Course #98770 - $29 • 10 Hours/Credits
PD is a neurodegenerative disease first described in 1817 by the English physician James Parkinson as "the shaking palsy" . This disorder is prominently characterized by the motor symptoms of resting tremor, rigidity, and bradykinesia. The non-motor features are increasingly identified and include sensory, autonomic, and neuropsychiatric symptoms that appear before motor dysfunction is evident. The onset is insidious and often asymmetrical. Numerous, potentially disabling non-motor symptoms are often present, and diagnosis is made clinically. Treatment is symptomatic and involves multidisciplinary care.
|A)||affects 100,000 Americans.|
|B)||occurs mainly in younger individuals.|
|C)||is more common in women than in men.|
|D)||is the second most frequent neurodegenerative disorder.|
Sporadic (idiopathic) PD is the second most frequent neurodegenerative disorder after Alzheimer disease . Roughly 1 million Americans currently have the disease, with 60,000 diagnosed each year. The mean age of onset is around 60 years. The population prevalence is 1% in persons 60 years of age or older and up to 4% in those 80 years of age or older. While mostly occurring in the elderly, persons in their 30s and 40s can develop PD. Women develop PD at lower rates and with later onset than men; the delayed onset has been attributed to the neuroprotective effects of estrogen on the nigrostriatal dopaminergic system [1,2]. The variable prevalence of PD throughout the world suggests that environmental and genetic factors interact with ethnic differences in disease pathogenesis .
|A)||10% to 20%|
|B)||40% to 50%|
|C)||60% to 80%|
|D)||95% to 100%|
PD is the most common neurodegenerative cause of parkinsonism, a syndrome characterized by progressive deterioration in motor abilities resulting from dopaminergic neuron loss in the substantia nigra pars compacta and ventral tegmental area. Dopamine neuron loss is most prominent in the ventral lateral substantia nigra; 60% to 80% of these neurons are lost when motor symptoms emerge and PD is diagnosed [8,12].
|D)||All of the above|
Evidence consistently suggests primary contribution to neurodegeneration in PD from oxidative stress, mitochondrial dysfunction, and neuroinflammation. Environmental and genetic factors induce mitochondrial dysfunction, resulting in abnormal accumulation of miscoded proteins (mostly alpha-synuclein) and generation of oxidative stress in enteric, peripheral, and central nervous systems. In turn, oxidative stress, excitotoxicity, and mitochondrial dysfunction promote the destruction of dopamine neurons and dopaminergic function in midbrain systems [12,38,39,40].
|A)||Most patients die directly from PD.|
|B)||Most patients die of indirect causes, such as aspiration pneumonia.|
|C)||Newly released pharmacologic agents may reverse end-stage decline.|
|D)||Patients diagnosed in their forties have the most rapid progression to end-stage PD.|
The progression of disease and disability in PD varies and is partially influenced by patient factors such as age. In general, from the mean age at diagnosis of 61 years, the mean time to death is 14 years overall. Survival time is a mean 24 years for patients diagnosed in their 40s and 9.7 years for patients diagnosed in their 70s . With the onset of subclinical non-motor symptoms decades before diagnosis, pathologic processes that underlie PD are probably active over a 40-year period in many patients .
Throughout the disease course, all patients experience deterioration in motor function associated with increased impairment and disability and declining quality of life. The later stages of the disease are characterized by reduced oral medication efficacy, increased medication-related side effects, dysphagia, cognitive dysfunction with conversion of mild cognitive impairment to dementia, reduced mobility with increased tendency to fall, and in many, dependence on others for activities of daily living. The mode of death often involves respiratory compromise from bronchopneumonia or aspiration .
|C)||Tremor at rest|
Tremor at rest
Akinesia (i.e., bradykinesia and hypokinesia)
It is important to note that postural instability, while a cardinal motor feature, is seldom present at diagnosis, as it usually appears later in the disease course .
Rest tremor, an initial symptom in 70% to 90% of patients, refers to a 4–6 Hz tremor in the fully resting limb, suppressed during movement initiation. Rest tremor is a rhythmic, oscillatory involuntary movement and one of the most characteristic signs in clinical medicine. The most distinguishing rest tremor is the "pill-rolling" type, with rubbing movements of thumb and index fingers against each other. Rest tremor is thought to initiate with nigrostriatal degeneration and subthalamic nucleus or globus pallidus disinhibition, or disrupted thalamo-cortical-cerebellar circuits leading to abnormal thalamic pacemaker cell function [4,7].
|A)||They rarely appear before formal diagnosis.|
|B)||They become less dominant as motor symptoms worsen.|
|C)||Around 60% of patients with PD report troubling non-motor symptoms.|
|D)||They substantially contribute to impaired quality of life and disease burden when unaddressed.|
The frequency and diversity of non-motor symptoms in PD is substantial, and includes autonomic, neuropsychiatric, olfactory, sensory, and sleep disorders that occur in 80% to 90% of patients (Table 4). Non-motor symptoms can manifest before, during, or after motor symptoms and may result in greater impairment of quality of life. The prevalence of cognitive, autonomic, and mood disorders is very high; progression can result in patients requiring care in a supervised environment .
|A)||patient history and physical examination.|
|B)||diagnosing parkinsonism and excluding Alzheimer disease.|
|C)||diagnosing parkinsonism, always using imaging exams to rule out other cause.|
|D)||interview and physical examination, confirmed by one or more imaging exam.|
Disease-specific screening tests or biomarkers for PD are not yet available, and definitive diagnosis is only possible at autopsy by confirmation of striatal dopamine neuron loss and Lewy body pathology . Idiopathic PD is diagnosed through patient history and physical examination. History or physical findings inconsistent with features of idiopathic PD are explored further to rule out or confirm an alternate diagnosis. Clinicians with limited experience caring for patients with PD should consider referring a patient with suspected disease to a physician with expertise in movement disorders to confirm diagnosis .
|A)||Rest tremor of a limb|
|B)||Unequivocal cerebellar abnormalities|
|C)||Presence of levodopa-induced dyskinesia|
|D)||Recurrent falls from impaired balance within three years of onset|
MDS CLINICAL DIAGNOSTIC CRITERIA FOR PD
|Absolute exclusion criteria||
Clear, dramatic benefit to dopaminergic therapy. During initial treatment, patient returned to normal or near-normal level of function. In the absence of documented initial response, dramatic response can be classified as:
It is also important to always assess for drug-induced parkinsonism. This is one of few reversible causes of the disorder, and identification by a complete medication evaluation will help avoid inappropriate treatment. The most frequent causes of drug-induced parkinsonism are typical antipsychotics (e.g., haloperidol, chlorpromazine), most atypical antipsychotics (e.g., riperidone, olanzapine), and the gastrointestinal agents prochlorperazine, promethazine, and metoclopramide. Infrequent causes are tetrabenazine, reserpine, methyldopa, flunarizine, cinnarizine, verapamil, valproic acid, and lithium.
|C)||Dementia with Lewy bodies|
|D)||Progressive supranuclear palsy|
Progressive supranuclear palsy
Dementia with Lewy bodies
Symptomatic syndromes of non-neurodegenerative underlying cause:
Infectious disease (acquired immunodeficiency syndrome, subacute sclerosing panencephalitis, postencephalitic parkinsonism, prion disease)
Neurotoxin exposure (carbon monoxide, manganese, MPTP)
Structural disorder (tumor, hydrocephalus, subdural hematoma, trauma)
Other secondary causes
|A)||Levodopa half-life is roughly six hours.|
|B)||Levodopa does not cross the blood-brain barrier.|
|C)||Levodopa is absorbed in the proximal small intestine.|
|D)||Approximately 80% of dopamine metabolized from levodopa reaches circulation.|
For the purpose of supplementing depleted brain dopamine to manage PD motor symptoms, exogenous dopamine is unable to cross the blood-brain barrier and is ineffective. Instead, levodopa is used for this purpose. Levodopa is a dopamine prodrug that crosses the blood-brain barrier, is converted by aromatic amino acid decarboxylase (AAAD) to dopamine in the substantia nigra pars compacta, and is stored in presynaptic dopamine neurons for subsequent use. Depleted striatal dopamine concentrations are increased, and parkinsonism symptoms are reduced. Levodopa was introduced for use in PD in the late 1960s, and remains the gold-standard treatment .
Levodopa is extensively metabolized to dopamine in the gut, causing only 30% to reach systemic circulation and distribution to the brain. Levodopa is always combined with carbidopa, a peripherally acting AAAD inhibitor. Carbidopa reduces peripheral conversion of levodopa to dopamine, which triples levodopa bioavailability and lowers dosage requirements. Carbidopa 75–100 mg/day is required to inhibit peripheral conversion of levodopa to dopamine. Carbidopa also decreases acute peripheral dopamine side effects, such as nausea, vomiting, and hypotension, and improves tolerability .
Levodopa carries a higher risk for the development of motor complications, and keeping the dose as low as possible for symptomatic management is suggested. No evidence has been found that using an extended-release levodopa/carbidopa formulation, or adding a catechol-O-methyltransferase (COMT) inhibitor, delays or prevents the development of motor fluctuations .
Because levodopa is absorbed in the proximal small intestine, food may delay absorption. Levodopa also competes with dietary proteins for transport into the brain. High-protein meals should be kept separate from levodopa dosing, and daily dietary protein intake should be reduced to approximately 0.8 g/kg (of body weight). Levodopa is metabolized in the gastrointestinal tract, kidneys, and liver, with 70% excreted in the urine. Levodopa half-life is roughly one hour. Dosing should be reduced 10% to 30% when other dopaminergic agents are added to carbidopa/levodopa. Available formulations in the United States are :
Carbidopa/levodopa tablet (Sinemet)
Carbidopa/levodopa orally disintegrating tablets (Parcopa ODT)
Carbidopa/levodopa sustained-release tablet (Sinemet CR)
Carbidopa/levodopa extended-release tablet (Rytary ER)
Carbidopa/levodopa enteral suspension (Duopa)
Amantadine is the only agent demonstrated to suppress levodopa-induced dyskinesia without worsening parkinsonism, and the American Academy of Family Physicians recommends that amantadine should be considered for treatment of dyskinesias in patients with advanced PD . However, use in frail elderly patients with advanced PD may result in confusion, hallucinations, and/or worsening motor symptoms .
The acetylcholinesterase inhibitor rivastigmine is the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild-to-moderate PD dementia. Other approved drugs for dementia, including donepezil, galantamine, and memantine, have been evaluated for the treatment of PD dementia, but their efficacy has not been clearly shown .
|A)||Dopamine agonists are preferred in older patients.|
|B)||Controlled-release levodopa delays the onset of motor complications.|
|C)||Levodopa is the most effective option for improving motor disability.|
|D)||Motor complications are minimized by keeping the levodopa dose greater than 600 mg/day.|
The choice of drug depends on the impact of improving motor disability (better with levodopa) compared with the risk of motor complications (more common in younger patients, delayed by agonists) and neuropsychiatric complications (more common in older and cognitively impaired patients, greater with agonists). Levodopa is the most effective symptomatic drug. However, controlled-release formulations or adding entacapone is not effective for delaying the onset of motor complications. Other treatments include MAO-B inhibitors (e.g., selegiline, rasagiline) or oral or transdermal dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). Initial treatment with an agonist can be recommended in younger patients. Ergot derivatives (e.g., bromocriptine, cabergoline) are not recommended due to the increased risk of fibrotic development . Amantadine and anticholinergic agents are also options. Rehabilitation in early-stage disease has seldom been evaluated, and therefore a recommendation for or against its use cannot be made .
Dose adjustments with dopamine agonists and levodopa preparations are made in response to clinical effect, emerging symptoms, and/or side effects. Risks of psychiatric side effects and dyskinesias are greater at higher doses, and treatment with the lowest dose possible to achieve benefit is favored; this better maintains patient function and quality of life. Patients older than 50 years of age who receive levodopa doses greater than 600 mg/day are more likely to develop dyskinesia .
The primary targets of deep brain stimulation are the subthalamic nucleus and the globus pallidus pars interna. Effectiveness of subthalamic nucleus stimulation in improving levodopa-responsive signs and symptoms has been reported by many short-term and long-term studies. The overall improvement of activities of daily living and motor UPDRS scores averaged 50% compared to pre-surgery. Levodopa-induced dyskinesias have been reduced by an average 69%. The most frequent post-surgical surgery-related adverse effects are infections (6.1%), migration or misplacement of the leads (5.1%), lead fractures (5%), intracranial hemorrhage (3%), and skin erosion (1.3%) .
|A)||older patients are more likely to develop complications.|
|B)||stimulation in advanced disease does not improve functional decline from non-motor features.|
|C)||PD features unresponsive to deep brain stimulation predominate advanced stage disease.|
|D)||All of the above|
While deep brain stimulation was formerly offered only in late-phase disease (mean: 13 to 14 years post-diagnosis), several considerations have now moved the timing for surgery forward . Deep brain stimulation produces motor improvement in symptoms responsive to dopaminergic drugs, but unresponsive features usually predominate in later disease. Performing deep brain stimulation at advanced stages of illness can alleviate some motor dysfunction features but does not benefit ongoing problems in well-being and occupational, social, and role functioning. In addition, older patients are more likely to develop surgical complications and/or worsening of axial motor functions.
|A)||Antipsychotic agents can exacerbate motor symptoms.|
|B)||Psychosis in PD develops in as many as 60% of patients.|
|C)||Dopaminergic agents can exacerbate psychotic symptoms.|
|D)||First-generation antipsychotics (e.g., haloperidol) are standard treatment.|
Psychosis in PD is common and multifactorial in etiology. Up to 60% of patients with PD develop psychosis. Following its onset, PD psychosis remains a persistent, lifelong problem for most patients . Pharmacologic management is challenging, in part because dopaminergic agents required for motor control can exacerbate psychotic symptoms, and antipsychotic agents can exacerbate motor symptoms . The onset of psychosis in PD predicts a poor prognosis, including increased likelihood of nursing home placement and early mortality .
The early clinical manifestations of PD-associated psychosis differ from other psychotic disorders in that hallucinations are common and patients initially remain lucid and connected with reality. Visual hallucinations are the most prevalent form. Functional MRI performed on patients with PD who are experiencing visual hallucinations show several abnormalities: altered cortical visual processing; decreased occipital response and increased caudate and frontal cortical activation to visual stimuli; overactive visual association cortex; and decreased primary visual cortex activity .
Auditory, tactile, olfactory, and gustatory hallucinations do occur, though less commonly and usually in combination with visual hallucinations. Confusion states, delusions, paranoia, agitation, and delirium may also develop.
The stage of PD at which psychotic features emerge has some diagnostic import. In newly suspected or recently diagnosed (within three months) cases of PD, the appearance of psychotic symptoms suggests early-onset dementia with Lewy bodies, but could also indicate an alternative neuropsychiatric diagnosis, such as Alzheimer disease with extrapyramidal symptoms or underlying functional (psychiatric) psychosis. Differences in the initial presentation of PD-associated psychosis do not substantively change the management approach (with some caveats) .
Risk factors for PD-associated psychosis include cognitive impairment, dementia, advanced age, sleep disturbances, and disease duration/severity . Psychosis is unrelated to total dose or duration of dopaminergic medication, and no differences have been found in the incidence rate among patients receiving levodopa versus those on dopamine agonists or anticholinergic drugs .
The association between sleep disturbance and PD psychosis is sufficiently robust to suggest REM sleep behavior disorder manifests from an evolving synucleinopathy in patients with PD-associated psychosis or dementia. Both factors may develop from a single epiphenomenon, such as neurodegeneration. Evidence also suggests contribution to PD psychosis from non-dopaminergic neurotransmitters, including serotoninergic or cholinergic systems .
Visual hallucinations require medication adjustment and possibly specific therapies if they are troublesome, threatening, or associated with behavioral change . Triggering factors, such as infection, metabolic disorders, fluid/electrolyte imbalance, and sleep disorder, should be controlled. In addition, steps should be taken to reduce polypharmacy. Tricyclic antidepressants and anxiolytics/sedatives should be reduced or stopped. Antiparkinsonism drugs should also be reassessed. Anticholinergics and amantadine should be halted, while dopamine agonists and MAO-B and COMT inhibitors should be reduced or halted. The levodopa dose may be reduced [74,123].
Unfortunately, most commonly used antipsychotic drugs have side effects that exacerbate PD. Consequently, atypical antipsychotics are often key in the management of PD-associated psychosis. Almost all antipsychotic drugs can exacerbate PD. Clozapine is the only antipsychotic with high-level evidence of efficacy; in some patients, it also improves motor function . Clozapine is widely recommended as the first-line choice, but it is associated with potentially fatal agranulocytosis, which develops in 1% of patients and makes routine blood neutrophil counts mandatory. Less serious side effects include sedation, tachycardia, orthostatic hypotension, and sialorrhea. Low-dose clozapine (less than 50 mg) also has efficacy, with less frequent and more tolerable side effects and rare agranulocytosis [125,126].
|B)||abruptly withdrawing dopaminergic medication.|
|C)||medication adjustments by non-PD specialists.|
|D)||All of the above|
With disease progression, patients with PD become more reliant on medication to maintain their ability to function. In addition to regular monitoring for drug-specific side effects, clinicians should be careful not to abruptly withdraw dopaminergic medication . Patients and family should be educated on the importance of medication compliance and regular dosing so as to avoid rapid changes in efficacy. Special attention is required during periods of intercurrent illness, such as gastroenteritis or abdominal surgery, which may result in interruption of dosage or poor intestinal absorption. These measures help to avoid the potential development of acute akinesia or neuroleptic malignant syndrome. "Drug holidays" are not recommended due to the risk of developing neuroleptic malignant syndrome.
Considering the risks of sudden changes in dopaminergic medication, patients with PD admitted to hospitals or care facilities should receive their medication at the appropriate times or be allowed self-medication. Medication adjustment should be reserved for specialists in PD management .