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To the Editor:

Deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) is a widely accepted treatment for cardinal motor symptoms in advanced Parkinson's disease (PD). Although the effect of STN-DBS on cognitive function or psychiatric symptoms is still debated [1], many previous reported studies excluded patients with apparent dementia or psychiatric problems before the surgery; therefore, we should carefully screen for psychiatric or cognitive problems before introducing this therapy. Multiplication of SNCA is a known causative factor of autosomal dominant familial PD, which has a very similar phenotype to sporadic PD. A recent study indicated that patients with duplication of SNCA frequently showed psychiatric problems [2]. However, there is only one report about STN-DBS of a patient with SNCA multiplication followed a short time after the surgery [3]. Here, we report on a patient genetically proven to have SNCA duplication who received STN-DBS to improve motor fluctuation and to reduce the use of antiparkinsonian drugs for a longer period (four years) after the surgery.

Case Report

The patient was a 41-year-old man with a six-year history of PD. He had a clear autosomal dominant-type familial history of parkinsonism and/or psychiatric problems. Genetic analysis revealed that he had duplication of SNCA (see case F-III-2 in Nishioka et al. and the familial tree also shown in the paper). His parkinsonian symptoms showed good response to a combination of levodopa/carbidopa and pramipexole. Two years after the start of treatment, he began to show the wearing-off phenomenon and peak-dose dyskinesia. Catechol-O-methylamine transferase inhibitor or an increase in the dosage of a dopamine receptor agonist, pramipexole, induced both visual and auditory hallucinations and delusions. He was admitted to our hospital to evaluate whether STN-DBS was a potential option four years after starting antiparkinsonian drug therapy. He took 600 mg of levodopa/carbidopa divided into six doses per day, 3 mg of pramipexole divided into three doses per day, and 2.5 mg of selegiline per day. Neither obvious dementia nor depression was observed at that time (Table 1). Unified Parkinson's Disease Rating Scale (UPDRS) part 3 score was 27 points during the “off” period and 10 points during the “on” period. Brain magnetic resonance imaging showed neither abnormal lesion nor regional atrophy that would cause secondary parkinsonism. Single-photon emission computed tomography study showed slight reduction of blood flow in the frontal lobe cortex and cardiac 123I-metaiodobenzylguanidine scintigraphy showed no obvious reduction of uptake. After the evaluation of his symptoms, Juntendo Ethical Committee approved the use of STN-DBS on him and he decided to receive bilateral STN-DBS. The surgical procedure has been described elsewhere [4]. The primary surgical target was determined by a combination of direct and indirect targeting using a neuronavigational computer workstation (Framelink, Medtronic, Minneapolis, MN, USA). Indirect targeting utilized the following coordinates: 12 mm lateral, 3 mm posterior, and 5 mm inferior to the middle point of the anterior commissure-posterior commissure line.

Table 1. Changes of Psychologic Battery, Parkinsonism (Evaluated by Unified Parkinson's Disease Rating Scale [UPDRS] Part 3), and LED
 Baseline (before the surgery)48 months after the surgery
  1. MMSE, Minimental State Examination; WCST, Wisconsin Card Sorting Test; SDS, Self-Rating Depression Scale; FAB, Frontal Assessment Battery; HAM-D, Hamilton Rating Scale for Depression; BDI, Beck depression index; LED, levodopa-equivalent dose.

MMSE2929
FAB1818
SDS index47.535
WCST (category achievement)66
HAM-D76
BDI56
UPDRS part 3 (off phase)2713
LED (mg)925650

Four years after the surgery, STN-DBS improved motor fluctuation (no obvious “off” phase, UPDRS part 3 score was ten points and he could reduce the dosage of antiparkinsonian drugs from 925 mg (before the surgery) to 650 mg (48 months after the surgery) (calculated as levodopa-equivalent dose (4). During the 48-month follow-up, there was no appearance of dementia or any psychiatric problems (Table 1), although psychoactive drugs were not being used. The final stimulation parameters were as follows: Lt: 2(+) 1(−), amplitude of 3.3 V, pulse width of 60 μsec, and frequency of 130 Hz; Rt: C(+) 2(−), amplitude of 3.3 V, pulse width of 60 μsec, and frequency of 130 Hz. Postoperative CT scan indicated that the lead located the optimal point of the STN (Table 2).

Table 2. The Lead Location
ContactLtRt
  1. The distance from the middle point of the anterior commissure-posterior commisure line.

  2. X = lateral, Y = posterior, Z = inferior (millimeter) from the point.

0X = 11.5, Y = 7.4, Z = 7.6X = 10.7, Y = 8.7, Z = 7.2
1X = 12.3, Y = 5.3, Z = 5.7X = 11.6, Y = 6.6, Z = 5.1
2X = 13.2, Y = 3.2, Z = 3.7X = 12.5, Y = 4.6, Z = 3.1
3X = 14.0, Y = 1.1, Z = 1.8X = 13.4, Y = 2.3, Z = 1.1

Discussion

The clinical phenotype of patients with duplication of SNCA was reported to be similar to that in sporadic PD and about half of patients showed motor fluctuation during the course of the disease [5]. This indicates that an SNCA patient can be a candidate for STN-DBS.

However, another report showed that more than half (7 out of 11) of the patients with duplication of SNCA showed psychiatric problems, such as dementia, hallucination, or depression, during the course of the disease and the prevalence of psychologic problems was higher than that in sporadic PD [2]. Furthermore, neuropathologic study of patients with duplication of SNCA showed very similar findings to those in dementia with Lewy bodies, which shows dementia in an early stage of the disease, and glial cytoplasmic inclusion, which is a hallmark of multiple system atrophy, also was observed in autopsied brains with multiplication of SNCA [6].

DBS has a risk of the appearance of psychologic side-effects, such as depression, hypomania, and delirium, after the surgery. In addition, patients who have obvious dementia or uncontrollable psychiatric problems should be excluded as candidates for this therapy because these symptoms may lead to poor outcome of the DBS.

Only one case report showed that an SNCA patient did not exhibit psychologic problems after a short period (one year) of STN-DBS [3]. Considering the relatively high risk of the appearance of psychologic problems during the course of the disease, it is necessary to follow the psychiatric outcome of SNCA patients who receive STN-DBS over a long period.

The mechanism that causes the psychiatric problems after STN-DBS is still unclear. Stimulation of the STN limbic region, which projects to the cortical limbic area, may be the cause. In this case, we carefully examined the optimal stimulation point that would not induce any psychiatric problems. This report demonstrates that STN-DBS can be safely performed in SNCA-positive patients and does not induce either cognitive or psychiatric problems for at least 48 months. This indicates that STN-DBS could be a therapeutic option for patients with duplication of SNCA, if the patient does not have preexisting dementia or uncontrollable psychiatric problems.

Conclusion

This is the first case report about a patient with SNCA multiplication who received STN-DBS with long-term follow-up. This report indicates that STN-DBS can be safely introduced to such patients who do not have any preexisting psychiatric problems.

Authorship Statements

Dr. Shimo drafted the paper. He also designed and conducted the study, data collection, and data analysis. Drs. Natori, Oyama, Nakajima, Ishii, and Arai conducted the data collection. Dr. Hattori designed the study. All authors approved the final manuscript.

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