Tremor

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Treatment Options for Parkinsons

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Tremor, although less specific than bradykinesia, is one of the most recognizable symptoms of PD. However, only half of all patients present with tremor as the initial manifestation of PD, and 15% never have tremor (45). Although tremor at rest (4-6 Hz) is the typical parkinsonian tremor, most patients also have tremor during activity, and this postural tremor (5-8 Hz) may be more disabling than the resting tremor. Postural tremor without parkinsonian features and without any other known etiology is often diagnosed as essential tremor (ET) (Table 2). However, isolated postural tremor clinically identical to ET may be the initial presentation of PD and may be found with higher-than-expected frequency in relatives of patients with PD (46,47). The two forms of postural tremors can be differentiated by a delay in the onset of tremor when arms assume an outstretched position. Although most patients with PD have a latency of a few seconds (up to a minute) before the tremor reemerges during postural holding, hence reemergent tremor, postural tremor of ET usually appears immediately after arms assume a horizontal posture (48). Since the reemer-gent tremor has similar frequency to that of rest tremor and both tremors generally respond to dopaminergic drugs, it is postulated that the reemergent tremor represents a variant of the more typical rest tremor. It has been postulated that the typical tremor at rest results from nigrostriatal degeneration and consequent disinhibition of the pacemaker cells in the thalamus (49). These thalamic neurons discharge rhythmically at 5 to 6 Hz, a frequency similar to the typical parkinsonian tremor at rest (50,51). Some support for the thalamic pacemaker theory of PD tremor also comes from the studies of Lee and Stein (52), which show that the resting 5 Hz tremor is remarkably constant and relatively resistant to resetting by mechanical perturbations. Furthermore, during stereotactic thalamotomy, 5 Hz discharges are usually recorded in the nucleus ventralis intermedius of the thalamus in parkinsonian subjects, even in the absence of visible tremor (53). This rhythmic bursting is not abolished by deafferentation or paralysis. Because the frequency (6 Hz) of the postural (action) tremor is the same as the frequency of the cogwheel phenomenon elicited

TABLE 2 Differential Diagnosis of Parkinsonian and Essential Tremor

Parkinsonian tremor

Essential tremor

Age at onset (years)

55-75

10-80

Sex

M > F

M < F

Family history

-

+

Site of involvement

Hands, legs, jaw, chin, tongue

Hands, head, voice

Characteristics

Supination-pronation

Flexion-extension

Influencing factors

Rest

T

i

Action

i

Î

Mental concentration,

T

i

walking

Frequency (Hz)

4-7

8-12

Electromyography

Alternating contractions

Simultaneous contractions

Associated features

Cogwheel rigidity (±)

Dystonia, Charcot-Marie-Tooth

disease

Neuropathology

Nigrostriatal degeneration,

No discernible pathology

Lewy bodies

Treatment

Anticholinergics, amantadine,

Alcohol, beta-blockers,

dopaminergic drugs

primidone, botulinum toxin

FIGURE 3 Parkinsonian cogwheel rigidity elicited by passive rotation of the wrist is enhanced by voluntary repetitive movement of the contralateral hand.

during passive movement, some authors have suggested that the postural tremor and cogwheel phenomenon have similar pathophysiologies (Fig. 3) (54).

The biochemical defect underlying either resting or postural parkinsonian tremor is unknown. Bernheimer et al. (55) showed that the severity of tremor paralleled the degree of homovanillic acid reduction in the pallidum. In contrast, bradyki-nesia correlated with dopamine depletion in the caudate nucleus. In an experimental monkey model of parkinsonian tremor, a pure lesion in the ascending dopaminer-gic nigrostriatal pathway is not sufficient to produce the alternating rest tremor (56). Experimental parkinsonian tremor requires nigrostriatal disconnection combined with a lesion involving the rubrotegmentospinal and the dentatorubrothalamic pathways. A typical PD tremor is observed in humans and animals exposed to MPTP, which presumably affects, rather selectively, the nigrostriatal dopaminergic system (57,58). However, the cerebellorubrothalamic system has not been examined in detail in this MPTP model. Furthermore, in MPTP subjects, a prominent action tremor was more typically seen than a tremor at rest.

In early studies, mechanical and optic devices were used to record tremor (59). EMG recordings and accelerometers, assisted by computer analysis, have been utilized to measure the characteristics of tremor. However, most accelerometers record tremor in a single plane. By using computed triaxial accelerometry, the distortion of the normal motion characteristics in patients with PD and ET during voluntary arm abduction-adduction movement was recorded (24). There was a good correlation between the reduction in the distortion and the clinical improvement in response to medications. However, the quantitative recordings of tremor, although accurate, are time-consuming, costly, and influenced by the emotional state of the patient. Moreover, it is questionable whether such recordings provide a reliable index of a meaningful therapeutic response.

RIGIDITY AND POSTURAL ABNORMALITIES

Rigidity is less variable than tremor, and it probably better reflects the patient's functional disability. Rigidity may contribute to subjective stiffness and tightness, a common complaint in patients with PD. However, there is relatively poor correlation between the sensory complaints experienced by most patients and the degree of rigidity (60,61). In mild cases, cogwheel rigidity can be brought out by a passive rotation of the wrist or flexion-extension of the forearm while the patient performs a repetitive voluntary movement in the contralateral arm (Fig. 3) (62). Rigidity may occur proximally (e.g., neck, shoulders, and hips) and distally (e.g., wrists and ankles). At times, it can cause discomfort and actual pain. Painful shoulder, probably due to rigidity but frequently misdiagnosed as arthritis, bursitis, or rotator cuff, is one of the most frequent initial manifestations of PD (63). Rigidity is often associated with postural deformity, resulting in flexed neck and trunk posture and flexed elbows and knees. Some patients develop ulnar deviation of hands (striatal hand), which can be confused with arthritis (64,65). Other skeletal abnormalities include neck flexion (dropped head or bent spine) (66) and truncal flexion (camp-tocormia) (Figs. 4 and 5) (67,68). Duvoisin and Marsden (69) studied 20 PD patients with scoliosis and found that 16 of the patients tilted away from the side with predominant parkinsonian symptoms but subsequent studies could not confirm this observation (70).

The neurophysiologic mechanisms of rigidity are poorly understood. Spinal monosynaptic reflexes are usually normal in PD. Recordings from muscle spindle afferents revealed an activity in rigid parkinsonian patients, not seen in normal controls. This suggested an increased fusimotor drive due to hyperactivity of both alpha and gamma motor neurons. However, this fusimotor overactivity probably is an epiphenomenon, reflecting the inability of PD patients to relax fully. Passive shortening of a rigid muscle, due to PD or seen in tense subjects, produces an involuntary contraction called the Westphal phenomenon. Although the mechanism of this sign

FIGURE 4 A 63-year-old woman with progressive scoliosis to the right side for 20 years and left hemiparkinsonism manifested by hand and leg tremor, rigidity, and bradykinesia. (A) Front view. (B) Back view.

FIGURE 5 A 44-year-old woman with Parkinson's disease showing typical dystonic ("striatal") hand with flexion at the metacarpophalengeal joints, extension at the proximal interphalangeal joints, and flexion of the distal interpha-langeal joints. The dystonia completely resolved with levodopa. Source: From Ref. 64.

FIGURE 5 A 44-year-old woman with Parkinson's disease showing typical dystonic ("striatal") hand with flexion at the metacarpophalengeal joints, extension at the proximal interphalangeal joints, and flexion of the distal interpha-langeal joints. The dystonia completely resolved with levodopa. Source: From Ref. 64.

is unknown, it probably is the result of excessive supraspinal drive on normal spinal mechanism. This shortening reaction may be abolished by procaine infiltration of the muscle. Thus, there is no convincing evidence of a primary defect of fusimotor function in parkinsonian rigidity (71).

The measurement of torque or resistance during passive flexion-extension movement has been used most extensively as an index of rigidity. It has been demonstrated that rigidity correlated with increased amplitude of the long-latency (transce-rebral) responses to sudden stretch. These long-latency stretch reflexes represent a positive (release) phenomenon, mediated by motor pathways that do not traverse the basal ganglia. The earlier techniques of passively flexing and extending the limbs were later refined by Mortimer and Webster (72), who designed a servo-controlled electronic device to move the limb at a constant angular velocity. They and others (73-75) demonstrated a close relationship between the enhanced long-latency stretch reflexes and the degree of activated rigidity. Using measurements of the tonic stretch reflex as an index of rigidity, Meyer and Adorjani (76) found an inverse correlation between the "dynamic sensitivity" (ratio between the increase in reflex EMG at a high vs. low angular velocity) and the severity of parkinsonian rigidity. In contrast, the "static" component of the tonic stretch reflex (the maximum reflex activity at greatest stretch or at sustained stretch) positively correlated with the severity of rigidity. Both the dynamic and the static components of the tonic stretch reflex may be reduced by antiparkinson drugs (76). Although Lee and Tatton (74) showed diminution of the amplitude of the reflex after treatment, correlating it with improvement in rigidity, the measurement of long-latency responses is quite cumbersome, time-consuming, and possibly unreliable (77). Moreover, a marked overlap in the long-latency response between PD and normal subjects has been noted (78).

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