Parkinson’s disease (PD) is a neurodegenerative disease with the core features of tremor, bradykinesia, rigidity, and postural instability. Additional motor features include decreased facial expression (hypomimia), decreased blink rate, small handwriting (micrographia), stooped posture, shuffling gait with reduced arm swing, festination (increasingly rapid small steps), difficulty turning when walking, and difficulty turning over in bed. The constellation of some or all of these motor features is referred to as parkinsonism. In addition to idiopathic PD, other causes of parkinsonism include:
Medications: most commonly antipsychotics and antiemetics (see “Drug-Induced Parkinsonism” below)
Cerebrovascular disease (vascular parkinsonism)
Toxins, including manganese and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (MPTP may contaminate the illicit synthetic opioid MPPP [1-methyl-4-phenyl-propionoxypiperidine].)
Metabolic conditions such as extrapontine myelinolysis
Neurodegenerative diseases aside from idiopathic PD, called the Parkinson-plus syndromes (see “Parkinson-Plus Syndromes” below):
Multiple systems atrophy (MSA)
Progressive supranuclear palsy (PSP)
Corticobasal syndrome (CBS)
Dementia with Lewy bodies (DLB)
Clinical Features of Parkinson’s Disease
Tremor, bradykinesia, and rigidity typically begin unilaterally in patients with idiopathic Parkinson’s disease, but usually become bilateral as the disease progresses (although commonly remains asymmetric). Some patients may have a tremor-predominant form of the disease without much rigidity or gait dysfunction, some patients may have no tremor at all and have predominant bradykinesia and rigidity (akinetic-rigid form), and some patients may have predominant postural instability and gait dysfunction. The tremor-predominant form of PD may have a more benign course than other forms of the disease.
Although most cases of Parkinson’s disease are idiopathic/sporadic, familial forms are associated with mutations in a growing number of genes including LRRK2 (autosomal dominant) and parkin (PARK2; autosomal recessive with onset in youth).
Tremor in Parkinson’s disease—The tremor of PD is most commonly a tremor of the hand(s) that is present at rest and resolves with movement, but may also reemerge after sustained posture (e.g., holding the arms and hands out straight). The tremor may be pill-rolling (flexion movements of the fingers and thumb giving the impression that the patient is rolling a pill in the hand), but this is not always the case. Rest tremor may emerge when distracting the patient, for example, by asking the patient to perform serial seven subtractions. The tremor typically presents unilaterally and, although it may become bilateral throughout the course of the disease, it often remains asymmetric in its severity. Tremor of the jaw may also be present, but tremor of the head (as is seen in essential tremor) is not typically a feature of Parkinson’s disease.
Bradykinesia in Parkinson’s disease—Bradykinesia denotes slowing of movements. This may be evident in observing the patient’s normal activities, and can be elicited on examination by testing finger tapping, foot tapping, or repeated pronation–supination movements (“as if screwing in a light bulb”). These movements should be tested one side at a time to avoid entrainment, which may mask asymmetries.
Rigidity in Parkinson’s disease—The side(s) of the body with tremor and/or bradykinesia may be noted to have cogwheel rigidity, whereby a joint appears to “click” through the passive range of motion rather than move smoothly when moved slowly through the range of motion by the examiner. This can be brought out by the technique of reinforcement, asking the patient to make circles or other repeated movements with the hand on the side opposite the limb being evaluated for rigidity. In idiopathic PD, rigidity is commonly asymmetric, affecting the limb(s) with tremor more so than the others. Axial rigidity can be evaluated for by moving the patient’s neck passively through its range of motion.
Postural instability in Parkinson’s disease—Postural instability tends to emerge later in the course of Parkinson’s disease (although it may be present earlier in the course of progressive supranuclear palsy; see “Progressive Supranuclear Palsy” below). Postural instability can be assessed using the pull test to look for retropulsion. The examiner stands behind the patient with the patient’s back to the examiner, preferably with a wall behind the examiner to break a fall should one occur. The examiner then explains that she or he will be pulling briskly on the patient’s shoulders and that the patient should maintain balance however necessary. After a brisk, forceful tug on the patient’s shoulders, the patient’s response is observed. Normally, a patient with intact postural stability will maintain balance with no steps or one or two steps backward. In a patient with postural instability due to parkinsonism, the patient will exhibit retropulsion, requiring several (more than three) small steps to regain balance, or in severe cases, the patient will simply fall backward.
Gait in Parkinson’s disease—Gait in PD is generally slow with small shuffling steps (marche à petit pas). Arm swing is usually diminished (usually more prominently on the side of greater tremor and/or rigidity). Turning is often difficult, requiring a number of small steps to turn. Some patients may start walking slowly and then accelerate with increasingly rapid small steps (festination). In advanced PD, some patients may develop freezing of gait, freezing in place and unable to proceed. Freezing may be able to be overcome by a visual stimulus (e.g., a line on the ground).
Other signs in Parkinson’s disease—When tapping slowly and rhythmically between the eyes, normal individuals will blink several times and then stop blinking. Patient’s with Parkinson’s disease may not extinguish the blink response and continue to blink with each tap, called Myerson’s sign or the glabellar sign.
Nonmotor aspects of Parkinson’s disease—Nonmotor features of PD include fatigue, depression, anxiety, dementia, autonomic dysfunction (including constipation, orthostatic hypotension, urinary dysfunction), decreased sense of smell, and REM sleep behavior disorder (RBD). In RBD, patients act out their dreams, which often involve kicking, punching, and/or running. RBD and olfactory dysfunction may precede the onset of Parkinson’s disease by years, and RBD is associated with a high risk of future development of a neurodegenerative disorder (most commonly synucleinopathies such as PD, multiple systems atrophy, and dementia with Lewy bodies). Dementia is typically not present at onset of parkinsonian symptoms in idiopathic PD. If dementia and parkinsonism arise concurrently, dementia with Lewy bodies should be considered (see “Dementia with Lewy Bodies” in Ch. 22). Autonomic dysfunction is usually a more prominent feature in multiple systems atrophy as compared to in PD.
Diagnosis and Differential Diagnosis of Parkinson’s Disease
Parkinson’s disease is a clinical diagnosis. A tremor-predominant presentation must be distinguished from essential tremor, drug-induced tremor, physiologic tremor, and hyperthyroidism. Asymmetry of tremor and accompanying bradykinesia and rigidity on the side of tremor are suggestive of PD. Early falls and/or impaired vertical gaze with parkinsonism suggest progressive supranuclear palsy (PSP). Early and severe autonomic dysfunction with parkinsonism suggests multiple system atrophy (MSA). Dementia and hallucinations arising before or concurrently with parkinsonism suggest dementia with Lewy bodies (DLB). Improvement in symptoms with levodopa is also suggestive of PD, although some Parkinson-plus syndromes may have an initial response to levodopa. When there is clinical ambiguity, a dopamine transporter SPECT (single photon emission computed tomography) scan can be used to look for asymmetric decreased activity in the basal ganglia. However, dopamine transporter SPECT only distinguishes a neurodegenerative parkinsonian syndrome from “not a neurodegenerative parkinsonian syndrome” (i.e., it does not distinguish between PD, multiple systems atrophy, progressive supranuclear palsy, and corticobasal syndrome). Dopamine transporter SPECT can be useful in a patient in whom there is a question of PD versus essential tremor (if the latter presents asymmetrically, as it sometimes does) or PD versus drug-induced parkinsonism (see “Drug-Induced Parkinsonism” below).
Treatment of Parkinson’s Disease
Pharmacologic treatment of PD is symptomatic, and therefore should begin when the disease begins to interfere with activities of daily living. For example, if the patient has a mild tremor in the nondominant hand that the patient does not feel is bothersome, treatment is not necessarily required. The available medications for PD include:
Levodopa: given combined with carbidopa. Carbidopa inhibits peripheral dopamine breakdown, increasing the amount of levodopa that enters the CNS and decreasing peripheral side effects such as nausea.
Dopamine agonists: pramipexole and ropinirole are the most commonly used agents in this category (pergolide is no longer in use due to cardiac valvular toxicity).
Catecholamine O-methyl transferase (COMT) inhibitors: entacapone and tolcapone are used with carbidopa-levodopa to potentiate its effect (tolcapone can rarely cause hepatotoxicity and so entacapone is more commonly used).
Anticholinergics: trihexyphenidyl is used predominantly for tremor.
Monoamine oxidase B (MAO-B) inhibitors: selegiline and rasagiline.
Amantadine: particularly useful in the treatment of dopamine replacement–induced dyskinesias (see “Treatment-induced dyskinesias in Parkinson’s disease” below)
In addition, exercise (aerobic and tai chi), speech therapy (for hypophonia if present), and psychiatric care (if depression, anxiety, or psychosis is present) are all important aspects of supportive care for PD.
Dopamine replacement with levodopa or a dopamine agonist is first-line therapy when the disease begins to become disabling. Levodopa is more effective than dopamine agonists and causes fewer initial side effects, but may be associated with a higher risk of subsequent motor complications (dyskinesias) than dopamine agonists. Side effects of dopamine agonists include daytime somnolence, peripheral edema, psychosis, hallucinations, and impulse control disorders (including hypersexuality, pathologic gambling). Side effects of levodopa include dizziness and nausea, which may be ameliorated by taking the medication with food (although this can decrease the absorption of the medication if the medication is taken with a high-protein meal).
Some practitioners suggest that younger patients should initially be treated with dopamine agonists, whereas patients who develop the disease later in life should begin immediately on levodopa. Advocates of this strategy prefer dopamine agonists in younger patients since these patients will likely survive longer with the disease and be prone to later treatment-related motor complications with levodopa. Given the efficacy of levodopa, however, some practitioners start directly with this medication in patients even if they are younger. As the disease progresses, nearly all patients with PD will ultimately require levodopa.
COMT inhibitors potentiate the effects of carbidopa-levodopa and can be added to this medication as the disease advances and response to levodopa decreases, a phenomenon called wearing off.
Anticholinergic medications such as trihexyphenidyl are most effective for tremor, and may be used in patients in whom tremor is the predominant disabling feature. Due to anticholinergic side effects such as confusion, this medication is often avoided in older adults.
MAO-B inhibitors and amantadine provide only minor symptomatic benefits and are sometimes used in early disease. Some data suggest a possible neuroprotective effect of rasagiline, but this is debated. Amantadine may also be useful in patients who develop dyskinesias (see “Treatment-induced dyskinesias in Parkinson’s disease” below).
Regimens involving multiple agents are inevitably necessary as the disease progresses, and must be individualized for each patient (Fig. 23–2). As the dopaminergic pathways continue to degenerate, the effect of levodopa may wear off quickly between doses (off states), requiring higher doses and/or increased dose frequency to maintain symptomatic relief (on states). Taking levodopa on an empty stomach may increase efficacy (although may also increase nausea). Additional strategies at this stage include adding a COMT inhibitor to potentiate the effect of levodopa, adding an MAO-B inhibitor, and/or adding a dopamine agonist. If a COMT inhibitor or a dopamine agonist is added, a dose reduction in levodopa may be necessary.
Algorithm showing possible treatment options in patients with Parkinson’s disease at various stages of the disease. See also algorithms in Connolly and Lang, 2014.
Treatment-induced dyskinesias in Parkinson’s disease—Degeneration of the dopaminergic pathway leads to hypersensitivity to dopamine replacement, which can cause dyskinesias (usually involuntary choreoathetoid movements). Dyskinesias usually arise after about 5 years of levodopa therapy (as mentioned above, this is part of the rationale given by some clinicians in delaying initiation of levodopa in younger patients). Dyskinesias can be treated with addition of amantadine or with lowering of levodopa dose, but this can lead to a “rock and hard place” scenario between the patient being “off” (parkinsonian) and “on” but dyskinetic. At this point, deep brain stimulation may be considered.
Deep brain stimulation in the treatment of Parkinson’s disease—Deep brain stimulation (DBS) is performed by surgical implantation of stimulating leads in the subthalamic nucleus (STN) or globus pallidus interna (GPi) connected to a stimulator that is placed in the soft tissue of the chest. The parameters of the stimulator can be adjusted by an external programming device. DBS increases the amount of time the patient spends in the “on” state without dyskinesias. Patients will not improve beyond their best response to levodopa and will still require medications, although often levodopa dosing can be decreased, which may account in part for the reduction in dyskinesias.
DBS only ameliorates motor symptoms, and generally does not lead to improvement in non-motor aspects of PD. Patients with cognitive impairment or psychiatric disease are generally not considered candidates for DBS. Surgical complications of DBS include intracerebral hemorrhage and intracranial infection, although these are not common occurrences. Hardware complications can occur due to lead breakage or migration. In addition to PD, DBS can also be considered in essential tremor and dystonia, although it is not currently used in Parkinson-plus disorders.
Parkinsonism can be induced by dopamine-blocking agents, most commonly:
Antipsychotics: more common with typical/first-generation antipsychotics, but can occur with atypical/second-generation antipsychotics
Dopamine antagonist antiemetics: metoclopramide, prochlorperazine
The rarely used antihypertensives reserpine and alpha-methlydopa
Drug-induced parkinsonism can also be seen rarely with antiepileptics (most commonly valproic acid, although this more commonly causes isolated tremor rather than parkinsonism).
In drug-induced parkinsonism, bradykinesia and rigidity are typically symmetric but can present asymmetrically as in PD. Tremor may be at rest, postural, or both. Symptoms generally emerge within months of starting the offending medication but can also emerge with change of dosage later in the course of medication treatment. Other associated drug-induced movement disorders such as tardive dyskinesia and akathisia may also be present (see “Tardive Dyskinesia” below), although drug-induced parkinsonism may be present in isolation. Treatment is ideally discontinuation of the offending medication when possible. If ongoing antipsychotic treatment is necessary for the underlying disorder, clozapine can be considered (although this requires monitoring of complete blood cell count [CBC] due to risk of developing agranulocytosis with this medication). Most cases of drug-induced parkinsonism are reversible, although this can take months. If a patient requires a particular typical or atypical antipsychotic for the underlying psychiatric condition and cannot be on a lower dose or changed to another medication, anticholinergic medication (e.g., benztropine) may be used as symptomatic treatment. Dopamine replacement is generally ineffective.
An important diagnostic consideration in older patients who develop parkinsonian symptoms while on antipsychotic medications or dopamine-blocking antiemetics is whether idiopathic PD is emerging or being in some way “unmasked” by antidopaminergic therapy. In such patients— especially if there is no improvement with removal of the offending agent—dopamine transporter imaging can be useful since this will be normal in drug-induced parkinsonism but abnormal in PD (or any Parkinson-plus syndrome).
The Parkinson-plus syndromes (also called atypical parkinsonism) are neurodegenerative diseases that cause parkinsonism but also have additional features not seen in Parkinson’s disease. The Parkinson-plus syndromes include multiple systems atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB) (see Table 23–3). With the exception of CBS, parkinsonism is typically symmetric at onset compared to the unilateral onset typically seen in Parkinson’s disease.
TABLE 23–3Clinical Features of the Parkinsonian Syndromes. ||Download (.pdf) TABLE 23–3 Clinical Features of the Parkinsonian Syndromes.
| ||Parkinson’s Disease ||Dementia With Lewy Bodies ||Multiple Systems Atrophy ||Progressive Supranuclear Palsy ||Corticobasal Syndrome |
|Distinguishing feature(s) ||Parkinsonism || |
|Autonomic dysfunction || |
Vertical gaze dysfunction
|Motor features (in addition to parkinsonism) ||Dyskinesias with dopamine replacement therapy ||N/A ||Cerebellar and/or pyramidal signs ||Prominent axial rigidity || |
|Symmetry of motor features ||Typically begins unilaterally, but may become bilateral ||Typically bilateral ||Typically bilateral ||Typically bilateral ||Typically unilateral |
|Dementia ||Late ||Early (visuospatial dysfunction prominent) ||Present in some patients ||Early (Executive dysfunction prominent) ||Late |
|Autonomic ||Late/mild ||Late ||Prominent ||Unusual ||Unusual |
|Speech ||Hypophonic ||Not usually impaired ||Dysarthric ||Dysarthric ||Not usually impaired |
|Other ||Treatment-induced dyskinesias ||Hallucinations, fluctuations ||Stridor ||Eye movement abnormalities (see text) ||N/A |
|Average age of onset ||60s ||50s–80s ||50s ||60s ||60s |
|Neuroimaginga ||No findings on structural neuroimaging ||Temporo-occipital hypometabolism on PET ||Hot cross buns sign in pons (Fig. 23–2) ||Humming bird and Mickey Mouse signs due to midbrain atrophy (Fig. 23–3) ||Asymmetric parietal/basal ganglia atrophy and hypometabolism |
|Response to levodopa ||Yes ||None or minimal/transient ||None or minimal/transient ||None or minimal/transient ||None or minimal/transient |
|Pathology ||Synuclein ||Synuclein ||Synuclein ||Tau ||Tau, AD |
Multiple systems atrophy (MSA) is a disease characterized by parkinsonism and/or cerebellar dysfunction accompanied by autonomic dysfunction. Two variants of the disease are recognized, which are named based on their predominant feature: MSA-P (P for parkinsonism; formerly called striatonigral degeneration) and MSA-C (C for cerebellar; formerly called olivopontocerebellar atrophy). Parkinsonian features, when present, are typically symmetric at onset (as compared to asymmetric in Parkinson’s disease), and tend to progress more rapidly than in Parkinson’s disease. Tremor is not a predominant feature, and when present is most commonly an action tremor as opposed to the rest tremor typically seen in Parkinson’s disease (although rest tremor can occur in MSA). Autonomic dysfunction in MSA can manifest as orthostatic hypotension, urinary incontinence, and/or erectile dysfunction. These autonomic features may also be seen in Parkinson’s disease and dementia with Lewy bodies, but are typically milder in those diseases.
Additional features of MSA can include anterocollis (forward flexed posture of the neck), Pisa syndrome (head, neck, and trunk flexion to one side like the leaning tower of Pisa), hyperreflexia and/or Babinski’s sign(s), dysarthria and/or dysphagia, nocturnal stridor, pseudobulbar affect (uncontrolled laughing and/or crying), and/or Raynaud’s phenomenon. Although parkinsonian features may initially respond to levodopa in some patients with MSA leading to diagnostic consideration of Parkinson’s disease, this response is generally not sustained, and levodopa may worsen orthostatic hypotension.
In MSA-C, MRI may reveal the “hot cross bun” sign (resembling a plus sign in a circle) in the pons due to degeneration of the crossing corticopontocerebellar fibers destined for the middle cerebellar peduncles (Fig. 23–3). MRI abnormalities may also be present in the putamen, and atrophy may be seen in the putamen, middle cerebellar peduncle, pons, and/or cerebellum; these structures may also demonstrate hypometabolism on PET. Dopamine transporter imaging may be abnormal (decreased uptake in basal ganglia), but this can occur in any neurodegenerative parkinsonian syndrome and does not distinguish between them. Treatment is supportive.
MRI in multiple systems atrophy. Axial FLAIR MRI demonstrating the “hot cross buns” sign and middle cerebellar peduncle atrophy in a patient with MSA-C.
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is characterized by gait dysfunction (leading to falls) and oculomotor dysfunction (most commonly problems with vertical gaze). The first symptom is usually falls, commonly backward. The vertical gaze palsy characteristic of the disease may not be present initially, leading to initial diagnostic consideration of Parkinson’s disease. However, tremor is rare in PSP, and most of the rigidity in PSP is axial (neck and back) rather than in the extremities as is commonly seen in Parkinson’s disease. Patients have difficulty looking up and down voluntarily, but since the problem is supranuclear (hence the name of the disease), vertical eye movements can be elicited with vertical oculocephalic maneuvers (since the cranial nerve 8—medial longitudinal fasciculus [MLF]—cranial nerves 3, 4, and 6 pathways are intact; see “Supranuclear Versus Nuclear Lesions Affecting Eye Movements” in Ch. 11). Before vertical gaze palsy develops, slowing of vertical saccades compared to horizontal saccades may be noted. Downgaze palsy is more specific for the disease, since decreased upward gaze can be seen in many neurodegenerative disorders as well as in normal elderly patients. Cognitive and behavioral changes are often present early in the disease.
Other features of PSP include dysarthria and/or dysphagia, a startled/surprised appearance of the face, retrocollis, and ocular motor findings including square-wave jerks (saccadic intrusions away from the point of focus), eyelid opening apraxia (difficulty reopening the eyes after closure), and failure to suppress the vestibulo-ocular reflex (see “The Vestibulo-Ocular Reflex” in Ch. 12). The clap sign (inability to clap only three times and then stop; i.e., patient keeps clapping due to motor perseveration) is often associated with PSP, but can be present in any neurodegenerative disease.
Neuroimaging can reveal midbrain atrophy without pontine atrophy, resulting in a “hummingbird” appearance of the brainstem in midsagittal view (Fig. 23–4A). However, the brainstem in this view looks like a bird even in normal patients, and the pattern of midbrain atrophy in PSP may be more easily identifiable in the axial plane as a “carving out” of the space between the cerebral peduncles creating a “Mickey Mouse” appearance (Fig. 23–4B). As in MSA, levodopa may be helpful initially but often is not, and any response is often mild and transient compared to Parkinson’s disease. Therefore, treatment is supportive.
MRI in progressive supranuclear palsy. A: Sagittal T1-weighted MRI demonstrating the hummingbird sign (midbrain atrophy with spared pons). B: Axial T1-weighted MRI demonstrating the Mickey Mouse sign (decreased anteroposterior size of the midbrain when measured from between the cerebral peduncles to the superior colliculi, leading to a “carved out” appearance between the cerebral peduncles).
Corticobasal Syndrome and Corticobasal Degeneration
Corticobasal syndrome (CBS) refers to a clinical phenotype, and corticobasal degeneration (CBD) refers to a pathologic diagnosis (based on a specific anatomic distribution of tau pathology). The clinical phenotype of CBS can be caused by CBD pathology, but also by Alzheimer’s disease (AD) pathology, progressive supranuclear palsy (PSP) pathology, frontotemporal dementia (FTD) pathology, or mixed pathology. CBD pathology can give rise to clinical syndromes of CBS, PSP, FTD, an AD-like picture, or a mixed phenotype.
Symptoms of CBS are typically asymmetric (like Parkinson’s disease, but unlike MSA and PSP), and the affected side may demonstrate both cortical findings (such as myoclonus, apraxia, sensory neglect, and/or the alien limb phenomenon [involuntary purposeful limb movements]) and subcortical findings (such as parkinsonism, dystonia). Dementia, dysarthria, and eye movement abnormalities (saccadic breakdown of smooth pursuit and/or slowed saccades) may be present. Neuroimaging may reveal asymmetric parietal cortical atrophy (most pronounced contralateral to the affected limb) and PET may demonstrate asymmetric decreased cortical and basal ganglia metabolism. Treatment is supportive.
Dementia With Lewy Bodies
In dementia with Lewy bodies (DLB), parkinsonism (usually symmetric) is accompanied by dementia, hallucinations, and fluctuations in level of arousal/mental state. Unlike Parkinson’s disease dementia, in which the motor features of parkinsonism precede the development of dementia by years, in DLB, dementia and parkinsonism usually arise concurrently. (For further discussion of DLB, see “Dementia With Lewy bodies” in Ch. 22.)