The term parkinsonism has evolved over time to refer to the constellation of signs in the clinical entity described by James Parkinson in 1817 (1). The 3 cardinal signs include resting tremor, rigidity, and bradykinesia. However, there are no specific criteria for the use of this term. For instance, does the presence of any of the core features alone constitute parkinsonism? Or is a threshold of motor signs needed before a patient would be labeled as having parkinsonism?
Parkinson’s disease (PD), the most common cause of parkinsonism (2), has a more specific definition, with gradations of diagnostic certainty (3–5). The definitive diagnosis of PD requires autopsy; however more rigorous clinical diagnostic criteria have emerged over the last 2 decades (6). The motor signs of early PD are usually asymmetric, and symptomatic improvement with dopaminergic drugs is significant and sustained. Familial parkinsonism and familial PD are entities that may follow an autosomal dominant (with variable penetrance) or autosomal recessive pattern of inheritance.
Early nonspecific features
The early symptoms of PD may be nonspecific, such as fatigue, reduced energy, joint stiffness (especially of the Ali Samii shoulder), muscles cramps, or vague sensory disturbances. Unilateral limb dystonia, especially in the foot, may accompany the sensation of limb stiffness (7). Dragging of one foot or tripping after walking a distance even in the absence of dystonia may occur. The patient may take a longer time to perform daily activities. The eyes may feel dry, with a sensation of burning due to the reduced frequency of blinking.
There may be a feeling of internal (usually asymmetric) quivering before the emergence of visible resting tremor (8). Slower and more effortful handwriting, with smaller letters (micrographia) may occur. Typing on the computer keyboard may become slower, with more typographical errors. The patient may complain of hoarseness or a soft voice (hypophonia), especially after speaking for a while. Family members may notice an asymmetrically reduced arm swing in the patient during ambulation. Drooling is usually not an early feature of PD, but it can rarely occur early in the course of the disease.
Sleep disturbances are common in early PD, even before the emergence of motor symptoms. Rapid eye- movement (REM) sleep behavior disorder is a common manifestation. It is due to the loss of the normal muscle atonia during REM sleep and is characterized by excessive movements while dreaming. The acting out of dreams can be quite violent and even injurious to the patient or the bed partner. One study found that amongpatients with PD and REM sleep behavior disorder, more than half developed the disorder before motor symptoms were present (9). Others have suggested that REM sleep behavior disorder is actually part of the overall dopamine deficiency syndrome seen in PD (10). Periodic limb movements during sleep, a common complaint usually voiced by the bed partner, may further fragment sleep.
Restless legs syndrome (RLS) and a sense of inner restlessness (restless body syndrome) are common in early PD. The clinical syndrome of akathisia (Greek term meaning “inability to sit still”) has similarities to RLS. RLS responds well to dopaminergic therapy, and akathisia is frequently brought on by dopamine antagonists, again suggesting a shared neurotransmitter mechanism. The prevalence of RLS in the general population is nearly 10% (11), while its prevalence in PD patients has been reported to be as high 21%, about twice that in the general population (12). The relationship between brain iron and dopamine deficiency, RLS, and PD remains to be elucidated.
Further early nonmotor manifestations include constipation, seborrheic dermatitis, decreased perception of smell (hyposmia), and dysautonomia, including bladder dysfunction. Constipation is a common early complaint. One study questions whether constipation is part of early PD or whether it is so prevalent before the presence of motor symptoms that it may be a marker of susceptibility to develop PD (13). Constipation may also be exacerbated by drugs, both dopaminergic and anticholinergic agents, used to treat motor symptoms.
The perplexing association between seborrheic dermatitis and PD and its improvement with levodopa treatment has been established for decades (14). The exact mechanism for seborrheic dermatitis is unclear. It is an ill-defined condition characterized by chronic scaling of the skin on the head and trunk, where sebaceous glands are prominent. Theories of why it occurs in PD patients have ranged from increased sebum excretion, to slow emptying of the pilosebaceous canal reservoir, and even to the possibility that a common potential environmental agent may lead to both seborrheic dermatitis and PD (15).
Hyposmia occurs early in PD and may precede motor symptoms by many years. It is such a well-recognized feature of PD that some are proposing olfactory dysfunction as a risk factor for developing PD (16). Hyposmia is bilateral and unrelated to the side of initial motor signs or antiparkinson drug therapy (17). A recent study suggests that a combination of idiopathic REM sleep behavior disorder and olfactory dysfunction had a high correlation with the presence of clinical and neuroimaging signs of nigrostriatal dysfunction (18).
The most common bladder symptoms in early PD are urinary frequency, urgency, and urge incontinence. These symptoms generally correlate with the severity of detrusor hyperreflexia (i.e., excessive detrusor muscle contraction at early stages of bladder filling) as measured by urodynamic testing (19). Obstructive uropathy due to an enlarged prostate further exacerbates bladder symptoms in older men with PD. Erectile dysfunction in men is also extremely common in any stage of PD (20).
Although the presence of early severe dementia together with motor parkinsonism points to a diagnosis other than PD, subtle abnormalities in cognition and executive function are common in early PD. Change in personality, difficulty with concentration, slowed thinking (bradyphrenia), and mood changes—especially depression and anxiety—may be present in early PD (21). Visual perception, recognition deficits, impaired tasks of executive function, planning and working memory, and information processing may all be impaired (22, 23). There is evidence that these cognitive deficits in PD significantly influence quality-of-life measures (24).
Correlation between symptoms and pathologic stages of Parkinsons disease
Braak et al. have proposed that PD is a synucleinopathy with 6 neuropathologic stages (25, 26). It is believed that the pathologic changes in PD begin years before motor symptoms appear. Table 1 summarizes the 6 pathologic stages proposed by Braak and colleagues.
Table 1 Pathologic Stages of Parkinsons disease Proposed by Braak et al.
Stage 1 Medulla oblongata and olfactory bulb lesions in dorsal nucleus of cranial nerves IX and X, intermediate reticular formation, olfactory bulb, and anterior olfactory nucleus
Stage 2 Pontine tegmentum pathology of stage 1 plus lesions in caudal raphe nuclei, gigantocellular reticular nucleus, and ceruleus-subceruleus complex
Stage 3 Midbrain pathology of stage 2 plus lesions in pars compacta of substantia nigra
Stage 4 Basal prosencephalon and mesocortex pathology of stage 3 plus prosencephalic lesions, anteromedial temporal mesocortex, and allocortex (CA-2 plexus)
Stage 5 Neocortex pathology of stage 4 plus lesions in prefrontal cortex and sensory association neocortical areas
Stage 6 Neocortex pathology of stage 5 plus lesions in first-order sensory association areas, premotor cortex, and even primary sensory and motor cortices
Source: Adapted from Braak et al. (25, 26).
During the presymptomatic (with regard to motor symptoms) stages 1 to 2, inclusion-body pathology is confined to the medulla oblongata, the dorsal motor nucleus of the vagus nerve and the reticular formation, the pontine tegmentum, the olfactory bulb, and the anterior olfactory nucleus. In addition, the first Lewy body pathology appears in the locus ceruleus. These pathologic changes may explain hyposmia, early mild dysautonomia, and early mood/cognitive complaints.
In stages 3 to 4, the substantia nigra and the basal portions of the midbrain and forebrain are involved. The pars compacta of the substantia nigra, where the dopaminergic neurons of the nigrostriatal pathway are located, are clearly involved by these stages. Other brain regions that show pathologic change include the cholinergic tegmental pedunculopontine nucleus, raphe nuclei, cholinergic magnocellular nuclei of the basal forebrain, and hypothalamic tuberomamillary nucleus. Braak hypothesizes that by stages 3 to 4, patients cross the threshold to manifest the motor symptoms of PD (26). Motor, cognitive, and autonomic complaints at these stages may be explicable by the underlying pathology.
In stages 5 to 6, the neurodegenerative process is widespread and involves much of the neocortex. The previously described pathologic changes in other regions are more pronounced and inclusion-body pathology is now present in the prefrontal and association cortices and even in primary neocortical areas. Therefore the damage to the autonomic, limbic, and somatomotor system that began in stages 1 to 2 is now compounded by the neocortical pathology. In advanced PD, motor symptoms are more severe and dysautonomia and cognitive impairment more pronounced, correlating with the widespread pathologic changes.
Cardinal motor features of early Parkinsons disease
Tremor is the most common presenting sign of early PD (27). Approximately 70% of patients notice tremor as the first symptom (28). Onset of tremor is usually in one hand; it may later involve the contralateral upper limb or ipsilateral lower limb. Typically, the tremor is a 3- to 5-Hz rhythmic “pill-rolling” movement of the thumb and index finger while the hand is at rest. There may be abduction and adduction of the thumb or flexion and extension of the wrist or of the metacarpophalangeal joints. The tremor may also extend to the forearm with pronation/ supination or even to the elbow and upper arm.
During early disease, tremor is often intermittent and is evident only under stress. Tremor is worsened by anxiety, fatigue, and sleep deprivation. It diminishes with voluntary activity but may reappear with static posture (e.g., outstretched hands) and is absent during sleep. Resting tremor is enhanced by mental task performance, such as “serial 7” subtractions, and by motor task performance in a different body part. The hand tremor may also be enhanced during ambulation. Compared with essential tremor, the resting tremor of PD is generally less likely to be exacerbated by caffeine or improved with alcohol.
The jaw, tongue, head, and trunk are rarely affected by tremor in PD, although the resting tremor in the arm can be so severe as to be “transmitted” to the trunk and head. Tremor limited to the head/neck is more likely a sign of essential tremor rather than of PD. Resting tremor in the ankles or the thighs may be seen only when the patient is supine or keeps the legs in a certain position. Lower limb resting tremor may be exacerbated by motor activity in the upper limbs, but it usually disappears with ambulation.
The mechanism of parkinsonian resting tremor is unknown but is thought to be due unmasking of a pathologic central oscillator at 3 to 5 Hz (29). The anatomic basis for resting tremor is likely different from the suspected classic neuropathology of PD (i.e., nigrostriatal degeneration). Functional neuroimaging of this pathway with positron emission tomography (PET) shows better neuroimaging correlation with bradykinesia and rigidity than with tremor (30). In addition, as in the case of essential tremor, lesioning of the ventral intermediate nucleus of the thalamus (a cerebellar relay nucleus) alleviates parkinsonian resting tremor (31). The exact mechanism by which pallidotomy, pallidal stimulation, or subthalamic stimulation improves resting tremor, in addition to improving rigidity and bradykinesia, is unclear.
Rigidity is an increased resistance to passive stretch (29). This resistance is nearly equal in both agonist and antagonist muscles and generally uniform throughout the range of motion of the joint being tested. It may be sustained (plastic or “lead pipe”) or intermittent and ratchetty (“cogwheel”). Although cogwheel rigidity is usually thought to be parkinsonian rigidity complicated by parkinsonian tremor, it may occur in the absence of tremor, and the frequency felt by the examiner tends to be higher than that of the visible resting tremor.
Rigidity is only one form of increased tone; it should be differentiated from spasticity, paratonia, pain-related guarding of the joints in arthritic patients, and even a cogwheel phenomenon seen in essential tremor. Spasticity is velocity-dependent (“clasp-knife”) and is associated with upper motor neuron signs such as pathologic hypereflexia, Babinski signs, and pyramidal distribution weakness. Gegenhalten or paratonic stiffness as seen in dementia is characterized by a resistance to passive movement proportional to the force applied by the examiner. Joint pain in the setting of arthritis can lead to local muscle spasm and guarding and cause increased tone (32). The cogwheel phenomenon may also be seen in severe essential tremor due to the interruption of passive movement by coarse tremor, especially if the patient fails to relax completely.
Rigidity is usually asymmetric in early PD. It is commonly present at one or both wrists and in the neck. Rigidity may also manifest as a slightly flexed elbow on the more affected side in early disease. Rigidity (and bradykinesia) may even lead to tendon contractures with limited joint range of motion despite dopaminergic therapy. Shoulder rigidity may predispose the patient to develop a frozen shoulder syndrome and early arthritis (33). As the disease progresses, the characteristic stooped posture is manifest, likely in part due to severe rigidity of the flexor musculature of the cervical and thoracic spine (34).
The pathogenesis of rigidity in PD is multifactorial, related to abnormal long-latency reflexes, abnormal background muscle contraction, and even changes in muscle and joint characteristics (29). As opposed to the monosynaptic spinal cord reflexes, long-latency stretch reflexes are mediated by a loop through the sensorimotor cortices, and their enhancement is likely related to abnormal excitability of this central loop (35). The overactivity in the dorsal premotor cortex in PD patients, as measured by transcranial magnetic stimulation (36), helps support the hypothesis that this is a contributor to rigidity.
Assessment of rigidity can be challenging and remains largely qualitative as judged by the examiner (37). Rigidity at the wrist is optimally assessed by passive movements of 30 degrees around the midposition with angular velocities of 140 to -190 degrees per second (38). Repeated tone examinations in both the sitting and lying positions may be necessary, as the PD patient does not relax well and there is slight muscle contraction at rest (29). Rigidity may be brought out or enhanced with contralateral motor activity (e.g., examining wrist tone while the patient does finger tapping with the other hand). Quantitative measurements of rigidity are difficult, but responses measured by controlled stretches may be accomplished by torque motors with good clinical correlation (39).
Although resting tremor may be the most visible sign of PD, bradykinesia is usually its most disabling component. Bradykinesia describes slowness of voluntary movements and poverty of normal associated movements; akinesia is an extension of bradykinesia implying nearly absent voluntary movement (40). There may be 2 reasons for akinesia: either the movement is too small to be seen or the time to generate movement is extremely long, so that the movement never really occurs. Using this distinction between bradykinesia and akinesia, reaction-time experiments can help evaluate both bradykinesia (through prolongation of movement time) and akinesia (through prolongation of reaction time).
Bradykinesia can be present as an early sign in different body parts. In the eyes it presents with saccadic hypometria (41) and in the face with reduced frequency of blinking and diminished facial animation. Hypophonia is likely a symptom of bradykinesia of the respiratory and the vocal cord muscles (42). In examining the patient for hypophonia, the patient is asked to say the months of the year loudly and clearly. In early PD, the voice lacks the natural fluctuations of volume and pitch and tends to fatigue quickly. In later stages there is slow initiation of speech, which becomes progressively softer (sometimes down to a whisper) and more monotonous. In early PD, dysarthria is usually absent, but it is a common problem in later stages. New-onset of stuttering or reemergence of childhood stuttering may be an early sign of PD (43).
Bradykinesia and rigidity are usually asymmetrically present in the same limb in early PD. Initially bradykinesia may be confined to the distal muscles of the hand, manifesting itself as micrographia (if the dominant hand is involved first) or slow finger tapping and impaired performance on fine motor tasks. Micrographia is best brought out by asking the patient to write continuously in cursive letters without resting or taking the pen off the paper. The proximal limb and truncal muscles tend to be involved later in the disease, but if one considers reduced arm swing to be a sign of bradykinesia, this can certainly be an early presenting sign. Before assessing bradykinesia, the examiner must exclude local arthritic pain, corticospinal tract or cerebellar signs, impaired cardiopulmonary reserve, and auditory, visual, or cognitive disturbances that may affect the patient’s comprehension or performance of the motor tasks.
Limb bradykinesia, as measured by the motor part of the Unified Parkinson Disease Rating Scale (44), is rated by having the patient tap the index finger to the thumb repeatedly, do alternating pronation/supination of the forearm, close the hand into a fist and open it sequentially, and tap the sole of the foot rhythmically to the floor while seated by lifting the foot about 10 cm each time. It is important that the patient perform these tasks for a long enough time (at least 15 seconds) per side to allow for motor fatigue to become apparent. The examiner should pay attention to the speed, amplitude, and the rhythmicity of the movements and how they change over the period during which the task is being performed.
Generalized bradykinesia is rated by the overall slowing of all body parts, including an evaluation of how easily the patient stands from a seated position with or without pushing off the arm rests and of the patient’s speed of ambulation.
More quantitative objective measures of limb bradykinesia in PD have been used. One of the simplest and most accurate tests is performance on the Purdue pegboard (45). The patient is asked to insert pegs in the holes on the pegboard, first with each hand separately and then with both at once, over a specified period of time. In a comparison between tapping on a contact board with a contact pencil and the insertion of pegs, both tasks proved to be useful tools for the objective evaluation of bradykinesia in PD, but peg insertion correlated better with disease severity (46). The superiority of the pegboard test over a tapping task as a marker of bradykinesia in PD was confirmed (47). Bradykinesia is correlated with nigrostriatal neuroimaging (30). Similarly, the Purdue pegboard score also correlates with nigrostriatal dysfunction measured by PET (48). Rapid alternate tapping with the index and middle fingers on two adjacent keys of a computerized electronic drum with simultaneous contralateral hand activation also showed significant correlation with fluorodopa PET scans (49).
The exact mechanism underlying bradykinesia is unclear (29), but it is thought to be related to decreased cortical activation due to impaired function in the basal ganglia–thalamocortical circuitry (50). Bradykinesia results from a failure of the basal ganglia’s output to reinforce the cortical mechanisms that prepare and execute the commands to move (51). Impairment of both motor cortex activation and deactivation measured by transcranial magnetic stimulation is an early feature of PD and may be a physiologic correlate of bradykinesia (52). Other human evidence supporting decreased cortical activation includes somatosensory evoked potential studies (53) and movement-related cortical potentials looking at the Bereitschaftspotential, which is a slow-rising negativity before self-paced voluntary movements (54). In addition, cerebral blood flow studies using PET show abnormal cortical blood flow in PD, which is normalized by stimulation of the subthalamic nucleus (55).
Postural Instability and Gait Disturbance
Although postural instability is included as one of the 4 motor signs of PD (56), only resting tremor, rigidity, and bradykinesia are considered to be the 3 cardinal features (57). Significant impairment of postural reflexes is rare in early PD and usually occurs about 5 years after the onset of the disease (58). In fact, the presence of severe early postural instability points to a diagnosis other than PD. Nevertheless, gait disturbance and mild postural instability can be present in early PD, especially in patients with an older age of onset (59).
In early PD, the posture may show a slight flexion of the neck or trunk with a slight lean to one side. Abnormalities of gait may include asymmetrically reduced arm swing, overall slowing of gait and early fatigue, shortened stride length and intermittent shuffle, or tripping over objects, sometimes in association with ankle dystonia and the inability to turn quickly. As the disease progresses, gait initiation becomes a problem, the steps become shorter and more uncertain, and there is festination. Fear of falling further contributes to a progressively hesitant gait (60). Freezing refers to difficulty initiating gait or stoppage of gait when turning or arriving at a real or perceived obstacle (61). Freezing is usually absent in early PD.
The mechanisms underlying postural instability and the gait disturbance are likely multifactorial (62). Many contributors to gait and balance problems—such as arthritic pain, sensory neuropathy, and visual problems— may have nothing to do with PD itself. Clinical tests for the evaluation of postural instability in patients with PD are numerous, but the most valid simple clinical test is an unexpected shoulder pull from behind (63). The patient is asked to stand with eyes open and feet comfortably apart and instructed to resist falling by taking one step back using either foot when necessary. This “pull test” should be performed by the examiner with a moderate pull consistently each time, while being prepared to catch the patient from behind if necessary and counting the number of steps taken by the patient to maintain balance (64). The pull test is usually normal in early PD, with no more that one step backward needed to recover. The timed “up and go” test is a simple and reliable timed ambulation test. The patient is timed and the number of steps counted while he or she rises from an armchair, walks 3 to 6 meters (10 to 20 feet), turns, walks back, and sits down again (65). The total number of steps counted should include all the steps needed to make a 180-degree U-turn.
The differential diagnosis of Parkinsons disease
The clinical diagnosis of PD relies heavily on history, neurologic examination, and improvement of motor signs with dopaminergic therapy (6). The differential diagnosis of parkinsonian syndromes is extensive (66, 67). It includes normal aging, essential tremor, drug-induced parkinsonism, the Parkinson-plus syndromes (progressive supranuclear palsy, corticobasal degeneration, the multiple-system atrophies, and dementia with Lewy bodies), vascular parkinsonism, normal-pressure hydrocephalus, and other less common diseases (68). Attention to distinct patterns of symptoms and signs and the time course of the disease can help to improve diagnostic accuracy (69).
There is little agreement on a definition of normal aging (70). Slowness of movement, stooped posture, stiffness, and postural instability are common in the elderly (71). Comorbid conditions such as arthritis can also contribute to reduced mobility and stiffness. Asymmetric motor signs and a more accelerated rate of symptom progression are more suggestive of PD. If the level of suspicion for PD is high enough, a trial of levodopa may be the only way to establish significant and sustained response to dopaminergic therapy and hence the clinical diagnosis of PD.
Essential tremor is characterized by action tremor rather than resting tremor (72). It tends to be bilateral but is frequently asymmetric; in half the cases, there is a family history. The frequency (8 Hz) of essential tremor is higher than that of PD, but it decreases with age. In severe cases, essential tremor may seem to be present at rest, making it difficult to differentiate from the tremor seen in PD. The presence of rigidity, bradykinesia, and response to dopaminergic therapy helps differentiate PD from essential tremor. However, some PD patients have a postural rather than a rest tremor or both postural and rest tremor, and some with long-standing essential tremor may develop parkinsonism (73).
Drug-induced parkinsonism usually occurs after exposure to neuroleptics. Antiemetic and promotility agents (e.g., promethazine, prochlorperazine, metoclopramide, and droperidol) (74), reserpine (75), tetrabenazine (76), and even some calcium channel blockers (e.g., flunarizine and cinnarizine) (77) can cause parkinsonism. The symptoms are symmetric, and drug-induced parkinsonism resolves when the offending drug is stopped, although resolution may require weeks to months.
Progressive Supranuclear Palsy
Progressive supranuclear palsy (PSP) is a rapidly progressive degenerative disease belonging to the family of tauopathies, with widespread pathology involving cortical and subcortical structures (78). In PSP, oculomotor disturbance, early postural instability with falls, and frontal dementia predominate. There is symmetric onset of parkinsonism, early postural instability, severe axial rigidity, absence of tremor, and poor response to dopaminergic therapy. Supranuclear gaze palsy, especially of downgaze, is the defining characteristic. Blepharospasm and eyelid opening apraxia are also common (79).
Corticobasal degeneration (CBD) usually manifests with markedly asymmetric parkinsonism and cortical signs (80). There is asymmetric limb dystonia and limb apraxia as well as corticospinal tract signs and earlier dementia than in PD. Cortical myoclonus, early oculomotor and eyelid abnormalities, cortical sensory signs (e.g., agraphesthesia), and the alien limb phenomenon may be present. There is poor response to dopaminergic medications. The variability of presentation of pathologically proven CBD is wide; for example, it can present as a primary frontotemporal dementing illness that can mimic the dementia seen in other neurodegenerative diseases (81).
Multiple-system atrophy (MSA) is a current term lumping together the previously split entities of olivopontocerebellar atrophy (OPCA), Shy-Drager syndrome, and striatonigral degeneration (82). MSA presents with parkinsonism as well as cerebellar, autonomic (orthostatic hypotension, bladder and bowel dysfunction, temperature dysregulation), and pyramidal dysfunction in various combinations (83, 84). MSA-P (formerly striatonigral degeneration) is characterized by symmetric parkinsonism without tremor and early postural instability. MSA-C (formerly OPCA) manifests itself with cerebellar signs and parkinsonism. Corticospinal tract signs and respiratory stridor may be seen in all types of MSA. There is no significant motor improvement with dopaminergic therapy. In fact, the severity of orthostatic hypotension often prevents an adequate trial of dopaminergic drugs.
Dementia with Lewy Bodies
Whether dementia with Lewy bodies (DLB) exists as a distinct clinical entity is controversial. The usual description of DLB indicates that it is characterized by progressive parkinsonism and early dementia. DLB is the second most common cause of neurodegenerative dementia in older people (85). Some estimates suggest that up to 30% of dementias may be due to DLB (86). The current consensus is to restrict a diagnosis of DLB to patients with parkinsonism who develop dementia before or within 12 months of the onset of motor symptoms (87). In DLB, there is minimal or no resting tremor. Early cognitive and psychiatric problems are present. Fluctuating cognition and level of interaction, early recurrent and well-formed hallucinations, REM behavior sleep disorder, and psychosis may be present even prior to dopaminergic therapy. Motor symptoms do not improve and psychiatric symptoms are exacerbated by small doses of dopaminergic medications.
Vascular parkinsonism is due to multiple infarcts in the basal ganglia and the subcortical white matter (88). Since there are no specific diagnostic criteria, true incidence and prevalence rates of vascular parkinsonism are not known, but some estimates suggest that this condition may account for up to 12% of all cases of parkinsonism (89). In vascular parkinsonism, the motor signs are symmetric, affecting the lower limbs more than the upper limbs, so-called lower-body parkinsonism. Gait difficulty is a common presentation. Resting tremor is usually absent. Dementia, pseudobulbar affect, urinary symptoms, and pyramidal signs frequently accompany vascular parkinsonism. There is no therapeutic response to dopaminergic therapy. Brain imaging reveals extensive small vessel disease in the basal ganglia and the subcortical white matter. Microvascular lesions are commonly seen on magnetic resonance imaging (MRI) in the older population, and PD patients are no exception. Therefore the mere presence of these lesions on imaging does not necessarily imply vascular parkinsonism.
Normal-pressure hydrocephalus (NPH) refers to chronic, communicating adult-onset hydrocephalus. Gait disturbance, urinary incontinence, and cognitive impairment make up the clinical triad of NPH without other signs of raised intracranial pressure (e.g., papilledema). NPH has been the subject of an intensive advertising campaign (90) that has raised patients’ concern about whether their parkinsonism is caused by this problem. Hydrocephalus can present with motor signs similar to those seen in vascular parkinsonism. It is hypothesized that the close proximity of the basal ganglia and their connections to the ventricular system may predispose them to mass effect or ischemic injury in the setting of ventriculomegaly (91). The gait disturbance of NPH does not respond to dopaminergic therapy or to external cues, while both are quite effective in improving gait and stride length in PD (92).
Neuroimaging in the diagnosis of early Parkinsons disease
PD is a clinical diagnosis; in typical cases, no laboratory test or neuroimaging is necessary. However, when the history or clinical findings are atypical, MRI may be helpful. Over the last 2 decades, functional neuroimaging of the nigrostriatal dopaminergic pathway with PET and single photon emission computed tomography (SPECT) has been refined as a tool in quantifying functional dopaminergic terminals in the striatum (93, 94).
Functional neuroimaging is still used only experimentally and not for the routine diagnosis of early PD or assessment of disease progression. Both SPECT and PET have been used in therapeutic trials that include disease progression as an outcome measure (95, 96). However, drug-induced changes in radiotracer binding might undermine the reliability of imaging studies of disease progression (97). For this reason, there is much controversy about the interpretation of the neuroimaging findings of those trials (98).
The 3 cardinal features of early PD are resting tremor, rigidity, and bradykinesia. Table 2 summarizes proposed diagnostic criteria for clinically possible, clinically probable, and clinically definite PD as well as the exclusionary criteria (68).
Table 2 Clinical Criteria for the Diagnosis or Exclusion of Parkinson Disease
1. Diagnostic Criteria
Clinically possible PD
One of the following: asymmetric resting tremor, asymmetric rigidity, or asymmetric bradykinesia
Clinically probable PD
Any 2 of the following: asymmetric resting tremor, asymmetric rigidity, or asymmetric bradykinesia
Clinically definite PD
Criteria for clinically probable PD
Definitive response to antiparkinsonian medications
2. Exclusionary criteria
Exposure to drugs that can cause parkinsonism, such as neuroleptics, some antiemetic medications, tetrabena zine, reserpine, flunarizine, and cinnarizine
Corticospinal tract signs
Eye movement abnormalities other than a slight limitation of upward gaze
Early moderate to severe gait disturbance or dementia
Evidence of severe subcortical white matter disease, hydrocephalus, or other structural lesions on MRI that may explain parkinsonian symptomatology
Source: Adapted from Samii et al. (68).
Postural instability is a rare occurrence in early PD and is less specific than the other 3 signs. Asymmetry of motor symptoms and signs is the rule rather that the exception in PD. However, asymmetry may be absent or may not be uniform for the different motor signs (e.g., in the same patient, tremor may be worse on one side and bradykinesia and rigidity worse on the other) (99). Exposure to drugs that can cause parkinsonism, cerebellar or corticospinal tract signs, oculomotor abnormalities other than slight limitation of upward gaze, severe dysautonomia, early moderate to severe gait disturbance or dementia, severe subcortical white matter disease, and hydrocephalus should point to a diagnosis other than PD. The heterogeneity in early clinical signs and subsequent disease progression has led some to divide PD into various subtypes depending on age of onset, tremor predominance, and rate of progression (100). Parkinson’s disease remains a clinical diagnosis based on its phenotype (101); there is no confirmatory diagnostic test. At present, functional neuroimaging of the nigrostriatal pathway with PET and SPECT are not unequivocal markers of disease progression in PD.
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