Benserazide

ABSTRACT

Dopamine replacement, with levo-dopa, is the mainstay of pharmacologic treatment of Parkinson disease (PD). Although the benefits of dopamine replacement on clinical rating scales are well documented, many physical therapists may not be aware of the specific effects of levo-dopa on the cardinal motor impairments in persons with PD. This paper reviews the positive and negative motor effects of dopamine replacement and discusses the implications for physical therapy practice. Through an increased understanding of the motor effects of dopamine replacement, physical therapists will have an improved ability to distinguish between the basic pathophysiology of PD, the complications of dopamine replacement, and how rehabilitation interventions may be affected by these factors.

INTRODUCTION

In I960, studies of cadaver brains of individuals with extrapyramidal movement disorders suggested that the loss of dopamine in a portion of the basal ganglia was characteristic for persons with Parkinson disease (PD).1,2 This neuroanatomic finding led to experimentation with dopamine replacement as a means of treating persons with PD. Although dopamine was determined to be the neurotransmitter that is deficient in the basal ganglia in those with PD, dopamine did not cross the blood-brain-barrier and therefore was ineffective at improving the cardinal signs associated with PD (the motor impairments of bradykinesia, tremor, rigidity, and postural instability). However, the utility of the dopamine precursor Levo-dopa (L-dopa) was studied and found to be effective.3

Levo-dopa (L-dopa), an amino acid that is a short-lived metabolite in the pathway that produces dopamine, had the advantage that it crossed the blood-brain barrier and then underwent enzymatic conversion to dopamine.4 Levo-dopa eventually came into widespread use after 1967 when dramatic improvements were noted in motor functions following oral ingestion.5-8 At present, L-dopa is available as an oral medication that is coupled with a dopamine decarboxylase inhibitor (carbidopa or benserazide) to minimize metabolism outside of the central nervous system. It is available in the United States under the trade name Sinemet(R) (manufactured by Merck & Co. Inc., Whitehouse Station, NJ, USA; marketed by Bristol-Meyers Squib Co., Princeton, NJ, USA) and outside the United States as Madopar(R) (F. Hoffmann-La Roche Ltd., Switzerland) (Table 1). While contemporary treatment of PD includes a variety of pharmacologic treatments (eg, dopamine agonists, Catechol-O-Methyl Transferase inhibitors), nonpharmacologic treatments (eg, rehabilitation interventions), and surgical interventions (eg, pallidotomy, deep brain stimulation), at this time, dopamine replacement with L-dopa remains the most effective and "widely used treatment.9-11

Because of the dramatic benefit of dopamine replacement on the clinical movement abilities of persons with PD, many physical therapists do not have the opportunity to see their clients in an off-medication state. This limited observation hinders the ability of the clinician to distinguish between the basic pathophysiology of PD and the motor effects (positive and negative) of dopamine replacement. In addition, although the positive effects of dopamine replacement are well documented (particularly with clinical rating scales), it is not a benign medication. In the majority of cases, long-term dopamine replacement therapy is eventually associated with motor response complications which may limit its clinical utility.

For this reason, the purposes of this article are: (1) to review the positive and negative motor effects of dopamine replacement on PD movement impairments and select movement tasks, (2) to review the epidemiology and pathophysiology of motor complications associated with dopamine replacement, and (3) to discuss the implications of dopamine replacement for physical therapy practice.

POSITIVE EFFECTS OF DOPAMINE REPLACEMENT ON PD PRIMARY MOVEMENT IMPAIRMENTS

Many studies describe the benefits of dopaminergic replacement in terms of outcomes on clinical rating scales (eg, Unified Parkinson's Disease Rating Scale [UPDRS], Columbia University Rating Scale [CURS], Webster Scale).4 While ordinal measurements such as the UDPRS are able to detect improvement in general observable function, they are unable to detect the underlying pathophysiologic mechanisms or specific physiologic deficits associated with bradykinesia, tremor, rigidity, and postural instability.12 Analysis of the literature regarding specific effects of dopamine replacement on more sensitive measures of the cardinal movement impairments of PD provides greater insight into the pathology of the movement deficits and the relative contribution of dopaminergic supplementation within the basal ganglia.12,13

Bradykinesia

Berardelli et al, in a recent review, define bradykinesia as encompassing all problems of slowness or absence of movement.14 Consistent with this view of bradykinesia, this review of the effects of dopamine replacement will include the direct measurement of movement velocity, the theorized primary cause of bradykinesia (insufficient recruitment of muscle force), and the theorized secondary contributors to bradykinesia (tremor, rigidity, and agonist muscle weakness).

Movement Velocity

There is strong agreement in the literature, in a variety of movement tasks, that dopamine replacement results in substantial increases in overall movement velocity as compared to the off medication state. Examinations of upper extremity movements (reaching, cyclical wrist movements) and gait illustrate these findings (Table 2). Taken together, the variables that improve after dopamine replacement appear to be more related to force control (eg, amount of movement) than to rhythmic temporal control (eg, cycle time, cadence).15-34

Volitional Electromyographic Activity of Agonist Muscles

Although not described as a classic motor impairment of PD, recent studies have suggested that agonist volitional electromyographic (EMG) activity is consistently impaired in persons with PD. The normal EMG pattern seen during ballistic uniarticular upper extremity (UE) movement is a triphasic agonist-antagonist-agonist pattern. In persons with PD, a uniform pathologic EMG finding associated with PD is under-recruitment of the initial agonist muscles of this triphasic pattern.15 Because of this under-recruitment, there is a need for multiple agonist bursts to complete a desired movement. Consistent findings, presented in Table 3, from multiple researchers demonstrate increased recruitment of the initial agonist EMG amplitude following dopamine replacement.15,19,21,23,24,26,27,33-35

However, the literature is less clear regarding the effects of dopamine replacement on the temporal aspects of EMG activity (burst duration, multiple agonist bursts). A recent study by Robichaud et al, examined both magnitude and temporal EMG factors during ballistic elbow movement and demonstrated dopamine replacement effects primarily isolated to the magnitude of EMG.33 Taken together, the research suggests that although dopamine replacement improves the magnitude of the initial agonist EMG burst, there appears to be little effect of dopamine replacement on temporal aspects (burst duration, multiple agonist bursts, timing of antagonist bursts) of EMG control. Therefore, dopamine replacement may preferentially affect only one of the determinants of force generation during ballistic arm movements and therefore is limited in its ability to improve muscle activation in persons with PD33 (Table 3).

Muscle Strength

Persons with PD consistently demonstrate muscle weakness as compared to individuals without the disease. The etiology of these strength deficits may arise in part via inactivity related atrophy, however, it appears dopamine deficiency may also play a role.24,36-39 Strength measurements performed on and off medication demonstrate the positive effect of dopamine replacement on peak torque production. The observed increases in strength are consistently noted despite differences in muscles tested (distal and proximal extremity muscles), and contraction types (isometric and concentric/eccentric isokinetic)24,40-41 (Table 3).

When considered together, the research regarding dopamine replacement on EMG and muscle strength suggests that increased EMG amplitude contributes to improved muscle strength. However, it should be noted that there is an incomplete understanding of how subtle changes in EMG relate to force output and measures of muscle strength.

Tremor

The clinical presentation of tremor in PD is not consistent; however, a resting tremor has been described as the classical form. Additional variants consistently described include action and postural tremor.42 Studies examining the effects of dopamine replacement on tremor overall have described a 50% reduction in tremor amplitude.42,43 In addition, one recent study describes a reduction in the EMG correlates of lower extremity (LE) tremor during static standing on a forceplate as a result of dopamine replacement.44 Although these studies support the effectiveness of dopamine replacement in reduction of tremor, Koller noted varied responses in his sample of participants.43 Some individuals demonstrated little or no response to dopamine replacement and better responses to other medications (eg, anticholinergics). Such findings suggest that tremor associated with PD may have multiple etiologies with contributions from dopaminergic and nondopaminergic pathways.42 Based on these results, the clinically observed response of tremor to dopamine replacement should be expected to vary between individuals.

Rigidity

Alterations in resting muscle tone have been described as one of the characteristic motor impairments of PD. Parkinsonian rigidity is mediated in part by transcortical mechanisms that cause an alteration in the long latency stretch reflex and central reflex gain.45 In addition, rigidity (as a hypertonic state) has been theorized to have contributions from passive connective tissue components.46

Studies examining static standing as well as responses to stretch during wrist movements consistently describe reductions in tonic EMG activity as a result of dopamine replacement. Burleigh et al and Horak et al both note dopamine replacement mediated reductions in the background amplitude of EMG during static standing that were more pronounced in distal lower extremity musculature (Gastrocnemius/Soleus and Tibialis Anterior).44,47 During reciprocating wrist flexion-extension movements, Johnson et al report dopamine replacement induced reductions in reflex EMG responses elicited by unexpected stretches.26,27,48 Such findings suggest that the active muscle contribution to rigidity is diminished by dopamine replacement. An acute effect of dopamine replacement on the passive elastic contributions to rigidity is unlikely but is unknown at this time.

Performance of Functional Tasks

Although the study of simple motor tasks may provide insight into the pathophysiology of individual cardinal motor impairments, the results may not accurately reflect the level of disability observed in persons with PD.49 In contrast, examination of tasks which require complex coordination of movement components (proximal and distal limb movements, bimanual coordination, postural and volitional movement components) may be more relevant to performance in daily life.49 In addition to the classic motor impairments associated with PD, there are reports of selective disruption of sequential voluntary movements in persons with PD.49-56

Results from research about a variety of motor tasks (two joint unilateral UE movements, bimanual distal UE fine motor tasks, combined postural/locomotor/UE lifting tasks) suggest that restoration of the capacity for overlap and simultaneous production of motor sequences following dopamine replacement is in part a product of dopaminergic pathways.49-56

One specific research paradigm that is illustrative of the effect of dopamine replacement on functional task performance is the Postural-Locomotor-Manual (PLM) test. In this paradigm, participants are asked to pick up a box from the ground (postural phase), walk forward while carrying the box (locomotor phase), and then place the box on a shelf at chin height (manual phase). Individuals without PD coordinate this test with simultaneous organization; that is with significant overlap between the task phases. Persons with PD during this test characteristically demonstrate more distinct sequencing (as opposed to simultaneous) performance of the components of the test compared to persons without PD. In persons with PD performing the PLM task, dopamine replacement results in a reduction of overall movement time, and a return to simultaneous rather than sequential organization of the three task components 49,53-56 (Figure 1). In summary, improvement of performance on functional movement tasks, such as the PLM task, is suggestive of dopamine replacement mediated enhancement of concurrent performance of movement tasks. Researchers examining this issue suggest that such improvements may reflect improvements in motor planning.51,52,54,55,57

NEGATIVE EFFECTS OF DOPAMINE REPLACEMENT ON MOVEMENT TASKS

Despite its widespread use and effectiveness, dopamine replacement treatment can cause significant adverse effects. Most clinicians are aware of chronic motor response complications (MRCs) such as dyskinesias and on-off phenomena; however, recent motor control studies have identified less well known acute negative motor effects of dopamine replacement that occur during the on-medication period.

Acute Negative Effects of Dopamine Replacement

The acute negative effects discussed here include production of excessive forces and increased movement errors, dopamine replacement related motor deterioration, and reactive postural control effects. First, during fingertip precision grip tasks, persons with PD on L-dopa display excessive production of manipulative forces that were not present prior to dopamine replacement.58-61 In addition, several studies have reported increased movement error in UE movement tasks as a result of dopamine replacement.26,62

Second, during on-medication periods, carefully observed persons with PD may demonstrate a transient deterioration of motor function prior to or following positive motor effects and before return to baseline motor function. The acute effects of dopamine replacement have been observed in UE (tapping, wrist movements), LE tasks (gait), and on clinical ratings (Webster scale) and therefore do not appear to be task specific.13,63,64 The etiology of these acute effects is unclear; however, researchers have speculated that these effects may reflect the inhibitory effects of dopamine on some aspects of basal ganglia function.63-65

Lastly, studies of postural control in persons with PD identify the presence of an additional potential negative effect of dopamine replacement.47,66 While force production and coordination of anticipatory postural tasks have been shown to improve in response to dopamine replacement,47,66 control of the center of mass (COM) during reactive postural control tasks is adversely affected. Specifically, dopamine replacement diminished distal LE background postural tone and lowered the magnitude of reactive EMG bursts in response to support surface displacements. These consequences reflected acute negative effects of dopamine replacement in the sense that they reduced the ability of the person with PD to resist external displacements of their COM.47,66 (For more detailed reading on this topic, the reader is referred to Frank et al, 2000 and Horak et al, 1996.)

These acute negative effects represent consequences of dopamine replacement not commonly recognized by physical therapists. There is a significant need for additional research in this area to confirm these findings and document their incidence and prevalence. Regardless, taken together, it appears that some factors that have previously been considered PD-mediated motor control problems are in fact related to dopamine replacement therapy.

Chronic Effects of Dopamine Replacement

The composite effects of disease progression and dopamine replacement eventually may limit the clinical utility of L-dopa in many individuals. The most common types of movement related complications (MRCs) are dyskinesias and motor fluctuations (wearing-off and on-off phenomena).

Dyskinesias are dynamic involuntary movements that are classically choreo-athetotic in nature. However, many reports in the literature include peak dose, biphasic, and square wave dyskinesias, and off-period dystonia in their overall descriptions of dyskinesias. The functional impact of dyskinesias can vary from negligible to completely disabling.67 A thorough discussion of the phenomenology of dyskinesias and other motor flucuations is beyond the scope of this review. For additional information, the reader is referred to recent journal supplements dealing specifically with dyskinesias (Movement Disorders, 1999; Annals of Neurology, 2000).

Depending on the sensitivity of the observational criteria and the operational definitions used, MRCs have been reported in as high as 84% of the individuals with the PD.68 Dyskinesia appears to occur most commonly and earliest, followed by wearing off and on-off phenomena.69 Although typically not observed upon the initiation of dopamine replacement, some authors have reported the onset of MRCs in as little as 18 to 28 months of dopamine replacement therapy.69 When considered together, the epidemiological research regarding MRCs indicates that the majority of persons with PD will develop MRCs alter greater than 5 years of dopamine replacement therapy.11,69-79

The pathophysiology of MRCs is thought to result from chronic exposure to the nonphysiologic stimulation of dopamine receptors. Under normal neural functioning, dopamine release within the basal ganglia is a tonic process with intermittent changes in synaptic concentrations. With the advance of PD, dopaminergic transmission within the basal ganglia becomes a more phasic process dependent on exogenous sources of dopamine via L-dopa, which results in neurophysiologic abnormalities in pathways through the basal ganglia.11,80

Despite consistent exposure to pulsatile dosing, not all persons with PD develop MRCs. Factors that have been identified in the literature as playing a role in the development of MRCs include: the severity of PD when dopamine replacement is initiated (persons at Hoehn and Yahr stage III were more likely to develop MRCs),71 the duration of dopamine replacement therapy (greater than 5 years associated with higher likelihood of MRCs),81 the age at diagnosis (age less than 60 associated with higher likelihood of MRCs),67,69,75,76,82 the cumulative L-dopa dose,69 and a large initial dopamine replacement response.82

Recent research has suggested that persons with dyskinesias undergo a conversion in the way that the basal ganglia respond to dopamine replacement compared to those without dyskinesias. As a result, dopamine receptors become supersensitized, creating an altered functional state of the basal ganglia that allows over activity of connections from the basal ganglia to the frontal lobe.67 When considered together, the results of these recent studies suggests that there is a significant pathologic plastic reorganization of the neurophysiologic response of the basal ganglia-thalamo-cortical circuit (including, but not necessarily limited to the thalamus, supplementary motor area, and primary motor cortex) to dopamine replacement in persons with MRCs.75,83,84

Although the presence of MRCs complicates the clinical management of the person with PD, some authors report positive aspects to their presence. In a recent longitudinal study, McColl et al report that the development of motor fluctuations is, for the most part, associated with a better long-term prognosis for functional independence because these persons have a greater capacity to respond to pharmacological treatment.85

Despite these negative effects, in most cases, the improvement in PD cardinal movement impairments far exceeds the problems. For this reason, many persons with PD choose to endure any acute or chronic negative effects in exchange for the improved movement abilities and lessened disability.13

CLINICAL IMPLICATIONS

Several important clinical implications for physical therapists emerge in the literature reviewed. First, although dopamine replacement will result in improvements in the cardinal movement impairments associated with PD, it will not restore movement control to normal levels and the response to dopamine replacement may be variable between individuals. Specifically, bradykinesia, EMG recruitment, muscle strength, tremor, and rigidity should all improve to variable degrees.

Second, in addition to the commonly described chronic effects of dopamine replacement, rehabilitation efforts may be affected by transient acute negative responses to dopamine replacement. These may include, but are not limited to excessive force production, increased movement errors, and control of the COM during reactive postural control tasks.

Third, in those physical therapy clients being treated with prolonged use of L-dopa (> 5 years), some form of movement related complications should be expected as the norm rather than the exception. As a result of these complications, pharmacologic management of these individuals may be changed. Persons with PD who begin experiencing MRCs may be changed to controlled release formulations of dopamine replacement medications (Sinemet CR(R); Madopar HSB(R)) in an effort to provide more prolonged stimulation to dopamine receptors.

In addition, 2 separate issues not discussed previously are particularly relevant to clinical practice. They are timing of physical therapy and the effect of exercise on dopamine pharmacotherapeutics.

Timing of Physical Therapy Treatment with Dopamine Replacement

Despite the lack of specific examinations of the effects of dopamine replacement on responses to exercise, research demonstrating improvements in UPDRS items related to activities of daily living, imply that exercise/rehabilitation training should take place while persons with PD are in an on-medication state.4,86 The improved movement competencies seen during on-medication states should allow the person with PD to participate to a greater degree in rehabilitative efforts.87

The Effect of Exercise on Dopamine Pharmacotherapeutics

An additional clinical concern is the relationship of exercise to L-dopa absorption, utilization, and subsequent motor effects. Physical therapists will likely treat persons with PD who experience a variety of effects of exercise on the physiologic effect of their dopamine replacement medications (in some exercise improves medication effects, in others, exercise decreases medication effects). Synthesis of the results of the few studies that have examined this issue suggests that as a result of aerobic exercise, L-dopa absorption improves (Table 4). However, the literature conflicts regarding whether there is an increased demand for L-dopa during exercise. Intriguingly, Reuter et al report a decrease in the duration and severity of dyskinesias during exercise.88 Large inter-subject variability and small sample sizes limit the conclusions that can he drawn from this research.88-91 Additional research with larger samples, control for severity and subtype of PD (tremor predominate vs. akinetic rigid predominate), and comparison of exercise types (aerobic training vs. strength training) is needed to better understand this issue (Table 4).

SUMMARY AND CONCLUSION

The current mainstay of pharmacologic therapy for persons with PD is dopamine replacement with L-dopa (Sinemet(R), Madopar(R)). Physical therapists can expect that dopamine replacement therapy will result in motor improvements in several important areas. Persons with PD taking L-dopa will generally move faster, have reduced tremor and rigidity, and improved muscle strength. Despite these improvements, dopamine replacement therapy does not return motor control of persons with PD to that of persons without PD.

Although dopamine replacement can produce a significant improvement in the severity of PD motor impairments, it also produces acute and chronic adverse effects that can limit rehabilitative treatment. Based on the literature reviewed, physical therapists can anticipate that the majority of persons with PD on dopamine replacement will develop motor complications of some type within 5 years of starting treatment. In addition, the movement abnormalities observed in persons with PD should be considered the composite effect of the neural pathology of PD and the consequence of dopamine replacement therapy.

Based on the observed improvements in the cardinal movement impairments of PD, functional task performance (eg, PLM-like tasks), and ordinal clinical measures, physical therapists should counsel persons with PD to participate in therapy and independent exercise in an on-medication state.

REFERENCES

1 Hornykiewicz O. Historical aspects and frontiers of Parkinson's disease research. Adv Exp Med Biol. 1977; 90:1-20.

2 Hornykiewicz O. How L-DOPA was discovered as a drug for Parkinson's disease 40 years ago. Wien Klin Wochenschr. 2001;113(22):855-862.

3 Birkmayer W, Hornykiewicz O. The effect of -3,4-dihydroxyphenylalanine (=DOPA) on akinesia in parkinsonism. Parkinsonism & Related Disorders. 1998;4(2):59-60.

4 Levodopa: management of Parkinson's disease. Mov Disord. 2002;17 Suppl 4:S23-37.

5 Cotzias GC, Papavasiliou PS, Gellene R. Experimental treatment of parkinsonism with L-Dopa. Neurology. 1968;18(3):276-277.

6 Cotzias GC. L-Dopa for Parkinsonism. N Engl J Med.1968;278(11):630.

7 Cotzias GC, Papavasiliou PS, Gellene R. Modification of Parkinsonism-chronic treatment with L-dopa. N Engl J Med. 1969;280(7):337-345.

8 Cotzias GC, Papavasiliou PS, Gellene R. L-dopa in parkinson's syndrome. N Engl J Med. 1969;281(5):272.

9 Lang AE, Lozano AM. Parkinson's disease. First of two parts. N Engl J Med.1998;339(15):1044-1053.

10 Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med. 1998;339(16):1130-1143.

11 Metman LV, Konitsiotis S, Chase TN. Pathophysiology of motor response complications in Parkinson's disease: hypotheses on the why, where, and what. Mov Disord. 2000;15(1):3-8.

12 Ramaker C, Marinus J, Stiggelbout AM, Van Hilten BJ. Systematic evaluation of rating scales for impairment and disability in Parkinson's disease. Mov Disord. 2002;17(5):867-876.

13 Gordon AM, Reilmann R. Getting a grasp on research: does treatment taint testing of parkinsonian patients? Brain.1999;122 (Pt 8):1597-1598.

14 Berardelli A, Rothwell JC, Thompson PD, Hallett M. Pathophysiology of bradykinesia in Parkinson's disease. Brain. 2001;124(Pt 11):2131-2146.

15 Berardelli A, Dick JP, Rothwell JC, Day BL, Marsden CD. Scaling of the size of the first agonist EMG burst during rapid wrist movements in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 1986;49(11): 1273-1279.

16 Blin O, Ferrandez AM, Pailhous J, Serratrice G. Dopa-sensitive and dopa-resistant gait parameters in Parkinson's disease. J Neurol Sci. 1991;103(1):51-54.

17 Ferrandez AM, Blin O. A comparison between the effect of intentional modulations and the action of L-dopa on gait in Parkinson's disease. Behav Brain Res. 1991;45 (2):177-183.

18 O'Sullivan JD, Said CM, Dillon LC, Hoffman M, Hughes AJ. Gait analysis in patients with Parkinson's disease and motor fluctuations: influence of levodopa and comparison with other measures of motor function. Mov Disord. 1998;13(6):900-906.

19 Robertson LT, Hammerstad JP. Jaw movement dysfunction related to Parkinson's disease and partially modified by levodopa. J Neurol Neurosurg Psychiatry. 1996;60(1):41-50.

20 Shan DE, Lee SJ, Chao LY, Yeh SI. Gait analysis in advanced Parkinson's disease-effect of levodopa and tolcapone. Can J Neurol Sci. Feb 2001;28(1):70-75.

21 Baroni A, Benvenuti F, Fantini L, Pantaleo T, Urbani F. Human ballistic arm abduction movements: effects of L-dopa treatment in Parkinson's disease. Neurology. 1984;34(7):868-876.

22 Burleigh-Jacobs A, Horak F, Nutt J, JA O. Step Initiation in Parkinson's Disease: Influence of Levodopa and External Sensory Triggers. Movement Disorders. 1997;12(2):206-215.

23 Cioni M, Richards CL, Malouin F, Bedard PJ, Lemieux R. Characteristics of the electromyographic patterns of lower limb muscles during gait in patients with Parkinson's disease when OFF and ON L-Dopa treatment. Ital J Neurol Sci. 1997;18(4):195-208.

24 Corcos DM, Chen CM, Quinn NP, McAuley J, Rothwell JC. Strength in Parkinson's disease: relationship to rate of force generation and clinical status. Ann Neural. 1996;39(1):79-88.

25 Forssberg H, Johnels B, Steg G. Is Parkinsonian Gait Caused by a Regression to an Immature Walking Pattern? Advances in Neurology. 1984;40:375-379.

26 Johnson MT, Mendez A, Kipnis AN, Silverstein P, Zwiebel F, Ebner TJ. Acute effects of levodopa on wrist movement in Parkinson's disease. Kinematics, volitional EMG modulation and reflex amplitude modulation. Brain. 1994;117 (Pt 6):1409-1422.

27 Johnson MT, Kipnis AN, Coltz JD, et al. Effects of levodopa and viscosity on the velocity and accuracy of visually guided tracking in Parkinson's disease. Brain. 1996;119(Pt 3):801-813.

28 Morris M, Iansek R, Matyas T, Summers J. The Pathogenesis of Gait Hypokinesia in Parkinson's Disease. Brain. 1994;117:1169-1181.

29 Morris M, Iansek R, Matyas T, Summers J. Stride Length Regulation in Parkinson's Disease. Normalization Strategies and Underlying Mechanisms. Brain. 1996; 119:551-568.

30 Morris M, Iansak R. Characteristics of motor disturbance in Parkinson's Disease and strategies for movement rehabilitation. J Human Mov Sci. 1996.

31 Morris ME, Matyas TA, Iansek R, Summers JJ. Temporal stability of gait in Parkinson's disease. Phys Ther. 1996;76(7):763-777; discussion 778-780.

32 Murray M, Sepic S, Gardner G, Downs W Walking patterns of men with Parkinsonism. American Journal of Physical Medicine. 1978;57:278-294.

33 Robichaud JA, Pfann KD, Comella CL, Corcos DM. Effect of medication on EMG patterns in individuals with Parkinson's disease. Mov Disord. 2002;17(5):950-960.

34 Weinrich M, Koch K, Garcia F, Angel RW. Axial versus distal motor impairment in Parkinson's disease. Neurology. 1988;38(4):540-545.

35 Pastor MA, Jahanshahi M, Artieda J, Obeso JA. Performance of repetitive wrist movements in Parkinson's disease. Brain. 1992;115 (Pt 3):875-891.

16 Glendinning DS, Enoka RM. Motor unit behavior in Parkinson's disease. Phys Ther 1994;74(1):61-70.

37 Kakinuma S, Nogaki H, Pramanik B, Morimatsu M. Muscle weakness in Parkinson's disease: isokinetic study of the lower limbs. Eur Neurol. 1998;39(4):218-222.

38 Nogaki H, Fukusako T, Sasabe F, Negoro K, Morimatsu M. Muscle strength in early Parkinson's disease. Mov Disord. 1995;10(2):225-226.

39 Nogaki H, Kakinuma S, Morimatsu M. Muscle weakness in Parkinson's disease: a follow-up study. Parkinsonism Relat Disord. 2001;8(1):57-62.

40 McAuley JH, Corcos DM, Rothwell JC, Quinn NP, Marsden CD. Levodopa reversible loss of the Piper frequency oscillation component in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2001;70(4):471-476.

41 Pedersen SW, Oberg B. Dynamic strength in Parkinson's disease. Quantitative measurements following withdrawal of medication. Eur Neurol. 1993;33(2):97-102.

42 Deuschl G, Raethjen J, Baron R, Lindemann M, Wilms H, Krack P. The pathophysiology of parkinsonian tremor: a review. J Neurol. 2000;247 Suppl 5:V33-48.

45 Koller WC. Pharmacologic treatment of parkinsonian tremor. Arch Neurol. 1986;43(2):126-127.

44 Burleigh A, Horak F, Nutt J, Frank J. Levodopa reduces muscle tone and lower extremity tremor in Parkinson's disease. Can J Neurol Sci. 1995;22(4):280-285.

45 Dietz V. Neurophysiology of gait disorders: present and future applications. Electroencephalogr Clin Neurophysiol. 1997;103(3):333-355.

46 Rogers MW. Motor control problems in Parkinson's disease. Contemporary Management of motor control problems: Proceedings of the II Step Conference. Alexandria, VA: APTA; 1991:195-208.

47 Horak FB, Frank J, Nutt J. Effects of dopamine on postural control in parkinsonian subjects: scaling, set, and tone. J Neurophysiol. 1996;75(6):2380-2396.

48 Johnson MT, Kipnis AN, Lee MC, Loewenson RB, Ebner TJ. Modulation of the stretch reflex during volitional sinusoidal tracking in Parkinson's disease. Brain. 1991;114 (Pt 1B):443-460.

49 Johnels B, Ingvarsson PE, Thorselius M, Valls M, Steg G. Disability profiles and objective quantitative assessment in Parkinson's disease. Acta Neurol Scand. 1989;79(3):227-238.

50 Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Simple and complex movements off and on treatment in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry. 1987;50(3):296-303.

51 Fattapposta F, Pierelli F, Traversa G, et al. Preprogramming and control activity of bimanual self-paced motor task in Parkinson's disease. Clin Neurophysiol. 2000; 111(5):873-883.

52 Fattapposta F, Pierelli F, My F, et al. L-dopa effects on preprogramming and control activity in a skilled motor act in Parkinson's disease. Clin Neurophysiol. 2002;113(2): 243-253.

53 Ingvarsson P, Johnels B, Lund S, Steg G. Coordination of manual, postural, and locomotor movements during simple goal-directed motor tasks in parkinsonian off and on states. Adv Neurol. 1987;45:375-382.

54 Ingvarsson PE, Johnels B, Steg G, Olsson T. Objective assessment in Parkinson's disease: optoelectronic movement and force analysis in clinical routine and research. Adv Neurol. 1999;80:447-458.

55 Johnels B, Ingvarsson PE, Steg G, Olsson T. The Posturo-Locomotion-Manual Test. A simple method for the characterization of neurological movement disturbances. Adv Neurol. 2001;87:91-100.

56 Johnels B, Ingvarsson PE, Matousek M, Steg G, Heinonen EH. Optoelectronic movement analysis in Parkinson's disease: effect of selegiline on the disability in de novo parkinsonian patients-a pilot study. Acta Neurol Scand Suppl. 1991;136:40-43.

57 Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Performance of simultaneous movements in patients with Parkinson's disease. Brain. 1986;109 (Pt 4):739-757.

58 Gordon AM. Object release in patients with Parkinson's disease. Neurosci Lett. 1997;232(1):1-4.

59 Gordon AM, Ingvarsson PE, Forssberg H. Anticipatory control of manipulative forces in Parkinson's disease. Exp Neurol. 1997;145(2 Pt 1):477-488.

60 Gordon AM. Task-dependent deficits during object release in Parkinson's disease. Exp Neurol. 1998;153(2): 287-298.

61 Ingvarsson PE, Gordon AM, Forssberg H. Coordination of manipulative forces in Parkinson's disease. Exp Neurol. 1997;145(2 Pt 1):489-501.

62 Feigin A, Ghilardi MF, Fukuda M, et al. Effects of levodopa infusion on motor activation responses in Parkinson's disease. Neurology. 2002;59(2):220-226.

63 Nutt JG, Gaucher ST, Woodward WR. Does an inhibitory action of levodopa contribute to motor fluctuations? Neurology. 1988;38(10):1553-1557.

64 Merollo M, Lees AJ. Beginning-of-dose motor detrioration following the acute administration of levodopa and apomorphine in Parkinson's disease. Journal of Neurology, Neurosurgery, and Psychiatry. 1992;55: 1024-1026.

65 Nutt JG. Response to L-dopa in PD: the long and the short of it. Neurology. 2000;54(10):1884-1885.

66 Frank JS, Horak FB, Nutt J. Centrally initiated postural adjustments in parkinsonian patients on and off levodopa. J Neurophysiol. 2000;84(5):2440-2448.

67 Blanchet PJ, Calon F, Morissette M, et al. Regulation of dopamine receptors and motor behavior following pulsatile and continuous dopaminergic replacement strategies in the MPTP primate model. Adv Neurol. 2001;86:337-344.

68 Chase TN, Mouradian MM, Engber TM. Motor response complications and the function of striatal efferent systems. Neurology. 1993;43(12 Suppl 6):S23-27.

69 Rajput AH, Fenton ME, Birdi S, et al. Clinical-pathological study of levodopa complications. Mov Disord. 2002;17 (2):289-296.

70 Bedard PJ, Blanchet PJ, Levesque D, et al. Pathophysiology of L-dopa-induced dyskinesias. Mov Disord. 1999; 14 Suppl 1:4-8.

71 Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease. Neurology. 1991;41(2 (Pt 1)):202-205.

72 Linazasoro G. [Physiopathology of parkinsonism and dyskinesias: lessons from surgical observations]]. Neurologia. 2001;16(1):17-29.

73 Nutt JG, Gancher ST. Parkinson's disease dyskinesias. Neurology. 1994;44(6):1187; author reply 1187-1188.

74 Obeso JA, Rodriguez-Oroz MC, Rodriguez M, DeLong MR, Olanow CW. Pathophysiology of levodopa-induced dyskinesias in Parkinson's disease: problems with the current model. Ann Neural. 2000;47(4 Suppl 1):S22-32; discussion S32-24.

75 Rascol O. L-dopa-induced peak-dose dyskinesias in patients with Parkinson's disease: a clinical pharmacologic approach. Mov Disord. 1999;14 Suppl 1:19-32.

76 Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med. 2000;342(20):1484-1491.

77 Reardon KA, Shiff M, Kempster PA. Evolution of motor fluctuations in Parkinson's disease: a longitudinal study over 6 years. Mov Disord. 1999;14(4):605-611.

78 Wenzelburger R, Zhang BR, Poepping M, et al. Dyskinesias and grip control in Parkinson's disease are normalized by chronic stimulation of the subthalamic nucleus. Ann Neurol. 2002;52(2):240-243.

79 Wenzelburger R, Zhang BR, Pohle S, et al. Force overflow and levodopa-induced dyskinesias in Parkinson's disease. Brain. 2002;125(Pt 4):871-879.

80 Tintner R, Jankovic J. Treatment options for Parkinson's disease. Curr Opin Neurol. 2002;15(4):467-476.

81 de Jong GJ, Meerwaldt JD, Schmitz PI. Factors that influence the occurrence of response variations in Parkinson's disease. Ann Neurol. 1987;22(1):4-7.

82 McColl CD, Reardon KA, Shiff M, Kempster PA. Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease. Mov Disord. 2002;17(6):1227-1234.

83 Hershey T, Black KJ, Stambuk MK, Carl JL, McGee-Minnich LA, Perlmutter JS. Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias. Proc Natl Acad Sci U S A. 1998;95(20): 12016-12021.

84 Rascol O, Sabatini U, Brefel C, et al. Cortical motor over-activation in parkinsonian patients with L-dopa-induced peak-dose dyskinesia. Brain 1998;121 (Pt 3): 527-533.

85 McColl C, Reardon K, Shiff M, Kempster P. Motor response to levodopa and the evolution of motor fluctuations in the first decade of treatment of Parkinson's disease. Mov Disord. 2002;17(6):1227-1234.

86 Agid Y, Ahlskog E, Albanese A, et al. Levodopa in the treatment of Parkinson's disease: a consensus meeting. Mov Disord. 1999;14(6):911-913.

87 Morris ME. Movement disorders in people with Parkinson disease: a model for physical therapy. Phys Ther. 2000;80(6):578-597.

88 Reuter I, Harder S, Engelhardt M, Baas H. The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. Mov Disord. 2000;15(5):862-868.

89 Goetz CG,Thelen JA, MacLeod CM, Carvey PM, Bartley EA, Stebbins GT. Blood levodopa levels and unified Parkinson's disease rating scale function: with and without exercise. Neurology. 1993;43(5):1040-1042.

90 Mouradian MM, Juncos JL, Serrati C, Fabbrini G, Palmeri S, Chase TN. Exercise and the anti-parkinsonian response to levodopa. Clin Neuropharmacol. 1987; 10(4):351-355.

91 Carter JH, Nutt JG, Woodward WR. The effect of exercise on levodopa absorption. Neurology. 1992;42(10):2042-2045.

Lee Dibble, PhD, PT, ATC1

1Associate Professor, Division of Physical Therapy, University of Utah (lee.dibble@hsc.utah.edu)

Copyright Neurology Report Sep 2003
Provided by ProQuest Information and Learning Company. All rights Reserved