Long-Term Follow-Up of Levodopa Responsiveness in Generalized Dystonia

ORIGINAL CONTRIBUTION Long-term Follow-up of Levodopa Responsiveness in Generalized Dystonia

Richard B. Dewey, Jr, MD; Manfred D. Muenter, MD; Asha Kishore, MD; Barry J. Snow, MD

Objectives: To assign an accurate diagnosis to pa- toms of dystonia as the drug was withheld. In each case, tients with dystonia based on the presence of sustained worsening of dystonia did not occur until 29 hours or levodopa responsiveness and to determine whether mo- more after levodopa withdrawal, providing evidence for tor fluctuations occur in patients with dystonia who are a response profile similar to the long duration response withheld from levodopa. described in Parkinson disease. No significant changes were seen in the dystonia scores of the 3 patients with Patients and Methods: Patients with generalized dys- idiopathic torsion dystonia who were withheld from le- tonia who responded to treatment in the 1970s with levodopa. vodopa/carbidopa were surveyed by phone and then examined during a 3-day levodopa holiday. Functional Conclusions: We suggest that the subjective feeling of imaging with fluorodopa positron emission tomogra- wearing off experienced by our patients with dopa- phy was performed on a subset of patients. responsive dystonia may have been for one of the non– motor effects of levodopa, such as mood elevation. Our Results: In the phone interview, 4 of 7 patients with a data provide objective evidence for the often-repeated as- diagnosis of dopa-responsive dystonia reported the wear- sertion that motor fluctuations (analogous to those in le- ing-off effect a short while (within 4-8 hours) after miss- vodopa-treated patients with Parkinson disease) do not ing a dose of levodopa. Five patients with dopa- occur in patients with dopa-responsive dystonia. responsive dystonia were examined repetitively during levodopa withdrawal, and 3 developed recurrent symp- Arch Neurol. 1998;55:1320-1323

ATIENTS WITH generalized ported the development of motor fluctua- idiopathic torsion dystonia tions. This case was surprising since, (ITD) have a variable re- according to Nygaard et al,3 motor fluc- sponse to treatment with le- tuations (such as the wearing-off effect) vodopa. Most have no re- do not occur in patients with DRD.3 In fact, Psponse or suffer worsening dystonia. A some authors have suggested that when distinct minority of patients report some motor fluctuations are seen in patients with improvement, which is almost always tran- presumed DRD, the correct diagnosis may sient.1 A very small subset of patients with in fact be juvenile-onset Parkinson dis- progressive idiopathic generalized dysto- ease rather than DRD.4 The aims of the cur- nia, however, have a dramatic and pro- rent study were (1) to reclassify patients longed response to relatively small doses as having either DRD or ITD based on the of levodopa, leading to the designation presence of sustained responsiveness to dopa-responsive dystonia (DRD). low-dose levodopa therapy and (2) One of us (M.D.M.) found levodopa to determine whether motor fluctua- therapy to be effective in 12 patients with tions, such as the wearing-off effect, oc- From the Departments of idiopathic generalized dystonia who were cur in patients with dystonia treated with Neurology, University of Texas treated in the 1970s.2 Several of these pa- levodopa. Southwestern Medical School, tients had only a partial and transient re- Dallas (Dr Dewey), Mayo sponse to levodopa, suggesting a diagno- Clinic Scottsdale, Scottsdale, RESULTS Ariz (Dr Muenter), and the sis of ITD. Others had a dramatic and Neurodegenerative Disorders prolonged beneficial response to the drug Eleven patients were reached by phone and Centre, University of British and therefore represent typical cases of surveyed regarding their illness after a Columbia, Vancouver DRD. One patient had otherwise typical mean of 18.5 years since initiation of treat- (Drs Kishore and Snow). DRD but during prolonged follow-up re- ment. Table 1 shows a summary of the

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 PATIENTS AND METHODS given their usual dose of levodopa/carbidopa and observed for a response. Clinical ratings were repeated after maximal clinical improvement (if any) occurred, and if no After conducting a detailed review of the medical records improvement was seen, 90 minutes later. A second “on- of the original 12 patients with dystonia who reported le- state” dystonia scoring was performed 6 hours after levodopa responsiveness in the 1970s, the patients were con- vodopa administration in patient 1. tacted by phone and surveyed regarding the course of their Subsequently, 6 patients underwent positron emis- illness since their last examination, with specific attention sion tomography (PET) scans with fluorodopa F 18 and to the issues of levodopa responsiveness and motor fluc- raclopride labeled with carbon 11 (11C) at the University tuations. Patients were then invited to travel to the Mayo of British Columbia, Vancouver. All PET studies were per- Clinic Scottsdale, Scottsdale, Ariz, for reexamination. All formed (using an ECAT 953B/31 tomograph) after a 12- travel and accommodation costs were funded through the hour withdrawal of medication. The fluorodopa F 18 PET study. Those patients who agreed to visit underwent de- scans were performed dynamically over a 2-hour period. tailed clinical evaluation for dystonia and parkinsonism over The analysis was performed using regions of interest that a 3-day period. While we did not expect to see parkinson- covered the heads of the caudates and 3 regions of interest ism in our patients with DRD, we included scoring for par- per slice that covered the putamen. The analysis was per- kinsonism because other investigators have suggested that formed using a graphical method and metabolite- these disorders can sometimes be confused.4 After provid- corrected blood input according to the method described ing informed consent, the patients who were still taking by Patlak and Blasberg.6 The full details of the method have levodopa/carbidopa (all 5 patients with DRD and 3 of the been described elsewhere.7 The 11C-raclopride scans were 4 patients with ITD) were asked not to take the drug for performed using the same sets of regions of interest placed up to 3 days, during which time they received 4 neuro- manually on the raclopride scans. After an injection of 5 logic examinations for both dystonia and parkinsonism. mCi, data were collected for 60 minutes. The analysis was “Off-levodopa” dystonia examinations were performed in the ratio of striatum to background for the period from 30 the morning (8 AM) and in the late afternoon (5 PM)toas- to 60 minutes. The definition of normal for both the fluo- sess for diurnal fluctuations. Dystonia was rated using the rodopa and raclopride scans was based on the 95% confi- Fahn-Marsden Dystonia Scale,5 while parkinsonism was as- dence limits of age-matched normal controls. The control sessed using the Unified Parkinson’s Disease Rating Scale subjects had no history of neurologic disease and were nor- motor section (items 18-31). After the final off-levodopa mal on neurologic examination. None were taking medi- clinical rating was performed on the third day, patients were cation that influenced the dopaminergic system.

Table 1. Clinical Features Based on Chart Review and Phone Interview

Duration of Patient No./ Daily Levodopa Effect of Wearing-Off Response to Diurnal Age at Onset, y Initial Symptom Dose, mg Levodopa Effect? Levodopa, h Fluctuations? Diagnosis* 1/7 Foot inversion when walking 100 Dramatic Yes 29 Yes DRD 11/5 Foot inversion when walking 100 Dramatic Yes 8 Yes DRD 8/7 Torticollis and dystonic posturing of arms 150 Dramatic Yes 4 Yes DRD 5/6 Involuntary movements of hands 300 Dramatic Yes 6 No DRD 4/5 Inversion of feet and flexion of toes 200 Dramatic Yes 7 Yes DRD 10/3 Foot inversion when walking 100 Dramatic Yes 24 Yes DRD 2/2 Foot inversion when walking 100 Dramatic Yes 17-25 Yes DRD 7/10 Truncal dystonia with retrocollis None Modest No Not applicable No ITD 6/9 Torticollis 500 Modest No Not applicable No ITD 9/12 Torticollis, right arm tremor 1000 Modest Yes 24 Yes ITD 3/43 Eyelid and facial twitching 1600 Modest Yes 4 No ITD

*DRD indicates dopa-responsive dystonia; ITD, idiopathic torsion dystonia.

clinical features of each case gathered from chart review within a mean of 6 hours after taking the last dose of le- and telephone interview. An important finding from the vodopa. survey was that all patients with DRD admitted to hav- Nine patients traveled to Mayo Clinic Scottsdale for ing experienced the wearing-off effect from levodopa, usu- detailed examination over a period of 3 days. Those still ally when a dose of the drug was inadvertently skipped. taking levodopa remained off the drug for up to 83 hours Three of the 7 patients with DRD had a relatively long (mean, 55.8 hours). Dystonia scores for each patient at duration response to a given dose, noting wearing off of each of the assessment examinations are shown in the effects 24 hours or more after the dose was missed. Figure 1 and Figure 2. Consistent with our expecta- Four of the 7, however, had short duration responses by tions, parkinsonism was not observed in any patient at history and developed a feeling of uneasiness that they any time during drug withdrawal. Diurnal fluctuation of thought presaged the recurrence of dystonic posturing dystonia severity (operationally defined here as a low-

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35 Patient No. Patient No. 45 1 4 8 3 7 30 2 5 6 9 25 35

20 25 15

10 15

Fahn-Marsden Dystonia Score 5 Fahn-Marsden Dystonia Score 5 0

–5 –5 Day 1 AM Day 2 AM Day 2 PM Day 3 Off Day 3 On Day 3 Late Day 1 AM Day 2 AM Day 2 PM Day 3 Off Day 3 On

Figure 1. Dystonia scores of patients with dopa-responsive dystonia during Figure 2. Dystonia scores of patients with idiopathic torsion dystonia during withdrawal from levodopa therapy and after rechallenge. Day 3 Off indicates withdrawal from levodopa therapy and after rechallenge. Day 3 Off indicates the period before levodopa was taken; Day 3 On, the period after response the period before levodopa was taken; Day 3 On, 90 minutes after the was seen. Patient 1 was given a late examination 6 hours after levodopa was administration of levodopa. Patient 7 had discontinued taking levodopa administered (Day 3 Late). No dystonia was detected in patients 5 and 8 years before the present study was begun. during the levodopa holiday.

ering of the dystonia score in the morning after a night of sleep) was seen in 1 patient with DRD (patient 1). This Table 2. Subjective/Objective Data Comparison for Drug Latency and Duration in Patients With Dopa-Responsive same patient also exhibited a slight loss of benefit from Dystonia for Whom Complete Data Are Available levodopa when tested 6 hours after rechallenge on day 3. Note that in the 3 patients with DRD for whom Duration of Response Latency to Onset of complete data are available, the time to first recurrence to Levodopa, h Drug Effect, h of dystonia was more than 24 hours after administra- Patient tion of the last dose of levodopa. Two patients presump- No. Phone Interview Observed Phone Interview Observed tively classified as having DRD did not exhibit dystonia 1293342 during our period of observation. One of them (patient 2 17-25 38.5 1 0.75 5) took a dose of levodopa 20 hours into the withdrawal 4 7 29 2 1.5 period before being examined by investigators because of leg cramps and fear that her dystonia was recurring. This dose of levodopa relieved her symptoms, and dys- to be due to mutations in the gene coding for guanosine tonia was not observed when she was seen later that day. triphosphate cyclohydrolase I, which leads to a defi- Patient 8 did not take levodopa for 61 hours and did not ciency of tetrahydrobiopterin.8 Since tetrahydrobiop- develop recurrent dystonia, which could indicate an terin is a key cofactor for tyrosine hydroxylase, this gene unusually long duration response to levodopa, the defect results in impaired synthesis of dopamine by ni- presence of a very mild form of DRD, or an incorrect gral neurons. An autopsy study was published recently diagnosis. Table 2 shows a comparison of the subjec- that showed normal numbers of nigral neurons associ- tive data from the phone interview regarding motor ated with marked dopamine deficiency,9 findings that con- fluctuations with the objective data generated by in- firm the nondegenerative nature of DRD. office scoring for the 3 patients with DRD for whom In light of the reports suggesting that motor fluc- complete information was available. tuations are not seen in DRD,4,10-12 we were surprised by Two patients with DRD underwent fluorodopa and the results of our phone interviews, in which several pa- raclopride PET scans in Vancouver, British Columbia. In tients with DRD reported a short duration response to patient 1, the fluorodopa scan was normal but high ra- levodopa. We predicted that if a true short duration re- clopride binding was observed. Both scans were normal sponse was present in these cases, we would observe re- in patient 2. Four patients with ITD underwent PET scans; current dystonia within several hours as patients were in 2 cases (patients 6 and 7), the results were uninter- withdrawn from levodopa. Our data showed that this was pretable owing to technical difficulties related to the pa- not the case, indicating that the subjective feeling of wear- tients’ cervical dystonia. The findings were normal in the ing off reported in the phone interview did not repre- other 2 patients, although raclopride scanning was not sent recurrent dystonia. Patients with ITD, on the other performed in patient 9. hand, who by history had a modest or transient benefit from levodopa therapy, were expected to maintain rela- COMMENT tively constant dystonia scores during the time of levodopa withdrawal, and our data confirmed this. A beneficial response to levodopa is uncommon in gen- Our results demonstrated that all patients with DRD eralized dystonia but, when present, is of enormous di- who developed dystonia during levodopa withdrawal ex- agnostic and therapeutic significance. Dopa-responsive perienced continued deterioration in dystonia scores dur- dystonia can be easily diagnosed when childhood-onset ing the second day off the drug. As such, this clinical ob- dystonia responds completely and persistently to small servation is analogous to the long duration response daily doses of levodopa. This disorder has been shown described in patients with Parkinson disease in whom pro-

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 gressive deterioration in motor scores was observed over ing in wide variability with regard to how this question several days of levodopa withdrawal.13 Since we termi- was answered in the phone interview. When querying nated the levodopa holiday on the third day, it is un- patients about wearing off, the physician must delve deeply known whether further worsening of dystonia would have into exactly what is meant by this term to avoid misun- been observed with a longer period of observation off derstanding. The PET studies revealed normal fluo- levodopa. rodopa uptake in cases of DRD and ITD, a finding that Improvement in dystonia scores occurred within sev- provides further evidence that neither disorder is due to eral hours of levodopa rechallenge in our patients with DRD, degeneration of nigral neurons. Clinical differentiation which parallels the short duration response to levodopa seen of DRD from ITD can be accomplished with a trial of le- in patients with Parkinson disease. That the dystonia score vodopa therapy, which should be used in all patients with of patient 1 improved and then worsened again by 6 hours childhood-onset dystonia. after administration echoes previous observations in Par- kinson disease that a single dose of levodopa may be in- Accepted for publication April 20, 1998. sufficient to restore the long duration response.14 These find- This study was supported in part by a grant from Mayo ings in our patients with DRD are thus consistent with an Clinic Scottsdale. intact population of nigral neurons capable of storage and Reprints: Richard B. Dewey, Jr, MD, University of Texas release of dopamine in a physiologic fashion. 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