Key Clinical Questions
Does the patient meet diagnostic criteria for idiopathic Parkinson’s disease (PD)?
What is the differential diagnosis of a patient with parkinsonian symptoms?
What is the pathophysiology of Parkinson’s disease?
What treatments are available, and how do they relate to the underlying pathophysiology?
What are the short- and long-term side effects that may occur in a PD patient on medication?
What are typical complications that may occur when a PD patient is admitted to the hospital?
Parkinson’s disease (PD) appears in 12 to 20/100,000 people per year, approaching a prevalence of 1 in 2000 people. Quality of life can be markedly affected due to a wide variety of factors, some of which have only recently been recognized, such as autonomic dysfunction.
The economic burden of Parkinson’s disease is high. On average, $4000 to $5000 can be spent per patient/year, and of that amount, roughly 33% to 40% may be indirect costs, such as lost productivity. On average, PD-affected patients are unable to work full time 3.4 years after diagnosis, and most file for disability by 5 years. In addition, having PD is a risk factor for nursing home placement.
Parkinson’s disease is caused by the loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc). How dopamine loss disrupts normal functioning of the basal ganglia is not fully understood, but it appears to result in pathological synchronization of neuronal firing throughout the region, which interferes with the production of both voluntary and involuntary movements.
Parkinson’s disease also has many nonmotor symptoms, with effects on cognition, behavior, and sleep. There is emerging evidence of a more widespread neurodegenerative process in PD, affecting brainstem, midbrain, and cortical structures, and probably involving neurotransmitters other than dopamine.
In most cases, the cause of PD is unknown. Mutations of genes associated with PD, such as parkin, DJ-1, GBA, and LRRK2, have recently been identified, although these still make up a minority of cases. The relationship of these mutations to dopaminergic neuron death is not known.
The pathological hallmark of PD is the presence of Lewy bodies in the neurons of the SNc. These are intracellular clumps of proteins, which include alpha-synuclein, ubiquitin, and others. Alpha-synuclein is thought to be a phospholipid-binding protein that helps vesicles dock with the plasma membrane. It is not known whether these inclusion bodies kill the neurons in which they develop, or more likely, whether they represent a “waste-basket” keeping damaged proteins out of the way of normal cellular functioning. In addition to being found in the brainstem, particularly in the SNc, in PD, Lewy bodies can be more widely distributed, and are found specifically in the cortex in the related disorder known as dementia with Lewy bodies (see below).
Patients who are early in their clinical course of PD have already lost about 80% of the SNc neurons, implying that the degenerative process begins long before symptoms are first seen, and that the basal ganglia can compensate until there is significant dopamine loss.
DIFFERENTIAL DIAGNOSIS OF PARKINSONISM
Parkinsonism refers to the presence of the slowness of movement (bradykinesia), absence of movement (akinesia), increased tone (rigidity), resting tremor, and impairment of postural reflexes. Some or all of these features may be seen in idiopathic PD, but they may also be due to a variety of other causes. These include several other neurodegenerative disorders known as the Parkinson-plus syndromes or atypical parkinsonism. Secondary parkinsonism refers to cases in which another etiology has been identified, such as medication or cerebrovascular disease.
Multiple system atrophy (MSA)
Multiple sytem atrophy may manifest as a spectrum of symptoms and can look similar to PD, especially in the early stages. Patients may have different combinations of parkinsonism, cerebellar findings, and autonomic problems.
MSA-parkinsonism (MSA-P) involves striatonigral degeneration, rather than the nigrostriatal degeneration seen in PD. Multiple system atrophy affects neurons postsynaptic to dopaminergic neurons, although MSA-P patients may be at least partially responsive to levodopa therapy. MSA-cerebellar (MSA-C) involves the olivocerebellar connections, with disproportionate involvement of the middle cerebellar peduncles, which carry fibers from the pon to the cerebellar cortex. MSA-autonomic (also known as Shy-Drager syndrome) is characterized by degeneration of the locus coeruleus, the dorsal motor nucleus of the vagus nerve, and the catecholamine-producing neurons of the ventrolateral medulla.
Pathologically, alpha-synuclein inclusions are found in glial cells, rather than neurons, as in PD. The locations of the inclusions determine the clinical spectrum of disease, and can include the SNc, locus coeruleus, putamen, inferior olives, pontine nuclei, cerebellar Purkinje cells, and the intermediolateral columns in the spinal cord.
The cause of MSA is not known, and it tends not to be inherited. There is no disease-modifying therapy; treatment is symptomatic. Parkinsonian MSA patients may have some response to levodopa, which should be increased to the maximum tolerated dose, which may be in grams of levodopa/day. Autonomic dysfunction can be managed with vasoconstrictors such as midodrine, and mineralocorticoids such as fludrocortisone to increase blood pressure. Urinary incontinence may be treated with antispasmodics and catheterization.
Physical and speech therapies may be useful. As with all parkinsonian disorders, swallowing is often affected, and should be evaluated to reduce the chances of aspiration, a major cause of morbidity and mortality.
Progressive supranuclear palsy (PSP)
Progressive supranuclear palsy (PSP) can be indistinguishable from PD in the early stages, but axial symptoms such as gait and balance impairment usually occur earlier and with greater severity than in PD. The name PSP refers to abnormal eye movements, classically affecting vertical gaze, and especially downward gaze. Mild dementia, particularly with frontal features, is more common in PSP. Dysarthria and dysphagia are typical, and early involvement of a speech therapist is important. Progressive supranuclear palsy, as with most atypical parkinsonian syndromes, shows a poor response to levodopa, but this should be tried as one of the few available pharmacotherapeutic options. The cause of PSP is not known, and it does not appear to be inherited.
PRACTICE POINT Patients with PSP tend to have a surprised appearance, with excessive eyelid retraction
Dementia with Lewy bodies (DLB)
Patients have features identical to idiopathic PD, with early dementia and behavioral abnormalities out of proportion to the accompanying motor symptoms. Visual hallucinations, which are usually benign and nondistressing, are a typical early feature.
Pathologically, DLB resembles PD in that affected cells have the same cytoplasmic inclusion bodies, Lewy bodies, but these are more widely distributed, and the affected area includes the cerebral cortex, in addition to the SNc. Cognitive symptoms are treated with acetylcholinesterase inhibitors, similar to Alzheimer’s disease. Motor symptoms may improve with levodopa, although this may worsen confusion.
PRACTICE POINT Patients with DLB are hypersensitive to antipsychotics, and may get very sedated or parkinsonian when they receive them
Corticobasal degeneration (CBD)
Corticobasal degeneration is a tauopathy that manifests with parkinsonian symptoms and dementia, but has unique neuropathological characteristics. Recent studies have shown that the typical corticobasal syndrome can be due to many pathologies, including Alzheimer’s disease and PSP, in addition to CBD. The neurologic symptoms are related to the distribution of the tau-immunoreactive inclusion bodies in the cortex and basal ganglia. There may be cortical symptoms, such as apraxia or aphasia, higher order sensory loss, or alien hand syndrome, in which one hand performs complex, involuntarily movements, such as picking at the hair or clothes. There may be asymmetric parkinsonism or limb dystonia. Imaging may show asymmetric atrophy of the frontoparietal cortex. Ballooned, achromatic neurons are seen on pathology.
Atherosclerosis and microvascular disease may lead to disruption of the fibers of the basal ganglia, causing parkinsonian symptoms without degeneration of the dopamine-producing cells. This is usually due to typical vascular risk factors, such as hypertension, diabetes, hyperlipidemia, smoking, or age. Patients may present with parkinsonian symptoms, but generally with early gait problems, including falling and freezing. There may also be marked postural tremor. Levodopa therapy should be attempted, although vascular parkinsonism patients are less responsive to levodopa than PD patients. The mainstay of treatment is physical therapy. Treatment is also geared toward minimizing future ischemic events by improving reversible risk factors (smoking cessation, lowering blood pressure, controlling blood sugar and cholesterol, etc) and treating with antiplatelet agents.
Numerous agents can block dopaminergic neurotransmission, resulting in parkinsonian symptoms. Classical antipsychotics, such as haloperidol, thioridazine, and perphenazine, work by blocking dopamine receptors. A predictable side effect of these medicines is the development of tremor, rigidity, and slowness of movement, indistinguishable from idiopathic PD. Some patients, particularly when hospitalized, are unaware of the nature of the drugs with which they have been treated. For example, if an elderly person who was recently discharged from hospital has new parkinsonian symptoms, it may be that he or she was given haloperidol to treat sundowning. In these cases, symptoms are usually, though not necessarily, bilateral. Treatment begins with discontinuing the offending agents. If symptoms persist for several months and interfere with activities of daily living, cautious, gradually increasing therapy with levodopa may be warranted. In this scenario, it is likely that the medication unmasked underlying idiopathic PD.
If absolutely essential for the management of psychosis or agitation, atypical antipsychotics with fewer parkinsonian side effects can be used, such as quetiapine and clozapine, starting at very low doses. Patients on clozapine need to have frequent blood tests to monitor for agranulocytosis.
Drug-induced parkinsonism may also be a side effect of antiemetics, such as metoclopromide, promethazine and prochlorperazine. These drugs work by blocking peripheral dopamine receptors, but they may cross the blood-brain barrier and block dopamine receptors in the central nervous system, causing parkinsonism. As with antipsychotics, these drugs are often prescribed too liberally to hospitalized patients and outpatients. Use of an antiemetic with a different mechanism of action, such as ondansetron, may be appropriate.
Although newer, atypical antipsychotics, such as risperidone and olanzepine, are not widely recognized as causing parkinsonism, they can certainly have this effect, especially in the older patient with frank or incipient dementia.
DIFFERENTIAL DIAGNOSIS: NON-PARKINSONIAN DISORDERS
Problems with walking, especially in the older patient, can be due to a wide variety of causes. These include pain, orthopedic problems, arthritis of the foot and ankle, fear of falling, and other neurologic causes such as peripheral neuropathy, in addition to the nonbasal ganglia disorders discussed here.
A condition that frequently brings patients to the neurologist for evaluation for possible PD is essential tremor (ET), previously known as benign familial tremor. However, it is often neither familial nor benign, as it may be very debilitating. In ET, the hand tremor is typically bilateral rather than unilateral, although it can be asymmetric. In contrast to the tremor of PD, it is absent at rest, and brought on by activity. There is little stiffness or postural instability, although severe tremor can affect walking and balance. Tremor in the neck may lead to head shaking. Tremor is worsened by stress and improved by relaxation. Alcohol can reduce the symptoms.
The diagnosis is made on clinical grounds. About 50% of ET cases are familial; an affected family member supports the diagnosis. If the tremor is not apparent on examination, the patient should be asked to do whatever brings the tremor out, such as writing or pouring water from one cup to another (over a sink!). Drawing a spiral is useful to bring out subtle tremor and to document tremor severity.
Reversible causes of tremor should be excluded, specifically hyperthyroidism and medications such as lithium, valproate, theophylline, cyclosporine, and caffeine. If tremor improves with alcohol intake, an alcoholic beverage might be useful in cases of embarrassment during social dinners (care should be taken that patient does not develop tolerance or dependence on alcohol). The two first-line medications are primidone, a once popular antiepileptic, and propranolol. Other anticonvulsants, such as gabapentin, levetiracetam, and topiramate, have been tried, with varying success. Deep brain stimulation (DBS) (surgical implantation of electrodes) in the motor nuclei of the thalamus can be an effective therapy.
Head tremor is not generally seen as a feature of PD. Its presence is strongly suggestive of ET. Conversely, rigidity and bradykinesia are not seen in patients with ET.
NORMAL PRESSURE HYDROCEPHALUS
Another condition causing gait difficulty which may be confused with PD is normal pressure hydrocephalus (NPH). This diagnosis is often raised in the parkinsonian patient by family members who have heard of impressive cures following ventriculoperitoneal shunt placement. The gait in NPH is characterized by a wide base, with slow, short steps, and the patient has difficulty lifting each foot off the ground, often referred to as magnetic gait. By contrast, PD patients usually do not have frozen steps with each step, and the stance is not widened.
The gait disorder in NPH is caused by dysfunction or destruction of the periventricular fibers from the leg region of the motor cortex. This syndrome is frequently misdiagnosed, leading to unnecessary placement of ventriculoperitoneal shunts. Nevertheless, the presence of the complete triad of cognitive dysfunction, urinary problems, and gait dysfunction supports this diagnosis. Although the diagnosis is primarily clinical, it may be suggested if neuroimaging demonstrates ventricular enlargement out of proportion to cortical atrophy of the cortex. The ideal diagnostic study is the short-term placement of a lumbar drain, with careful monitoring of gait. However, placebo effects can occur with this procedure, and care should be taken to avoid false positive interpretations, as placement of a ventriculoperitoneal shunt is not a benign procedure.
Cerebellar dysfunction causes a wide-based, ataxic gait, distinct from the shuffling, parkinsonian gait. However, the basal ganglia may be involved in cerebellar disorders, and parkinsonian symptoms may be seen in some of the autosomal dominantly inherited spinocerebellar ataxias and in the cerebellar form of MSA. The diagnosis is supported by the presence of abnormalities of eye movements and limb or truncal ataxia.
Narrowing of the cervical canal with compression of the spinal cord may cause spasticity and interfere with walking. This may be detected as a clasp-knife increase in tone of the lower extremities, distinguishable from the lead-pipe rigidity of PD (see below). Increased activity of the deep tendon reflexes at the knees and ankles, with positive Babinski signs, helps to localize the lesion to the cervical spinal cord. In some cases, PD may be responsible for structural abnormalities in the spine, causing increased wear and tear on the vertebra from abnormal posture. Scoliosis and other spinal abnormalities are recognized sequelae of longstanding PD.
Atrophy of the small muscles of the hands due to cervical radiculopathy can be a sign of cervical spine disease.
There is no definitive test for PD prior to autopsy. The diagnosis is determined by the presence of major clinical criteria, as delineated by the UK Brain Bank, namely bradykinesia with resting tremor, rigidity, or postural instability, not related to another known etiology. Nonmotor symptoms, such as REM sleep behavior disorder, depression, anxiety, impaired cognition, muscle aches, insomnia, daytime somnolence, impaired olfaction, and constipation may precede the onset of motor symptoms (Figure 210-1).
Natural history of Parkinson disease, with neuropathologic correlation. (Reproduced, with permission, from Fauci AS, Braunwald E, Kasper DL, et al. Harrison’s Principles of Internal Medicine, 17th ed. New York, NY: McGraw-Hill 2008. Fig. 366-2.)
Unilateral tremor is the most common initial motor symptom (Table 210-1). Despite subsequent involvement of the contralateral side, the disease usually continues to be somewhat asymmetric. The tremor is present at rest, and is often observed when the patient is distracted and relaxed. There may be a component of action tremor or of postural tremor, but if either of these is the major symptom in the absence of parkinsonian signs, then another diagnosis, such as ET, should be considered. The postural tremor of PD tends to manifest after patients have held their hands outstretched for a few seconds, known as an emergent tremor, rather than immediately as in ET. However, PD and ET are both common conditions, and may occasionally coexist.
TABLE 210-1Initial Symptoms in Patients with Parkinson Diseases ||Download (.pdf) TABLE 210-1 Initial Symptoms in Patients with Parkinson Diseases
|Symptom ||Percentage of Patients |
|Tremor ||70 |
|Gait disturbance ||11 |
|Stiffness ||10 |
|Slowness ||10 |
|Muscle aches ||8 |
|Loss of dexterity ||7 |
|Handwriting disturbance ||5 |
|Depression, nervousness, other psychiatric disturbance ||4 |
|Speech disturbance ||3 |
The resting tremor of PD increases with walking and when the opposite hand performs repetitive movements.
For diagnosis of PD, exclusion of the atypical and secondary parkinsonism is required. Early falling (within 5 years of disease onset), prominent autonomic dysfunction, early dementia, and visual hallucinations suggest atypical parkinsonism. Patients should be asked about the use of neuroleptics and antiemetics.
The neurologic examination focuses on parkinsonian features. The limbs and neck are examined for rigidity. Spasticity may be difficult to distinguish from rigidity. Spasticity, the increase in tone that appears following an upper motor lesion such as a stroke or spinal cord injury, is velocity-dependent, being almost minimal when the limb is moved slowly, and becoming highly resistant when force is applied suddenly. This is known as clasp-knife rigidity. In parkinsonian rigidity, the muscle tone is unchanged regardless of the velocity with which force is applied. This is known as lead-pipe rigidity.
Bradykinesia, slowness of movement, is evaluated by having the patient perform repetitive tasks using one limb at a time: tapping the index finger on the thumb, opening and closing fists, pronating-supinating the hand on the knee, and tapping each heel on the ground. (It is not necessary to tap all the fingers to the thumb in sequence—this requires frontal lobe function and can confuse the examination.) There is usually an asymmetry between the speed of each side. A positive glabellar tap test, where the patient continues to blink with repetitive tapping between the eyebrows, is seen in PD.
Mild bradykinesia is often dismissed as being due to age, but this is not seen in normal aging. If possible, compare the patient’s spontaneous facial movements and hand gesticulations to those of someone of similar age.
Postural stability and gait are evaluated in several ways. The patient is asked to stand up without the use of his or her arms (these may be crossed over the chest). Walking is observed, with attention to arm swing, stride length, posture (either forward or sideways tilt), and the ability to pivot and turn. If the patient cannot pivot and requires multiple little steps in order to turn, this is referred to as turning “en bloc.” Patients may freeze, especially on turning or in doorways, and be unable to take a step without help. Festination (hurrying) may occur, with patients taking rapid small steps without being able to stop, until they fall forward. Balance is tested using the pull test. The patient is told to stand with feet at shoulder width, warned what is to come and instructed to take a couple of steps to try and stop themselves from falling. The patient is then pulled firmly backward from the shoulders (the physician should position the hands either side of the patient in order to be prepared to catch him or her if necessary). If the patient requires more than 2 to 3 steps backward to restore balance, or would fall if not caught by the examiner, then postural reflexes are impaired.
There are no blood tests or brain scans which confirm the diagnosis of PD. At present, in the absence of molecular therapies, genetic testing is not clinically useful. Similarly, brain imaging is not useful for diagnosing PD, although a brain MRI may have features that raise the possibility of MSA, PSP, or vascular parkinsonism. Cerebellar or pontine atrophy is more consistent with MSA, while midbrain atrophy would indicate PSP. Iron deposition in the striatum may be seen in MSA.
Imaging of the dopamine transporters localized on the presynaptic nigrostriatal axon terminals, marketed as DaTscan, can be used to determine whether a tremor is due to PD or ET. However, this imaging modality does not reliably distinguish between PD and other causes of parkinsonism. It is currently approved only to support the diagnosis of PD, and does not replace clinical evaluation. Fluoro-deoxy-glucose positron emission tomography (FDG-PET) scans are sometimes used in a research setting to refine the diagnosis.
The diagnosis of PD becomes more evident over time, as the clinical progression and response to medication can be observed. While atypical parkinsonian disorders often respond partially to levodopa, a sustained motor response to levodopa over several years supports the diagnosis of idiopathic PD.
The most widely used scale for evaluating the severity of PD is the Unified Parkinson’s Disease Rating Scale (UDPRS), which has recently been refined and revised. This rating scale has sections dedicated to cognitive and psychiatric symptoms, activities of daily living, physical examination, and medication-related and autonomic symptoms. The scale is used to measure severity of disease as well as progression, and scores can be compared at serial visits. Disease severity may also be evaluated in the setting of a medication trial, both for clarifying the diagnosis and for estimating medication effect.
Parkinson’s disease is usually not the primary reason for hospital admission, unless the presenting complaint relates to falls and gait disorder. Up to 80% of PD patient admissions are due to comorbid issues. Tremor, stiffness, or otherwise unexplained gait problems are sometimes recognized in patients admitted for other reasons, leading to a new diagnosis of PD.
Parkinson’s disease is a characterized by slow, gradual progression, and any sudden deterioration is always due to another cause. As with many neurologic conditions, any metabolic derangement can exacerbate the symptoms of the underlying disorder. The health care provider must exclude acute infections, specifically of the urinary or respiratory tract, or electrolyte disturbances, with dehydration being the most common. Adverse effects from new medications should be excluded. New neurological signs may indicate a stroke, or subdural hematoma or cord injury following a fall.
Patients who have deep brain stimulation electrodes implanted will acutely deteriorate if their DBS batteries wear out, and they may become extremely rigid and unable to walk. They may even have a clinical appearance that resembles neuroleptic malignant syndrome, with severe rigidity and rhabdomyolysis. These patients should be treated with aggressive dopaminergic therapy and hydration. Contact should be made with a neurosurgeon as soon as possible to schedule a battery replacement. This situation should be avoided by calculation of battery life and monitoring.
To minimize the chance of complications due to under- or overtreatment while in hospital, it is vital that patients continue to take their medications as they did at home. Careful attention must be paid to dosage and timing. Undertreatment results in impaired mobility with the risk of falls, aspiration, deep venous thrombosis, constipation, and decubiti. It can also worsen confusion. Overtreatment causes dyskinesia, falls, agitation, confusion, and hallucinations.
As timing of PD medications is critical for patients with more than mild disease, it is essential that medications are taken on time. In the hospital this may be difficult, as medication every 3 hours or even less is a departure from typical administration schedules. If a patient with PD is admitted to the ward, nursing staff must be educated that PD medications should be given on a schedule closest to the patient’s home schedule (but that the patient should not be woken during the night to take the next dose). In extreme cases, when the patient takes medication every 3 hours or more frequently, it may be helpful for pharmacy to become involved. Medication errors frequently arise due to the different formulations available for carbidopa-levodopa (Table 210-2). The pharmacy should be made aware of which formulation is desired, especially when different ones are taken by the same patient.
TABLE 210-2Some Available Formulations of Carbidopa−Levodopa ||Download (.pdf) TABLE 210-2 Some Available Formulations of Carbidopa−Levodopa
|Drug Name (Trade Name) ||Comment |
|Carbidopa-levodopa(Sinemet)10/100* ||75 mg daily of carbidopa is required to inhibit dopa-decarboxylase; thus, three times daily dosing of this formulation is inadequate |
|Carbidopa-levodopa(Sinemet) 25/100 ||This is the most commonly used formulation. In most patients, it can be started at one-half tablet three times daily and increased to one tablet three times daily |
|Carbidopa-levodopa(Sinemet) 25/250 ||Highest strength formulation |
|Carbidopa-levodopa orally disintegrating (Parcopa) 10/100, 25/100, 25/250 ||Sublingual formulation can be useful in patients with dysphagia. There is no improvement in efficacy or release time |
|Carbidopa/levodopa(Sinemet) CR 25/100 ||With the controlled-release formulation, patients often report that they do not feel the medication “kicking in” as they do with regular-release tablets. Serum levels can be erratic. This formulation is most useful for overnight or early morning symptoms |
|Carbidopa/levodopa(Sinemet) CR 50/200 |
Although drug holidays were previously utilized to manage medication complications, these are a thing of the past, with risks and little benefit. Amantadine should never be suddenly stopped as this can cause a withdrawal syndrome.
Another cause for emergency room visits is caregiver burnout. The decompensation may not be in the patient, but rather in the home situation.
Elderly patients may become deconditioned after even a short hospital stay. This is especially true of parkinsonian patients, and may be compounded by disruptions in medication administration. Parkinsonian patients admitted to the hospital should receive physical and occupational therapy as soon as possible. They may also benefit from a posthospital rehabilitation course prior to returning home.
Current American Academy of Neurology guidelines suggest starting patients on an MAO-B inhibitor such as selegiline, which provides mild symptomatic benefit. When dopaminergic therapy is required, it is controversial whether patients should be started on levodopa, which is more effective for motor symptoms, but which may hasten the appearance of levodopa-induced dyskinesia (see below), or on dopamine agonists (ropinirole and pramipexole), which are slightly less efficacious.
We prefer to use dopamine agonists in younger patients in an attempt to delay the onset of dyskinesia. Younger patients are more likely to tolerate the necessary slow titration of these medications, and have fewer side effects. When functioning is no longer adequately treated, levodopa should be added. Levodopa should be used in older patients, particularly if gait and balance are already compromised by other factors, including normal aging, and effective treatment needs to be instituted quickly for safety reasons. Drugs used in PD are summarized in Table 210-3 and a treatment algorithm is suggested in Figure 210-2.
Suggested treatment algorithm for symptomatic Parkinson disease. (Reproduced, with permission, from Fauci AS, Braunwald E, Kasper DL, et al. Harrison’s Principles of Internal Medicine, 17th ed. New York, NY: McGraw-Hill 2008. Fig. 366-4.)
TABLE 210-3Drugs Commonly Used in the Treatment of Parkinson Disease ||Download (.pdf) TABLE 210-3 Drugs Commonly Used in the Treatment of Parkinson Disease
|Medication ||Starting Dose ||Target Dose ||Main Benefit ||Side Effects |
|Carbidopa-levodopa (Sinemet) ||12.5-50 mg three times daily ||Up to 50-200 mg every 3 h ||Reduction of tremor and bradykinesia; less effect on postural difficulties ||Nausea, dyskinesias, orthostatic hypotension, hallucinations, confusion |
|Controlled release carbidopa−levodopa ||25-100 mg once daily ||Up to 50-200 mg every 4 h ||May prolong levodopa effects || |
|Dopamine agonists |
|Ropinirole ||0.25 mg three times daily ||9-24 mg daily ||Moderate effects on all aspects; reduced motor fluctuations of levodopa ||Orthostatic hypotension, excessive and abrupt sleepiness, confusion, hallucinations |
|Pramipexole ||0.125 mg three times daily ||0.75-3 mg daily ||As above ||As above |
|Glutamate antagonist |
|Amantadine (Symmetrel) ||100 mg daily ||100 mg twice or three times daily ||Smoothing of motor fluctuations ||Leg swelling, congestive heart failure, prostatic outlet obstruction, confusion, hallucinations, insomnia |
|Benztropine (Cogentin) ||0.5 mg daily ||Up to 4 mg daily ||Tremor reduction, less effect on other features ||Atropinic effects: dry mouth, urinary outlet obstruction, confusion, psychosis, sedation |
|Trihexyphenidyl (Artane) ||0.5 mg twice daily ||Up to 2 mg three times daily ||As above ||As above |
|COMT inhibitors |
|Entacapone ||200 mg with levodopa ||Up to 8 times a day ||Prolonged effect of levodopa ||Urine discoloration, diarrhea, increased dyskinesias |
|MAO-B inhibitors || || || || |
|Rasagiline ||0.5 mg ||1 mg daily ||Reduced “off” time, questionable neuroprotection ||Hallucinations, confusion |
|Selegiline ||5 mg ||5 mg twice daily || |
Mild symptomatic effect, reduced off time, mild psychomotor stimulation, antidepressant effect
|Nightmares, agitation |
Levodopa, the biochemical precursor to dopamine, has been the mainstay of treatment since the early 1970s. Levodopa is metabolized in plasma by dopa decarboxylase to dopamine. Dopamine, a polar molecule, cannot cross the blood-brain barrier. As a result, only a limited amount of ingested levodopa is transported into the brain. In addition, dopamine produced in the periphery leads to severe nausea. To combat this problem, carbidopa, a dopa decarboxylase inhibitor, is coformulated with levodopa. This minimizes peripheral metabolism of levodopa, reducing nausea, and enables more of it to cross the blood-brain barrier via the large neutral amino acid transporter. Extra carbidopa (25 mg) taken with each dose can help reduce peripheral side effects.
Other levodopa side effects include hypotension, arrhythmias, vivid dreams, hallucinations, and somnolence. There may be effects upon mood, including emotional lability, increased libido, or anxiety. Confusion and loss of mental acuity can also occur. Unfortunately, decreased mental acuity and orthostatic hypotension tend to be late features of PD itself, so it may be difficult to distinguish between disease-related and medication-induced symptoms.
As PD progresses, higher doses of levodopa are required for functioning, and in most patients involuntary choreiform movements known as levodopa-induced dyskinesia will appear. These are often more troubling to caregivers than to patients, and do not require dose modification, but can sometimes be violent and disabling.
The long-acting form of carbidopa-levodopa (brand name Sinemet CR) can be useful in certain situations, although the term “controlled release” is something of a misnomer. Given the erratic bioavailability of this formulation, as compared with the standard preparation, it is most useful when given at bedtime for overnight symptoms, when attempting to maintain some drug in the system until morning. Although many patients experience sleep benefit, this formulation can be useful for those who experience early-morning foot cramps or motor difficulties prior to their first morning medication dose.
Although often prescribed by non-specialists, controlled-release levodopa/carbidopa rarely gives the same motor benefits as regular levodopa/carbidopa. It is equivalent to about two-thirds of the equivalent regular dose, and does not provide the kick to switch on and improve motor symptoms.
INHIBITORS OF DOPAMINE METABOLISM
An alternative to taking exogenous levodopa is to inhibit metabolism of dopamine. There are two primary pathways for dopamine breakdown, each utilizing either monoamine oxidase (MAO) or catechol-O-methyl transferase (COMT). Medications that inhibit either of these enzymes result in delayed metabolism of dopamine. Monoamine oxidase inhibitors can be taken alone or along with levodopa. COMT inhibitors are only prescribed as adjuncts to levodopa. One agent from each class may be combined for a synergistic effect. This may be queried by pharmacies, but use of these medications in combination is both safe and effective. Taken as an adjunct to carbidopa-levodopa, these medicines permit the dosing interval to be lengthened slightly and improve quality of life, as the patient is less bound to the clock and does not have to take pills as frequently. It may also be possible to lower the dose of levodopa with COMT inhibitor use. The earliest COMT inhibitor, tolcapone, carries the risk of liver toxicity, but is more effective as it inhibits both peripheral and central COMT. Liver enzymes should be monitored regularly in patients on this drug. The more recently developed COMT inhibitor, entacapone, is better tolerated, although less effective, as it inhibits only peripheral COMT. Entacapone is available formulated with carbidopa-levodopa to reduce pill burden, although it also increases the expense.
There are two versions of MAO, and both break down dopamine equally. MAO-A inhibitors have been used primarily as antidepressants, and require compliance with a low-tyramine diet to avoid increased norepinephrine levels and hypertensive crisis, and avoidance of SSRI antidepressants which can lead to serotonin syndrome. MAO-B inhibitors, which are currently used for treatment of PD, have a lower risk of this occurring, except at high doses. Dietary restriction or avoidance of SSRIs or SNRIs is not required with MAO-B inhibitors, despite the information provided by the manufacturer.
Initial evidence suggested a neuroprotective effect of the first MAO-B inhibitor, selegiline, but this was subsequently questioned. Selegiline has a mild symptomatic effect, and may improve depression and fatigue. However, its metabolic products include methamphetamine, and it should be taken early in the day to reduce the likelihood of insomnia and nightmares. Rasagiline has a mild symptomatic effect, but has not been shown conclusively to slow disease progression. Either of these medications may help reduce motor fluctuations in more advanced disease.
Warning patients that entacapone will turn their urine orange may save a call to your office.
Rather than replacing missing dopamine in the presynaptic nerve terminal, dopamine agonists act directly upon the postsynaptic dopamine receptor. Pramipexole and ropinirole are oral formulations, while rotigotine is used in transdermal form. The dopaminergic ergot derivatives (pergolide and bromocriptine) are no longer widely used, as they may cause pulmonary or cardiac valve fibrosis.
This class of medications should be started at a low dose and increased slowly to reduce the likelihood and severity of side effects such as confusion, sedation, and hallucinations. They should be used with particular caution in the elderly. Other side effects of dopamine agonists are lower extremity edema, impulse control disorders, and sleep attacks. Sleep attacks occur more frequently in people who are already sleep deprived, as is often seen in PD. Impulse control disorders, such as shopping, cleaning, gambling, internet use, or hypersexuality, usually occur in individuals with predispositions to these behaviors. Patients should be asked about these behaviors, as the connection to medication use may not be recognized.
Apomorphine is an injectable dopamine agonist that can be used in situations when the patient needs to have a rapid response and cannot wait for the effect of carbidopa-levodopa. Typically, patients still in the workforce are the ones who utilize this option.
These medications, which include benztropine and trihexyphenidyl, were used prior to the discovery of levodopa. These agents are believed to be most useful when used in younger patients with a chief complaint of tremor, although studies have yet to show this unequivocally. Anticholinergics should be used with caution, particularly in the elderly, who are particularly susceptible to side effects including hallucinations, cognitive impairment, and urinary retention. These effects are usually reversible when the drug is discontinued.
The antiviral drug amantadine was noted to reduce the symptoms of PD prior to the levodopa era. It is effective both for primary PD symptoms and for levodopa-induced dyskinesias. It acts by blocking glutamatergic NMDA receptors. Glutamate hyperfunction may be seen both in the setting of dopamine depletion and parkinsonism, and as part of the pathophysiology of dyskinesia. As would be predicted from blockade of glutamate receptors, amantadine can cause confusion and hallucinations.
Neurosurgical options are now state of the art for the treatment of PD in selected patients whose symptoms are no longer controlled by optimal medical therapy. Historically, surgical destruction of specific structures in the basal ganglia (lesioning or ablative therapy) predated the development of levodopa, but became obsolete after this medication was discovered. Currently, stimulation of basal ganglia targets via deep brain stimulation (DBS) is preferred to ablative therapy, as having fewer side effects and being less destructive. However, ablation may be indicated in patients who require surgery, but who cannot have DBS electrodes implanted for medical or logistical reasons, such as residence remote from programming sites.
Deep brain stimulation delivers electrical impulses directly to a nucleus in the basal ganglia that partially reverses the effects of dopamine depletion. It is unclear exactly how DBS works, but while the original hypothesis was that it inhibited the target area, recent evidence suggests that it may alter the excitatory outputs of the target zone. Both inhibitory and stimulatory effects have been reported. DBS may also work by normalization of pathological hypersynchronization in the setting of dopamine depletion.
Most DBS patients experience improvement at least in terms of motor symptoms and side effects. DBS appears to be equivalent to levodopa, in that the optimal effect is as good as the patient’s best on-medication state, but not better. Patients are able to decrease the amount of medication they take, typically by 50% to 70%, and no longer experience severe motor fluctuations. What DBS does not improve, and may indeed worsen, are the nonmotor effects, including depression, apathy, and impaired cognition. Speech may also be adversely affected. Some of these effects may be attributable to decreased doses of dopaminergic medication.
Brain MRI can generally be performed on patients with DBS, but body MRI scans should be avoided due to the higher energy levels and greater risk of thermal injury from heating up of electrodes. When brain MRIs are performed, the voltage should be set to zero and the stimulation switched off. Patients undergoing tests involving electricity, such as electrocardiograms, should turn their DBS off temporarily, which they can do using their own remote control on/off device. Any change of stimulation settings should be performed by a trained DBS programmer. More specific issues, such as the safety of electrocautery for dental or surgical procedures, should be directed to the patient’s neurosurgeon or to the device company.
DBS performed on patients without PD, such as patients with atypical parkinsonism syndromes, do not have good outcomes. Patients should be evaluated for DBS by a movement disorders specialist for appropriate patient selection.
Nonpharmacologic treatments are an essential part of care of the PD patient. A multidisciplinary team approach can be utilized to provide effective comprehensive care for the PD patient. In PD, speech can be severely hypophonic and challenging to a hearing-impaired caregiver. Speech therapists can provide exercises, such as the Lee Silverman Voice Therapy (LSVT), to optimize speech output. A swallowing evaluation should be considered in patients who have progressed to the stage of balance impairment, even if they do not report coughing when they drink water. Use of thickened liquids may reduce the likelihood of a fatal pneumonia. Severe dysphagia may eventually warrant percutaneous gastrostomy tube placement.
Early attention to posture and mobility is vital. Evaluation by physical and occupational therapists is invaluable. Assistive walking devices including canes, walkers and wheelchairs should be used appropriately. Patients should be encouraged to stay active, with all the attendant medical and psychological benefits this entails. Data from animal models suggest that exercise has a beneficial effect upon brain chemistry. Music therapy may be very helpful as people with PD can move better to the external stimulus provided by music.
Patients with PD lose weight for reasons which are not entirely explained by motor difficulties and dysphagia. Malnutrition may worsen PD symptoms, and increases the risks of falls and infection. Diets high in vitamins E and C may reduce risk of PD, probably due to their antioxidant properties. Dietary vitamins appear to be more beneficial than vitamins in nutritional supplements. Adequate calcium and vitamin D intake is important for bone health, as PD patients are at high risk for falls.
High protein meals can interfere with the effects of medication, as amino acids compete with levodopa for uptake in the gut. However, taking medication on an empty stomach can cause nausea. Some patients find it helpful to ingest most of their daily protein at the evening meal, when the need for motor function is decreased.
Older patients with impaired mobility tend to drink less fluid to reduce urinary frequency and the risk of incontinence, putting them at risk for dehydration. This can aggravate orthostatic hypotension, which may be a feature of PD and may also be exacerbated by medications, thus contributing to fall risk. Constipation is a common PD symptom, and is also relieved with increased fluid intake, as well as a high fiber diet and regular physical activity. Despite these measures, regular administration of a stool softener is usually required.
ISSUES IN HOSPITALIZED PD PATIENTS
In advanced disease, the therapeutic effects of levodopa wear off more quickly. After excluding decompensation due to metabolic disturbances and infection there are several potential strategies to follow. Drug dosage or frequency may be increased, or an inhibitor of dopamine metabolism such as entacapone, rasagiline, or selegiline may be prescribed. These choices are guided by efficacy of the current dose, medication side effects, and patient preference.
Choreiform or dystonic movements may occur at peak blood levels of dopaminergic medications (peak-dose dyskinesia), but can also occur when medication is taking effect or wearing off (on-off dyskinesia). Dyskinesia occurs more typically with levodopa, but may be seen with dopamine agonists. It may manifest in any part of the body, and may include behavior that appears to be restless fidgeting or facial twitches. More severe forms may include toe-curling dystonia, violent limb movements, or even difficulty breathing due to involvement of the diaphragm. These symptoms usually resolve as the levodopa dose wears off, and the patient is often left with a window of time during which their PD symptoms are controlled and their dyskinesia is less severe. This window is soon followed by medication off time, as PD symptoms return. In some cases, motor fluctuations can involve nonmotor features, such as sweating, cardiac arrhythmias, and anxiety. The temporal relationship of these symptoms to medication intake suggests the diagnosis and management.
For most patients, the dyskinesia is mild enough that they prefer the medication on-state to the rigid, akinetic off-state. In many cases, the spouse or caregiver is more bothered by the abnormal dyskinetic movements more than the patient. Patients generally prefer dyskinesia to being undermedicated. Amantadine may be helpful in controlling dyskinesia, most likely due to its antiglutamatergic actions.
As PD progresses, pharyngeal muscle dysfunction may develop, and the patient may have trouble swallowing. The risk of aspiration is increased by undertreatment while hospitalized. Management in hospitalized patients may include limiting the diet to avoid thin liquids and eating meals while sitting in a chair, but ideally should include a formal speech and swallowing evaluation.
Falling is a frequent PD symptom and reason for emergency room visits. However, a sudden increase in falls should not be blamed on PD alone. As discussed above, PD does not rapidly progress, and secondary causes should be sought, such as infections, metabolic derangements, spinal cord injury, stroke, and subdural hematoma.
Cognition and behavior are frequently affected in moderate to advanced stages of PD. With more sensitive testing, deficits can be detected even in relatively early stages. The typical deficits that develop are dysfunction in executive function and decision making (frontal type dementia). There is also slowing of information processing, known as subcortical dementia. This is in comparison to the memory dysfunction and other cortical functions typical of Alzheimer’s disease. Along with these changes can appear personality changes such as disinhibition or apathy. Poor judgment, increased risk taking, and lack of insight may contribute to increased falls.
Individuals with, and even without, cognitive decline may have visual hallucinations. These often consist of animals and people, especially children, and are usually non-threatening, at least in the initial stages. Hallucinations may be worsened by many PD medications, in particular the dopamine agonists.
Elderly patients admitted to the hospital, regardless of diagnosis, often become more confused in the evenings and may become prone to sundowning and agitation. Exposure to daylight during daytime may be helpful. Typical antipsychotic medications should not be used, as these may worsen parkinsonism. Atypical antipsychotics such as quetiapine may be given in very low doses, but may cause sedation or hypotension. Benzodiazepines tend to worsen confusion in this population.
Depression in PD is more than a predictable response to a chronic, progressive illness. It seems to be an organic depression, and responds to antidepressants. The older, less selective, antidepressants may be more effective, rather than selective serotonin reuptake inhibitors, although they may also have more side effects. Some patients are prone to anxiety, which may worsen with disease progression, and can exacerbate motor symptoms. In addition, anxiety may be a feature of either the off-state, or peak-dose dyskinesia. Apathy and fatigue appear to be distinct features in PD, without good therapies at present. MAO-B inhibitors can have a mild stimulant effect in some patients.
Parkinson’s disease patients may be caught in a vicious cycle of sleep difficulties. PD and associated medications may contribute to nocturnal awakenings and insomnia, while daytime somnolence may exacerbate neurologic symptoms. REM sleep behavior disorder can occur particularly in men with PD, and often predate the development of frank motor symptoms. In this disorder the sufferer acts out his dreams, and may kick and thrash during sleep, resulting in injury to the patient and to the bed partner. This can be effectively treated with low doses of clonazepam, possibly through reduction of REM sleep.
In the hospital, it is important for night staff to be aware of this sleep dysregulation, as the patient may request a sleep aid. The patient may try to walk to the nursing station or bathroom if he or she cannot sleep, with the danger of falling, especially if medication has not been given recently. Parkinson’s disease patients with gait dysfunction should be classified as fall risks and therefore need to be accompanied to the bathroom, or instructed to use a urinal, or bedside commode especially at night.
Autonomic Nervous System Problems
Marked autonomic dysregulation suggests the diagnosis of MSA, but it can also occur in idiopathic PD. Orthostatic drops in blood pressure can result in unsteadiness, lightheadedness, and even loss of consciousness. Use of antihypertensive medications should be reassessed, and dose reduction or even cessation may be necessary. Patients should stay hydrated, liberalize salt intake, wear compression stockings, and sleep with the head of the bed raised by 30°. If these measures do not work, a blood pressure raising agent such as fludrocortisone or midodrine may be used. These drugs should not be used late in the day, due to the risk of nocturnal hypertension.
Parkinson’s disease patients may develop neurogenic bladder, leading to nocturia and sleep disturbance. Giving an anticholinergic agent at bedtime may improve nocturia, in addition to promoting sedation and having mild antiparkinsonian effects. Unfortunately, anticholinergics have cognitive and hallucinatory side effects, and may result in nocturnal falls. In addition, bladder dysfunction may make patients prone to urinary tract infections.
Patients may complain of excess salivation, due to impaired swallowing. This can be cautiously treated with peripherally-acting anticholinergic agents, such as propantheline, or with botulinum toxin injections into the salivary glands. Rimabotulinum toxin B is preferred, as it appears to have a stronger anticholinergic effect.
Constipation is very common in PD and may predate the diagnosis. Unfortunately, levodopa therapy is often unhelpful in resolving constipation, and entacapone may even make it worse. For hospitalized PD patients, it should be ensured that they have regular bowel movements, as limited mobility will worsen their pre-existing constipation. Nausea should be treated with nondopamine blocking antiemetics.
Parkinson’s disease continues to respond to medications even in advanced disease. However, higher and more frequent dosing may be required, and the results are less predictable, with dose failures and sudden off periods. The medication schedule is often simplified as the disease progresses, until only levodopa/carbidopa is given. It is important to ensure that PD medications continue to be given despite impaired swallowing, as inadequate treatment can result in significant pain and worsened bradykinesia. Levodopa/carbidopa can be administered ground up in apple sauce. An orally-disintegrating formulation of levodopa/carbidopa, marketed as Parcopa, may also be useful.
The terminal phase of PD and other parkinsonian disorders is similar to that of other neurodegenerative conditions such as Alzheimer’s disease, with progressive debility and vulnerability to pneumonia and urinary tract infections. Constipation and falls are common. Aspiration is a particular risk due to dysphagia, kyphosis, and hypokinesia. Weight loss is typical, and a feeding tube may be considered to facilitate safe and adequate nutrition. It has not yet been determined whether feeding tubes enhance quality of life, or reduce mortality, in advanced PD. Patients, families, and physicians should consider early planning of advanced directives regarding difficult issues such as gastrostomy tube placement and preferred place of death, as patients with severe PD may be physically and cognitively unable to engage in such decision making. Palliative care physicians may help facilitate these discussions.
DISCHARGE PLANNING CHECKLIST
Do the patient and caregiver understand changes to medications?
Has follow-up with the treating neurologist been scheduled in the next 2 to 4 weeks?
Home safety evaluation: are additional items required, for example shower chair, bathroom railings, hospital bed? Should a visiting nurse assess the home situation?
Is outpatient physical therapy indicated? Are new assistive devices required?
Has the caregiver been educated on the appropriate consistency diet and any new nutritional needs, such as high-calorie supplements?
Have the needs of the caregiver been addressed? Have mechanisms of support been discussed, including home health aides and support groups? Have future respite admissions been considered?
et al. Reasons for hospitalization in Parkinson’s disease: a case-control study. Parkinsonism Relat Disord
MP, van Domburg
et al. Deterioration of Parkinson’s disease during hospitalization: survey of 684 patients. BMC Neurol
et al. Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23:2129–2170.
et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med
van der Marck
et al. Consensus-based clinical practice recommendations for the examination and management of falls in patients with Parkinson’s disease. Parkinsonism Relat Disord
RW. Palliative care and end-of-life planning in Parkinson’s disease. J Neural Transm
For patients and caregivers.