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CASE REPORT
Year : 2018  |  Volume : 66  |  Issue : 7  |  Page : 135-137

Implications of secondary unresponsiveness to dopaminergic drugs with preserved response to subthalamic nucleus stimulation in Parkinson's disease


1 Department of Clinical Neurosciences; Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Clinical Neurosciences, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
4 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication1-Mar-2018

Correspondence Address:
Dr. Pramod K Pal
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.226454

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 » Abstract 


Improvement in motor symptoms with levodopa is one of the hallmark features of Parkinson's disease (PD). The response to levodopa may reduce during the course of the illness. Few studies have also reported reduced response to levodopa in patients with PD several years after deep brain stimulation (DBS) of the subthalamic nucleus (STN) on both the sides. In this study, we report an extreme unresponsiveness to levodopa in the presence of a good response to STN stimulation in a patient 5 years after the DBS proceudre had been carried out. The implications of this phenomenon are also discussed.


Keywords: Deep brain stimulation, levodopa, Parkinson's disease
Key Message: Levodopa responsiveness may be completely absent in patients with PD, despite of the presence of a long term good response to subthalamic nucleus deep brain stimulation.


How to cite this article:
Lenka A, Jhunjhunwala KR, Stezin A, Manjunath M, Srinivas D, Yadav R, Pal PK. Implications of secondary unresponsiveness to dopaminergic drugs with preserved response to subthalamic nucleus stimulation in Parkinson's disease. Neurol India 2018;66, Suppl S1:135-7

How to cite this URL:
Lenka A, Jhunjhunwala KR, Stezin A, Manjunath M, Srinivas D, Yadav R, Pal PK. Implications of secondary unresponsiveness to dopaminergic drugs with preserved response to subthalamic nucleus stimulation in Parkinson's disease. Neurol India [serial online] 2018 [cited 2018 Dec 16];66, Suppl S1:135-7. Available from: http://www.neurologyindia.com/text.asp?2018/66/7/135/226454




Deep brain stimulation (DBS) has revolutionized the management of patients with Parkinson's disease (PD) having motor fluctuations.[1] Longitudinal studies have unequivocally reported improvement in motor functions after DBS, during the drug OFF-state. Although studies have reported reduction of levodopa responsiveness after DBS,[2],[3] none have reported nearly complete absence of response to dopaminergic drugs. Here, we describe an extreme example of levodopa unresponsiveness in a patient with PD who failed to get any significant improvement with levodopa or pramipexole, 5 years after stimulation of bilateral subthalamic nucleus (STN), though his response to STN stimulation remained good. The implications of this observation in the management of PD and the selection criteria for DBS are discussed.


 » Case History Top


A 51-year old man was referred to us in 2010 with symptoms of PD since 10 years. Initially during the onset of PD, he had stiffness and tremor of the left hand. Four years later, he developed tremor of the right hand and a slow, short stepped gait with freezing and festination. During the initial 3–4 years, he had a good response to levodopa. Later, he reported the presence of a wearing off peak-dose dyskinesia, and an OFF - state painful toe dystonia. Magnetic resonance imaging (MRI) of the brain was normal. The motor score of Unified Parkinson's Disease Rating Scale (UPDRS-III) during the OFF state was 49; and, the best ON score was 25 (an improvement of approximately 49%). Considering the good response to levodopa, and due to the absence of any contraindications for conducting the procedure, he was advised to undergo bilateral STN DBS.

DBS was done without any intraoperative and postoperative complications. Details of the stimulation parameters are provided in [Table 1]. Based on the previous evidence that has revealed that a low- frequency stimulation provides an improvement in the gait of patients undergoing this treatment,[4] we reduced the frequency of stimulation from 130 Hz to 90 Hz at 6 months after the performance of DBS, as he was having significant gait disturbance. After the placement of DBS device, there was a significant improvement in the OFF state UPDRS-III score and a reduction in motor fluctuations. The medication dosage as well as stimulation parameters were carefully monitored until 18 months post-DBS and he showed a consistent improvement later.
Table 1: UPDRS motor scores at different states of stimulation and drug combination

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At a 5 year post-DBS follow-up, he complained of worsening of motor symptoms not related to the timing of medications. His clinical examination, following his admission, did not reveal any signs suggestive of Parkinson plus disorders. He was assessed using the UPDRS-III in the following states with and without DBS stimulation [Table 1] and [Video 1]: (i) drug OFF; (ii) after 200 mg of levodopa + 50 mg carbidopa; (iii) after 2 mg of pramipexole. While there was a 70% improvement in the UPDRS-III scores after switching the stimulator on in the drug-OFF state (off stimulation-74, on stimulation-21), no significant improvement in the UPDRS-III scores was noted after levodopa (UPDRS-III: 68) or pramipexole (UPDRS-III: 71) administration. Dyskinesias were absent in any state. The same exercise was carried out twice during the hospital stay but improvement was not seen on either occasion when the stimulator had been switched off.


 » Discussion Top


This case raises two questions: (i) why is there reduction in the response to levodopa after DBS; and, (ii) how does DBS improve the motor symptoms even in the absence of response to levodopa. Piboolnurak et al., reported an approximately 31% decrease in the levodopa response after 5 years,[3] whereas another study reported an approximately 25% decrease in the response 3–4 years after STN DBS.[2] However, to the best of our knowledge, this is the first report describing >80% decrease in levodopa response (pre-DBS response 49%, post-DBS response 8%). Although the exact mechanism of the decrease in levodopa response is not clear, this may be secondary to the gradual progression of the disease pathology in PD. Functional imaging studies have also confirmed that nigral degeneration in PD continues even after STN-DBS.[4],[5] Other mechanisms that could presumably be responsible for the decrease in levodopa response could be reduced sensitivity of dopaminergic receptors secondary to reduction in the dose of dopaminergic medications after DBS, and changes in neuronal circuits due to chronic stimulation reflecting neuronal plasticity. In addition to the lack of clinical benefit with levodopa and pramipexole, another interesting observation was the absence of levodopa-induced dyskinesia, which was present before DBS was performed. This may again be explained by the possible long-term plastic changes in the dopaminergic system.

The loss of levodopa responsiveness may have important implications for patients in developing countries. Considering the high cost of DBS as well as battery replacement, some patients, especially those with young-onset PD, may not be able afford periodic battery replacements. In such situations, reverting to medical management would be challenging in those patients who develop secondary unresponsiveness to dopaminergic medications. Although DBS at the earlier stage of PD is advised, gradual reduction in response to levodopa after DBS may raise concerns regarding whether or not DBS at an early age is actually advisable. As a consistent response to DBS was observed even in the absence of levodopa response, it is likely that the mechanism of improvement following DBS, which is not yet fully understood, is probably different from that of levodopa. As the response to DBS may not be reflected by the response to levodopa, as observed in this case, it invites speculation whether or not significant levodopa responsiveness is mandatory for selecting patients for DBS. Longitudinal studies in the future involving more patients may provide better insight into the cause of reduced post-DBS levodopa response.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Okun MS. Deep-brain stimulation for Parkinson's disease. N Engl J Med 2012;367:1529-38.  Back to cited text no. 1
[PUBMED]    
2.
Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, et al. Bilateral deep brain stimulation in Parkinson's disease: A multicentre study with 4 years follow-up. Brain 2005;128:2240-9.  Back to cited text no. 2
[PUBMED]    
3.
Piboolnurak P, Lang AE, Lozano AM, Miyasaki JM, Saint-Cyr JA, Poon YY, et al. Levodopa response in long-term bilateral subthalamic stimulation for Parkinson's disease. Mov Disord 2007;23:990-7.  Back to cited text no. 3
    
4.
Moreau C, Defebvre L, Destée A, Bleuse S, Clement F, Blatt JL, et al. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008;71:80-4.  Back to cited text no. 4
    
5.
Hilker R, Portman AT, Voges J, Staal MJ, Burghaus L, van Laar T, et al. Disease progression continues in patients with advanced Parkinson's disease and effective subthalamic nucleus stimulation. J Neurol Neurosurg Psychiatry 2005;76:1217-21.  Back to cited text no. 5
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