Re: 파킨슨 증상 tremer 떨림 탐구!! - 원심성 근수축저항운동

[문형철]

Tremor Other Hyperkinet Mov (N Y)

. 2022 Sep 13;12:29. doi: 10.5334/tohm.712

Tremor in Parkinson’s Disease: From Pathophysiology to Advanced Therapies

Ali H Abusrair 1,2, Walaa Elsekaily 3, Saeed Bohlega 4

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PMCID: PMC9504742  PMID: 36211804

Abstract

Background:

Tremor is one of the most preval‎ent symptoms in Parkinson’s Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD.

Methods:

A structured literature search through Embase was conducted using the terms “Parkinson’s Disease” AND “tremor” OR “etiology” OR “management” OR “drug resistance” OR “therapy” OR “rehabilitation” OR “surgery.” After initial screening, eligible articles were selected with a focus on published literature in the last 10 years.

Discussion:

The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its long-term efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are non-invasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor.

배경:
떨림은 

파킨슨병(PD)에서 가장 흔하게 나타나는 증상 중 하나입니다. 

특히 본태성/경직성 아형에 비해 

떨림이 우세한 PD 환자의 경우 

도파민성 약제에 대한 반응이 상대적으로 좋지 않을 수 있기 때문에 

떨림의 진행과 관리가 어려울 수 있습니다. 

이 리뷰에서는 본태성 떨림의 근본적인 발병 기전과 치료 방식에 대한 최근의 발전을 강조하고자 합니다.

연구 방법:
“파킨슨병” 및 ‘떨림’ 또는 ‘병인’ 또는 ‘관리’ 또는 ‘약물 내성’ 또는 ‘치료’ 또는 ‘재활’ 또는 ‘수술’이라는 용어를 사용하여 Embase를 통한 구조화된 문헌 검색을 수행했습니다. 1차 심사 후, 지난 10년간 발표된 문헌을 중심으로 적격 논문을 선정했습니다.

토론:
본태성 진전의 근본적인 병태생리는 

여전히 복잡하고 불완전하게 이해되고 있습니다. 

대뇌-탈라모-피질 회로 및 기저핵의 고출력 신경 진동 외에도 

후퇴 영역의 도파민성 뉴런의 신경 퇴화가 중요한 역할을 합니다. 

레보도파는 

떨림을 포함한 

모든 운동 증상에 대한 1차 치료 옵션입니다. 

도파민 작용제 또는 항콜린제를 추가하면 

떨림이 더 감소할 수 있습니다. 

보툴리눔 독소 주사는 

고급 치료법을 원하지 않는 약제 내성 진전 환자에게 효과적인 대안입니다. 

뇌심부자극술은 

장기적인 효과, 가역성, 다른 운동 증상 및 변동에 대한 효과로 인해 

가장 잘 확립된 고급 치료법입니다. 

자기 공명 유도 집속 초음파는 

절개가 필요 없다는 장점이 있는 유망한 치료법입니다. 

대뇌피질 및 말초 전기 자극은 

난치성 진전을 억제하는 데 좋은 효과가 입증된 

비침습적 혁신 기술입니다.

Keywords: Parkinson’s Disease, Tremor, Levodopa-resistant, DBS

1 Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder defined by a constellation of cardinal features that include tremor, bradykinesia, rigidity, and postural instability [1,2]. The spectrum of motor and non-motor manifestations of the disease is further expanding [3]. Tremor is one of the most common motor symptoms in PD and is reported to affect up to 75% of patients during their disease course. Moreover, tremor can be the predominant and most troublesome motor symptom [4,5,6,7]. While several forms of tremor can develop in patients with PD, the typical pill-rolling tremor at rest is the most common [6]. Both kinetic and re-emergent postural forms can also coexist, which may result in substantial functional impairment [6,7,8].

PD is recognised to be heterogeneous, and growing evidence of clinical subgroups has emerged based on the predominant symptom associated with each subtype [9,10,11,12]. In comparison to other PD subtypes, tremor-dominant PD tends to have a slower disease progression, less debilitating non-motor symptoms, decreased probability of developing levodopa-induced dyskinesia (LID), and potential resistance to dopaminergic agents [6,12]. In addition, the response to dopaminergic agents, if any, tends to be higher in resting and re-emergent tremor, whereas the response for kinetic tremor is relatively poor [7,13,14,15]. This phenotype constitutes up to 8% of PD cases as examined in postmortem clinicopathologic studies [16,17].

The purpose of this review is to highlight the underlying pathophysiological mechanisms of tremor in PD and recent advances in therapeutic options.

1 소개

파킨슨병(PD)은

진전, 서동증, 경직 및 자세 불안정성을 포함하는 주요 특징으로 정의되는

진행성 신경 퇴행성 질환입니다 [1,2].

이 질환의 운동 및 비운동 증상의 스펙트럼은 더욱 확대되고 있습니다 [3].

떨림은

파킨슨병에서 가장 흔한 운동 증상 중 하나이며,

질병이 진행되는 동안 환자의 최대 75%까지 영향을 미치는 것으로 보고되고 있습니다.

또한

떨림은 가장 문제가 되는 주요한 운동 증상일 수 있습니다 [4,5,6,7].

파킨슨병 환자에서 여러 형태의 진전이 발생할 수 있지만,

안정 시 전형적인 알약 굴림 진전이 가장 흔합니다[6].

운동성 및 재출현성 자세 형태도 공존할 수 있으며,

이는 상당한 기능 장애를 초래할 수 있습니다 [6,7,8].

PD는

이질적인 것으로 인식되고 있으며,

각 아형과 관련된 주요 증상에 따라 임상 하위 그룹에 대한 증거가 증가하고 있습니다 [9,10,11,12].

다른 PD 아형에 비해

진전 우세형 PD는 질병 진행 속도가 느리고,

비운동 증상이 덜 쇠약해지며,

레보도파 유발 운동 이상증(LID) 발생 가능성이 낮고,

도파민 제제에 대한 잠재적 내성이 있는 경향이 있습니다[6,12].

또한,

도파민성 약제에 대한 반응은

휴식 및 재출현성 진전에서는 더 높은 경향이 있는 반면,

운동성 진전에 대한 반응은 상대적으로 낮습니다 [7,13,14,15].

이 표현형은

사후 임상병리학적 연구에서 조사된 바와 같이 P

D 사례의 최대 8%를 차지합니다 [16,17].

이 리뷰의 목적은

본태성 진전의 근본적인 병태생리학적 메커니즘과

근 치료 옵션의 발전을 강조하는 것입니다.

2 Methods

A structured search of Embase database was conducted, using the following keywords: “Parkinson’s Disease” AND “tremor” OR “etiology” OR “management” OR “drug resistance” OR “therapy” OR “rehabilitation” OR “surgery.” Articles were included if the format was a guideline, original article, review, letter to the editor, or case series. Results from the last 10 years (2012–2022) were prioritized to highlight the most recent advances in pathophysiology and management of tremor in PD. The search included English-language articles only. Articles were excluded if: the subjects were animals, the format was a case report, or the topic was not relevant. Articles were also excluded if there was an overlap between essential tremor (ET) and PD. This resulted in a total of 785 articles. In the final screening process, a total of 169 relevant articles were selected for review (Figure 1).

Figure 1.

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Flow diagram summarizing the steps involved in the literature search.

3 Discussion

3.1 Pathophysiology

The pathophysiology of tremor in PD is complex and remains incompletely understood. The onset, severity, and progression of tremor are hypothesized to be multifactorial. It is thought to have a distinct pathophysiologic mechanism from classic nigrostriatal dopamine depletion [18,19,20,21].

3.1 병리 생리학

본태성 진전의 병태생리는 복잡하며 아직 불완전하게 이해되고 있습니다.

진전의 발병, 중증도 및 진행은 다인성 가설로 추정됩니다. 전

형적인 흑질 도파민 고갈과는 다른 병리 생리학적 메커니즘이 있는 것으로 생각됩니다 [18,19,20,21].

The dimmer-switch model

The dimmer-switch model proposes a synchronous oscillatory activity in two separate, but partially overlapping, central pathways [22,23,24]. Cerebello-thalamo-cortical and basal ganglion-cortical loops cause an alteration in normal central neural oscillations and eventually trigger tremor episodes (Figure 2) [22]. This proposed model is based on neurophysiologic, neuroimaging, and intraoperative monitoring studies during functional stereotactic neurosurgical procedures [19,25,26,27]. In addition, stereotactic interventions in anatomic structures related to both pathways (the subthalamic nucleus (STN), ventral intermediate nucleus (Vim), and the internal globus pallidus (GPi)) can suppress tremor, further supporting the role of these structures in the underlying pathogenesis [28]. This model suggests that the basal ganglia is the key structure where a transient activation generates tremor, thus acting the “switch” role [23,24]. First, an oscillatory activity in the striatum causes an increased inhibitory output to the thalamus, which in addition to GPi bursting activity, would generate rhythmic bursting in the thalamic anterior ventrolateral nucleus (VLa) [29]. This eventually projects into the motor cortex where both circuits converge [21,23,26]. The primary motor and premotor cortices are the main areas where this convergence, as well as tremor-related activity, occurs [30,31]. Convergence at this level drives the cerebello-thalamo-cortical circuit, which modulates tremor amplitude, thus acting as the “dimmer” on the switch [31,32]. The role of both circuits was examined through combing functional MRI studies with electromyography (EMG), in which cerebral responses and co-fluctuation can be identified according to any spontaneous variations in tremor amplitude, as peripherally measured with EMG [25,29]. Cerebral activity was found to be time-locked to the onset of high-amplitude tremor episodes and was localized to both the basal ganglia and the cerebello-thalamo-cortical circuit [23]. Furthermore, maximal activity of the basal ganglia structures was detected at the onset of tremor episodes, thus supporting the specific role of the basal ganglia as a driving force for tremor generation, while subsequent tremor amplitude-related activity was localized only to structures related to the cerebello-thalamo-cortical circuit (VLp, cerebellum, and the motor cortex) [23,24]. Patients with tremor-dominant PD were also found to have an increased functional connectivity between the two circuits when compared to non-tremor PD patients, which additionally supports the role of this integrated network model in PD tremor pathogenesis [24].

디머-스위치 모델

디머-스위치 모델은 두 개의 분리된, 그러나 부분적으로 겹치는 중심 경로에서 동기적인 진동 활동을 제안합니다 [22,23,24].

소뇌-탈라모-피질 및 기저핵-피질 루프는

정상적인 중추 신경 진동의 변화를 일으키고

결국 진전 에피소드를 유발합니다(그림 2) [22].

이 제안된 모델은

기능적 정위 신경외과 수술 중 신경생리학, 신경영상 및 수술 중 모니터링 연구를

기반으로 합니다

[19,25,26,27].

또한

두 경로와 관련된 해부학적 구조(시상하핵(STN), 복측 중간핵(Vim), 내측 구상체(GPi))에

정위적 개입을 하면 진전을 억제하여

본적인 발병 기전에서 이러한 구조의 역할을 더욱 뒷받침할 수 있습니다[28].

이 모델은

기저핵이 일시적인 활성화가 떨림을 생성하는 핵심 구조이며,

따라서 “스위치” 역할을 한다고 제안합니다 [23,24].

첫째,

선조체의 진동 활동은 시상으로의 억제 출력 증가를 유발하고,

이는 GPi 파열 활동과 더불어 시상 전복측핵(VLa)에서 리듬성 파열을 생성합니다[29].

이것은 결국 두 회로가 수렴하는 운동 피질로 투사됩니다 [21,23,26].

일차 운동 피질과 전운동 피질은

이러한 수렴과 떨림 관련 활동이 일어나는 주요 영역입니다 [30,31].

이 수준에서의 수렴은 떨림 진폭을 조절하는

소뇌-탈라모-피질 회로를 구동하여 스위치의 “디머” 역할을 합니다 [31,32].

두 회로의 역할은 기능적 MRI 연구와 근전도(EMG)를 결합하여 조사되었는데, 근전도로 말초적으로 측정된 떨림 진폭의 자발적인 변화에 따라 대뇌 반응과 공변동을 확인할 수 있습니다 [25,29]. 대뇌 활동은 고진폭 진전 에피소드의 시작에 시간적으로 고정되어 있는 것으로 밝혀졌으며 기저핵과 소뇌-탈라모-피질 회로 모두에 국한되어 있습니다 [23]. 또한, 진전 에피소드가 시작될 때 기저핵 구조의 최대 활동이 감지되어 진전 발생의 원동력으로서 기저핵의 특정 역할을 뒷받침하는 반면, 후속 진전 진폭 관련 활동은 소뇌-탈라모 피질 회로 (VLp, 소뇌 및 운동 피질)와 관련된 구조에만 국한되었습니다 [23,24]. 또한 진전 우세 PD 환자는 비진전 PD 환자에 비해 두 회로 간의 기능적 연결성이 증가하는 것으로 나타났으며, 이는 PD 진전 병인에서 이 통합 네트워크 모델의 역할을 추가로 뒷받침합니다 [24].

Figure 2.

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Cerebral neuronal and neurochemical basis of tremor in Parkinson’s Disease. The figure shows the main circuits of the dimmer-switch model (A), which includes the cerebello-thalamo-cortical circuit (in red) and the basal ganglia-cortical circuit (in green). The basal ganglia (B) is the key structure that triggers the initiation of tremor. The striatum increases inhibitory output to the globus pallidus internus (Gpi), which in turn stimulates the anterior ventrolateral (VLa) nucleus of the thalamus. This trigger further propagates to the cerebral cortex, where convergence of both circuits occurs. This convergence stimulates the cerebello-thalamo-cortical circuit, which alters tremor amplitude. The figure also shows the main nuclei proposed to have major neurochemical role in tremor pathogenesis:

1. Degeneration in the retrorubral area (RRA) leads to reduced dopaminergic projections to the subthalamic region, the basal ganglia, and the ventrolateral thalamus

2. Reduced serotonergic projections result from degenerative raphe nuclei (RN).

3. Increased noradrenergic projection from the locus coeruleus (LC).

While the pathophysiologic basis for tremor subtypes in PD remains elusive, insights into the origin of resting and postural components was investigated through non-invasive transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) and the cerebellum. Resetting resting and postural PD tremor can be achieved with M1 stimulation, whereas cerebellar stimulation can reset the postural component only [33,34]. These findings suggest that this cortical area controls the amplitude and the rhythm of resting and postural tremor in PD, while postural tremor modulation is more related to the cerebellum.

파킨슨병에서 떨림의 대뇌 신경세포 및 신경화학적 기초.

그림은 소뇌-탈라모-피질 회로(빨간색)와 기저핵-피질 회로(녹색)를 포함하는 디머-스위치 모델(A)의 주요 회로를 보여줍니다. 기저핵(B)은 떨림의 시작을 촉발하는 핵심 구조입니다. 선조체는 내측 구상체(Gpi)로의 억제 출력을 증가시키고, 이는 다시 시상 전복측(VLa) 핵을 자극합니다. 이 트리거는 대뇌 피질로 더 전파되어 두 회로의 융합이 일어납니다. 이 수렴은 소뇌-탈라모-피질 회로를 자극하여 떨림의 진폭을 변화시킵니다. 그림은 떨림 병인에서 주요 신경 화학적 역할을 하는 것으로 추정되는 주요 핵을 보여줍니다:

1. 시상하부 영역, 기저핵 및 복측 시상으로의 도파민성 투영이 감소하는 시상하부 영역(RRA)의 퇴화

2. 세로토닌 투영 감소는 퇴행성 라페핵(RN)으로 인해 발생합니다.

3. 시교차상핵(LC)의 노르아드레날린성 투사 증가.

본태성 진전 아형에 대한 병태생리학적 근거는 아직 명확하게 밝혀지지 않았지만, 일차 운동 피질(M1)과 소뇌의 비침습적 경두개 자기 자극(TMS)을 통해 휴식 및 자세 성분의 기원에 대한 통찰력을 조사했습니다. 휴식 및 자세 PD 진전을 재설정하는 것은 M1 자극으로 달성 할 수있는 반면 소뇌 자극은 자세 구성 요소 만 재설정 할 수 있습니다 [33,34]. 이러한 결과는 이 피질 영역이 PD에서 휴식 및 자세 진전의 진폭과 리듬을 조절하는 반면, 자세 진전 조절은 소뇌와 더 관련이 있음을 시사합니다.

Role of Dopamine and other neurotransmitters

Degeneration of dopaminergic neurons in the retrorubral area (RRA) of the midbrain, more so than in the substantia nigra pars compacta, may correlate with the generation of tremor in PD [35]. Loss of dopaminergic projections from the RRA to the subthalamic region, the basal ganglia, and the ventrolateral thalamus result in dopamine depletion in these regions and represents one of the main neurochemical bases of tremor generation in PD [30,36,37,38]. Tremor severity was found to correlate with dopamine transporter (DAT) density in the pallidum, while other motor symptoms correlate with DAT density in the striatum [30]. This suggests a more selective pallidal dopamine depletion that leads to basal ganglia dysfunction, which subsequently drives tremor episodes in PD.

In addition to dopamine, other neurotransmitters have been proposed to play a critical role in the pathogenesis of tremor in PD. In patients with tremor-dominant PD, locus coeruleus interneurons have relatively less degeneration, and noradrenaline (NA) receptor binding is increased compared to other PD phenotypes and healthy controls [37,39]. Noradrenaline contribution in parkinsonian tremor is reflected by the effect of cognitive stress, which activates the noradrenergic system, release NA, and result in tremor amplitude aggravation tremor amplitude aggravation [40]. This potential role has also been examined through the administration of intravenous adrenaline in PD patients, which has resulted in an increase in tremor amplitude [24].

The magnitude and severity of tremor are more attributed to serotonin deficiency. Loss of serotonin transporters in the raphe nuclei in the midbrain has been shown to be correlated with more severe tremor [7,19]. Furthermore, 123I-FP-CIT measurement of the median raphe serotonin transporter availability, compared to the putamen dopamine transporter uptake, has shown that more severe tremor scores are correlated with lower raphe/putamen uptake ratio values [41]. In addition, this group of patients tend to have relatively small clinical benefit when receiving acute dopaminergic therapy. Both findings are indicative that more severe, and dopaminergic resistant, tremor are suggestive of more severe raphe nucleus dysfunction [7,41,42].

Due to the impact produced by anticholinergic drugs in PD tremor reduction, acetylcholine has been proposed to contribute to the development of tremor in PD [21,24]. Dopamine deficiency is thought to result in hyperactive striatal cholinergic interneurons, which in turn reduces the release of dopamine and exacerbates PD symptoms, including tremor [19,43].

도파민 및 기타 신경전달물질의 역할

중뇌의 흑질질보다 더 많은 중뇌의 후퇴핵 영역(RRA)에 있는

도파민성 뉴런의 퇴화는

본태성 진전 발생과 관련이 있을 수 있습니다[35].

시상하부 영역, 기저핵, 복측 시상으로의 도파민 투영이 손실되면 이 영역에서 도파민이 고갈되며,

이는 PD에서 진전 발생의 주요 신경화학적 기반 중 하나입니다 [30,36,37,38].

떨림의 심각도는 구상체의 도파민 수송체(DAT) 밀도와 상관관계가 있는 것으로 밝혀졌으며,

다른 운동 증상은 선조체의 DAT 밀도와 상관관계가 있습니다 [30].

이는 보다 선택적인 시상 도파민 고갈이 기저핵 기능 장애로 이어져

본태성 진전 증상을 유발한다는 것을 시사합니다.

도파민 외에도 다른 신경전달물질이 본태성 진전증의 발병에 중요한 역할을 하는 것으로 제안되었습니다.

진전 우세 PD 환자의 경우, 추체강 내 뉴런은 상대적으로 퇴행이 적고 다른 PD 표현형 및 건강한 대조군에 비해 노르아드레날린(NA) 수용체 결합이 증가합니다 [37,39]. 파킨슨병 진전에서의 노르아드레날린 기여는 인지 스트레스의 효과에 의해 반영되며, 이는 노르아드레날린 시스템을 활성화하고 NA를 방출하며 진전 진폭 악화 진전 진폭 악화를 초래합니다 [40]. 이러한 잠재적 역할은 PD 환자에게 정맥 내 아드레날린을 투여하여 진전 진폭을 증가시킨 결과에서도 조사되었습니다 [24].

떨림의 크기와 심각성은 세로토닌 결핍에 더 많이 기인합니다. 중뇌의 라페핵에서 세로토닌 수송체의 손실은 더 심한 진전과 상관관계가 있는 것으로 나타났습니다 [7,19]. 또한, 푸타멘 도파민 수송체 흡수율과 비교한 123I-FP-CIT 측정 결과, 더 심한 진전 점수는 더 낮은 푸타멘/푸타멘 흡수율 값과 상관관계가 있는 것으로 나타났습니다 [41]. 또한 이 환자 그룹은 급성 도파민 치료를 받을 때 임상적 이점이 상대적으로 적은 경향이 있습니다. 두 결과 모두 더 심하고 도파민성 저항성 진전은 더 심각한 라페핵 기능 장애를 시사합니다 [7,41,42].

PD 진전 감소에서 항콜린성 약물에 의해 생성되는 영향으로 인해 아세틸콜린은 PD의 진전 발생에 기여하는 것으로 제안되었습니다 [21,24]. 도파민 결핍은 과잉 활동적인 선조체 콜린성 뉴런을 초래하여 도파민 방출을 감소시키고 떨림을 포함한 PD 증상을 악화시키는 것으로 생각됩니다 [19,43].

3.2 Phenomenology

The classical tremor in PD is usually asymmetric, predominantly “pill-rolling,” resting tremor of 4–6 Hz frequency that is often suppressed with voluntary movements [8,9,10,44]. It is not uncommon, however, to have the resting component combined with either kinetic and/or postural tremor [44,45,46]. Kinetic tremor is apparent during hand movements such as writing or during finger-to-nose examination. Postural tremor presents while stretching out arms against gravity [45]. Re-emergent tremor is a form of postural tremor, in which a “re-emergence” of tremor appears after a short latency (seconds) when hands are kept in an anti-gravity posture [46]. In the literature, action tremor is usually referred to as either kinetic or postural tremor. Tremor in PD was recently subclassified into four categories based on its phenomenology: Type I, in which tremor is of a pure resting component of 4–6 Hz; Type II, where resting tremor is associated with an action component of similar frequency; Type III, in which patients have an isolated action tremor; and Type IV, where a mixed resting and action tremor coexist, each with variable frequency, and the patient may have features of ET in addition to PD [8].

3.2 현상학

본태성 진전은 일반적으로 비대칭적이고, 주로 “알약을 굴리는” 4-6Hz 주파수의 안정 시 진전으로 자발적 움직임으로 억제되는 경우가 많습니다[8,9,10,44]. 그러나 휴식 중 떨림이 운동성 및/또는 자세성 떨림과 함께 나타나는 경우도 드물지 않습니다[44,45,46].

운동성 진전은

글씨를 쓰거나 손가락을 코에 대고 검사하는 등의 손동작 중에 나타납니다.

자세성 진전은 중력에 대항하여

팔을 뻗을 때 나타납니다 [45].

재출현성 진전은 자세성 진전의 한 형태로,

손을 반중력 자세로 유지할 때 짧은 지연 시간(초) 후에 떨림이 “재출현”하는 증상입니다[46].

문헌에서 본태성 진전은 일반적으로 운동성 진전 또는 자세성 진전으로 불립니다.

최근 본태성 진전은 현상학에 따라 네 가지 범주로 세분화되었습니다:

떨림이 4-6Hz의 순수한 휴식 성분인 유형 I,

휴식 떨림이 유사한 주파수의 활동 성분과 연관된 유형 II,

환자가 고립된 활동 떨림을 갖는 유형 III,

휴식과 활동 떨림이 혼합되어 각각 가변 주파수를 갖는 유형 IV,

환자가 PD 외에 본태성 진전의 특징을 가질 수 있는 유형 [8]이 있습니다.

3.3 Management

3.3.1 Pharmacotherapy

Levodopa and other dopaminergic agents remain the first-line therapeutic option for all motor symptoms in PD, including tremor [47,48,49,50,51,52]. However, the choice of the optimal agent might be driven or limited by individualized factors. Disease-related characteristics, like tremor severity and sensitivity to levodopa, in addition to patient-related factors such as age, functional and cognitive status, can guide the choice of pharmacotherapy (Table 1; Figure 3) [47,51].

3.3.1 약물 요법

레보도파 및 기타 도파민 제제는 떨림을 포함한 파킨슨병의 모든 운동 증상에 대한 일차 치료 옵션으로 남아 있습니다[47,48,49,50,51,52]. 그러나 최적의 약제 선택은 개별적인 요인에 의해 좌우되거나 제한될 수 있습니다. 연령, 기능 및 인지 상태와 같은 환자 관련 요인 외에도 진전 중증도 및 레보도파에 대한 민감도와 같은 질병 관련 특성이 약물 요법 선택의 지침이 될 수 있습니다(표 1; 그림 3) [47,51].

Table 1.

Pharmacotherapeutic options in the treatment of Parkinson’s disease tremor.

MEDICATIONMECHANISM OF ACTIxxONSTARTING DOSAGE (MG)TITRATIONMAXIMUM (MG)SIDE EFFECTSCOMMENTS

Levodopa	Metabolic precursor of dopamine	Levodopa-carbidopa 100/25 mg TID	Increase by 1–2 tablets every week	1200–1500 mg/day in 3–4 divided doses	Nausea, vomiting, postural hypotension, confusion or hallucinations	Dose and frequency can be increased as tolerated
		Levodopa-benserazide 100/25 mg TID
Dopamine Agonists	Stimulate dopamine receptors	Pramipexole 0.125 mg TID	Slow titration every 5–7 days	4.5 mg/day	Somnolence, constipation, dizziness, hallucinations, sleep attacks and ICD.
		Pramipexole ER 0.375 mg TID
		Rotigotine transdermal patch 2 mg/24 hours	May increase by 2 mg/24 hours at weekly intervals	8 mg/24 hours
		Ropinirole 0.25 mg TID	Slow titration at weekly intervals	24 mg/day
		Ropinirole ER 2 mg OD
MAOB-I	Inhibits monoamine oxidase enzyme	Selegiline 2.5–5 mg OD	Slow titration at weekly intervals	10 mg/day in 2 divided doses	Headache, dizziness, insomnia, nausea
		Rasagiline 0.5 mg OD		1 mg/day
Anticholinergics	Antagonise the effects of acetylcholine at muscarinic receptors postsynaptic to striatal interneurons	Benztropine 0.5mg/day	Increase by 0.5 mg every 5–7 days	6 mg/day in 2 to 4 divided doses	Memory impairment, confusion, and hallucinations plus peripheral antimuscarinic side effects.	Rapid withdrawal can result in exacerbation of parkinsonism
		Trihexyphenidyl 1 mg/day	Gradual increase by 2 mg at 3–5 days interval	12–15 mg/day in 3 to 4 divided doses
Clozapine	Has anticholinergic and anti-serotonergic properties	12.5 mg	Add 12.5mg every 1 to 2 weeks	75–100 mg/day	Agranulocytosis, sedation, hypotension, hypersalivation and fever have been reported.	Requires routine blood monitoring for blood count
Clonazepam	Enhances GABA activity	0.5mg OD	Increase by 0.5 mg every 3–4 days	6 mg/day	sedation, memory loss and confusion.
Propranolol	β1- and β2-receptor blocker	Regular 10–20 mg BID	Titration at 3–7 days interval	320 mg/day	Sedation, insomnia, depression, hypotension, diarrhea, constipation and impotence	Rapid withdrawal can result in arrythmias
		ER 60–80 mg OD

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GABA: gamma-aminobutyric acid; OD: once daily, BID: twice per day. TID: three times per day; ER: Extended Release; ICD: Impulse Control Disorder.

Figure 3.

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Algorithm for the treatment of Parkinson Disease with predominant symptomatic tremor. † No strong evidence to support long term, sustained efficacy, and safety. Currently, the modality is mostly applied within the scope of clinical trials and registries.

Levodopa

The effect of levodopa is known to be greatest for bradykinesia, while the effect on tremor control is relatively variable [50,52,53,54]. Favorable effects are more pronounced for resting and re-emergent components compared to kinetic or pure postural tremor [46,55]. Overall, it ranges widely from no objective clinical response to 80% tremor reduction [56,57]. This inconsistent response has led to the proposed classification of tremor into three subtypes: dopamine-responsive, dopamine-resistant, and a partially overlapping intermediate group [58,59,60]. The dose and duration required to consider tremor as dopamine-resistant have not yet been determined. Based on this classification, dopamine-resistant was defined according to its response during a levodopa challenge test (LCT), in which higher doses of levodopa are tested in an OFF state. Patients with dopamine-resistant PD tremor demonstrate a lack of clinical and electrophysiologic response despite receiving up to double their usual dose of levodopa during the test [59].

Poor response in some patients might be attributed, in part, to pseudoresistance, a phenomenon in which levodopa sensitive symptoms falsely appear to be resistant [15,52,60]. This occurs in the context of multiple underlying mechanisms that contribute to a suboptimal response [60]. Factors leading to pseudoresistance include gastrointestinal dysfunction causing poor absorption or high protein diets interfering with levodopa. Moreover, cognitive stress is a known factor that attenuates the therapeutic effect of dopamine [24,52,60].

As the effect of levodopa is expected to be dose-dependent for tremor control, a dose increase might eventually be required, even if other symptoms show a robust response to lower doses [61]. However, the main challenge remains related to the maximum dose, which may be limited because of the potential dose-related side effects like nausea, vomiting, dyskinesias, or hallucinations. Furthermore, some studies have suggested that tremor might be worsen with a higher levodopa dosage [62].

Dopamine Agonists (DAs)

Pramipexole, apomorphine, and other DAs can augment the effect of levodopa, hence, providing greater tremor control [63,64]. They can be used as an initial monotherapy, or as adjuvant addition to levodopa [50,65]. Both pramipexole and pergolide produce a similar degree of resting tremor suppression when used as monotherapy [66]. The addition of pramipexole to levodopa results in an estimated 45% reduction in the Unified Parkinson’s Disease Rating Scale (UPDRS) tremor scores and significantly lower tremor occurrence during waking hours as recorded by long-term electromyography (EMG) [63]. Apomorphine is a potent, relatively short-acting DA that can be administered with a continuous subcutaneous infusion pump, or an intermittent sublingual, and subcutaneous injection [67,68]. Apomorphine can provide a comparable effect on tremor produced by levodopa, but with a considerably lower mean duration of effect [69,70].

Levodopa and DAs have comparable dopaminergic side effect profiles [49,69]. An additional dose-dependent side effect linked to DAs is the development of impulse control disorder (ICD), which is estimated to have up to a 50% five-year cumulative incidence risk [71]. Treatment of early PD with DAs can be associated with a reduced risk of motor fluctuations in the first five years after initiation, especially with younger patients [72,73].

Anticholinergics

Anticholinergic medications, including trihexyphenidyl and benztropine, can be considered if tremor control is inadequate with dopaminergic agents [15,74]. Anticholinergics are effective in improving PD tremor and other motor symptoms, but with a high risk of neuropsychiatric and cognitive adverse events [75]. These factors have limited the use of anticholinergics as they were a common reason for non-compliance. In addition, outcome measures of these agents vary widely. A significant improvement in tremor was found in some studies, while others have shown poor tremor response, but with improvement in bradykinesia and rigidity [75]. Due to the potential adverse effects, anticholinergics should only be used for tremor-dominant PD patients who are young and have failed to improve with dopaminergic agents [15,74]. It is important to utilize a slow taper, if required, as rapid discontinuation may manifest with acute exacerbation of parkinsonism [76].

Monoamine Oxidase B (MAO-B) Inhibitors

MAO-B inhibitors act by increasing the bioavailability of central monoamines, including dopamine. They can be very effective at improving motor and non-motor symptoms in the early stages of PD, which might delay the need for levodopa [77]. The ameliorating beneficial effects of MAO-B inhibitors on motor symptoms are notably greater in akinetic/rigid PD compared to tremor-dominant PD [78]. However, rasagiline was selectively studied as a monotherapy, or as an adjuvant therapy to levodopa in patients with tremor-dominant PD, and found to have a significant effect on tremor reduction as early as 10 weeks from treatment initiation [79,80].

모노아민 산화효소 B(MAO-B) 억제제

MAO-B 억제제는 도파민을 포함한 중추 모노아민의 생체 이용률을 높이는 방식으로 작용합니다. 이 약물은 파킨슨병 초기에 운동 및 비운동 증상을 개선하는 데 매우 효과적일 수 있으며, 레보도파의 필요성을 지연시킬 수 있습니다[77]. 운동 증상에 대한 MAO-B 억제제의 개선 효과는 떨림이 우세한 PD에 비해 운동성/경직성 PD에서 특히 더 큽니다 [78]. 그러나 라사길린은 단독 요법 또는 진전 우세형 PD 환자에서 레보도파의 보조 요법으로 선택적으로 연구되었으며, 치료 시작 후 10주 이내에 진전 감소에 상당한 효과가 있는 것으로 밝혀졌습니다 [79,80].

Clozapine

Clozapine is an antipsychotic agent that is commonly used in the treatment of schizophrenia and drug-induced psychosis [81]. The exact mechanism by which it exerts its anti-tremor effect is not fully understood but may be attributed to its anticholinergic and antiserotonergic properties [82]. Resting and postural tremor can be reduced in up to 72% of PD patients, and tremor scores can be reduced by 64% [83]. In addition to its anti-tremor effect, the advantage of its anti-psychotic action might be of significance in patients experiencing psychosis [82]. One major limitation of clozapine is the risk of developing agranulocytosis, which mandates frequent blood monitoring [84].

Beta-blockers

Propranolol is a non-selective beta-blocker that has been widely used in the treatment of ET. In PD tremor, the use of propranolol and other beta-blockers lacks evidence to determine efficacy and safety [85]. Propranolol can improve the postural component of PD tremor, and it is clinically useful in the context of associated anxiety and stress that aggravate tremor [86]. However, the efficacy is usually not sustained, and a large proportion of patients eventually discontinue the medication because of rapid tolerance, loss of initial response and the increased risk of orthostatic hypotension [85]. Like anticholinergics, beta-blockers should be tapered gradually to prevent withdrawal symptoms [87].

Other agents

Zuranolone is a novel gamma-aminobutyric acid (GABA) receptor positive allosteric modulator that improves tremor scores by 40% when used as an adjuvant agent with dopaminergic therapies [88]. Other therapeutic options include clonazepam, budipine, zonisamide, amantadine, and mirtazapine, all of which have shown variable degrees of nonsustained tremor control [65].

3.3.2 Botulinum toxin injections

Botulinum neurotoxins (BoNT) are proteins derived from the bacterium Clostridium botulinum. They act at the cholinergic presynaptic nerve terminals by cleaving and inactivating SNARE proteins and subsequently inhibiting the release of acetylcholine. This, in turn, prevents muscle contraction and results in paralysis of injected skeletal muscles. In addition, BoNT blocks gamma motoneurons and reduces muscle spindle afferent input to the central nervous system [89,90,91,92]. BoNT type A (BoNT-A) has been widely used to treat tremor and other movement disorders, and it can be a rescue option for patients who for patient who have pharmacologically-refractory tremor and considered poor candidates for advanced therapies [90,91]. The reported success rate is variable and is influenced by factors such as dose, muscles selected, technique, and provider experience [92,93,94]. The Yale Technique and Sensor-Based Kinematics have been proposed as safe and supportive methods that can enhance efficacy [95]. The Sensor-Based Kinematics method uses motion sensors to analyze angular tremor amplitude, which provides better individualized muscle selection [94,95]. The Yale Technique uses EMG guidance of determined muscles to further enhance accurate muscle selection and success rate [95].

Forearm flexors and extensors are traditionally targeted muscles. A fixed, initially low, BoNT dose is suggested to avoid dose-dependent weakness [91,92,95]. Forearm flexors are prioritized over extensors because of the relatively higher rate of extensor finger weakness [96,97]. The long-term effect of BoNT injections was demonstrated with a mean follow-up duration of 29 months, with over 80% of patients reporting moderate or marked improvement at their first and last visits [92,98]. The mean UPDRS scores for resting and kinetic tremor were significantly reduced when compared to baseline when BoNT injections were coupled with kinematic guidance [98].

3.3.3 Advanced therapies (Table 2)Table 2.

Advanced surgical modalities for Parkinson’s Disease tremor.

MODALITYSELECTION CRITERIATARGETSADVERSE EVENTS

A. DBS	- Diagnosis of IPD with ≥ five-years disease duration - Age ≤ 75* - Medication-refractory symptoms or fluctuations - Dopaminergic responsiveness confirmed by LCT** - Intact cognitive status - No intracranial pathology on neuroimaging	STN, GPi, Vim, PSA	Cognitive decline, cerebral hemorrhage, infection, hardware failure, delayed lead migration, and death
B. Lesioning therapies
MRgFUS	- Diagnosis of IPD - Medication-refractory symptoms or fluctuations - Intact cognitive status - No intracranial pathology on neuroimaging - No history of DBS or prior stereotactic ablation - No bleeding liability - Skull density ratio ≥0.45	Thalamotomy, Subthalamotomy, Pallidotomy	Headache, dizziness and vertigo, transient ataxia, paresthesia, and weakness
GK		Thalamotomy, Subthalamotomy	Transient paresthesia and hemiparesis, dysphagia, and death
RF		Thalamotomy	Transient paresthesia, hemiparesis, dysarthria, ataxia, confusion, cognitive decline, and intracerebral hemorrhage

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IPD: Idiopathic Parkinson’s Disease; * No consensus agreement; ** May not be reliable indicator in the case of tremor-dominant PD.

Deep Brain Stimulation (DBS)

In the last three decades, deep brain stimulation (DBS) has risen as the most common advanced surgical modality in PD [99]. This is due to its long-term efficacy in improving refractory and poorly-controlled motor symptoms and fluctuations [100,101,102,103,104]. Candidacy for DBS is based on a detailed eval‎uation, which incorporates cognitive status, responsiveness to levodopa in the LCT, and the nature of associated symptoms and motor fluctuations [105,106]. A cutoff of 30% improvement in the UPDRS III during the LCT was established as a threshold for levodopa and potential DBS responsiveness. However, patients with dopamine-resistant tremor might show a poor response in the LCT [59,107,108,109]. Hence, the LCT may not be a reliable indicator for candidacy and repressiveness to DBS in the case of refractory PD tremor [110,111]. DBS electrodes replace and mimic the therapeutic effect produced by lesioning therapies but without inducing significant brain lesions, which provides the advantage of reversibility. Furthermore, DBS can be applied to both cerebral hemispheres, an option currently limited to one side only in lesioning therapies [119,120].

The therapeutic mechanism of DBS is not well understood [112,113,114]. Electrode placements in structures with neural oscillatory activity (i.e., the basal ganglia and cerebello-thalamo-cortical loops) could disrupt this oscillatory activity and, hence, alter tremor generation and/or amplitude [115,116]. Several imaging studies have investigated patterns of metabolic changes before and after DBS electrode placement. Patients with tremor-dominant PD display a distinct pattern, a tremor-related metabolic pattern (PDTP), which correlates with tremor severity and is characterized by an increased activity in the cerebellar dentate nucleus and primary motor cortex. In non-tremor dominant PD, a pattern with hypermetabolism in the pons, globus pallidus, and the thalamus can be seen (PD-related metabolic pattern: PDRP), and it correlates with the severity of other motor symptoms [115]. Interestingly, Vim DBS can only reduce PDTP activity, while STN and GPi DBS can reduce both PDTP and PDRP activities [117,118]. These findings explain why such targets would improve all motor symptoms, including tremor, while Vim selectively improves tremor only.

DBS target selection for patients with tremor-dominant PD is individualized. Placement of electrodes in the STN, Vim, GPi, and the posterior subthalamic area (PSA) are reportedly effective in alleviating PD tremor [121,122,123,124]. However, STN and GPi have an apparent benefit compared to other targets as they improve all motor symptoms [121]. Both targets have comparable efficacy and can reduce resting and kinetic tremor components [124]. Interestingly, STN-DBS can achieve better outcomes for arm tremor compared to chin and lower extremity tremor [125]. STN-DBS may be superior to GPi-DBS for controlling dopamine-resistant tremor [126]. Compared to other targets, Vim-DBS is associated with better improvement in UPDRS tremor scores in the off state, which would allow for greater medication reduction [121]. This factor would arguably favor Vim over other targets for PD tremor. However, the evolution of other PD symptoms and motor fluctuations can pose a challenge, as Vim is not the preferred target [127,128]. Therefore, selecting Vim should be reserved for patients with a long-standing, mostly unilaterally-dominant tremor as the main symptom in the absence of other motor features or fluctuations. Dual implantation of the GPi and Vim can be applied for patients with dopamine-resistant tremor, who have other motor symptoms or fluctuations that would benefit from GPi stimulation [129].

The long-term efficacy of DBS is well-documented for treating motor complications of PD and maintaining improvement in quality of life (QoL) [130,131,132]. Both STN and GPi targets can provide a relatively comparable, persistent benefit in the first few years after electrode implantation [133,134,135]. For GPi-DBS, fewer patients exhibited cognitive decline, gait disorders, or speech difficulties compared to STN-targeting DBS [134]. However, additional, long-term benefits in core motor symptoms are more consistent with STN-targeting DBS [132]. Bilateral Vim-DBS is potentially associated with dysarthria, loss of balance, and incoordination over the long term [136,137].

Lesioning Therapies (LTs)

LTs can successfully be utilized for the treatment of PD motor symptoms and are considered one of the most effective therapies for the management of refractory tremor in PD [138]. MRI-guided focused ultrasound (MRgFUS), Gamma Knife (GK), and radiofrequency (RF) thermoablation are the main and available LT modalities in practice [138,139,140,141].

Although LTs originally fell out of favor with the advancement of DBS, there is a growing interest in LTs in recent years with the introduction of incisionless therapies like MRgFUS or GK [139]. Both therapies have the advantage of not requiring general anesthesia, and compared to DBS, have fewer side effects related to surgical interventions [140]. In addition, LTs might offer alternative surgical options to DBS for underserved and remote areas where resources and distance can limit ongoing treatment and monitoring. Both MRgFUS and RF thermoablation have the advantage of providing a real-time assessment of the benefit during the procedure before reaching a final, clinically-based lesioning [139]. Compared to the immediate results of other modalities, the benefits and adverse effects related to GK lesioning are expected to develop several months after the procedure [141]. Unlike DBS, lesioning therapies produce permanent lesioning, which is considered a major drawback. Furthermore, evidence of the long-term efficacy of DBS in PD is immense compared to the relatively small and short-term investigational data addressing the efficacy and safety of LTs [100,130,131,142].

심부 뇌 자극(DBS)

지난 30년 동안, 뇌심부자극술(DBS)은 파킨슨병에서 가장 보편적인 첨단 수술법으로 부상했습니다[99]. 이는 불응성 및 잘 조절되지 않는 운동 증상과 변동을 개선하는 데 장기적인 효과가 있기 때문입니다 [100,101,102,103,104]. DBS 후보군은 인지 상태, LCT에서 레보도파에 대한 반응성, 관련 증상 및 운동 변동의 특성을 통합하는 상세한 평가를 기반으로 합니다 [105,106]. 레보도파 및 잠재적 DBS 반응성에 대한 임계값으로 LCT 중 UPDRS III에서 30% 개선의 컷오프가 설정되었습니다. 그러나 도파민 저항성 진전 환자는 LCT에서 반응이 좋지 않을 수 있습니다 [59,107,108,109]. 따라서 LCT는 불응성 PD 진전의 경우 DBS에 대한 후보성 및 억제성에 대한 신뢰할 수 있는 지표가 아닐 수 있습니다 [110,111]. DBS 전극은 병변 치료로 인한 치료 효과를 대체하고 모방하지만 심각한 뇌 병변을 유발하지 않으므로 가역성이라는 이점을 제공합니다. 또한, 현재 병변 치료에서 한쪽으로만 제한되는 옵션인 DBS는 양쪽 대뇌 반구에 모두 적용될 수 있습니다 [119,120].

DBS의 치료 메커니즘은 잘 알려져 있지 않습니다 [112,113,114]. 신경 진동 활동이 있는 구조(예: 기저핵 및 대뇌-탈라모-피질 루프)에 전극을 배치하면 이러한 진동 활동을 방해하여 진전 발생 및/또는 진폭을 변화시킬 수 있습니다 [115,116]. 여러 영상 연구에서 DBS 전극 삽입 전후의 대사 변화 패턴을 조사했습니다. 본태성 진전 환자는 떨림의 정도와 상관관계가 있으며 소뇌 치상핵과 일차 운동 피질의 활동이 증가하는 특징이 있는 뚜렷한 패턴, 즉 떨림 관련 대사 패턴(PDTP)을 보입니다. 비진전 우성 PD에서는 폰, 구상체 및 시상에서 과대 대사 패턴을 볼 수 있으며 (PD 관련 대사 패턴 : PDRP) 다른 운동 증상의 심각성과 상관 관계가 있습니다 [115]. 흥미롭게도 Vim DBS는 PDTP 활동만 감소시킬 수 있는 반면, STN과 GPi DBS는 PDTP와 PDRP 활동을 모두 감소시킬 수 있습니다 [117,118]. 이러한 결과는 이러한 표적이 떨림을 포함한 모든 운동 증상을 개선하는 반면, Vim은 떨림만 선택적으로 개선하는 이유를 설명합니다.

떨림이 우세한 본태성 PD 환자를 위한 DBS 표적 선택은 개별화됩니다. STN, Vim, GPi 및 시상하부(PSA)에 전극을 배치하는 것이 PD 진전 완화에 효과적인 것으로 보고되었습니다[121,122,123,124]. 그러나 STN과 GPi는 모든 운동 증상을 개선하기 때문에 다른 표적에 비해 명백한 이점이 있습니다 [121]. 두 표적 모두 비슷한 효능을 가지고 있으며 휴식 및 운동성 진전 성분을 줄일 수 있습니다 [124]. 흥미롭게도 STN-DBS는 턱과 하지 떨림에 비해 팔 떨림에 대해 더 나은 결과를 얻을 수 있습니다 [125]. STN-DBS는 도파민 저항성 진전 제어에 있어 GPi-DBS보다 우수할 수 있습니다 [126]. 다른 표적에 비해 Vim-DBS는 오프 상태에서 UPDRS 떨림 점수를 더 잘 개선하여 약물을 더 많이 줄일 수 있는 것과 관련이 있습니다 [121]. 이 요인은 다른 PD 떨림 표적 치료법보다 Vim을 더 선호하게 만들 수 있습니다. 그러나 다른 PD 증상과 운동 변동의 진화는 Vim이 선호되는 표적이 아니기 때문에 문제가 될 수 있습니다 [127,128]. 따라서 다른 운동 특징이나 변동이 없는 상태에서 오랫동안 주로 일방적으로 우세한 떨림이 주된 증상인 환자에게는 Vim을 선택해야 합니다. 도파민 저항성 진전 환자 중 다른 운동 증상이나 변동이 있어 GPi 자극이 도움이 될 수 있는 환자에게는 GPi와 Vim의 이중 이식이 적용될 수 있습니다[129].

DBS의 장기적인 효과는 PD의 운동 합병증을 치료하고 삶의 질(QoL)을 개선하는 데 잘 입증되어 있습니다[130,131,132]. STN과 GPi 표적 모두 전극 이식 후 처음 몇 년 동안 비교적 비슷하고 지속적인 이점을 제공할 수 있습니다 [133,134,135]. GPi-DBS의 경우, STN 표적 DBS에 비해 인지 기능 저하, 보행 장애 또는 언어 장애를 보이는 환자의 수가 더 적었습니다 [134]. 그러나 핵심 운동 증상에 대한 추가적이고 장기적인 이점은 STN 표적 DBS와 더 일관성이 있습니다 [132]. 양측 Vim-DBS는 장기적으로 구음장애, 균형감각 상실, 협응력 저하와 관련이 있을 가능성이 있습니다 [136,137].

병변 치료(LT)

LT는 본태성 운동 증상의 치료에 성공적으로 활용될 수 있으며 본태성 떨림의 관리를 위한 가장 효과적인 치료법 중 하나로 간주됩니다 [138]. MRI 유도 집속 초음파(MRgFUS), 감마나이프(GK), 고주파(RF) 열 소작술이 실제로 사용 가능한 주요 LT 치료법입니다[138,139,140,141].

LT는 원래 DBS의 발전과 함께 선호도가 떨어졌지만, 최근 몇 년 동안 MRgFUS 또는 GK와 같은 절개 없는 치료법이 도입되면서 LT에 대한 관심이 증가하고 있습니다 [139]. 두 치료법 모두 전신 마취가 필요하지 않다는 장점이 있으며, DBS에 비해 외과적 개입과 관련된 부작용이 적습니다 [140]. 또한 LT는 자원과 거리로 인해 지속적인 치료와 모니터링이 제한될 수 있는 소외 지역 및 외딴 지역에서 DBS를 대체할 수 있는 수술 옵션을 제공할 수 있습니다. MRgFUS와 RF 열소작술은 모두 최종 임상 기반 병변에 도달하기 전에 시술 중 이점을 실시간으로 평가할 수 있다는 장점이 있습니다 [139]. 다른 모달리티의 즉각적인 결과와 비교할 때, GK 병변과 관련된 이점과 부작용은 시술 후 몇 달 후에 나타날 것으로 예상됩니다 [141]. DBS와 달리 병변 치료는 영구적인 병변을 생성하며, 이는 주요 단점으로 간주됩니다. 또한, PD에서 DBS의 장기적인 효능에 대한 증거는 LT의 효능과 안전성을 다루는 상대적으로 작고 단기적인 연구 데이터에 비해 엄청납니다 [100,130,131,142].

MRI-guided focused ultrasound (MRgFUS)

MRgFUS has recently emerged as a very promising therapeutic option for refractory tremor in PD. Safety and efficacy were first demonstrated in the treatment of ET, leading to its Food and Drug Administration (FDA) approval as a rescue management modality for medication-refractory tremor [126]. While available data is encouraging and has confirmed an overall improvement in tremor scores and QoL in PD, there is a lack of sufficient/high quality evidence to suggest the regular use of MRgFUS in PD with refractory tremor [142].

MRgFUS lesioning is conducted through minimally invasive thermal ablation with phased-array transducers, which enable precise, incisionless transcranial delivery of acoustic energy [123]. Like ET, the most common examined anatomic target in PD tremor is the Vim nucleus of the thalamus [139,143,144]. In one RCT, STN was the main target, while other small case series have studied the pallido-thalamic tract (PTT) and GPi [145]. MRgFUS thalamotomy can achieve an estimated improvement in the clinical rating scale for tremor sub-scores by a median of seven points, as well as in on-medication median UPDRS motor scores by eight points when compared to pre-intervention [146,147]. As with thalamotomy, MRgFUS subthalamotomy was also found to achieve improvement in the UPDRS-III (including tremor scores), QoL, and ADLs as measured in the UPDRS-II [146]. MRgFUS of the PTT has been found to be as safe and effective, and up to 88% of mean tremor reduction has been achieved with this target [148].

Currently, the modality is applied mostly for unilateral lesioning to control the most affected side [139]. Staged bilateral lesioning remains controversial, with a growing number of reports, only in ET, showing good overall efficacy and a similar safety profile to unilateral lesioning [149].

Most side effects are transient, usually subsiding by three to 12 months after the procedure [150]. The most common procedural side effects are headache, dizziness, and vertigo. Ablation-related side effects include transient ataxia, paresthesias, and weakness [143,144,145,146,147,148,149,150]. Additionally, MRgFUS subthalamotomy can result in dyskinesia in the off-medication state in up to 22% of patients, which can persistent up to three months [145]. Compared to DBS, cognitive decline appears to be minimal and tends to be limited to verbal fluency and inhibition [144].

GK Thalamotomy

GK radiosurgery is an incisionless lesioning procedure in which high-dose radiation is applied to pre-specified brain targets [139,151,152]. The modality is dependent on pre-procedural, imaging-based planning [154]. The absence of real-time targeting may result in an unpredictable effect. Most reports on GK radiosurgery have a small sample size, and no randomized trials have addressed its efficacy compared to other modalities [153]. GK lesioning is reported to achieve improvements of UPDRS tremor items by 71% and 60% at 12 and 52 months, respectively [154]. Patients report 88% complete or near-complete alleviation of PD tremor [151,153]. GK thalamotomy could be a preferred option for patients with advanced age or associated comorbidities who are not candidates for DBS. Adverse events are generally rare and usually transient [140]. However, serious events like thalamic hemorrhage have been reported [155].

RF Thermoablation

Unlike MRgFUS and GK treatments, RF ablation is performed through a frontal burr hole of the skull and requires brain penetration with a special electrode [156,157]. The electrode can be heated to sub-ablative thermal temperatures to produce a “test lesion.” Subsequently, a higher temperature is applied to produce a permanent lesion at the desired target [139]. RF ablation was the modality of choice for tremor in PD before the introduction of DBS in the late 1980s. Cost is relatively lower than other modalities [139]. Lesioning through RF thermoablation in PD is usually implemented through targeting the GPi, the thalamus, or the STN. The modality seems to achieve the highest tremor control in PD when targeting the thalamus, with improvements reaching up to 74%. In most cases, the use is limited to one side, as bilateral RF thalamotomy is typically associated with a high rate of adverse effects [156,157]. Complications are usually transient and result from local edema produced after ablation, which ultimately recover as the edema resolves [139]. One of the main concerns regarding the procedure is the potential risk of intracerebral hemorrhage and subsequent neurological deficits. These could occur at the entry point, in the electrode path, or at the final ablation site [157].

Levodopa/Carbidopa Intestinal Gel (LCIG)

LCIG is administered continuously by a portable pump via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube [158]. LCIG provides a more stable plasma concentration in patients with poorly controlled motor symptoms or fluctuations in advanced PD [159]. The modality is considered an optimal option for those excluded from surgical interventions who require sustained dopaminergic therapy for refractory motor symptoms. The improvement is reflected in the UPDRS part III, including tremor sub-scores. A complete resolution in resting tremor after 12 months of LCIG treatment was reported in up to 78% of patients who had baseline resting tremor pre-treatment [160]. No current evidence to support the role of LCIG in patients with tremor-dominant PD.

3.3.4 Physical therapy and rehabilitation

Physical therapy and intense rehabilitation can improve various motor and non-motor aspects of PD, in addition to their potential long-term effect in slowing disease progression [166,167,168]. Specialized rehabilitation techniques, like aerobic and resistance exercises, have demonstrated improvement in global motor functions. Among resistance exercises, eccentric-based exercises have specifically shown a favorable effect in improving tremor [168]. The efficacy is noted on tremor amplitude at rest, with no clear benefit on postural or kinetic tremor. Resting tremor amplitude decreased by 56% in participants who went through eccentric-based exercise sessions [167,168]. In addition, hand movement and cycling exercises are additional and effective methods for reducing tremor amplitude and frequency [168].

Portable assistive devices have been found to enhance Activities of Daily Living (ADL) and QoL [169]. Liftware Steady and Gyenno Spoon can significantly improve handling utensils. Other limb weights and handheld devices might be optimal for handwriting.

3.3.4 물리 치료 및 재활

물리 치료와 강도 높은 재활은 질병 진행을 늦추는 잠재적 장기 효과 외에도 PD의 다양한 운동 및 비운동 측면을 개선할 수 있습니다[166,167,168]. 유산소 운동 및 저항 운동과 같은 전문 재활 기술은 전반적인 운동 기능의 개선을 입증했습니다.

저항 운동 중에서도 편심 기반 운동은

특히 떨림 개선에 유리한 효과를 보였습니다 [168].

이러한 효과는

안정 시 진전 진폭에서 나타났으며,

자세 또는 운동성 진전에는 뚜렷한 효과가 없었습니다.

편심 기반 운동 세션을 진행한 참가자의

휴식 시 진전 진폭은 56% 감소했습니다 [167,168].

또한 손 운동과 자전거 운동은

떨림 진폭과 빈도를 줄이는 데 효과적인 추가 방법입니다 [168].

휴대용 보조 기기는 일상 생활 활동(ADL)과 삶의 질을 향상시키는 것으로 밝혀졌습니다 [169]. 리프트웨어 스테디와 겐노 스푼은 도구를 다루는 능력을 크게 향상시킬 수 있습니다. 다른 사지 보조기 및 휴대용 기기는 필기에 최적일 수 있습니다.

3.3.5 Non-invasive cortical and peripheral electrical stimulation

Non-invasive stimulation techniques are emerging new modalities for tremor reduction. It is regarded as complementary methods for treating tremor in PD via tailored central or peripheral stimulation [161]. In practise, neither modality is frequently used or readily available.

The therapeutic effect of cortical stimulation has been observed through the application of high-frequency repetitive transcranial magnetic stimulation (rTMS) and anodal transcranial direct current stimulation (tDCS) [161]. Both techniques act by identifying the timing of cortical oscillations, followed by stimulating the motor cortex to induce phase cancellation of the rest-tremor rhythm [162]. Slow alternating periods of phase cancellation, with stimulation delivered at these specified phase alignments, demonstrate controlled suppression of the ongoing tremor. Improvement of the UPDRS-III baseline motor scores, along with tremor reduction, has been achieved in 50% of patients [163].

Peripheral electrical stimulation can suppress tremor through three modalities: functional electrical stimulation (FES), sensory electrical stimulation (SES), and transcutaneous electrical nerve stimulation (TENS) [164]. The FES method performs the best in tremor attenuation. FES induces muscle contraction to modulate its intrinsic property for suppressing tremor [165]. Surface EMG can be used to assess tremor reduction, and further adjust FES if required, without affecting voluntary movements [166]. Outcomes vary widely from 7% to 90% reductions in tremor amplitude [164].

3.3.5 비침습적 피질 및 말초 전기 자극

비침습적 자극 기술은 진전 감소를 위한 새로운 치료법으로 떠오르고 있습니다. 이는 맞춤형 중추 또는 말초 자극을 통해 본태성 진전을 치료하는 보완적인 방법으로 간주됩니다 [161]. 실제로 두 가지 방식 모두 자주 사용되거나 쉽게 구할 수 있는 것은 아닙니다.

피질 자극의 치료 효과는

고주파 반복 경두개 자기 자극(rTMS)과 양극 경두개 직류 자극(tDCS)의 적용을 통해 관찰되었습니다 [161].

두 기술 모두 피질 진동의 타이밍을 파악한 다음 운동 피질을 자극하여 휴식-진전 리듬의 위상 제거를 유도하는 방식으로 작동합니다 [162]. 이러한 특정 위상 정렬에서 자극을 전달하는 느린 교대 위상 제거 기간은 진행 중인 떨림의 제어된 억제를 보여줍니다. 환자의 50%에서 떨림 감소와 함께 UPDRS-III 기준 운동 점수의 개선이 이루어졌습니다 [163].

말초 전기 자극은

기능적 전기 자극(FES),

감각 전기 자극(SES),

경피적 전기 신경 자극(TENS)의 세 가지 방식을 통해 떨림을 억제할 수 있습니다 [164].

functional electrical stimulation (FES),

sensory electrical stimulation (SES), and

transcutaneous electrical nerve stimulation (TENS)

FES 방법은 떨림 감쇠에 가장 효과적입니다.

FES는 근육 수축을 유도하여

근육의 고유한 특성을 조절하여 떨림을 억제합니다 [165].

표면 근전도는 자발적 움직임에 영향을 주지 않으면서

떨림 감소를 평가하고 필요한 경우 FES를 추가로 조정하는 데

사용할 수 있습니다 [166].

결과는 진전 진폭의 7%에서 90% 감소까지 매우 다양합니다 [164].

4 Conclusion

Tremor is one of the most common symptoms associated with PD. The complexity of PD tremor and the wide and unpredictable response to therapeutic modalities remain challenging. Poor response to dopaminergic agents is common, reflecting the role of multiple underlying pathophysiologic processes. Evidence for advanced modalities is heterogeneous, with no sufficient comparative studies to address their efficacy in this specific group of PD patients. Despite promising results, long term data of newer advanced modalities, like MRgFUS, shall be sought to ensure safety and sustained efficacy.

Disclosures

Parts of Figure 2 were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

Competing Interests

The authors have no competing interests to declare.

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