management
List the most common complications

4. PARKINSON’S DISEASE Prevalence increases with age (starts 40s-60s)
Seen in all ethnic groups, M:F about 1.5:1
Second most common neurodegenerative disease
Genetics’ role greater when younger onset
CO poisoning, rural residence, pesticide or herbicide exposure, MPTP, encephalitis
Parkinson’s disease is a common ailment seen in the elderly population. It typically becomes clinically apparent when a person is in his/her 40s, 50s, or 60s, and the prevalence of the disorder increases with age. It is a bit more common in men than women, and it is seen in all ethnic groups. It is the second most common neurodegenerative disease, after Alzheimer’s disease. Genetic influence is most pronounced in individuals who develop symptoms at a younger age, although in general, first-degree relatives are at roughly twice the risk of developing the disease. Risk factors for the disease, shown in various studies, include a history of carbon monoxide poisoning, residing in a rural (as opposed to urban) area, exposure to pesticides or herbicides, use of the recreational drug MPTP, and previous encephalitis.

5. Nigrostriatal Dopaminergic Neurons
Striatum
Idiopathic parkinsonism, or true parkinson’s disease, results from a depletion of the neurotransmitter dopamine in the corpus striatum. This depletion results from the death of dopaminergic neurons that project from the substantia nigra to the striatum. It is believed that the resulting imbalance in the striatum between dopamine and acetylcholine produces most of the manifestations of the disease.
Substantia nigra

6. Substantia nigra, Normal
Substantia nigra, PD
This slide compares the appearance of a normal patient’s substantia nigra to that of a patient with parkinson’s disease. Note the diminished staining in the lower picture, revealing the neuronal loss in this area. Not shown in these photos are Lewy bodies (which might be apparent on microscopic sections). Lewy bodies are the pathologic hallmark of parkinson’s disease. A major component of these cellular inclusions is a protein called alpha-synuclein, and for this reason parkinson’s disease is one of a group of neurodegenerative diseases known as synucleinopathies.

7. CARDINAL FEATURES OF PARKINSON’S DISEASE
TRAP (any combination)
Tremor
Rigidity
Akinesia/Bradykinesia
Postural instability
Onset usually asymmetric
Diagnosis clinical
One way to remember the cardinal features of parkinson’s disease is to use the mnemonic TRAP – you might say that many unfortunate people with this disease are ‘trapped’ in their movement disorder. ‘T’ stands for tremor, a characteristic but not universal component of the clinical picture. ‘R’ stands for rigidity. ‘A’ stands for akinesia or bradykinesia. And ‘P’ stands for postural instability, with a tendency to fall. Persons with parkinson’s disease can show these features in any combination. It’s important also to remember that, at the onset of the disease, the signs and symptoms of parkinson’s tend to appear asymmetrically. So, it’s typical for a patient to notice, for example, that his right arm was “stiffer” and had a worse tremor when the disease first struck him. Finally, the diagnosis of parkinson’s disease is clinical; laboratory work and radiologic studies are useful only to the extent that they help to rule out other ailments.

8. TREMOR OF PARKINSON’S Rest, 3-6 Hz, pill-rolling
Emotional stress may exacerbate
Inhibition by movement or sleep
Absent in ~20%
The tremor of parkinson’s disease is a characteristic one: it is present at rest, for example with a patient’s hands simply placed on his lap. The frequency is around 3 to 6 cycles per second. The hand tremor classically has a pill-rolling quality, that is, it has a sequential pronation-supination appearance. Emotional stress or anxiety tends to worsen the tremor, making its amplitude more pronounced. Intentional movements and sleep inhibit the tremor. Lastly, absence of a tremor does not rule out parkinson’s disease as a diagnosis in a patient, as some 20% of patients with the disease don’t have the tremor.

9. BRADYKINESIA Slowed voluntary movements Less arm swing when walking
Reduced facial expression, less blinking
Identify by rapid alternating movements during examination
Bradykinesia indicates the characteristic slowing of voluntary movements seen in parkinson’s disease. (Akinesia can be thought of as a near absence of such voluntary movements.) One manifestation of bradykinesia is the reduced arm swing during ambulation noted in many patients with parkinson’s disease. Another manifestation is the so-called “masked facies” or reduced facial expression seen in some patients. Many patients have a reduced frequency of blinking that contributes to their unusual overall facial expression. During physical examination, bradykinesia can be elicited during rapid-alternating-movements maneuvers, for example, asking the patient to rapidly pronate and supinate the hands, or to rapidly open and close the hands or tap the tips of the index fingers and thumbs together.

10. OTHER FINDINGS Facial and scalp seborrhea Myerson’s sign Drooling
Hypophonia, micrographia
Gait: shuffling, less arm swing, flexed, trouble starting and stopping
Cognitive decline
Normal: strength, DTR, Babinski
This slide lists other common findings seen in patients with parkinson’s disease. Many of these patients have seborrhea, characteristically affecting parts of the face and the scalp. Myerson’s sign refers to the tendency of some individuals to persistently blink in response to repetitive tapping of the forehead (a normal response, in contrast, would be to blink two or three times, then stop, even as the forehead tapping is continued). Many patients with parkinson’s have difficulty with drooling, which is a result not of excess salivation but rather of problems with proper handling of their oral secretions. Hypophonia refers to the soft, sometimes barely audible, speech of many patients with parkinson’s disease. Often patients or families notice that the handwriting of individuals with parkinson’s disease becomes smaller and less legible over the years; this writing problem is termed ‘micrographia.’ In addition to the reduction in arm swing mentioned earlier, parkinson’s patients develop other gait peculiarities, including a shuffling quality, the adoption of a flexed posture, and difficulty with starting to walk and stopping while walking. Some patients with parkinson’s disease suffer a cognitive decline that can progress to dementia. Finally, it’s important to add that some neurologic findings or deficits are NOT characteristic of parkinson’s disease. For example, these patients generally have normal strength (except, perhaps, for mild global losses associated with deconditioning). They also should demonstrate symmetric deep tendon reflexes, and downgoing toes during the Babinski test.

11. DIFFERENTIAL DIAGNOSIS
Depression – facial expression, activity level
Drug-induced – onset usually symmetric
Essential tremor – possibly FH+
Shy-Drager – parkinsonism + autonomic insufficiency + other signs
PSP
Lewy Body Dementia – parkinsonism, fluctuating cognition, psychosis
A number of other conditions should be considered in the differential diagnosis of a patient with suspected parkinson’s disease. Elders with depression may superficially resemble those with parkinson’s if their mood disorder causes changes in facial expression and reduced activity level. Drug-induced movement disorders, which are discussed a bit more in the next module in this series, may resemble parkinson’s disease as well. Next, one should remember that, of course, not all tremors are from parkinson’s disease, and essential tremor illustrates the point. Patients with essential tremor may have a positive family history for this disorder, and they generally do not demonstrate the rigidity, bradykinesia, or postural instability seen in patients with parkinson’s disease. Shy-Drager syndrome and multiple system atrophy certainly resemble idiopathic parkinson’s disease, as parkinsonism is an intrinsic part of these ailments as well, but patients with these diseases also demonstrate other neurologic problems, such as autonomic insufficiency, and pyramidal or cerebellar features. PSP, short for progressive supranuclear palsy, is a disease that, like parkinson’s, is associated with movement difficulties and falls; it is discussed more in the next module. Last, Lewy-Body dementia is a dementing disorder in which patients show progressive cognitive decline over years, but with fluctuations that may resemble delirium. Patients with Lewy Body dementia also may experience delusions and often-bizarre visual hallucinations. Because they show many characteristics of parkinson’s disease, such as rigidity and a tendency to fall, this disorder also belongs in your differential diagnosis.

12. TREATMENT Successful levodopa trial makes diagnosis more likely
Drug aim: restore DA/ACh balance in striatum
No drugs convincingly slow progression
Wait to start drugs until bothersome symptoms or functional impairments
Let’s turn to the subject of therapy for parkinson’s disease. One useful tip to bear in mind is that treatment trials often have diagnostic value, in the sense that if a patient who has a disease you think is parkinson’s, and he shows great improvement with one of the drugs used to treat this disorder, then your suspicion is more likely to be correct. Pharmacologically, the drugs used to treat parkinson’s generally act by working to restore the balance between the dopaminergic and cholinergic systems in the corpus striatum. Unfortunately, none of the available drugs has been convincingly shown to slow the progression of the disease; rather, they improve to greater or lesser degrees the signs and symptoms only. Because these drugs do not appear to slow progression, and because they all have adverse effects, it is best not to prescribe them until a patient is bothered quite a bit by symptoms of his disease, or is experiencing problems with self-care or mobility.

13. DRUG TREATMENT Important to individualize
Each patient’s tolerance for side effects?
When is need for mobility greatest?
This slide emphasizes three overall points about drug treatment of parkinson’s disease. First, perhaps more than for most diseases, the drug regimen for parkinson’s needs to be tailored to the individual patient in terms of drugs used, doses, frequency, and timing of administration. Second, different patients have very different tolerance for the foreseeable adverse effects of these medicines. And third, one key to constructing a workable regimen is to work with the patient to determine: when during the day is his need for mobility greatest?

14. DRUG TREATMENT
Amantadine – for mild symptoms, risk of confusion and mood problems in elders
Anticholinergics
Benztropine, trihexyphenidyl
Confusion…
Agitation and restlessness…
Urinary retention…
This slide lists, really for the sake of completeness, some agents that may be used to treat some people with parkinson’s disease, but which find much less use with elderly patients. Amantadine may be useful for persons with mild symptoms, but its tendency to cause confusion or depression makes it risky to use with older patients. The class of anticholinergics, which includes benztropine and trihexyphenidyl, is also best avoided, as these drugs can also cause confusion, not to mention agitation, restlessness, urinary retention, constipation, and dry mouth.

15. LEVODOPA Converted by body to DA Most effective drug
Combined with carbidopa to inhibit breakdown outside the brain (less nausea, hypotension, arrhythmias)
Sinemet (25/100) start one tid, increase gradually as needed
Controlled-release can reduce fluctuations
All things considered, levodopa is probably the best drug to use in treating elders with parkinson’s disease. Levodopa, you may recall, is converted by the body to dopamine, the active agent in nerve synapses. In order to reduce serious side effects like nausea, hypotension, and cardiac arrhythmias, levodopa is administered in combination with carbidopa. This combination of carbidopa and levodopa is sold under the trade name Sinemet in various formulations. In treating elders newly diagnosed with parkinson’s disease, we recommend using the 25/100 formulation of immediate-release Sinemet (containing 25 mg of carbidopa in combination with 100 mg of levodopa). This formulation is started with one pill given three times a day, with additional doses added as needed. Controlled-release Sinemet smoothes out serum levels of levodopa, and can help to reduce motor fluctuations.

16. LEVODOPA, cont’d Amino acids compete for absorption
Take on empty stomach, or soda crackers
Last meal of day has most protein
Contraindications: psychosis, narrow-angle glaucoma, MAO-A inhibitors
Doesn’t help: autonomic dysfunction, postural instability, dementia, speaking and swallowing
Because amino acids compete with levodopa for absorption in the gut, it can be important to follow certain principles in taking the drug. First, the drug should generally be taken on an empty stomach, or with soda crackers. Second, it is best to plan meals in which the last meal of the day contains the greatest amount of protein, since problems that might arise from amino acid competition in the gut for levodopa would be expected to occur in the evening or at night, when control of motor symptoms is probably less important. Contraindications to use of levodopa preparations include psychotic disorders, narrow-angle glaucoma, and concurrent use of monoamine oxidase type A inhibitors. Finally, and unfortunately, levodopa (and, for that matter, all medications for parkinson’s disease) tends not be provide significant benefit in managing autonomic dysfunction, postural instability, dementia, or problems with speaking and swallowing.

17. DOPAMINE AGONISTS Fewer dyskinesias than levodopa
Approved as monotherapy, or as adjunct to levodopa
Adjunctive therapy  reduce levodopa  fewer dyskinesias, motor fluctuations
Many adverse effects; patients with cognitive impairment may tolerate levodopa better
Dopamine agonists provide an alternative to levodopa in the treatment of parkinson’s disease, and are approved either as monotherapy or as agents that can be used in combination with levodopa. Studies show they may induce fewer dyskinesias – or drug-induced abnormal movements – than levodopa. By combining dopamine agonists with levodopa, you may be able to reduce the dose of the latter drug, and this often decreases the frequency of dyskinesias or motor fluctuations. Nevertheless, dopamine agonists as a group have many adverse effects, and many clinicians find that patients with cognitive impairment tolerate levodopa better.

18. LEVODOPA VS. DA AGONIST DA agonist Perhaps worse motor performance
But less risk of motor complications
Greater odds of adverse drug effects
Overall, in comparing levodopa and dopamine agonists, the consensus is probably that dopamine agonists produce worse motor performance than levodopa in patients with parkinson’s disease, although they also have lower risk of motor complications like dyskinesias. And, they have greater odds of cause other adverse drug effects.

19. DA AGONISTS, cont’d Newer: pramipexole and ropinirole
Older (ergot): bromocriptine and pergolide
Slow dose titration to minimize adverse effects
Fatigue, sleepiness, nausea, dyskinesias, confusion, edema, orthostatic changes, dizziness, flushing and diaphoresis
This slide lists the dopamine agonists used in treating parkinson’s disease. The newer agents are pramipexole and ropinirole. Bromocriptine and pergolide are older, ergot-based agents. Dopamine agonists require a slow, scheduled upward dose titration in order to minimize adverse side effects. Commonly-reported adverse effects of these agents include: fatigue and somnolence, nausea, dyskinesias as with levodopa, confusion, edema, orthostatic blood pressure changes, dizziness, flushing, and sweatiness.

20. COMT INHIBITORS Inhibit Catechol O-Methyl Transferase
Reduce breakdown of levodopa
Smoother blood levels, reduced response fluctuations
Tolcapone – rare fulminant liver failure, avoid in liver disease, monitor LFTs
Entacapone – LFTs not necessary
Watch for diarrhea; reduce Sinemet dose 1/3
Another important class of drugs used to treat idiopathic parkinson’s disease is the COMT inhibitors, tolcapone and entacapone. These drugs work by inhibiting the enzyme catechol O-methyl transferase, thereby slowing down the breakdown of levodopa. As a result, the oscillation of blood levels of levodopa are less extreme, and consequently patients may show reduced fluctuations in their motor response. Tolcapone has been associated with rare episodes of fulminant liver failure, so this drug should be avoided in patients with liver disease. Patients started on the drug will need frequent monitoring of liver function tests. Entacapone has not been associated with liver failure, and liver function tests are therefore not necessary with its use. A commonly-reported side effect of COMT inhibitors is diarrhea or loose stools. Finally, because these drugs act by reducing the breakdown of levodopa, it is important to reduce the dose of co-administered Sinemet, typically by about a third.

21. SURGICAL TREATMENTS Ablation (eg, pallidotomy) or DBS
IDEAL CANDIDATE: cognitively intact, responds to dopaminergic drugs but progressive motor symptoms, can withstand procedure
Neurologist evaluation
Various surgical treatments exist for parkinson’s disease, although they are seldom used in the treatment of frail, elderly patients. These treatments can be categorized either as ablative procedures – for example, pallidotomy – in which selected tissues are resected or destroyed, and deep brain stimulation, which involves the careful placement of electrodes in selected areas. Patients who might be good candidates for these procedures have the following characteristics: They are cognitively intact; they still show a response to dopaminergic drugs, although their motor symptoms have been progressing; and they are vigorous enough to withstand the procedures. Patients who appear to be good candidates and who might consider such treatments should be referred to a neurologist who specializes in parkinson’s disease for an evaluation.

22. OTHER TREATMENTS
Physical Therapy – gait training, strength exercises, assistive devices
Improves mood, strength, flexibility, mobility
Front-wheel walkers typically best
Occupational Therapy – techniques and devices for eating, bathing, etc.
Speech Therapy – speaking, swallowing
Other treatments are crucial for optimal management of parkinson’s disease. Physical therapists provide important gait training and strengthening exercises, as well as with selection of appropriate devices to assist with ambulation. Exercise has been shown to help with mood, strength, flexibility, and mobility. Occupational therapists are also very helpful in the provision of training and assistive devices for daily living activities like eating, bathing or showering, toileting, and so forth. Many parkinson’s patients with difficulties speaking or swallowing, or with drooling problems, may benefit from speech therapy consultation.

23. GEROPSYCHIATRIC COMPLICATIONS IN PD
Psychosis usually due to drug adverse effect
Try reduce dopaminergic dose
Quetiapine, olanzapine, risperidone may help
Clozapine most effective, risk of agranulocytosis
Dementia
Late development, up to ~30%
If earlier, consider Lewy Body Dementia
Depression – in up to ~40%
Several psychiatric complications are commonly seen in patients with parkison’s disease. First, psychotic syndromes are commonly observed; these are usually the result of adverse effects from drugs prescribed for the movement disorder. The best initial approach in management of these patients is to consider a reduction in the dose of the dopaminergic agent. If this is unsuccessful, or if it results in an intolerable worsening of the parkinsonian symptoms, a trial of a low-dose atypical antipsychotic can be considered. Although clozapine is probably the most effective drug for this purpose, its use is associated with a small risk of a potentially catastrophic problem, namely agranulocytosis, and so other agents such as quetiapine, olanzapine, or risperidone are generally employed first. Another geropsychiatric complication of parkinson’s disease, dementia, is seen eventually in up to about 30% of patients. Remember that patients with cognitive decline that develops much earlier in the course of their apparent parkinson’s disease may instead have Lewy Body dementia. Finally, depression is extremely common in patients with parkinson’s disease, with some studies showing up to 40% of patients eventually developing this mood disorder.

24. GASTROINTESTINAL COMPLICATIONS
Dysphagia
Primarily oropharyngeal
Cause of drooling
Choking, coughing, aspiration
Treat: speech therapy
A common complication in patients with later stages of parkinson’s disease is dysphagia. The dysphagia of parkinson’s disease is primarily oropharyngeal (not esophageal), as patients have difficulty transferring boluses of food and drink from the oral cavity to the inlet of the esophagus. This is the functional deficit that can lead to difficulties handling saliva, and drooling can result. As with other patients who have oropharyngeal dysphagia, these patients may complain of coughing or choking during meals, and may have recurrent aspiration episodes that can lead to pneumonia and nutritional problems. Therapy is primarily with speech therapy.

25. GI COMPLICATIONS, cont’d
Constipation
Slowed colonic transport
Abundant fluids with high-fiber diet
Stool softeners, senna or sorbitol
Avoid anticholinergic medications
Periodic enemas, disimpaction may be needed
Many parkinsons’s patients experience serious problems with constipation. This arises from slowed transport of colonic contents. To manage this, patients should be advised to drink abundant fluids in conjunction with a high-fiber diet. Stool softeners, such as docusate, and laxatives, such as senna or sorbitol, can be extremely helpful. Anticholinergic agents further slow GI tract mobility, and should be avoided. Despite the above measures, some patients nevertheless require periodic administration of enemas or manual disimpaction. Patients with serious, chronic constipation should target to move their bowels at a frequency of at least every three days.

26. Post-test question one
Consider the case of a 78-year-old man with advanced Parkinson's disease who consults you for problems with worsening dyskinesias and excessive drooling. On physical examination you find he has rigidity in both upper extremities, more pronounced on the right, and he also has a pronounced pill-rolling tremor in his right hand. He shows very little spontaneous movement, and his face is expressionless, with rare blinking. On sternal nudge he steps back three steps and almost falls. Which of the following is NOT considered a cardinal feature of his parkinson?s disease?
Rigidity
Dyskinesias
Tremor
Bradykinesia
Postural instability

27. Correct Answer:    Dyskinesias
Feedback: The answer is (b) Dyskinesias. The other four are part of the cardinal tetrad of Parkinson's disease, which can be remembered using the "TRAP" mnemonic: T for tremor, R for rigidity, A for akinesia or bradykinesia, and P for postural instability. Let's move on to a second question about this patient

28. Post-test question 2
The best way to treat excessive drooling in a patient with Parkinson's disease is with an anticholinergic agent such as trihexyphenidyl.
True
False

29. Correct Answer: False
Feedback:As you probably surmised this is false. The drooling in Parkinson's patients results from improper handling of saliva in the oral cavity, not from excess production. This patient may benefit from referral to a speech pathologist. Use of an anticholinergic agent may precipitate confusion, urinary retention, visual complaints, or constipation. End