Reckless generosity in Parkinson\'s disease

Movement Disorders Vol. 25, No. 2, 2010, pp. 221–242
2010 Movement Disorder Society

Brief Reports

Reckless Generosity in Parkinson’s Disease

CASE SERIES Case 1 A 23-year-old male was diagnosed with PD in 1990. There was a past history of alcohol abuse and illicit drug use. He was strongly levodopa (L-dopa) responsive, and developed disabling dyskinesias after selfescalating his dose to over 800 mg/day. Pramipexole was introduced in 2002, after previous trials of cabergoline and ropinirole had proved ineffective, which permitted the reduction of L-dopa to 200 mg/day. Within 3 years, he had increased his pramipexole from 3 mg (salt dose) to 6 mg/day and also increased his Ldopa back up to 600 mg/day. Amantadine was introduced to curb increasing dyskinesias and it too was increased by the patient from 300 to 500 mg/day. Cyclothymia related to his dopamine replacement therapy was noted, with anxiety and low mood occurring during off phases. From 2005 onwards, he developed a number of impulsive behaviors, with pathological gambling being the most prominent. By 2008, he had lost £30,000 on slot machines, leading to severe debt and legal problems. He also developed an intense fascination with body-building, which would consume countless hours each day often at the expense of food and sleep. He had also started to shop compulsively, buying 60 bottles of aftershave at one time. When interviewed during a hospital admission, he described feeling compelled to give gifts to family members, friends, and even casual acquaintances. On receiving his weekly disability allowance check, he would immediately give away over half of it in the form of cash or pointless gifts, leaving him insufficient allowance money to buy food, or pay bills. He described how giving his money away led to great pleasure, even when it resulted in his electricity supply being disconnected repeatedly. Psychiatric assessment confirmed he did not meet criteria for a manic episode.

Sean S. O’Sullivan, MRCPI,1 Andrew H. Evans, MD,2 Niall P. Quinn, FRCP,3 Andrew D. Lawrence, PhD,4 and Andrew J. Lees, FMedAcadSci1* 1

Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, London, United Kingdom; 2Department of Neurology, Royal Melbourne Hospital, Parkville, Australia; 3Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London, United Kingdom; 4Wales Institute of Cognitive Neuroscience, School of Psychology, Cardiff University, United Kingdom

Abstract: There is an increasing awareness of impulsivecompulsive phenomena in patients treated for Parkinson’s disease (PD). We describe another, potentially related phenomenon putatively associated with the use of dopamine agonists in 3 patients with PD, characterized by excessive and inappropriate philanthropy.
2010 Movement Disorder Society Key words: impulse control disorders; Parkinson’s disease; dopamine agonists; generosity

There is an increasing awareness of impulsive-compulsive phenomena in patients treated for Parkinson’s disease (PD). Pathological gambling and hypersexuality have been the most widely reported impulsive behaviors, but compulsive shopping and binge eating are also well recognized.1 We describe another, potentially related phenomenon putatively associated with the use of dopamine agonists in 3 patients with PD, characterized by excessive and inappropriate philanthropy.

*Correspondence to: Dr. Andrew J. Lees, Reta Lila Weston Institute of Neurological Studies, UCL, 1 Wakefield Street, London WC1N 1PJ, United Kingdom. E-mail: [email protected] Potential conflict of interest: SSOS is supported by the Reta Lila Weston Trust. The authors have no financial disclosures related to research covered in this article. Received 28 April 2009; Revised 3 June 2009; Accepted 6 June 2009 Published online 13 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22687

Case 2 A 49-year-old male writer was diagnosed with PD in 1995. There was no history of alcohol or other substance abuse. He was commenced on L-dopa, with an excellent motor response. Within 5 years, he was taking 600 mg L-dopa/day, and had become aware of a

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S.S. O’SULLIVAN ET AL. TABLE 1. Summary of cases of reckless generosity

Case Age PD no. Gender onset 1

M

23

Previous psychiatric history

Age of reckless generosity onset

Alcohol and illicit drug abuse

41

Medications taken at onset of reckless generosity Pramipexole 6 mg/day L-dopa

2

M

49

58

3

F

23

66

Other ICDs or DDS

Intervention

Outcome

PG DDS

Reduction of pramipexole

Partial improvement in ICDs and reckless generosity

600 mg/day Amantadine 500 mg/day Pramipexole 3 mg/day

CS Punding HS

L-dopa

Punding PG

600 mg/day Pramipexole 6 mg/day

L-dopa

400 mg/day Entacapone 800 mg/day

Discontinuation of Full resolution pramipexole of ICDs and reckless generosity Discontinuation of Significant reduction pramipexole of ICDs and reckless generosity

CS

ICD, impulse control disorder; DDS, dopamine dysregulation syndrome; PG, pathological gambling; CS, compulsive shopping; HS, hypersexuality.

feeling of euphoria after taking each dose followed by transient severe depression once the drug wore off. He also experienced an increase in libido. In 2006, he was commenced on pramipexole 3 mg (salt dose)/day, which led to a further troublesome increase in libido and affairs with female colleagues. He now often stayed up all night writing endlessly, and on some occasions would continue incessantly for up to 48 hours. Upon re-reading his output in a more relaxed ‘‘off-medication’’ state, he would realize the quality of his literary output was extremely poor. Shortly after commencing pramipexole, he developed an uncharacteristic interest in helping local drug addicts. This involved the unsolicited donation of food and money. One of the female addicts took advantage of his generosity and over a year, £20,000 was given as gifts and loans. There was a total lack of insight and it was only in hindsight that he realized that he had been hoodwinked. He reported that he had felt compelled to give his money to this person, and that ‘‘the veil was lifted’’ from his eyes only when the pramipexole was discontinued. Case 3 A 28-year-old female was diagnosed with PD in 1968, after a 5 year history of symptoms. She was subsequently found to have a homozygous parkin mutation. She was commenced on L-dopa in 1970 with marked benefit. There was no past history of addictive behaviors. Her PD progressed slowly, and by 2006 she was taking 600 mg of L-dopa/day. She was then started on pramipexole for end-of-dose deterioration and this was increased up to 6 mg (salt dose)/day, in addition to 400 mg/day of L-dopa, and entacapone. Soon after

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this she became obsessed with internet bingo gambling, spending approximately £100/week. She would wake at 5 AM, and start playing bingo online, even before taking medications or food. In addition to gambling, she also developed compulsive online shopping, including buying a greenhouse and three motorized scooters on eBay. At the same time, she started to give money away to friends and family members, despite financial strain. She justified her generosity by stating that if she did not give the money away she would only have spent it on gambling or impulsive purchases. She developed hypomania and tried to move house impulsively, before medical intervention could be initiated. Discontinuation of the pramipexole has led to a partial resolution of her gambling, shopping, and excessive generosity. See Table 1 for the summary of the three cases.

DISCUSSION ‘‘He who cannot give anything away cannot feel anything either.’’—Friedrich Nietzsche. Generosity is the act of giving without coercion, felt by some philosophers to be a vital aspect of our humanity. Studies of human brain activity during charitable giving have indicated that giving activates the mesolimbic reward regions of the brain, such as the midbrain ventral tegmental area, the dorsal and ventral striatum, and the subgenual cingulate.2,3 Making an anonymous charitable donation activated the ventral striatum more intensely than did receiving a pure monetary reward.2 Increased dopaminergic release is observed in the ventral striatum after L-dopa challenge in patients with PD and dopamine dysregulation syn-

RECKLESS GENEROSITY IN PARKINSON’S DISEASE drome, which is frequently comorbid with other impulsive-compulsive behaviors,4 and the subgenual cingulate is preferentially activated by the dopamine agonist pramipexole.5 Oxytocin increases have also been associated with increased generosity, with authors suggesting that its effects on striatal dopamine release could provide a link between hormonal and functional imaging study results.6 Alternatively, reckless generosity may reflect impaired decision-making, also implicated in other impulse control disorders (ICDs), and which has been demonstrated in patients with PD performing poorly on tests such as the Iowa Gambling Task.7 Impaired Iowa Gambling Task performance in the elderly has been linked to increased susceptibility to fraudulent advertizing.8 Dopaminergic medications have been shown to influence reward behaviors in PD, and medicated patients with PD display an insensitivity to the negative consequences of actions than that seen in normal controls.9 We describe the development of excessive generosity in 3 patients with PD, occurring soon after the commencement of a dopamine agonist. This was associated with punding behaviors in two cases, one of whom also had dopamine dysregulation syndrome. Other impulsive-compulsive behaviors were present in all cases. In our experience, it is not uncommon for patients with compulsive shopping tendencies to give away frequent presents, by way of justifying their excessive spending on unnecessary goods. However, in the above cases, the giving of presents and/or money was their primary motivation and one patient did not exhibit compulsive shopping. Excessive generosity has been described in a patient with PD, during an episode of medication-induced mania.10 However, in our patients reckless generosity occurred without mania, although one patient subsequently went on to develop hypomania. The occurrence of hypomania after the onset of ICDs has previously been noted in patients with PD who develop pathological gambling.11 In all cases, the generosity combined with other impulsive-compulsive phenomena caused significant financial strains. Having identified four such cases (these three and one other whom we have been unable to contact for consent for his case to be reported), we fear this problem may be not that uncommon, but is probably under-recognized and under-reported. It may be related to dysfunctional dopaminergic reward pathways in some PD cases, and which can lead to enhanced ‘‘spill over’’ from drug rewards to other rewards,4 including altruistic or social

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rewards. The possibility of this adverse effect should be mentioned to patients considering or taking dopamine agonists, and to their carers, and should be actively enquired about by treating physicians. Acknowledgments: SSOS is supported by the Reta Lila Weston Trust. Sean O’Sullivan has received honoraria from Britannia Pharmaceuticals. Employment: University College London. All other FD categories: None. Andrew Evans has served on advisory boards and received honoraria from Boehringer Ingelheim and Novartis. He has no other financial disclosures. Niall Quinn: Advisory board and honoraria from UCB. Honorarium from GSK. All other FD categories: None. Andrew Lawrence: Grants: UK Medical Research Council; UK Parkinson’s Disease Society; Wales Institute of Cognitive Neuroscience. Employment: Cardiff University. All other categories: None. Andrew Lees: advisory boards—Genus, Novartis, Teva, Medo, Boehringer Ingleheim, GSK, Ipsen, Lundbeck. Grants: PSP association, Reta Lila Weston Trust. All other categories: none. Author Roles: All authors were involved in the writing, reviewing, and critiquing of this article.

REFERENCES 1. Lim SY, Evans AH, Miyasaki JM. Impulse control and related disorders in Parkinson’s disease: review. Ann N Y Acad Sci 2008;1142:85–107. 2. Moll J, Krueger F, Zahn R, Pardini M, de Oliveira-Souza R, Grafman J. Human fronto-mesolimbic networks guide decisions about charitable donation. Proc Natl Acad Sci USA 2006;103: 15623–15628. 3. Harbaugh WT, Mayr U, Burghart DR. Neural responses to taxation and voluntary giving reveal motives for charitable donations. Science 2007;316:1622–1625. 4. Evans AH, Pavese N, Lawrence AD, et al. Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Ann Neurol 2006;59:852–858. 5. Black KJ, Hershey T, Koller JM, et al. A possible substrate for dopamine-related changes in mood and behavior: prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc Natl Acad Sci USA 2002;99:17113–17118. 6. Zak PJ, Stanton AA, Ahmadi S. Oxytocin increases generosity in humans. PLoS One 2007;2:e1128. 7. Mimura M, Oeda R, Kawamura M. Impaired decision-making in Parkinson’s disease. Parkinsonism Relat Disord 2006;12:169– 175. 8. Denburg NL, Tranel D, Bechara A. The ability to decide advantageously declines prematurely in some normal older persons. Neuropsychologia 2005;43:1099–1106. 9. Frank MJ, Seeberger LC, O’Reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science 2004; 306:1940–1943. 10. Cannas A, Solla P, Manca E, Floris G, Tacconi P, Marrosu MG. Ultrarapid mood cycling in a Parkinsonian patient: is not always simply an ‘‘on-off’’ fluctuation—a case report. Parkinsonism Relat Disord 2008;14:262–263. 11. Voon V, Thomsen T, Miyasaki JM, et al. Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease. Arch Neurol 2007;64:212–216.

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AUINGER ET AL.

The Relationship Between Uric Acid Levels and Huntington’s Disease Progression Peggy Auinger, MS,1* Karl Kieburtz, MD,1 and Michael P. McDermott, PhD1,2 1

Departments of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA; 2 Departments of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

Abstract: Uric acid (UA) may be associated with the progression of Parkinson’s disease and related neurodegenerative conditions; however, its association with Huntington’s disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington’s Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, P 5 0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression.
2010 Movement Disorder Society Key words: Huntington’s disease; uric acid; progression

Uric acid (UA) is a known antioxidant with greater blood concentrations found in humans compared with shorter-lived mammals, suggesting an evolutionary benefit.1 UA is a scavenger of oxygen radicals, and oxidative damage has been hypothesized to contribute to aging and neurodegeneration.2 Higher UA levels may serve a potential therapeutic role against oxidative damage associated with neurodegenerative diseases.

*Correspondence to: Peggy Auinger, Department of Neurology, University of Rochester, 1351 Mt. Hope Ave., Rochester 14620, NY. E-mail: [email protected] Potential confilct of interest: Nothing to report. Received 12 January 2009; Revised 8 July 2009; Accepted 30 October 2009 Published online 8 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22907

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Studies suggest that UA could be a novel target for neuroprotective therapies. UA has been found to be protective in reducing brain injury after ischemic stroke.3 Lower serum UA concentrations have been found in persons with Alzheimer’s disease compared to healthy controls and persons with higher UA levels have been shown to have a lower risk of developing Parkinson’s disease (PD).4,5 In addition, UA concentrations have been found to be reduced in Huntington’s disease (HD) as compared with controls in several regions of the cerebral cortex.6 Higher UA concentrations have been linked to slower clinical progression of PD among those with early PD.7 It is plausible that this association may also exist with other neurodegenerative diseases such as HD, and that serum UA may be a potential biomarker of clinical progression in HD. The objective of this study was to examine the relationship between baseline UA levels and the level of functional decline in HD patients over a 30 month period.

SUBJECTS AND METHODS Evaluation in Huntington’s Disease (CARE-HD) clinical trial was the source of data for this study.8 This was a multicenter, randomized, double-blind, parallel group clinical trial conducted during July 1997– February 2002. The 347 participating subjects were randomized to receive either coenzyme Q10 (600 mg/ day), remacemide (600 mg/day), both treatments, or matching placebo and were evaluated with clinical assessments over a 30 month period. Subjects had a confirmatory CAG repeat expansion (>39) consistent with HD, early HD defined as stages I or II of illness (total functional capacity (TFC) >7), and were 14 years of age or older. Subjects were excluded if there was clinical evidence of unstable medical or psychiatric illness, history of serious alcohol or drug abuse within the preceding year, use of any investigational drug within 30 days of the study, or use of coenzyme Q10 or remacemide in the previous 3 months. All subjects gave written informed consent. The initial study concluded that neither coenzyme Q10 nor remacemide produced significant slowing in functional decline in early HD. At each visit, participants were evaluated using the Unified Huntington’s Disease Rating Scale (UHDRS), a standardized instrument assessing the clinical features and course of HD.9 This instrument consists of functional, motor, cognitive, and behavioral components. Functional measures included the TFC, Functional

URIC ACID AND HD PROGRESSION Assessment, and Independence Scale. Measures of motor function included the total motor score, maximal dystonia score, and maximal chorea score. Cognitive measures included the Stroop Interference Test, Symbol Digit Modalities Test, and Verbal Fluency Test. Behavior was assessed by frequency and severity of various behaviors, including anxiety, obsessions, and delusions. Supplemental neuropsychological tests included the Brief Test of Attention, Conditional Associative Learning Test (CALT), Hopkins Verbal Learning Test, Trail Making Tests A and B, as well as the Hamilton Depression Inventory.10–14 Blood samples collected during the study were used for routine safety laboratory assessments by a centralized laboratory. Serum UA levels were obtained from these blood samples at baseline and at months 1, 8, 20, and 30. CAG repeat length was determined for subjects who had never been tested, known repeat length was used for those previously tested. Baseline UA levels were categorized into quintiles to minimize the influence of any extreme observations on the results. The outcomes were change in scores from baseline to 30 months for each UHDRS measure and supplemental test. Change in TFC score was considered the primary outcome measure as it has been shown to provide a reliable, valid measure of early HD progression and is commonly used as the primary outcome measure in HD clinical trials.8,9,15 The TFC specifically assesses capacity to work, handle finances, perform domestic chores, and carry out activities of daily living and required care level. Analysis of covariance was used to assess the association between baseline UA quintile and the change in score from baseline to 30 months for each outcome with gender, study site, baseline age, CAG repeat length, and baseline value of the outcome as covariates.16 Models that further adjusted for treatment assignment did not appreciably alter the results and are not presented here. Tests for

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linear trend among the UA quintiles were performed by testing significance of a linear contrast among the adjusted group means in the analysis of covariance models. Since men generally have higher UA levels than women, an interaction term for gender and UA was assessed in additional analyses to determine if the association between UA and functional decline was different for men and women. Regression-based multiple imputation was used to account for missing data for the 38 subjects who withdrew before the 30 month visit. The imputation model included treatment assignment, study site, and values of the outcome variable at all prior visits. The multiple imputation approach appropriately accounts for the uncertainty associated with the imputed values in the computation of standard errors and P-values.17 RESULTS Subjects ranged in age from 18–75 years (mean 47.9 yr); 51% were male. Baseline UA levels ranged from 1.8–9.6 mg/dL (mean 4.5 mg/dl). The average baseline TFC, CAG repeat length, age, and years of education of the subjects were similar across the UA quintiles. Subjects in the highest UA quintile had lower mean total motor scores at baseline than subjects in the first and third quintiles. Caucasians comprised the majority of the sample and were distributed comparably among the 5 groups. As expected, men had higher baseline UA levels than women (Table 1). An independent association controlling for gender, study site, baseline age, CAG repeat length, and baseline TFC score was found between baseline UA quintile and the primary outcome, change in TFC over 30 months (adjusted mean worsening in TFC scores: 3.17, 2.99, 2.95, 2.28, 2.21 from lowest to highest quintile, P 5 0.03 for linear trend, partial R2 5 0.034). A tendency toward less worsening in total motor scores was

TABLE 1. Subject characteristics at baseline by baseline uric acid quintile Uric acid quintile

Sample size Uric acid (mg/dL), range Total functional capacity, mean (SD) Total motor score, mean (SD) CAG repeat length, mean (SD) Age (yr), mean (SD) Education (yr), mean (SD) Caucasian, % Male Gender, %

1st

2nd

3rd

4th

5th

66 1.8–3.3 9.9 (1.6) 33.5 (14.2) 45.4 (3.8) 46.4 (9.7) 13.2 (2.0) 95.5 6.1

63 3.4–4.0 9.8 (1.9) 32.8 (14.2) 46.0 (4.5) 47.0 (11.0) 14.2 (2.5) 93.7 19.1

72 4.1–4.6 10.4 (1.8) 33.2 (14.3) 45.2 (4.8) 47.3 (11.2) 14.0 (3.0) 95.8 61.1

76 4.7–5.5 10.1 (1.9) 29.4 (14.4) 44.2 (2.9) 49.6 (9.0) 14.6 (2.8) 94.7 72.4

70 5.6–9.6 10.6 (1.8) 26.8 (12.5) 44.5 (4.2) 49.1 (11.3) 14.4 (3.3) 95.7 87.1

SD 5 standard deviation

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21.28 20.63 2.30 25.99 0.57 0.28 0.47

13.02 (1.52) 2.26 (0.43) 2.10 (0.67)

(0.54) (2.38) (3.81) (1.15) (0.07) (0.05) (0.62)

21.10 23.82 2.09 24.54 0.59 0.28 1.16 (0.49) (2.55) (4.00) (1.15) (0.07) (0.06) (0.62)

0.70 (0.61) 3.41 (1.85)

(1.47) 26.78 (1.46) (1.07) 24.40 (1.09) (1.73) 211.77 (1.68) (0.89) 23.20 (0.81) (0.95) 25.21 (0.97)

1.44 (0.64) 3.65 (1.93)

26.86 24.86 212.03 24.20 24.86

14.27 (1.57) 2.69 (0.45) 3.15 (0.69) (1.27) (0.93) (1.51) (0.74) (0.79)

20.78 24.79 1.26 24.72 0.43 0.23 20.69

(1.29) (0.89) (1.50) (0.73) (0.78)

0.74 (0.53) 2.82 (1.60)

24.90 23.15 29.86 23.68 26.06

12.15 (1.36) 2.74 (0.38) 2.45 (0.58)

(0.40) 21.60 (0.40) (2.09) 0.66 (2.02) (3.27) 7.28 (3.31) (0.90) 23.79 (0.92) (0.06) 0.51 (0.05) (0.04) 0.31 (0.04) (0.55) 20.86 (0.53)

0.49 (0.54) 2.50 (1.59)

25.86 23.51 29.71 22.08 25.86

11.56 (1.34) 2.15 (0.38) 2.50 (0.57) (1.35) (0.98) (1.60) (0.78) (0.86)

21.01 23.97 0.92 24.40 0.45 0.23 20.06

(0.43) (2.12) (3.14) (0.99) (0.06) (0.05) (0.60)

0.38 (0.58) 1.07 (1.70)

24.34 22.37 27.94 23.50 24.59

9.70 (1.43) 1.75 (0.40) 1.72 (0.63)

0.99 0.80 0.85 0.31 0.16 0.69 0.15

0.36 0.39

0.18 0.10 0.10 0.76 0.93

0.07 0.37 0.30

0.235 0.491 0.384 0.251 0.205 0.369 0.400

0.347 0.366

0.146 0.144 0.170 0.105 0.243

0.249 0.321 0.230

0.224 0.188

0.110

P-value for linear trend Full model R2

0.12 0.37

5th

24.28 (0.59) 24.81 (0.56) 24.14 (0.50) 23.11 (0.51) 23.53 (0.53) 211.31 (1.51) 212.19 (1.46) 212.64 (1.26) 29.48 (1.27) 210.25 (1.38)

22.95 (0.29) 22.28 (0.29)

4th 0.03

22.99 (0.34)

3rd 22.21 (0.31)

23.17 (0.34)

2nd

0.006 0.015 0.012 0.006 0.021 0.012 0.015

0.006 0.010

0.012 0.019 0.023 0.008 0.012

0.030 0.023 0.014

0.015 0.010

0.034

Uric acid partial R2

CALT 5 Conditional Associative Learning Test. Values are adjusted mean change in outcome (standard error) obtained from an analysis of covariance model that included baseline uric acid quintile (categorical), gender, study site, baseline age, CAG repeat length, and the baseline value of the outcome variable.

Primary Outcome Total functional capacity Secondary outcomes Other functional assessments Total functional assessment Independence scale Motor assessments Total motor score Maximal dystonia Maximal chorea Cognitive assessments Stroop color naming Stroop interference test Stroop word reading Symbol digit modalities test Verbal fluency test Behavioral assessments Behavioral frequency total Behavioral frequency x Severity total Neuropsychological tests Brief test of attention CALT trials to criterion CALT number of errors Hopkins verbal learning test Trail making A (log transformed) Trail making B (log transformed) Hamilton depression inventory

1st

Uric acid quintile

TABLE 2. Adjusted mean change in assessments over 30 months by baseline uric acid quintile

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URIC ACID AND HD PROGRESSION also found with increasing UA levels (adjusted mean worsening in scores: 14.27, 13.02, 11.56, 12.15, 9.70 from lowest to highest quintile, P 5 0.07 for linear trend, partial R2 5 0.030). No other secondary outcomes based on cognitive, behavioral, neuropsychological, or depression measures were significantly associated with UA quintile (Table 2). There was no evidence for any of the outcome variables that the association between baseline UA quintile and outcome depended on gender (P > 0.05 for all interaction terms). DISCUSSION This study demonstrated an association between higher baseline UA levels and slower HD progression, particularly as measured by TFC. There was also a modest trend toward less worsening in total motor scores with increasing UA levels. This relationship was not demonstrated with cognitive, behavioral, or neuropsychological outcomes. Further study is needed to confirm these associations as well as to examine possible relationships between UA levels and biologic markers of HD progression when valid and reliable markers are identified. Despite the discovery that HD is a genetic disorder, the etiology of neuronal death in HD as a result of this genetic mutation is unclear. Oxidative damage and metabolic dysfunction have been suggested to have a role in the pathogenesis of HD. The protein product of the genetic mutation in HD, huntingtin, has been suggested to interact with mitochondria resulting in impaired mitochondrial function.18 Reactive oxygen species production appears to be increased in damaged mitochondria.2 UA is known to be an effective scavenger of reactive oxygen species and has the ability to bind iron, an inducer of oxidative stress.3 The antioxidant properties of UA support the possibility of a protective effect of UA levels on progressive neurodegeneration in HD. The initial CARE-HD study concluded that coenzyme Q10, another potentially important antioxidant in the study of HD, did not result in significant slowing in functional decline in early HD when given over a 30 month period. There were observed trends of a small benefit with 600 mg/day of coenzyme Q10; however, a treatment recommendation was not warranted.8 The relationship UA, coenzyme Q10, and other antioxidants may have with HD progression is unclear and future studies targeting plausible biological mechanisms as seen with UA may help clarify this association. Limitations of this study include not being able to control for possible confounders that were not assessed

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in this study. Also, the CARE-HD study was limited to subjects with early HD. It is unclear how disease severity may affect the results and how representative these findings are in a broader HD population. Strengths of this study include the longitudinal design, the rigorous collection of clinical assessments in a controlled trial, the use of a central laboratory, and the relatively large sample size of subjects with HD. UA may have therapeutic implications for slowing the progression of HD. Clinical trials assessing dietary or pharmacologic changes in UA levels may be warranted to confirm and expand on these findings. The observed slowing of HD progression with higher UA levels emphasizes the importance of improving the understanding of this relationship, as well as the role of UA as a potential predictor and modifiable factor affecting the rate of HD progression. Acknowledgments: The CARE-HD study was supported primarily by NIH, NINDS (#NS R01-35284), and also by General Clinical Research Centers (grants RR00052, RR00645, RR00042, RR00044, RR01066, RR07122), AstraZeneca, and Vitaline. We thank the Huntington Study Group CARE-HD investigators and coordinators for their work on this study. Financial Disclosures: Peggy Auinger—none. Karl Kieburtz—Grant support: National Institutes of Health (NEI, NINDS, NIA), Michael J. Fox Foundation, Medivation, Neurosearch, Pfizer; Consultancies: Abbott, Biogen Idec, Ceregene, EMD Serono, FoldRx, Impax, Ipsen, Lilly, Lundbeck, Merz, Neurosearch, Novartis, Orion, Prestwick, ScheringPlough, Solvay, Teva, UCB Pharma, Food and Drug Administration, National Institutes of Health (NINDS); Legal Consulting: Pfizer, Welding Rod Litigation Defendents. Michael P. McDermott - Grant support: National Institutes of Health, Food and Drug Administration, Spinal Muscular Atrophy Foundation, Michael J. Fox Foundation, Muscular Dystrophy Association, Medivation, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Neurosearch Sweden AB; Employment University of Rochester; Consultancies: Boehringer Ingelheim Pharmaceuticals, Inc., Teva Pharmaceuticals, Ltd.; Honoraria: National Institutes of Health; Contracts: National Institutes of Health. No disclosures for this work. Author Roles: Peggy Auinger—research organization and execution; statistical execution, review, and critique; writing of first draft and critical review of manuscript; Karl Kieburtz— research conception, organization, and execution; statistical review and critique; critical review of manuscript; Michael P. McDermott—research organization and execution; statistical design, review, and critique; critical review of manuscript.

REFERENCES 1. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 1981;78:6858–6862.

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2. Beal MF. Mitochondria take center stage in aging and neurodegeneration. Ann Neurol 2005;58:495–505. 3. Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res 1998;53:613–625. 4. Kim TS, Pae CU, Yoon SJ, et al. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2006;21:344–348. 5. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Serum uric acid levels and the risk of Parkinson disease. Ann Neurol 2005;58:797–800. 6. Beal MF, Matson WR, Storey E, et al. Kynurenic acid concentrations are reduced in Huntington’s disease cerebral cortex. J Neurol Sci 1992;108:80–87. 7. Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol 2008;65:716–723. 8. The Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001;57:397–404. 9. The Huntington Study Group. Unified Huntington’s disease rating scale: reliability and consistency. Mov Disord 1996;11:136– 142. 10. Schretlen D, Brandt J, Bobholz JH. Validation of the brief test of attention in patients with Huntington’s disease and amnesia. Clin Neuropsychol 1996;10:90–95. 11. Petrides M. Nonspatial conditional learning impaired in patients with unilateral frontal but not unilateral temporal lobe excisions. Neuropsychologia 1990;28:137–149. 12. Shapiro AM, Benedict RH, Schretlan D, Brandt J. Construct and concurrent validity of the Hopkins verbal learning test-revised. Clin Neuropsychol 1999;13:348–358. 13. Reitan R, Wolfson D. The Halstead-Reitan neuropsychological test battery. In: Wedding D, Horton AM, Webster JS, editors. The Neuropsychological handbook. New York: Springer; 1986. p 134–160. 14. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278–296. 15. Shoulson I, Kurlan R, Rubin A, et al. Assessment of functional capacity in neurodegenerative movement disorders: Huntington’s disease as a prototype. In: Munsat TL, editor. Quantification of neurologic deficit. Boston: Butterworths; 1989. p 271–283. 16. Ravina BR, Romer M, Constantinescu R, et al. The relationship between CAG repeat length and clinical progression in Huntington’s disease. Mov Disord 2008;23:1223–1227. 17. Little RJA, Rubin DB. Statistical analysis with missing data, Second ed. Hoboken: Wiley; 2002. 18. Browne SE, Beal MF. Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 2006;8:2061–2073.

Parkinsonism in Patients with a History of Amphetamine Exposure Chadwick W. Christine, MD,1* Elisabeth R. Garwood, BS,2 Lauren E. Schrock, MD,3 Daniel E. Austin,4 and Charles E. McCulloch, PhD5 1

Department of Neurology, University of California, San Francisco, California, USA; 2Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; 3 Department of Neurology, University of Utah, Salt Lake City, Utah, USA; 4Colby College, Waterville, Maine, USA; 5Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA Abstract: We recently found a higher rate of prolonged amphetamine exposure in patients diagnosed with Parkinson’s disease (PD) than in spouse/caregiver controls. Since distinguishing features have been described in some patients with parkinsonism due to environment exposures (e.g., manganese), we sought to compare the clinical features of PD patients with prolonged amphetamine exposure with unexposed PD patients methcathinone. Prolonged exposure was defined as a minimum of twice a week for ‡3 months, or weekly use ‡1 year. We reviewed the clinical records of patients with PD who had participated in a telephone survey of drug and environmental exposures and compared the clinical features of patients with a history of prolonged amphetamine exposure to patients who had no such exposure. Records were available for 16 of 17 (94%) patients with prior amphetamine exposure and 127 of 137 (92%) of those unexposed. Age at diagnosis was younger in the amphetamine-exposed group (49.8 6 8.2 years vs. 53.1 6 7.4 years; P < 0.05), but other features, including presenting symptoms, initial and later treatments, development of motor fluctuations, and MRI findings were similar between these groups. Because we did not detect clinical features that differentiate parkinsonism in patients with prolonged amphetamine exposure, research to determine whether amphetamine exposure is a risk factor for parkinsonism will require detailed histories of medication and recreational drug use.
2010 Movement Disorder Society Key words: neurotoxin; selective vulnerability; neurotoxicant

*Correspondence to: Dr. Chadwick W. Christine, Department of Neurology, UCSF, 400 Parnassus Avenue, Box 0348, San Francisco, CA 94143. E-mail: [email protected] Potential conflict of interest: Nothing to report. Received 22 April 2009; Revised 19 September 2009; Accepted 30 October 2009 Published online 8 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22915

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PARKINSONISM WITH AMPHETAMINE EXPOSURE

INTRODUCTION Strong genetic causes of Parkinson’s disease (PD) likely account for 10–15% of cases.1 The balance appears to be secondary to environmental factors or a combination of weaker genetic and environmental influences.2 Although pesticide exposure is well established as a risk factor for PD,3 other environmental factors likely exist. Amphetamine drugs have been raised as a possible risk factor for PD.4 They have been used both therapeutically and recreationally since the 1930s and their use is common. In the United States, about 5% of adults 35 years and older have used nonprescribed amphetamines at least once.5 Moreover, they remain accepted treatments for attention-deficit hyperactivity disorder and narcolepsy. Increasing evidence supports a plausible biologic mechanism. For example, in human methamphetamine users, there is loss of dopamine axonal proteins consistent with injury to axon terminals of dopaminergic neurons.6,7 Numerous studies in animals confirm that amphetamine causes acute injury to axon terminals of dopaminergic neurons.8,9 In a study of environmental exposures, we found a higher rate of prolonged amphetamine exposure in patients with PD than spouse or caregiver controls.10 We undertook this study to determine if the parkinsonian phenotype of exposed patients differed from those who were not exposed.

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Subjects were excluded from further analysis if a diagnosis of atypical parkinsonism was determined subsequent to the initial study. Records were reviewed to determine the following measurements (if appropriate): Age when first PD symptom developed, type of first symptoms, age at first use and type of first PD medication, age when levodopa (L-dopa) treatment began, age when motor fluctuations developed, age when the patient underwent treatment with deep brain stimulation (DBS), age dementia was diagnosed, age when last evaluated at UCSF, and age of death. MRI reports from unexposed patients were selected to match age and gender with the available MRI reports from exposed patients. Reports were reviewed for description of atrophy, basal ganglia abnormalities, and presence of foci of T2 hyperintensity. In addition, all available scans of those with prolonged exposure were reviewed for evidence of atypical findings. The analysis includes observations from all subjects, even from those for whom incomplete data was available. Proportions were compared using Fisher’s exact test. Differences in means between the two groups were compared using Student’s t-test. Time from diagnosis to event times were analyzed using the log rank survival test, and was censored on death for nonfatal outcomes. Hazard ratios were determined using Cox proportional hazards regression. All data analyses were performed with Stata 10. RESULTS

PATIENTS AND METHODS We reviewed all available hospital and outpatient records from subjects diagnosed with PD who participated in our prior case–control study of environmental and chemical exposures.10 In the original study, subjects were asked a number of questions regarding prior medication use, environmental exposures, and other health-related behaviors. The UCSF Institutional Review Board approved both the original survey and this follow-up study. To be eligible for the initial study, subjects must have been evaluated in the UCSF Neurology Practice between January 2001 and June 2004 and have received a diagnosis of ‘‘probable idiopathic PD’’ between the ages of 40 and 64 according to established clinical criteria.11 Amphetamine exposure was defined as prior use of amphetamine, methamphetamine, or dextroamphetamine. Prolonged exposure was defined as a minimum of twice a week ‡3 months, or weekly use ‡1 year.

Four subjects in the nonexposed group were excluded from analysis because atypical features became apparent and the diagnosis was changed to atypical parkinsonism. Records were available for 16 of 17 (94%) with prolonged amphetamine exposure and 127 of 137 (92%) who had no exposure. Amphetamine was used for a prescribed purpose by seven subjects, while nine used it recreationally. Age at diagnosis, gender, age at onset, and presenting symptoms were similar in subjects with and without amphetamine exposure (Table 1). Because of the small number of exposed subjects and the similarities between the prescribed and nonprescribed groups, we did an analysis comparing all subjects with prolonged amphetamine exposure to unexposed subjects. In this analysis, the age at diagnosis of PD was younger in the amphetamine exposed group than the nonexposed group (49.8 6 8.2 years vs. 53.1 6 7.4 years; P < 0.05). Proportions of patients receiving initial treatments and of those reaching disease hallmarks (wearing off, dyskinesias, dementia, and

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C.W. CHRISTINE ET AL. TABLE 1. Demographic characteristics, initial symptom(s) at diagnosis, and treatment of subjects according to prolonged amphetamine exposure

Male Age at initial symptom Age at diagnosis Asymmetrical symptoms Tremor Bradykinesia Rigidity Gait abnormality Initial treatment Amantadine Monamine oxidase inhibitor Dopamine agonist Anticholinergic Later treatments Levodopa Deep brain stimulation Disease progression Wearing off Dyskinesia Dementia

Not exposed (n 5 137)

Prescribed amphetamine (n 5 7)

Prescribed amphetamine versus not exposed

Nonprescribed use (n 5 9)

Nonprescribed use versus not exposed

N (%)

N (%)

P

N (%)

P

85/137 (62%) 51.3 6 7.5 53.1 6 7.4 127/131 (97%) 87/131 (66%) 49/131 (37%) 18/131 (14%) 7/131 (5%)

2/7 (29%) 49.6 6 5.9 50 6 5.8 7/7 (100%) 5/7 (71%) 3/7 (43%) 1/7 (14%) 0/7 (0%)

0.11 0.27a 0.14a 1.00 1.00 1.00 1.00 1.00

5/9 (56%) 47.2 6 9.5 49.7 6 10 7/8 (88%) 5/9 (56%) 4/9 (44%) 0/9 (0%) 1/9 (11%)

0.73 0.06a 0.09a 0.26 0.49 0.73 0.60 0.42

0/7 2/7 1/7 1/7

(0%) (29%) (14%) (14%)

1.00 0.64 1.00 0.56

1/9 1/9 1/9 2/9

(11%) (11%) (11%) (22%)

0.50 0.69 0.68 0.27

116/133 (87%) 52/131 (40%)

6/7 (86%) 3/7 (43%)

1.00 1.00

7/9 (78%) 3/9 (33%)

0.35 1.00

73/132 (55%) 59/131 (45%) 15/130 (12%)

4/7 (57%) 4/7 (57%) 1/7 (14%)

1.00 0.70 0.59

7/9 (78%) 4/9 (44%) 0/8 (0%)

0.30 1.00 0.60

9/130 27/131 30/131 14/131

(7%) (21%) (23%) (11%)

P-values from Fisher’s exact test unless otherwise noted. a Student’s t-test.

use of DBS) were similar between the two groups. Moreover, survival analysis curves were prepared for a number of endpoints, including time to first treatment, time to L-dopa, time to wearing off, time to development of dyskinesia, time to dementia, and time to DBS. None of the survival analyses demonstrated a significant difference between groups. All subjects responded well to standard PD treatments including DBS. Brain MRI reports were available for 11 exposed and unexposed patients; the mean age at the time of scan was 54.5 in the exposed group and 53.7 in the unexposed group. Rates of reported foci of T2 prolongation were similar (54% in the exposed vs. 46% in the unexposed) and each cohort had one patient with diffuse atrophy (9%). Review of the images in 10 exposed subjects by one author (C.W.C.) revealed no consistent abnormalities in the basal ganglia or substantia nigra. DISCUSSION In this study, we were unable to identify distinguishing features in subjects with prolonged exposure to amphetamine. Although we found a slightly earlier age at diagnosis in the amphetamine exposed group, no clinical or obvious MRI findings distinguished these two groups. Moreover, the response to treatments and rate

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of development of disease complications (motor fluctuations and dementia) were similar. However, because of the relatively small sample size and retrospective design, differences between these groups cannot be excluded entirely. Even though we did not have high power for all outcomes tested, the narrow Cox confidence intervals (data not shown) for a number of measures (e.g., initiation of pharmacological treatment, initiation of L-dopa) provides assurance that these cohorts are relatively similar for these outcomes. These findings contrast with parkinsonism described in manganese toxicity—as described in some welders,12 some with liver failure,13 and some methcathinone users14—in which a number of clinical features differ from PD. An autopsy study of young methamphetamine users found that dopamine levels were reduced more in the caudate than the putamen, a pattern opposite that seen in PD.15 The authors use this finding to explain why parkinsonism is not a feature of young human methamphetamine users (mean age at autopsy, 31 years). However, since dopaminergic neurons are lost with aging,16 their finding of a 50% reduction of putaminal dopamine does not contradict our hypothesis that by damaging dopaminergic neurons, remote amphetamine exposure is risk factor for the later development of PD.

PARKINSONISM WITH AMPHETAMINE EXPOSURE Our inability to identify unique clinical features in the amphetamine-exposed individuals does not preclude amphetamine as a risk factor for PD. However, the lack of a distinct clinical phenotype or biological marker may prevent clinicians who do not obtain a detailed history of amphetamine exposure from appreciating this potential association. Further research to determine whether amphetamine exposure is a risk factor for PD will require detailed histories of prescribed and recreational amphetamine exposure. Acknowledgments: C.W.C was supported by UCSF Department of Neurology funds and support from Genzyme through a grant to the University of California and a research grant from Amgen. E.R.G. was supported by Doris Duke Charitable Foundation Fellowship. L.E.S. has been supported by the San Francisco VA PADREC. D.E.A.’s work was selfsupported. C.E.M. was supported by numerous NIH grants and a research grant from Amgen Inc.

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10. Garwood ER, Bekele W, McCulloch CE, Christine CW. Amphetamine exposure is elevated in Parkinson’s disease. Neurotoxicology 2006;27:1003–1006. 11. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33–39. 12. Josephs KA, Ahlskog JE, Klos KJ, et al. Neurologic manifestations in welders with pallidal MRI T1 hyperintensity. Neurology 2005;64:2033–2039. 13. Klos KJ, Ahlskog JE, Josephs KA, Fealey RD, Cowl CT, Kumar N. Neurologic spectrum of chronic liver failure and basal ganglia T1 hyperintensity on magnetic resonance imaging: probable manganese neurotoxicity. Arch Neurol 2005;62:1385– 1390. 14. Stepens A, Logina I, Liguts V, et al. A Parkinsonian syndrome in methcathinone users and the role of manganese. N Engl J Med 2008;358:1009–1017. 15. Moszczynska A, Fitzmaurice P, Ang L, et al. Why is Parkinsonism not a feature of human methamphetamine users? Brain 2004;127:363–370. 16. Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O. Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem 1992;58:642–648.

Author Roles: C.W.C. conceived, designed, and organized the study, gathered and analyzed data, and wrote the first draft and final draft of the manuscript. E.R.G. gathered data, performing the statistical analysis, and reviewed and critiqued the manuscript. L.E.S. helped in the initial design of the study gathered data, and reviewed critiqued a final draft of the manuscript. D.E.A. gathered study data and reviewed and critiqued the final draft of the manuscript. C.E.M. was involved in the study design, statistical analysis, and extensively reviewed and critiqued the manuscript.

REFERENCES 1. Gasser T. Update on the genetics of Parkinson’s disease. Mov Disord 2007;22 (Suppl 17):S343–S350. 2. Chade AR, Kasten M, Tanner CM. Nongenetic causes of Parkinson’s disease. J Neural Transm Suppl 2006;70:147–151. 3. Elbaz A, Moisan F. Update in the epidemiology of Parkinson’s disease. Curr Opin Neurol 2008;21:454–460. 4. Guilarte TR. Is methamphetamine abuse a risk factor in Parkinsonism? Neurotoxicology 2001;22:725–731. 5. Substance Abuse and Mental Health Services Administration OoAS. National household survey on drug abuse: main findings 1998, Rockville, MD: US Department of Health and Human Services; 2002. p 32. 6. Mccann UD, Wong DF, Yokoi F, Villemagne V, Dannals RF, Ricaurte GA. Reduced striatal dopamine transporter density in abstinent methamphetamine and methcathinone users: evidence from positron emission tomography studies with [11C]WIN35,428. J Neurosci 1998;18:8417–8422. 7. Wilson JM, Kalasinsky KS, Levey AI, et al. Striatal dopamine nerve terminal markers in human, chronic methamphetamine users. Nat Med 1996;2:699–703. 8. Davidson C, Gow AJ, Lee TH, Ellinwood EH. Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment. Brain Res Brain Res Rev 2001;36:1–22. 9. Ricaurte GA, Mechan AO, Yuan J, et al. Amphetamine treatment similar to that used in the treatment of adult attention-deficit/ hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates. J Pharmacol Exp Ther 2005;315:91–98.

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Long-Term Deep Brain Stimulation for Essential Tremor: 12-Year Clinicopathologic Follow-Up Daniel J. DiLorenzo, MD, PhD,1 Joseph Jankovic, MD,2* Richard K. Simpson, MD,1 Hidehiro Takei, MD,3 and Suzanne Z. Powell, MD3 1 Department of Neurosurgery, The Methodist Hospital, Houston, Texas, USA; 2Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; 3 Department of Pathology, The Methodist Hospital, Houston, Texas, USA

Video

Abstract: We describe the clinical course and postmortem pathological findings in a patient with essential tremor (ET) treated with deep brain stimulation (DBS) for 12 years. This 75 year old woman had a 13-year history of progressive ET prior to implantation of bilateral quadripolar DBS electrodes in the region of her ventral intermediate thalamic nuclei in 1996, producing immediate relief of arm tremor. Histopathological examination of the brain, performed 12 years after the initial implantation, demonstrated electrode catheter tracts rimmed by 20–25 micron fibrous sheaths, with multinucleated giant cells and reactive gliosis. Lymphocytic infiltration was seen by L26 immunoreactivity with CD3 (T cells) staining predominating over CD20 (B cells). Cerebellar axonal spheroids and Purkinje cell loss were found. The minimal foreign body reaction and gliosis around the electrodes 12 years after implantation supports the long-term safety of DBS. The case represents the longest reported follow-up with autopsy examination after DBS and confirmed histological changes associated with ET.
2010 Movement Disorder Society

Additional Supporting Information may be found in the online version of this article. *Correspondence to: Joseph Jankovic, MD, Baylor College of Medicine, Department of Neurology, The Smith Tower, Suite 1801, 6550 Fannin, Houston, Texas 77030, USA. E-mail: [email protected] Potential conflict of interest: Dr. Jankovic has received research grants from Medtronic and St. Jude Medical. Dr. DiLorenzo is the founder of and stockholder of two neural implant / neurostimulator companies: NeuroVista (originally NeuroBionics, then BioNeuronics) and Barinetics. Dr. Simpson is a consultant and speaker for Medtronic. Drs. Powell and Taki have nothing to disclose. Received 19 April 2009; Revised 18 October 2009; Accepted 6 November 2009 Published online 8 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22935

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Key words: deep brain stimulation; essential tremor; postmortem; clinicopathologic

Despite widespread acceptance of deep brain stimulation (DBS) for treatment of neurological disorders for over a quarter century, the long-term effects of electrode implantation and stimulation of human brain have not been well characterized, partially because of paucity of clinicopathologic data on patients treated with DBS. We describe the clinical course and postmortem brain gross and histological findings in a patient following 12-year DBS treatment for essential tremor (ET). This case, which represents the longest follow-up of DBS with clinicopathologic analysis, describes brain autopsy findings in ET and provides insights into long-term brain-electrode interactions.

METHODS Patient Data The patient was a right-handed woman who initially presented in 1983 at age 62 yr with left hand tremor while holding objects, with progression to involve the right hand 2 years later. She was diagnosed with ET by a neurologist 9 years after the onset of her tremor but failed to respond adequately to propranolol, primidone, and clonazepam. By 1995, she was disabled by her tremor as she had marked difficulty eating and drinking, and was embarrassed by her tremor in public. At age 75 yr, after 13 years of progressive symptoms, she underwent implantation of a quadripolar DBS electrode (Model 3382; Medtronic, Minneapolis, MN) into the region of her left ventral intermediate (VIM) thalamic nucleus in January 1996 for her right and dominant sided arm tremor, according to previously described method.1 This quadripolar electrode had four platinum/iridium contacts, each with a length of 2.5 mm and an inter-electrode spacing of 1 mm. The AC-PC line was 25.9-mm long. The left VIM nucleus target coordinates were 12 mm lateral to midline and 1 mm inferior to and 3 mm posterior to the midcommissural point. She had marked improvement in her right hand tremor and modest improvement in the left (ipsilateral) hand (Video). Seven months following her first DBS implantation, she underwent DBS implantation on the right VIM to control the left sided tremor. The right VIM target coordinates were 13 mm lateral to midline and 1 mm below and 4 mm posterior to the mid-commissural point.

DBS FOR ET WITH 12-YEAR CLINICOPATHOLOGIC FOLLOW-UP She experienced excellent control of her ET bilaterally, with the exception of two temporary periods of hardware failure. The left VIM intracranial electrode fractured at 15 months after initial implantation and was replaced 2 months later. The fracture occurred in the intracranial portion of the lead, 2.8 cm from the proximal end and involved all four conductor wires. The right implantable pulse generator (IPG) malfunctioned in February 1999 and was promptly replaced. This was characterized by intermittent lapsing of the stimulation current and its occasional restoration by the patient applying the pressure on the chest over the IPG. Both the original and replacement were Itrel II IPGs (Medtronic). Her most recent stimulation parameter adjustments, on January 16, 2008, were as follows: right VIM 2.8 volts, 135 Hz, and 60 ls pulse width, with case positive and electrode 0 negative. Electrode impedances were 1,340, 1,340, 1,284, and 1,467 ohms with respect to the case, respectively, for electrodes 0 to 3. Left VIM settings were 2.5 volts, 185 Hz, and 90 ls pulse width, with case positive and electrode 2 negative. Electrode impedances were >2,000, >2,000, 1,400, and 1,834 ohms with respect to the case, respectively, for electrodes 0 to 3; from these last measurements, left electrodes 0 and 1 may have been fractured. Impedances were measured using nominal currents delivered by the IPG in test mode. A brain magnetic resonance imaging (MRI), performed on June 29, 2007, as part of routine evaluation of anatomical structures and electrode placement, demonstrated the following electrode tip positions: right— lateral: 11.3 mm, posterior: 4.8 mm, inferior: 5.3 mm; left—lateral: 11.9 mm, posterior: 3.8 mm, inferior: 5.7 mm. These coordinates are with respect to the midcommisural point (center of the AC-PC line). These measurements were obtained using a Siemens Leonardo workstation, which facilitates cross-referencing of images in three planes. The process comprised the following steps: (1) The midsagittal plane was aligned with the third ventricle in both the axial and coronal projections. (2) On the midsagittal image, a line was drawn from the center of the AC to the PC, and the midpoint is indicated by the workstation. (3) The central axial plane is aligned with the AC-PC line. (4) The central coronal plane, which is perpendicular to the axial plane, is selected to pass through the midpoint of the AC-PC line. (5) Images are reformatted into sets of axial, coronal, and sagittal images, parallel to these defined axes. (6) Electrode tips are defined as the center of the black susceptibility artifact on the most caudal or distal electrode (Fig. 1).

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Although her tremor amplitude was at least 75% lower with the DBS turned on compared that with the DBS off, she developed postural instability, which confined her to a wheelchair. In January 2008, she was admitted for physical therapy for muscle disuse atrophy but was discharged after 6 weeks with minimal improvement. She died in her sleep on March 29, 2008, and the brain was harvested within 12 hours.

RESULTS Neuropathology The weight of the brain was 1200 g after immersion fixation for 1 week in 20% formalin. It was carefully sectioned in the coronal plane, tissue blocks were embedded in paraffin, and 4 micron sections were cut and stained (Fig. 2).

Gross Neuropathology The electrodes were visible entering the surface of the middle gyri in the frontal cortices and terminating in the right thalamus just above the substantia nigra and extending to the left substantia nigra. Electrodes were left in place during initial brain cutting to preserve the spatial relationship between electrode contacts and anatomical structures, as seen in Figure 2a–f. Examination of the gross brain specimen sections confirms radiological findings with an electrode tip location 5 mm below the intended target on the left. The electrode tip is seen projecting from the left substantia nigra in Figure 2d, and a corresponding tract is seen in the caudal portion of the left substantia nigra in the brainstem in Figure 2b. The electrode diameter is 1.27 mm, and the location is 8.5 mm lateral to midline on the left and 2 mm lateral to the lateral border of the red nucleus, in the posterolateral edge of the substantia nigra. As seen in Figure 2c,e, bilateral electrodes pass along the lateral edge of the anterior thalamus at the level of the mammillary bodies, directed slightly posteriorly and about 12 degrees medially. The proximal electrodes (2 and 3) are in or near the VIM nucleus of the thalamus, and the distal electrodes are in (left) or adjacent and above (right) the substantia nigra. As seen in Figure 2e, the electrode trajectory places the distal electrodes in or adjacent to the subthalamic nuclei (STN) bilaterally. The left distal electrode center is 2.5 mm from the lateral border of the red nucleus, seen in Figure 2b,d,e. Tissue activation volumes may be estimated as a sphere with a radius of 2.5 mm.2 With final stimulation settings using right

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FIG. 1. MRI of the brain at 11 years and 5 months (June 2007) after initial implantation. Electrode is visible in thalamus, or just below, bilaterally (left: axial T1, upper right: sagittal T1, lower right: coronal T1).

electrode 0 negative with respect to the case, it is possible that some stimulation of the substantia nigra and red nucleus, as well as the STN may have occurred. Similarly, with final stimulation settings using left electrode 2 negative with respect to the case, stimulation of structures including the substantia nigra and red nucleus, as well as the STN may have occurred. VIM stimulation is likely to have been achieved with stimulation of more rostral electrodes, i.e., electrodes 3 and 2, bilaterally. Histopathology Histopathologic analysis of the thalami demonstrated fibrous sheaths lining the electrode tracts with thicknesses of 20 and 25 l on the right and left, respectively. Fibrillary gliosis did not extend beyond 500 l of the tissueelectrode interface. Reactive astrocytes, characterized by multiple long delicate processes highlighted with GFAP immunostaining, were found bilaterally within 1 mm of the tissue-electrode interface, more on the right. Numerous macrophages (KP-1 immunostain) and some multinucleated giant cells were found bilaterally. In the implanted thalamic sections, numerous mononuclear leukocytes, highlighted with leukocyte common antigen, were seen bilaterally. T lymphocytes

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(CD3 immunoreactive) were more frequently seen than B lymphocytes (L26 immunoreactive). No axonal spheroids, hemorrhage, or perifocal edema were noted on hematoxylin and eosin stained sections in the thalami. Patchy loss of cerebellar Purkinje cells was found, with ‘‘empty baskets,’’ associated mild Bergmann’s gliosis, occasional ‘‘torpedos’’ (axonal spheroids of Purkinje cells), and occasional phosphorylated neurofilament protein immunoreactive Purkinje cells (Fig. 3). Other findings included accentuated axonal terminals of basket cells around some of the Purkinje cells and very rare ectopic Purkinje cells within the molecular layer, both of which were highlighted with phosphorylated neurofilament proteins. No alpha synuclein immunoreactive Lewy bodies were identified in the cerebellum or brainstem. Other cerebellar findings included slightly widened sulci, severe atherosclerosis, partially gliotic dentate nucleus amidst otherwise well preserved nuclei, scattered light yellow finely granular globular structures adjacent to the Purkinje cell soma, some of which appeared to be located within the dendrites of Purkinje cells, and gliotic deep white matter. The midbrain contained a well-pigmented and populated substantia nigra. Alpha synuclein immunostain was negative, and no Lewy bodies were identified. Sections

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FIG. 2. Gross brain specimen revealing normal gross anatomy and DBS electrode tip position. (A) Ventral brain surface sectioned at the midbrain revealing normal brain size and a DBS electrode tip in the left posterolateral substantia nigra. (B) Caudal brainstem and cerebellum section distal to midbrain section revealing normal gross anatomy and electrode tract in the posterolateral left substantia nigra. (C) Ventral surface of coronal brain slice through mammillary bodies revealing proximal portion of bilateral DBS electrode arrays passing along the lateral aspects of the thalami. (D) Dorsal and caudal surfaces of caudal portion of coronal brain slice revealing left DBS electrode tip in the posterolateral portion of the substantia nigra. (E) Labeled neural structures corresponding to C with dotted lines representing estimated electrode trajectories along lateral thalami (Th) and STN. (F) Labeled neural structures corresponding to D, with left DBS electrode tip in left posterolateral substantia nigra (SN). Labels: LV, lateral ventricle; 3V, third ventricle; Th, thalamus; Ca, caudate; Fo, fornix; LD, lateral dorsal nucleus of the thalamus; DM, dorsomedial nucleus of the thalamus; Vpm, ventralposteromedial (VPM) nucleus of the thalamus; STN, subthalamic nucleus; MB, mammillary body; OT, optic tract; Put, putamen; GPe, globus pallidus externus; GPi, globus pallidus internus; CP, cerebral peduncle; SN, substantia nigra; RN, red nucleus; ELL, electrode, left. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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FIG. 3. Histopathology of cerebellum. Large high power image (1003) demonstrates a ‘‘torpedo’’ (axonal spheroid), indicated with a thin arrow and highlighted with neurofilament due to damage to Purkinjie cells. Low power inset (203): hematoxylin and eosin demonstrating significant loss of Purkinjie cells, indicated with block arrows in both inset and high power image. Both are nonspecific findings in ET. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

of the pons showed well-pigmented and populated loci cerulei, with mild pigment incontinence. Tau immunostain revealed rare globose tangles in the loci cerulei. DISCUSSION This case, notable for a more than a 12-yr (146 mo) interval between initial implantation and autopsy, represents the longest follow-up of a patient implanted with DBS with postmortem clinicopathologic analysis. The second longest reported follow-up after DBS implantation, reported in 2008, is 6 years.3 Similar to other reports of DBS in ET,4 our patient showed marked reduction not only of the contralateral tremor but also realized modest improvement in her ipsilateral tremor (Video).5,6 Our case is also notable for being the second case in which postmortem analysis was performed on a patient implanted with DBS for ET. The first case, reported in 2000, had a 16month follow-up; however, no neuropathologic analysis of the cerebellum was presented in that case.7 Furthermore, this case adds to the growing literature characterizing neuropathologic findings in ET and is the first case in which cerebellar pathology has been analyzed in an ET patient who has undergone DBS implantation. Many aspects of ET, including clinical features, imaging studies, pathologic findings, and DBS results

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point to the cerebellum as playing an important role in the pathophysiology of this disorder. Fractional anisotropy, a metric of white matter organization, is reduced in diffusion tensor imaging in the cerebellum and in multiple regions in the brainstem, including the anterolateral pons, retrorubral area of the midbrain, and deep white matter of the cerebrum.8 Bilateral activation of the cerebellum in ET has been demonstrated by functional MRI.9 ET has been found to resolve acutely following a cerebellar infarct.10 Symptoms of ET are effectively treated with high-frequency stimulation of thalamic targets, including the VIM, which comprise cerebellar outflow pathways.11,12 Despite the high prevalence of ET, few patients have been studied at autopsy. Until recently, it was believed that there were no identifiable changes in the brains of patients with ET.13 Cerebellar pathology, however, has recently been described in the brains of patients with ET.14–16 In one of the largest clinicopathologic studies, involving 33 ET and 21 control brains, the major cerebellar pathological changes were found to be a marked reduction in the number of Purkinje cells and a 7-fold increase in Purkinje cell torpedoes.17 Other findings include degeneration of the dentate nucleus, Purkinje cell heterotopias, and dendrite swellings.17

DBS FOR ET WITH 12-YEAR CLINICOPATHOLOGIC FOLLOW-UP The long-term MRI and postmortem follow-up in our case reveal an electrode position, 5 mm more caudal than originally intended. Electrode migration was reported by Henderson et al.18 and provided information on the centromedian-parafascicular complex in a case of mistargeting of the VIM with a DBS electrode. In this case, it is possible that some component of efficacy may have been conferred through activation of one of the nuclear structures or fiber pathways in the vicinity of the electrodes, more caudal to the originally targeted VIM. These may potentially include such structures as the red nucleus, substantia nigra, adjacent white matter fiber tracts, STN, and zona incerta, Indeed, DBS targeting the latter two structures have been reported to be effective in the control of tremor.3,19,20 {Plaha, 2008 #68} {Diamond, 2007 #69}. Further evaluation of these and other targets in the treatment of disabling tremors is warranted.

LEGENDS TO THE VIDEO Segment 1. Patient within 1 month after implantation of left VIM DBS showing high-amplitude distal and proximal arm tremor. Right arm tremor markedly improved when the DBS was turned on, but there was also a modest improvement in the left (ipsilateral) tremor.

Acknowledgments: We thank support provided by the National Parkinson Foundation (NPF) to the NPF Center of Excellence at Baylor College of Medicine (to J.J.). We also thank Dr. Susan Weathers for providing Cartesian coordinate measurements of electrode tip locations from the MRI image presented in this case. Financial Disclosures: Dr. Jankovic has received research support from Allergan, Inc; Boehringer-Ingelheim, Inc; Ceregene, Inc; Chelsea Therapeutics; Helis Foundation; Huntington’s Disease Society of America; Huntington Study Group; Impax Pharmaceuticals; Ipsen Limited; Lundbeck; Medtronic; Merz Pharmaceuticals; National Institutes of Health; National Parkinson Foundation; Neurogen; Novartis; Ortho-McNeil; St. Jude Medical; Teva; University of Rochester; Parkinson Study Group. Dr. Jankovic has served as a consultant to Allergan, Inc; Biovail; Michael J Fox Foundation for Parkinson Research; Merz Pharmaceuticals; Lundbeck Inc; Teva. Dr. DiLorenzo is the founder of and stockholder of two neural implant / neurostimulator companies: NeuroVista (originally NeuroBionics, then BioNeuronics) and Barinetics. Dr. Simpson is a consultant and speaker for Medtronic. Drs. Powell and Taki have nothing to disclose. Author’s Roles: Daniel J. DiLorenzo, Research Project: Organization and Execution; Manuscript: Writing of Initial Draft. Joseph Jankovic, Research Project: Conception and Organization; Manuscript: Review and Critique. Richard K

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Simpson, Manuscript: Review and Critique. Hidehiro Takei, Research Project: Execution; Manuscript: Review and Critique. Suzanne Z Powell, Manuscript: Review and Critique.

REFERENCES 1. Kenney C, Simpson R, Hunter C, Ondo W, Almaguer M, Davidson A, Jankovic J. Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 2007;106:621–625. 2. McIntyre CC, Mori S, Sherman DL, Thakor NV, Vitek JL. Electric field and stimulating influence generated by deep brain stimulation of the subthalamic nucleus. Clin Neurophysiol 2004;115: 589. 3. Guehl D, Vital A, Cuny E, Spampinato U, Rougier A, Bioulac B, Burbaud P. Postmortem proof of effectiveness of zona incerta stimulation in Parkinson disease. Neurology 2008;70(16 Pt 2): 1489–1490. 4. Pahwa R, Lyons KE, Wilkinson SB, et al. Long-term evaluation of deep brain stimulation of the thalamus. [See comment]. J Neurosurg 2006;104:506–512. 5. Ondo W, Dat Vuong K, Almaguer M, Jankovic J, Simpson RK. Thalamic deep brain stimulation: effects on the nontarget limbs. Mov Disord 2001;16:1137–1142. 6. Kovacs N, Pal E, Merkli H, Kellenyi L, Nagy F, Janszky J, Balas I. Bilateral effects of unilateral thalamic deep brain stimulation: a case report. Mov Disord 2008;23:276–279. 7. Boockvar JA, Telfeian A, Baltuch GH, et al. Long-term deep brain stimulation in a patient with essential tremor: clinical response and postmortem correlation with stimulator termination sites in ventral thalamus. Case report. J Neurosurg 2000;93:140– 144. 8. Shin DH, Han BS, Kim HS, Lee PH. Diffusion tensor imaging in patients with essential tremor. AJNR Am J Neuroradiol 2008;29: 151–153. 9. Bucher S, Seelos K, Dodel R, Reiser M, Oertel W. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol 1997 1997;41:32–40. 10. Dupuis M, Delwaide P, Boucquey D, Gonsette R. Homolateral disappearance of essential tremor after cerebellar stroke. Mov Disord 1989;4:183–187. 11. Schuurman PR, Bosch DA, Bossuyt PM, et al. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor.[See comment]. N Engl J Med 2000;342:461– 468. 12. Benabid A, Pollak P, Seigneuret E, Hoffmann D, Gay E, Perret J. Chronic VIM thalamic stimulation in Parkinson’s disease, essential tremor, and extra-pyramidal dyskinesias. Acta Neurochir Suppl 1993;58:39–44. 13. Lambert D, Waters C. Essential tremor. Curr Treat Opt Neurol 1999;1:6–13. 14. Louis ED, Vonsattel JP, Honig LS, Lawton A, Moskowitz C, Ford B, Frucht S. Essential tremor associated with pathologic changes in the cerebellum. Arch Neurol 2006;63: 1189–1193. 15. Axelrad JE, Louis ED, Honig LS, et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol 2008;65:101–107. 16. Louis ED, Vonsattel JP. The emerging neuropathology of essential tremor. Mov Disord 2008;23:174–182. 17. Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130(Pt 12):3297–3307. 18. Henderson JM, O’Sullivan DJ, Pell M, Fung VS, Hely MA, Morris JG, Halliday GM. Lesion of thalamic centromedian-parafascicular complex after chronic deep brain stimulation. Neurology 2001;56:1576–1579.

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19. Plaha P, Khan S, Gill SS. Bilateral stimulation of the caudal zona incerta nucleus for tremor control. J Neurol Neurosurg Psychiatry 2008;79:504–513. 20. Diamond A, Shahed J, Jankovic J. The effects of subthalamic nucleus deep brain stimulation on parkinsonian tremor. J Neurol Sci 2007;260:199–203.

B Cell Depletion Therapy for New-Onset OpsoclonusMyoclonus Michael R. Pranzatelli, MD,1* Elizabeth D. Tate, C-FNP, MN,1 Jennifer A. Swan, BS,1 Anna L. Travelstead, BS, MT,2 Jerry A. Colliver, PhD,3 Steven J. Verhulst, PhD,3 Carl J. Crosley, MD,4 William D. Graf, MD,5 Suja A. Joseph, MD,6 Howard M. Kelfer, MD,7 and G. Praveen Raju, MD, PhD8 1 National Pediatric Myoclonus Center and Departments of Neurology, Southern Illinois University School of Medicine, Springfield, Illinois, USA; 2Flow Cytometry Facility, Southern Illinois University School of Medicine, Springfield, Illinois, USA; 3Biostatistics and Research Consulting, Southern Illinois University School of Medicine, Springfield, Illinois, USA; 4Department of Neurology, SUNY, Syracuse, New York, USA; 5Section of Child Neurology, Children’s Mercy Hospitals and Clinics, Kansas City, Missouri, USA; 6 Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; 7Department of Neurology, Cook Children’s Medical Center, Fort Worth, Texas, USA; 8 Department of Pediatrics, Harvard Medical School, Children’s Hospital Boston, Boston, Massachusetts, USA

Video Abstract: Twelve immunotherapy-naı¨ve children with opsoclonus-myoclonus syndrome and CSF B cell expansion received rituximab, adrenocorticotropic hormone (ACTH), and IVIg. Motor severity lessened 73% by 6 mo and 81% at 1 yr (P < 0.0001). Opsoclonus and action myoclonus disappeared rapidly, whereas gait ataxia and some other motor components improved more slowly. ACTH dose was tapered by 87%. Reduction in total CSF B cells was profound at 6 mo (-93%). By study end, peripheral B cells Additional Supporting Information may be found in the online version of this article. *Correspondence to: Michael R. Pranzatelli, SIU-SOM, P.O. Box 19643, Springfield, Illinois 62794-9643. E-mail: [email protected] Potential conflict of interest: Dr. Pranzatelli has clinical trial contracts and/or research grants from Genentech/IDEC and Questcor. He was a paid ad hoc consultant for two Genentech B cell conferences. Received 19 May 2009; Revised 27 October 2009; Accepted 9 November 2009 Published online 8 January 2010 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.22941

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returned to 53% of baseline and serum IgM levels to 63%. Overall clinical response trailed peripheral B cell and IgM depletion, but improvement continued after their levels recovered. All but one non-ambulatory subject became ambulatory without additional chemotherapy; two relapsed and remitted; four had rituximab-related or possibly related adverse events; and two had low-titer human antichimeric antibody. Combination of rituximab with conventional agents as initial therapy was effective and safe. A controlled trial with long-term safety monitoring is indicated.
2010 Movement Disorder Society Key words: ACTH; anti-B cell agent; dancing eyes; Kinsbourne syndrome; neuroblastoma; paraneoplastic syndrome; rituximab

The unique combination of opsoclonus and myoclonus has come to connote a paraneoplastic syndrome and B cell pathology within the CNS.1 Treatment failure, partial response, and neurological relapse compromise the outcome of opsoclonus-myoclonus syndrome (OMS).2 Rituximab, the prototypic chimeric anti-B cell monoclonal antibody (anti-CD20), has been applied to the therapy of various autoimmune neurological disorders.3 We demonstrated previously that its adjunctive use treats the characteristic CSF B cell expansion in pediatric OMS4 with clinical benefit,5–7 as recent case reports attest.8–11 This study was designed to look at the feasibility and safety of combining rituximab together with adrenocorticotropic hormone (ACTH) and IVIg, the two most commonly used conventional therapies for OMS,2 as initial therapy for untreated patients. Such an approach to gaining more complete neurological remission and preventing relapse of OMS is new. PATIENTS AND METHODS Study Design This was a 1-yr, investigator-sponsored, open- and off-label, prospective study, with video-documented evaluations and blinded scoring of clinical efficacy. The primary study end point was preset at 6 mo after the final rituximab, because cerebrospinal fluid (CSF) testing also was done then. ‘‘Relapse’’ was defined as distinct OMS worsening or symptom reappearance lasting at least 72 h. Failure to walk within 6 mo or respond to measures for relapse by 1 mo indicated a need for additional immunotherapy. For comparison, the OMS relapse frequency in patients treated only with conventional agents is 50 to 70%.2,12 Subjects Children with OMS were recruited to the National Pediatric Myoclonus Center and examined by the prin-

RITUXIMAB IN OMS cipal investigator (M.P.). New referrals for OMS average 30 to 40 annually and about 25% are untreated. Parents of 12 untreated children meeting inclusion and exclusion criteria (all those approached) signed informed consent for this Institutional Review Board approved study (SCRIHS protocol 04-112), which was conducted from 2004 to 2007 (IND 11,771). The demographic data (means 6 SD) were as follows: age 1.9 6 0.4 yr, range 1.3 to 2.6 yr; OMS onset age 1.6 6 0.5 yr; OMS duration 0.3 6 0.2 yr; OMS score 23 6 5. The categorical subgroups included five boys and seven girls, seven acute and five subacute cases, six moderate and six severe cases, two neuroblastomas, and four prior relapsers. Treatments Subcutaneous IV ports were placed in eight toddlers with poor venous access. The doses of rituximab, ACTH, and IVIg were chosen to match those used in our adjunctive trial.5 ACTH and IVIg were started before rituximab, with 3 to 7 d in between the sequential introduction of agents. Rituximab (Rituxan; South San Francisco, CA)/Biogen IDEC (San Diego, CA) was given IV (1 mg/mL in D5¼ NS) once weekly for four consecutive weeks at a dose of 375 mg/m2. Patients were premedicated with oral acetaminophen (15 mg/kg), diphenhydramine IV (1.5 mg/kg up to 25 mg), and dexamethasone IV (0.05–0.08 mg/kg up to 1 mg).13 Rituximab was infused at 20 mL for 30 min, 40 mL for 30 min, and then 60 mL/h. A 52-week protocol for ACTH1–39, extending our previous protocol,14 was initiated. Acthar Gel (80 IU/mL; Questcor Pharmaceuticals, Union City, CA) was injected IM at 75 IU/m2 twice a day for 1 week, daily for 1 week, on alternate days for 2 weeks, then slowly tapered to a final dose of 5 IU/m2 at 1 yr. IVIg was induced at 2 g/kg (divided over 2 days) and maintained at 1 g/kg once a month with acetaminophen and diphenhydramine pretreatments. Clinical evaluations were made about 1 mo after IVIg. Concomitant prophylactic treatments were trimethoprim-sulfamethoxazole, ranitidine HCl, calcium with vitamin D, and a 2-g low sodium diet. Patients received speech, occupational, and physical therapy. Repeated Measures Lumbar puncture was performed at baseline and 6 mo after completion of rituximab, using methods to obtain CSF atraumatically in children.4 In fresh CSF and corresponding blood, the expression of lymphocyte surface antigens was investigated by flow cytometry,

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using a comprehensive panel of monoclonal antibodies to adhesion proteins in combination with anti-CD3 and anti-CD45 antibodies.4 CSF-quantitative Ig was measured by Nephelometry at Specialty Labs (Santa Monica, CA). Blood for complete blood count, quantitative Ig, blood lymphocyte subsets, human anti-chimeric antibody (HACA) was collected at baseline and at intervals. The HACA assay, a proprietary bridging ELISA assay of Genentech, was performed by Covance Laboratories (Chantilly, VA), using rituximab as the capture reagent and biotinylated rituximab and streptavidin-horseradish peroxidase (Jackson ImmunoResearch Laboratories, West Grove, PA) for detection. A calibrator curve was prepared with proprietary goat polyclonal antibodies to rituximab. Serum Ig was quantitated by the Tina-quant antigen-antibody turbity assay in the clinical laboratory (St. John’s Hospital, Springfield, IL). Clinical outcome was rated by the co-investigator (E.T.) from videotapes using a validated 12-item motor evaluation scale.15 Each item was scored in increasing severity from 0 to 3.1 Subscores were converted to a total score to designate mild (0–12), moderate (13–24), and severe (25–36) categories. The rater was blinded to the order (pretreatment vs. treatment) in all subjects. Statistical Procedures The level of significance was P < 0.05. Time-course data were analyzed on the Statistical Analysis System by one-way analysis of variance (ANOVA) with repeated measures, and follow-up comparisons of means were made by the least square means procedure. Bonferroni corrections were made for multiple comparisons. CSF data were analyzed by paired t tests, and correlation analysis by Pearson correlations. RESULTS OMS Motor Severity Treatment reduced the total score (ANOVA, P < 0.0001; Fig. 1A). At the 6-mo evaluation, all subjects had improved by ‡6 scale points, 8 by ‡12 points, 7 by ‡18 points, and 1 by ‡ 24 points. Opsoclonus and action myoclonus disappeared rapidly in parallel with B cell depletion, but some other motor components, such as gait ataxia, improved more slowly (Fig. 1B). Clinical improvement continued even as blood B cells and serum IgM began to recover (Fig. 1D). Treatment had functional impact. Seven children were not ambulating independently at the initial visit, but 6 mo after completion of rituximab, only one

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FIG. 1. (A) Clinical efficacy (reduction in motor severity) and effect on immunological measures. Data are total score means 6 SEM. Asterisks indicate significant differences compared with the score at initial evaluation. The initiation of rituximab is denoted by time 5 0, and time 5 2 represents the 1-mo evaluation after completion of rituximab. Compared with baseline, mean total score decreased by 43% at 1 mo, 59% at 3 mo, 73% at 6 mo, and 81% at 1 yr (P < 0.0001). (B) Mean subscores for key motor components of OMS Scale (scale items 1, 7, and 11). Upper extremity action myoclonus was scored as reaches target with no jerks (0), minimal jerks (1), moderate to severe jerks (2), or unable to reach target due to jerks (3). (C) Dot plots of CD191 B cell frequency in CSF. For pediatric neurological controls of mean age (6SD) 9.3 6 1.2 yr (n 5 16), the median CSF B cell frequency was 0.71% (National Pediatric Myoclonus Center database). (D) The relation between changes in total score, blood B cells, and serum IgM concentration is shown. IgM was still below the reference range in five of nine subjects at 1 yr.

was not walking. He received additional immunotherapy and was ambulatory at 1 yr. ACTH dose was tapered steadily, a total decrease of 87% (P 5 0.0001) by 1 yr. The subsequent time points differed significantly from the first. CSF Immunophenotype At baseline, the frequency of total B cells was 4.4 6 1.6% (normal  1%). Six mo after the final rituximab, there was significant reduction in total B cell frequency (Fig. 1C) and 83% reduction in the CSF-toblood B cell ratio (P 5 0.001). CSF B cells were undetectable in five of 11 children. CD191 and CD201 B cells (Fig. 1E) were correlated (r 5 0.87, P < 0.0001).

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Blood Immunophenotype Treatment with rituximab depleted both relative and absolute blood B cell pools. Total blood B cells (CD32CD191) plummeted to 0% by 1 mo after the last rituximab infusion, corresponding to a reduction in total B cell counts from 1,377 (1,001–1,753, 95% CI) to 1.7 (0.2–3.1) per mm3 (P 5 0.0002). Six mo after the last rituximab infusion, the reduction in B cell frequency (261%) was still significant (P < 0.0001). Quantitative Immunoglobulins Serum IgM concentration declined rapidly and returned to 63% of the pretreatment values by 12 mo (P < 0.0001). Serum IgG and IgA levels did not

RITUXIMAB IN OMS change significantly. Baseline CSF IgG concentrations were normal at 0.79 mg/dL (0.7–0.9, 95% CI) and not reduced by rituximab. Six of 11 subjects initially had detectable CSF IgM; by 6 mo, only one had detectable levels (NS). Serum HACA HACA was measured in eight children. Two children (25%) developed HACA antibodies, one at 6 mo and the other at 12 mo (Table 1). The antibody concentrations were low (