The Persistence of Dopamine Dysregulation Syndrome after Pallidal Deep Brain Stimulation in Parkinson's Disease

Abstract

Background

Dopamine dysregulation syndrome (DDS) is a debilitating complication of Parkinson's disease (PD) dopamine replacement therapy (DRT) in which patients pathologically and/or compulsively use dopaminergic drugs to treat motor symptoms. Studies examining DDS outcomes following deep brain stimulation (DBS) are limited and have focused on subthalamic targeting.

Cases

Here, we present DDS outcomes in six patients from the Emory Movement Disorders clinic who underwent unilateral or bilateral DBS implantation of the globus pallidus internus (GPi). Despite motor improvements and/or initial reductions in DRT dosing, all six patients continued to meet clinical criteria for DDS 6 months post‐surgery, displaying persistent pathological medication use, mood disturbances, and social impairment. Anxiety surrounding levodopa use was the most persistent DDS feature following surgery.

Conclusion

These results indicate that pallidal DBS is not a suitable treatment for DDS and its associated symptoms.

Introduction

Dopamine replacement therapy (DRT) is the mainstay of treatment for the motor features of Parkinson's disease (PD), but can also trigger a disabling neuropsychiatric condition called dopamine dysregulation syndrome (DDS). Patients with DDS pathologically and/or compulsively use DRT, often characterized by self‐administration of dopaminergic drugs in excess of what is required to treat motor symptoms, an insistence on DRT dose escalation despite adverse effects, and severe mood disturbances surrounding dopaminergic use. ¹ , ² DDS is often under recognized in the clinical setting, as patients tend to minimize symptoms. Once diagnosed, DDS is then extremely difficult to manage given there are no established guidelines.

Deep brain stimulation (DBS) is a well‐established surgical treatment for PD motor symptoms and often allows patients to reduce DRT post‐procedure. Studies examining DDS outcomes following DBS remain limited. A handful of case series, primarily focused on the efficacy of subthalamic nucleus (STN) stimulation in DDS, have yielded mixed results. Although some report resolution of DDS following STN stimulation, others have observed worsened dysregulation. ³ , ⁴ , ⁵ , ⁶ Additionally, de novo cases of DDS have been reported following STN DBS. ³ , ⁶ Meanwhile, much less data exists on the effects of globus pallidus internus (GPi) stimulation on DDS, despite evidence indicating this target generates fewer adverse psychiatric effects compared to STN while allowing for equivalent motor benefit. ⁷ In one case series examining the effects of multiple advanced PD therapies on DDS, two patients who underwent GPi DBS experienced resolution of dysregulation symptoms. ⁵ However, a separate case series described persistent DDS in its two patients with GPi stimulation. ⁴ Therefore, additional information is necessary to assess the effect of DBS on DDS outcomes, particularly in the case of GPi stimulation.

To this end, we present a retrospective analysis of DDS outcomes in six individuals who underwent GPi DBS lead placement. We examine not only post‐surgical persistence of DDS, but also key associated mood and behavioral features. By describing these outcomes, we aim to guide physicians in the management of this complex condition.

Case Series

We performed a detailed retrospective chart review of six patients from the Emory University Movement Disorders clinic who underwent either unilateral or bilateral GPi DBS lead placement in the setting of clinically defined DDS. The presence of DDS before surgery was determined based on four criteria, adapted from the seminal paper by Giovannoni et al., ² including (1) a clinical diagnosis of levodopa‐responsive PD by a movement disorders specialist; (2) an established pattern of compulsive and/or pathological DRT use; (3) impairment in social or occupational functioning; and (4) emotional withdrawal related to DRT. All six included patients were required to have clear documentation of the first three criteria before DBS lead placement, whereas the presence of the fourth criterion was examined in each case, but not required for inclusion. Compulsive and/or pathological DRT use required documentation of a perceived need for dopamine therapy in excess of that required to treat parkinsonian symptoms. ² , ⁶ Associated behaviors were often used to establish pathological usage, such as medication hoarding and an unwillingness to reduce dosage despite disabling side effects. The persistence of DDS and its associated features were then examined in each patient post‐procedure. Motor outcomes were also assessed using part III of the Unified Parkinson's Disease Rating Scale (UPDRS) or the revised Movement Disorders Society version of this scale (MDS‐UPDRS). To harmonize this motor data, UPDRS values were converted to MDS‐UPDRS values where appropriate by adding 7 points to the total motor score, according to published recommendations. ⁸

Baseline DDS Characteristics

All six patients were male with a mean age of PD diagnosis of 41.0 ± 15.7 years (Table 1). All demonstrated significant motor improvements with levodopa, dropping on average 22.7 points on the MDS‐UPDRS part III after taking medication. The average levodopa daily dose (LDD) across patients was 1714.7 ± 742.5 mg before surgery. Two of the six patients were also taking dopamine agonists at the time of surgery. All patients featured documented motor fluctuations, including two with painful off‐medication dystonia. Severe levodopa‐induced dyskinesia was documented in five patients before surgery. Depression/dysphoria and anxiety were endorsed by all patients at baseline. Nearly all patients (n = 5) also experienced psychosis before surgery, most commonly visual hallucinations attributed to high doses of dopaminergic medication. All patients harbored at least one DDS‐associated behavioral feature, with hobbyism, hypersexuality, and dopaminergic drug seeking occurring most frequently.

TABLE 1.

Baseline demographics and disease characteristics

Baseline demographics and disease characteristics	All cases (n = 6)
Age of PD onset, mean y (SD)	41.0 (15.7)
Age at surgery, mean y (SD)	54.9 (14.9)
Sex, n (%)
Male	6 (100.0)
Female	0 (0.0)
Unmarried status, n (%)	2 (33.3)
History of substance abuse, n (%)	2 (33.3)
History of mood disorder, n (%)	3 (50.0)
Motor symptoms
Off‐med MDS‐UPDRS part III, mean (SD)	38.1 (9.6) a
On‐med MDS‐UPDRS part III, mean (SD)	15.4 (5.2) a
Motor fluctuations, n (%)	6 (100.0)
Severe dyskinesia, n (%)	5 (83.3)
Painful off‐med dystonia, n (%)	2 (33.3)
Dopaminergic medications b
LDD, mean mg (SD)	1714.7 (742.5)
Dopamine agonist use, n (%)	2 (33.3)
Mood symptoms, n (%)
Depression/dysphoria	6 (100.0)
Anxiety	6 (100.0)
Hypomania/mania	3 (50.0)
Aggression/irritability	4 (66.7)
Psychosis	5 (83.3)
Behavioral symptoms, n (%)
Punding	1 (16.7)
Hobbyism	2 (33.3)
Shopping	0 (0.0)
Hypersexuality	3 (50.0)
Drug seeking c	3 (50.0)
Drug hoarding c	0 (0.0)

Abbreviations: PD, Parkinson's disease; SD, standard deviation; off‐med, off medication; on‐med, on medication; MDS‐UPDRS, Movement Disorders Society Unified Parkinson's Disease Rating Scale; LDD, levodopa daily dose; DBS, deep brain stimulation; UPDRS, Unified Parkinson's Disease Rating Scale; GPi, globus pallidus internus.

^a Motor function was assessed before and after DBS with Part III of the UPDRS or MDS‐UPDRS. To facilitate comparisons, UPDRS values were converted to MDS‐UPDRS values by adding 7 points to the total motor score. The baseline off‐ and on‐med MDS‐UPDRS values for one patient who received GPi lead placement were missing.

^b LDD and dopamine agonist information reflect patient's medication use just before surgery. LDD comprises only the daily milligrams of levodopa consumed and not other dopaminergic drugs.

^c Drug seeking and hoarding refer only to dopaminergic medications and not any other substances.

Post‐DBS DDS Characteristics

Table 2 comprises a summary of several outcome variables for each patient at 6 months post‐surgery, including changes in motor function, LDD, and DDS diagnosis and features. For five of the six patients, we were able to examine the percent change in off‐medication UPDRS or MDS‐UPDRS part III scores at 6 months post‐surgery. All five demonstrated motor improvements after surgery, with score reductions ranging from 17% to 48% (Table 2). These improvements were consistent with previously reported motor outcomes for unilateral and bilateral GPi DBS. ⁷ , ⁹ All six patients reported decreases in LDD within the first 6 months post‐surgery (mean = −22.3%). The two patients who were also taking dopamine agonists at the time of surgery continued these medications following the procedure, which included pramipexole in case 1 and a combination of pramipexole and apomorphine in case 3.

TABLE 2.

DDS outcomes at 6 months post‐surgery

DDS outcomes at 6 mo post‐surgery	Cases
	1	2	3	4	5	6
GPi lead laterality	Unilateral	Bilateral	Bilateral	Unilateral	Bilateral	Unilateral
% change in off‐med UPDRS or MDS‐UPDRS part III a	–	−37.0	−48.0	−16.7	−41.0	−46.2
% change in LDD	−25.7	−29.2	−17.6	−35.3	−11.7	−14.3
Post‐DBS DDS	Y	Y	Y	Y	Y	Y
Post‐DBS mood
Symptoms
Depression/dysphoria	–	✓	✓	–	–	✓
Anxiety	✓	✓	✓	–	✓	✓
Hypomania/mania	✓	✓	–	–	✓ b	–
Aggression/irritability	✓	–	–	–	–	–
Psychosis	✓	–	–	–	✓	✓
Post‐DBS behavioral
Symptoms
Punding	–	–	–	–	–	–
Hobbyism	–	–	✓	–	–	✓
Shopping	–	–	–	–	–	–
Hypersexuality	–	–	–	–	✓ b	✓ b
Drug seeking	✓	–	–	–	✓	✓ b
Drug hoarding	–	–	–	✓	–	–

Abbreviations: DDS, dopamine dysregulation syndrome; GPi, globus pallidus internus; off‐med, off medication; UPDRS, Unified Parkinson's Disease Rating Scale; MDS UPDRS, Movement Disorder Society Unified Parkinson's Disease Rating Scale; LDD, levodopa daily dose; DBS, deep brain stimulation.

^a The % change for cases who underwent unilateral surgery reflects off‐medication motor scores for the contralateral treated side only. We were unable to compute the % change for case 1 given incomplete documentation in the clinical record.

^b This notation indicates newly present symptoms post‐surgery. The remaining check marks without this notation indicate persistent symptoms that were present pre‐ and post‐surgery.

Despite motor improvements and/or initial reductions in LDD, all six patients continued to meet DDS criteria at 6 months post‐surgery (Table 2). Persistent pathological DRT use often manifested as difficulty maintaining or open resistance to implemented LDD decreases. For example, case 2 was resistant to lowering his excessive dopamine doses despite considerable motor improvements with bilateral GPi stimulation because of persistent anxiety and fear of wearing off. Even with decreased doses, his levodopa use was still driven by “emotional rather than physical needs.” Similarly, case 6 continued taking his levodopa nearly every hour or “when he felt like it,” resisting recommendations to further reduce his intake. In addition, he experienced new symptoms of hypersexuality following surgery. Accordingly, by 1 year post‐surgery, the majority of our cases (n = 4) had returned to or in some instances surpassed their pre‐surgical baseline levodopa doses (Fig. 1). These cases often demonstrated continued dysregulation up to 2 years post‐procedure.

FIG. 1.

Post‐surgical levodopa daily dosing. Reported levodopa daily dosages (LDDs) were extracted from the clinical record before and up to 2 years after surgery for all cases. LDD comprises only the daily milligrams of levodopa consumed and not other dopaminergic drugs. Despite all experiencing initial reductions in LDD post‐surgery, five of the six patients had either returned to or exceeded their baseline dose by 1 to 2 years following DBS.

Across all cases, anxiety surrounding levodopa use was the most persistent associated symptom (Table 2). Drug seeking behaviors also remained challenging, persisting in two cases and newly occurring in one patient post‐surgery. In addition, psychosis persisted in three of the five patients affected at baseline. Yet, certain symptoms appeared to improve with DBS, such as depression and/or dysphoria, which were reported in all six patients before surgery, but only three afterward. We observed similar decreases in hypomania, aggression, irritability, and several compulsive behaviors.

Discussion

In this study, we examined the impact of DBS on DDS in a PD population following GPi implantation. Previous case studies evaluating stimulation in DDS have primarily focused on STN implantation. Therefore, our cohort of GPi‐stimulated individuals provides new findings. Despite motor improvements and/or initial reductions in DRT dosing, all patients in our cohort continued to demonstrate core features of DDS following surgery, including pathological medication use, social impairment, and mood disturbances. Anxiety surrounding DRT dosing was one of the most persistent symptoms, present in nearly all patients 6 months post‐surgery and often remaining years later. These results indicate that pallidal DBS is not a suitable treatment for DDS.

The persistence of DDS among our patient population indicates that GPi DBS does not meaningfully impact its pathophysiology. DDS and impulse control disorders in PD have been linked to the sensitization of dopaminergic circuits in the ventral striatum (ie, nucleus accumbens), causing enhanced dopamine release in response to DRT and resultant long‐term reward circuitry disruption that contributes to addiction behaviors. Continued drug‐induced sensitization to lower doses of DRT could explain the persistence of DDS in DBS patients despite significant motor improvements. Yet, it is possible other DBS targets may provide a more therapeutic impact on DDS pathophysiology. For instance, direct stimulation of the nucleus accumbens, which has been studied more extensively in psychiatric disorders, has been shown to benefit various comorbid drug addictions and could ultimately prove beneficial for dopamine dysregulation. ¹⁰

Our results agree with the literature establishing DDS as a markedly persistent condition that is difficult to treat. In a long‐term retrospective review of DDS patients from the Queens Square Brain Bank, DDS symptoms persisted in nearly half of patients despite phased reductions in levodopa dosing. ¹ For many of these affected patients, DDS was a lifelong condition that remained present until death. Therefore, in addition to treatments, preventing and/or mitigating the risk of DDS before onset is critical. Our small case series was limited in its ability to assess risk factors for persistent DDS. Yet, certain factors that have been linked to refractory DDS were highly prevalent throughout our cohort, most notably dopamine agonist exposure. ¹ Although only two were still taking these drugs at the time of surgery, all but one patient in our series had been exposed previously to dopamine agonists. Additional research is needed to determine how this and other patient‐specific factors contribute to persistent dysregulation.

Another limitation of our study was the absence of sufficient objective measures quantifying the severity of DDS pre‐ and post‐surgery. Therefore, it was difficult to determine whether GPi stimulation worsened any aspects of dysregulation. Only two of the six patients developed new DDS symptoms in the 6 months following surgery, whereas the others maintained similar symptom constellations. Therefore, although our results indicate GPi stimulation should not be used to treat DDS, they do not necessarily support DDS as a blanket contraindication to this procedure in those who otherwise stand to benefit from a motor perspective. In such cases, our results can help clinicians manage expectations regarding DDS when considering this patient population for surgical therapy.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

N. D.: 1B, 1C, 2A, 2B, 3A

S. A. F.: 1A, 2C, 3B

R. T.: 1C, 2C, 3B

L. H.: 1A, 1B, 1C, 2A, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: The retrospective chart review performed in this study was approved by the Emory University Institutional Review Board and conducted under its guidelines. Patient information was de‐identified and the privacy rights of these patients were observed. Informed patient consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: N.D. has no financial disclosures. S.A.F. has the following disclosures: has received honoraria from Lundbeck, Biogen, and Takeda; has received grants from Medtronics, Boston Scientific, Sun Pharmaceuticals Advanced Research Company, Aspen, Biohaven, Neurocrine, Voyager, Prilenia Therapeutics, CHDI Foundation, The Michael J. Fox Foundation, National Institutes of Health (NIH) 1 P50 NS123103‐01, NIH 1R01NS125294–01, and Parkinson Foundation; royalties from Demos, Blackwell Futura, Springer for textbooks, Uptodate, and Other Cronos. R.T. has no financial disclosures. L.H. has active grant support from the NIH (K23NS119964, U01NS128433, and P50NS123103).

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available because of privacy or ethical restrictions.