Re: 뇌혈관 병변이 multiple system atrophy를 일으키기도 한다는 논문..

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Parkinsonism Relat Disord. Author manuscript; available in PMC 2022 Jul 28.

Published in final edited form as:

Parkinsonism Relat Disord. 2020 Jun; 75: 34–40.

Published online 2020 May 16. doi: 10.1016/j.parkreldis.2020.05.018

PMCID: PMC9330728

NIHMSID: NIHMS1597319

PMID: 32450546

Cerebrovascular pathology and misdiagnosis of multiple system atrophy: An autopsy study

Shunsuke Koga, MD, PhD,1 Shanu F. Roemer, MD,1 Philip W. Tipton, MD,2 Phillip A. Low, MD,3 Keith A. Josephs, MD,4 and Dennis W. Dickson, MD1

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Abstract

Background:

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by a combination of dysautonomia, parkinsonism, and cerebellar ataxia. Other disorders can mimic MSA, but it is unknown whether cerebrovascular pathology, so-called “vascular parkinsonism,” can mimic MSA. This study aimed to determine the clinicopathological features and red flags for vascular parkinsonism masquerading as MSA.

Methods:

Using a brain bank database, we screened 270 patients with an antemortem diagnosis of MSA, who did not have pathologic evidence of MSA, but rather cerebrovascular pathology, including leukoencephalopathy, lacunar infarcts, and microinfarcts. Histologic sections from the neocortex, basal ganglia, thalamus, brainstem, and cerebellum were reviewed. Medical records were reviewed to characterize the clinical features. The probability of a clinical diagnosis of MSA was assigned retrospectively, guided by current consensus criteria.

Results:

Four patients had cerebrovascular pathology without neurodegenerative processes. Chronic ischemic changes in periventricular white matter, subcortical leukoencephalopathy, lacunar infarcts, or microinfarcts were detected in basal ganglia of all patients. Cerebrovascular pathology that might contribute to autonomic failure was not identified. Clinically, two patients were diagnosed with possible MSA-parkinsonism, one with probable MSA-parkinsonism, and one with possible MSA-cerebellar type; however, they also had one or more non-supporting features of MSA (e.g., onset >75-year-old, dementia), vascular risk factors, and other etiologies (e.g., autonomic neuropathy) that could cause autonomic failure.

Conclusions:

When combined with cerebrovascular risk factors and comorbidities, cerebrovascular pathology may masquerade as MSA. The important lesson from this study is that the diagnosis of MSA requires exclusion of other causes, including cerebrovascular disease.

다계통위축증(MSA)은 자율신경 이상증, 파킨슨병, 소뇌 운동실조증이 복합적으로 나타나는 진행성 신경 퇴행성 질환입니다.

다른 질환도 MSA를 모방할 수 있지만,

소위 '혈관성 파킨슨병'으로 불리는 뇌혈관 병리가

MSA를 모방할 수 있는지 여부는 알려지지 않았습니다.

이 연구는 MSA를 가장한 혈관성 파킨슨병의 임상 병리학적 특징과 위험 신호를 확인하는 것을 목표로 했습니다.

연구 방법:

뇌은행 데이터베이스를 사용하여

MSA의 병리학적 증거는 없지만

백질뇌병증, 열공 경색, 미세 경색 등의 뇌혈관 병리가 있는

270명의 환자를 대상으로 MSA의 사망 전 진단을 받았습니다.

신피질, 기저핵, 시상, 뇌간 및 소뇌의 조직학적 절편을 검토했습니다. 임상적 특징을 파악하기 위해 의료 기록을 검토했습니다. 현재 합의된 기준에 따라 후향적으로 MSA의 임상적 진단 확률을 할당했습니다.

결과:

4명의 환자는

신경 퇴행성 과정이 없는

뇌혈관 병리를 가지고 있었습니다.

모든 환자의 기저핵에서

뇌실 주위 백질, 피질하 백질뇌병증, 열공성 경색 또는

미세 경색의 만성 허혈성 변화가 발견되었습니다.

자율신경 장애를 유발할 수 있는 뇌혈관 병리는 확인되지 않았습니다.

임상적으로 2명의 환자는

MSA-파킨슨병 가능성,

1명은 MSA-파킨슨병 가능성,

1명은 MSA-소뇌 유형으로 진단되었지만,

이들은 자율신경실조를 유발할 수 있는 MSA의 비지지 특징(예: 75세 이상의 발병, 치매), 혈관 위험 요인, 기타 원인(예: 자율신경병증)을 하나 이상 가지고 있었습니다.

결론

뇌혈관 위험 인자 및 동반 질환과 결합하면

뇌혈관 병리가

MSA로 가장할 수 있습니다.

이 연구에서 얻은 중요한 교훈은 다계통위축증을 진단하려면 뇌혈관 질환을 포함한 다른 원인을 배제해야 한다는 것입니다.

Keywords: multiple system atrophy (MSA), cerebrovascular pathology, vascular parkinsonism, neuropathology

1. Introduction

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by a combination of autonomic failure, parkinsonism, and cerebellar ataxia [1]. The current consensus diagnostic criteria for MSA define three degrees of certainty: definite, probable, and possible [1]. A diagnosis of definite MSA requires pathological confirmation. Neuronal loss and gliosis in striatonigral and olivopontocerebellar systems, as well as glial cytoplasmic inclusions composed of α-synuclein, are the pathologic hallmark of MSA [2]. A diagnosis of probable or possible MSA requires autonomic failure with parkinsonism and/or cerebellar involvement in which other causes are excluded [1]. Diagnostic specificity of the criteria is suboptimal [3]. Patients with other neurodegenerative or non-neurodegenerative diseases are sometimes diagnosed with MSA [4–6]. Autopsy-based studies on clinical diagnostic accuracy of MSA have shown that dementia with Lewy bodies, progressive supranuclear palsy, and Parkinson’s disease were common causes of misdiagnosis [4, 6]. In addition, about 1% of autopsy cases have cerebrovascular pathology without any other neurodegenerative pathology to account for the MSA-like syndrome [4, 6].

Accumulating evidence indicates that cerebrovascular pathology, including multiple ischemic lesions in basal ganglia, thalamus, and subcortical white matter, can present with parkinsonism, which is referred to as “vascular parkinsonism” [7–9]. Vascular parkinsonism usually has an insidious onset and symmetric, lower body-predominant parkinsonism [10]. Some patients with vascular parkinsonism can mimic progressive supranuclear palsy or corticobasal syndrome [11–14]. Glass et al. reported clinical features of 28 patients with vascular parkinsonism, and two were clinically diagnosed with MSA [10]. Taken together, a few patients with vascular parkinsonism present as MSA, but their pathology has not been studied in detail.

We herein describe four patients with a clinical diagnosis of MSA in which cerebrovascular pathology was considered to be the likely cause of many of the clinical manifestations. All patients presented with autonomic dysfunction with parkinsonism or cerebellar ataxia; however, they also had one or more non-supporting features of MSA, as well as vascular risk factors. This case series emphasizes that exclusion of other etiologies is important before applying diagnostic criteria for MSA.

1. 소개

다계통위축증(MSA)은

자율신경실조증, 파킨슨병, 소뇌 운동실조증의 조합을 특징으로 하는

진행성 신경 퇴행성 질환입니다[1].

현재 합의된 MSA 진단 기준은

확실성, 가능성, 가능성의 세 가지 확실성을 정의합니다[1].

확실한 MSA 진단을 위해서는

병리학적인 확인이 필요합니다.

선조체 및 흑질 소뇌계의 신경세포 손실과 신경교증,

α-시뉴클린으로 구성된 신경교 세포질 내포물은

MSA의 병리학적인 특징입니다[2].

MSA가 의심되거나 가능성이 있다고 진단하려면

다른 원인이 배제된 파킨슨증 및/또는

소뇌 침범을 동반한 자율 기능 부전이 필요합니다[1].

이 기준의 진단 특이성은 차선책입니다 [3].

다른 신경 퇴행성 또는

비신경 퇴행성 질환을 가진 환자도 때때로

pd으로 진단됩니다 [4-6].

루이소체 치매,

진행성 핵상 마비,

파킨슨병의 임상 진단 정확도에 대한 부검 기반 연구에 따르면

오진의 흔한 원인은 루이소체 치매였습니다 [4, 6].

또한 부검 사례의 약 1%는 다른 신경 퇴행성 병리 없이 뇌혈관 병리만 있어 MSA 유사 증후군을 설명할 수 있습니다 [4, 6].

축적된 증거에 따르면

기저핵, 시상 및 피질하 백질의

여러 허혈성 병변을 포함한

뇌혈관 병리가 파킨슨병과 함께 나타날 수 있으며,

이를 "혈관성 파킨슨병"이라고 합니다[7-9].

혈관성 파킨슨병은

대개 교묘하게 발병하며 대칭적이고 하체가 우세한 파킨슨병을 보입니다[10].

일부 혈관성 파킨슨병 환자는

진행성 핵상 마비 또는 피질 기저부 증후군을 모방할 수 있습니다 [11-14].

Glass 등은 혈관성 파킨슨병 환자 28명의 임상적 특징을 보고했으며, 2명은 임상적으로 MSA로 진단되었습니다 [10]. 종합하면, 혈관성 파킨슨병 환자 중 일부가 MSA로 나타나지만 그 병리에 대해서는 자세히 연구되지 않았습니다.

여기에서는

뇌혈관 병리가 많은 임상 증상의 원인일 가능성이 있는 것으로 간주되는

MSA 임상 진단을 받은 환자 4명에 대해 설명합니다.

모든 환자들은 파킨슨병 또는 소뇌 운동 실조증을 동반한 자율 기능 장애를 보였지만, 혈관 위험 요인뿐만 아니라 MSA의 비지지적 특징을 한 가지 이상 가지고 있었습니다. 이 사례 시리즈는 PD의 진단 기준을 적용하기 전에 다른 원인을 배제하는 것이 중요하다는 점을 강조합니다.

2. Materials and Methods

2.1. Subjects

Cases included in this study were from the Mayo Clinic brain bank and acquired between 1998 and 2019. During this time frame, 270 patients had an antemortem diagnosis of MSA, of which 184 had autopsy-confirmed MSA, 82 had other neurodegenerative disorders, and four cases had primarily cerebrovascular disease. We systematically eval‎uated the clinical and pathologic features of those with cerebrovascular disease. Autopsies on all cases were performed with the consent of the legal next-of-kin or an individual with power-of-attorney. Studies on de-identified autopsy samples are considered exempt from human subject research by the Mayo Clinic Institutional Review Board.

2.2. Neuropathological Assessment

All cases underwent a standardized neuropathological assessment of formalin-fixed left hemibrains, including macroscopic eval‎uation, hematoxylin-eosin stains, thioflavin S fluorescent microscopy, and immunohistochemistry for α-synuclein (NACP, 1:3000, Mayo Clinic antibody, FL) [15], phospho-tau (CP13, 1:1000, from Dr. Peter Davies, Feinstein Institute, North Shore Hospital, NY), and phospho-TDP-43 (pS409/410, 1:5000, Cosmo Bio, Tokyo, Japan). Brain regions sampled included neocortex (x6), hippocampus (x2), amygdala, basal ganglia (x2), thalamus, midbrain, pons, medulla, and cerebellum (x2). Cerebrovascular pathologies that were assessed included macroscopic and microscopic infarcts and hemorrhages, foci of ischemic gliosis, dilation of perivascular spaces (cribriform change), and leukoencephalopathy. Assessment of large and small vessels in the brain parenchyma, leptomeninges, and at the base of the brain (Circle of Willis) was assessed for the presence and severity of arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy. Luxol fast blue staining was used to confirm‎ white matter pathology in cases with leukoencephalopathy. Braak neurofibrillary tangle (NFT) stages and Thal amyloid phases were assigned based upon the distribution of amyloid plaques and NFT with thioflavin S fluorescent microscopy [16–18].

2.3. Clinical Assessment

The following clinical information was abstracted from available medical records by three investigators (SK, SFR, PWT): demographic information, clinical diagnoses, past medical history, risk factors for cerebrovascular disease, imaging findings, autonomic function testing, clinical symptoms, and neurological signs. We focused on autonomic failure (e.g., orthostatic hypotension, urinary problems, and erectile dysfunction), parkinsonism (e.g., resting tremor, cogwheel rigidity, postural instability, and bradykinesia), and cerebellar ataxia [1]. The specialty of physicians who eval‎uated patients (i.e., movement disorder specialist, autonomic disorder specialist) was also noted.

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3. Results

3.1. Demographic and clinical features of MSA

We identified four patients with a clinical diagnosis of MSA who lacked MSA pathology but instead had cerebrovascular pathology. Demographic and clinical features of vascular MSA are summarized in Table 1.

Table 1:

Clinical summary of four vascular MSA patients

Case 1Case 2Case 3Case 4

Age at death	74	88	69	57
Sex	M	M	M	M
Disease duration, years	4	6	3	11
Clinical diagnosis	MSA-P	MSA-P	MSA-P	MSA-C
Autonomic failure	+	+	+	+
Orthostatic hypotension	−	+	+	+
Urinary incontinence	+	+	+	−
Sudomotor dysfunction	+	+	NA	+
Parkinsonism	+	+	+	−
Cerebellar ataxia	+	+	−	+
Pyramidal signs	−	−	−	−
Cognitive impairment	−	−	+	−
Hallucinations	−	+	−	−
REM sleep behavior disorder	−	−	−	−
Depression	−	+	+	−
Peripheral neuropathy	+	−	−	+
Hypertension	+	+	+	−
Dyslipidemia	+	−	−	+
Diabetes mellitus	+	−	+	−
Transient ischemic attack	−	−	−	−
Stroke	+	−	−	−
Autonomic reflex screen	+	+	Urodynamic test	+
Specialty of physicians	Autonomic disorders; Movement disorders	Autonomic disorders; Movement disorders	Movement disorders	General neurology
Supporting features	Anterocollis	Myoclonus	−	−
Non-supporting features	Neuropathy	Hallucinations; onset after 75 years old	Dementia	Neuropathy

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+indicates presence;

−indicates absence of symptoms, signs or past medical history. NA indicates not available in medical records.

Case 1 was a 74-year-old Caucasian man with a history of hypertension, dyslipidemia, and long-standing insulin-dependent diabetes mellitus with subsequent retinopathy, peripheral neuropathy, and chronic kidney disease. He was initially eval‎uated by a movement disorders specialist at age 71, at which time he described a one-year history of progressive changes in his posture with shuffling gait and falls. He was diagnosed with Parkinson’s disease and started on levodopa, which resulted in improved facial expression‎ and less shuffling when walking. Neurological examination was notable for hypomimia, slowed saccadic eye movements, mixed dysarthria with ataxic and hyperkinetic features, diffuse areflexia, anterocollis, rigidity most pronounced in the neck, postural instability, and gait abnormalities, including decreased arm swing, impaired tandem walking, and turning en bloc. He required 10 steps to turn 360°. Vasomotor, sudomotor, and trophic changes were noted in the distal extremities.

Autonomic reflex screen showed generalized autonomic failure as evidence by a composite autonomic severity score (CASS) of 7 (CASS: 0 = none, 1–3 = mild, 4–6 = moderate and 7–10 = severe [19]) with cardiovagal, sudomotor, and adrenergic impairment. Orthostatic hypotension was not present. He developed urinary incontinence, but urinary retention was not noted. MRI of the brain demonstrated a chronic lacunar infarct in the right cerebellar hemisphere, as well as bilateral subcortical lacunar infarcts, and both subcortical and periventricular FLAIR sequence hyperintensities consistent with small vessel ischemic changes. Axial susceptibility-weighted imaging showed hypointensities in the lateral putamen, which was suggestive of MSA (Figure 1A–D) [20]. Based on parkinsonism, autonomic failure, anterocollis, and MRI findings, he was clinically diagnosed with possible MSA-P [1].

Figure 1:

Brain MRI findings of a patient (Case 1) at age 71 (A–D) and a patient (Case 2) at age 85 (E–G). Axial FLAIR sequence shows a chronic lacunar infarct (arrow) in the right cerebellar hemisphere (A) and extensive small vessel disease with subcortical lacunar infarctions (B, arrows). Axial susceptibility-weighted imaging sequence shows hypointensities (arrows) in the lateral putamen (C, D). Axial FLAIR sequence reveals dilation of vessels (arrowheads) in the putamen, hyperintensities (arrows) in the left lateral putamen (E), hyperintensities (arrows) in the periventricular, and subcortical white matter (F). A sagittal section on T1-weighted image discloses cerebellar atrophy (G, arrows). Lateral ventricles are moderately enlarged in the both patients (B, E–G).

Case 2 was an 88-year-old Caucasian man with a history of hypertension and depression. At the age of 82, he had an affective disorder with paranoid ideation, delusional thinking, and non-threatening auditory hallucinations. Symptoms improved with haloperidol; however, the development of parkinsonism prompted a medication change to aripiprazole and venlafaxine. He developed gait impairment leading to falls and poorly responded to dopaminergic medications. He developed urinary incontinence and orthostatic hypotension, which was treated with midodrine and fludrocortisone. At age 85, his examination revealed symmetrical bradykinesia, mild-to-moderate cogwheel rigidity, short stride length with ataxic features, and postural instability. Autonomic reflex screen showed mild-to-moderate cardiovascular adrenergic impairment and patchy postganglionic sympathetic sudomotor abnormality. CASS was 4. Brain MRI revealed mild dilation of the lateral ventricles, cerebellar atrophy, and moderate chronic ischemic changes within the deep white matter, subcortical white matter, and lateral basal ganglia bilaterally (Figure 1E–G). Based on levodopa unresponsive parkinsonism, the lack of resting tremor, and severe autonomic failure, he was clinically diagnosed with possible MSA-P.

Case 3 was a 69-year-old Caucasian man who had multiple vascular risk factors, including hypertension, diabetes, obesity, and coronary artery disease, as well as a surgical history of coronary artery bypass graft, pacemaker implantation, and resection of metastatic melanoma. He had erectile dysfunction since age 63. At age 66, he presented with urinary incontinence, syncope, difficulty with gait and balance, anxiety disorder with mood swings and cognitive impairment characterized by disorientation, forgetfulness, and bradyphrenia. He had orthostatic hypotension and prescribed fludrocortisone. At age 67, his neurological examination revealed bradykinesia, symmetric upper extremity rigidity, intention tremor, incoordination of the left arm, micrographia, postural instability, wide-based shuffling gait, and prominent square wave jerks. He developed dysphagia with a softened voice. Urodynamic testing revealed neurogenic bladder dysfunction. A CT scan of the head showed changes consistent with small vessel ischemic pathology in periventricular white matter. At age 68, he scored 18/30 on the Mini-Mental Status Examination. He was treated with levodopa, but the responsiveness was not documented. Based on the combination of autonomic failure and parkinsonism, he was clinically diagnosed with probable MSA-P.

Case 4 was a 57-year-old Caucasian man who had a history of dyslipidemia and peripheral neuropathy. At the age of 46, he underwent eval‎uation for a wide-based gait. Autonomic reflex screen showed mild distal postganglionic sudomotor impairment and normal adrenergic and cardiovagal function with normal orthostatic blood pressure. His CASS was 1. He subsequently developed autonomic failure, including orthostatic hypotension, frequent urination, and xerostomia. At age 56, his neurological eval‎uation was notable for intention tremor and upper extremity incoordination, suggestive of cerebellar ataxia. He was diagnosed with possible MSA-C.

3.2. Pathological features of vascular MSA

Pathological features of vascular MSA are summarized in Table 2. By definition, none of the patients had α-synuclein pathology consistent with MSA, nor did they have Lewy-related pathology, tauopathy, or TDP-43 proteinopathy. Instead, all four patients had arteriosclerotic vascular pathology with chronic ischemic changes in periventricular white matter, as well as more extensive subcortical leukoencephalopathy. Microscopic infarcts were detected in all four patients; the putamen was most often affected, followed by the thalamus. Alzheimer-type pathology was minimal; the mean Braak NFT stage was II, and the mean Thal amyloid phase was 1.

3.2. 혈관성 MSA의 병리학적인 특징

혈관성 MSA의 병리학적인 특징은 표 2에 요약되어 있습니다. 정의상, 환자 중 누구도 MSA와 일치하는 α-시누클레인 병리가 없었으며, 루이 관련 병리, 타우병증 또는 TDP-43 단백질 병증도 없었습니다. 대신 네 환자 모두 뇌실 주위 백질에 만성 허혈성 변화를 동반한 동맥경화성 혈관 병리와 더 광범위한 피질하 백질뇌병증이 있었습니다. 네 환자 모두에서 미세한 경색이 발견되었으며, 뇌실이 가장 자주 영향을 받았고 그다음으로 시상이 영향을 받았습니다. 알츠하이머형 병리는 미미했으며, 평균 Braak NFT 단계는 2단계, 평균 Thal 아밀로이드 단계는 1단계였습니다.

Table 2:

Pathological features and Infarct distribution in patients with vascular MSA

Pathologic featuresCase 1Case 2Case 3Case 4

Brain weight, g	1080	1240	1120	1320
Braak neurofibrillary tangle stage	II	III	II	0
Thal amyloid phase	2	3	1	0
Arteriosclerosis/atherosclerosis	+/+	+/+	+/+	−/−
Cerebral amyloid angiopathy	−	−	−	−
Infarct distribution
Frontal lobe	−	−	−	−
Temporal lobe	−	−	−	−
Parietal lobe	−	−	++*	−
Occipital lobe	−	−	−	+*
Motor cortex	−	−	−	−
Periventricular white matter	+	+	+	+
Subcortical leukoencephalopathy	+	+	+	+
Caudate/putamen	+	+	++	++
Globus pallidus	+	−	−	++
Basal nucleus	+	−	−	−
Thalamus	+	+	−	++
Hypothalamus	−	−	−	+
Subthalamic nucleus	−	−	−	+
Amygdala	+	−	−	−
Hippocampus	+	−	−	−
Red nucleus	−	−	−	−
Substantia nigra	−	−	+	−
Oculomotor nerve complex	−	−	−	−
Superior colliculus	−	−	−	−
Locus coeruleus	−	−	−	−
Pontine tegmentum	−	−	−	−
Pontine base	−	+	+	−
Medullary tegmentum	−	−	−	−
Inferior olivary nucleus	−	−	−	−
Cerebellum	−	−	−	−

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*Acute hemorrhagic infarct.

+indicates microinfarct and

++indicates macroscopic infarct.

Case 1 had no apparent cerebrovascular pathology in the left hemisphere on gross examination. Microscopically, the neocortex was relatively unremarkable. The subcortical and deep white matter had diffuse myelinated fiber loss and gliosis, in addition to the multiple small cystic or partially cystic chronic infarcts (Figure 2A, ​,B).B). The periventricular white matter had extensive ischemic softening and gliosis (Figure 2C, ​,D).D). The blood vessels in the cerebral white matter had severe arteriosclerotic hyalinosis, and there were collagen deposition and blood pigment in the perivascular spaces (Figure 2E). There were small chronic infarcts in the hippocampus (Figure 2F) and basolateral amygdala (Figure 2G). The basal ganglia were remarkable for severe arteriosclerotic small vessel disease, with cribriform change and multiple microinfarcts and a larger lacunar infarct in the putamen. There was also a slit-like lesion filled with hemosiderin-filled macrophages, consistent with a small chronic hemorrhage (Figure 2H). There was marked cribriform change in the globus pallidus. The thalamus had arteriosclerotic small vessel disease, with cribriform change and multiple microinfarcts, as well as a cystic lacunar infarct. There was focal Wallerian degeneration in the internal capsule.

Figure 2:

Representative microscopic findings of cerebrovascular pathologies from four patients Case 1. Case 1 has a chronic infarct with diffuse myelinated fiber loss in the periventricular white matter (A). The higher magnification image of the box in A shows myelinated fiber loss (B). The extensive ischemic softening and gliosis are seen in the periventricular white matter (C and D). The blood vessel in the deep white matter shows severe narrowing the lumen due to hyalinosis (E). Hippocampus has a cystic infarct (F). Severe arteries sclerosis in the amygdala (G). Case 2 has microscopic infarct in the periventricular white matter, associated with diffuse atrophy (H and I) and arteriosclerosis (J). Severe atherosclerosis is observed in the lenticulostriate arteries (K). Microscopic infarct in the pons (L). Case 3 has microscopic infarct in the caudate (M) and pons (N). Severe atherosclerosis is observed in the lenticulostriate arteries (O). Case 4 has multiple chronic infarcts in the putamen and globus pallidus in (P). The internal capsule near the infarct in the putamen has numerous spheroids (Q). The longitudinal fibers have vacuolation with activated macrophages, consistent with Wallerian degeneration (R). A–C: Luxol Fast Blue Stain, D–P: hematoxylin-eosin stain, Q: immunohistochemistry for APP, R: immunohistochemistry for Iba-1. Bars: 4 mm in A, C, and P; 500 μm in F; 200 μm in D, K, and O; 100 μm in B, G–J, L–N, Q, and R; 50 μm in E.

Case 2 had no apparent cerebrovascular pathology in the left hemisphere on gross examination. Microscopic examination revealed an infarct in the periventricular white matter, associated with diffuse atrophy, dilation of perivascular space, and gliosis throughout the centrum semiovale (Figure 2I, ​,J).J). Severe arteriosclerosis was observed in the lenticulostriate arteries (Figure 2K). The pontine base also had an infarct (Figure 2L).

Case 3 had no apparent cerebrovascular pathology in the left hemisphere on gross examination. Microscopic examination revealed several small infarcts in the caudate nucleus (Figure 2M) and pontine base (Figure 2N), as well as microinfarcts in the lateral geniculate nucleus and foci of ischemic gliosis in the globus pallidus. There was also subcortical arteriosclerotic leukoencephalopathy. Dilation of perivascular spaces, arteriosclerosis, and atherosclerosis were observed in the cortex and basal ganglia (Figure 2O).

Case 4 had an acute hemorrhagic infarct in cortical gray and subcortical white matter in the left occipital lobe. The basal ganglia had partially cystic infarcts affecting most of the globus pallidus, as well as the medial and rostral parts of the putamen (Figure 2P). The infarcts were filled with lipid-laden macrophages, and there was gliosis with numerous spheroids in the surrounding tissues (Figure 2Q). The thalamus, hypothalamus, subthalamic nucleus, and posterior limb of internal capsule had large partially cystic infarcts, similar in histologic age to the lesions in the basal ganglia. White matter tracts caudal to the infarcts had vacuolation with activated macrophages, consistent with early Wallerian degeneration (Figure 2R).

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4. Discussion

In this retrospective clinicopathological study based on a referral brain bank, we identified four patients with clinically diagnosed MSA who failed to meet pathologic criteria for MSA. Instead, each patient had cerebrovascular pathology as the best explanation for their clinical presentations. Several autopsy studies have suggested that vascular parkinsonism can mimic MSA; however, cerebrovascular pathology was not described [4, 6, 10]. To our knowledge, this is the largest clinicopathological study of vascular MSA.

agnosis of MSA is reasonable in these cases; however, had the consideration of “red flags” against MSA been noted, it may have increased diagnostic accuracy. The criteria explicitly state this caveat for autonomic failure as follows: other disorders known to cause orthostatic hypotension, such as diabetes mellitus with autonomic neuropathy, should be excluded or at least taken into account [1]. On the other hand, vascular and drug-induced mechanisms were not specifically mentioned as possible causes of parkinsonism [1, 3]. Case 1 had the diabetic triad of neuropathy, retinopathy, and nephropathy, as well as generalized autonomic failure. All autonomic abnormalities in this patient are better ascribed to diabetic autonomic neuropathy. This finding, as well as MRI evidence of cerebrovascular pathology, should have led to a diagnosis of vascular parkinsonism with diabetic autonomic neuropathy. Case 2 had multiple “red flags” against MSA. The patient was 85 at the age of onset, had affective symptoms and persistent hallucinations, which suggest a diagnosis other than MSA. Moreover, the development of parkinsonism was noted only after haloperidol. He had a relatively low CASS and MRI changes more typical of vascular disease than MSA. Case 3 had a clinical phenotype dominated by cognitive and affective complaints, as well as multiple vascular risk factors and CT findings supportive of vascular disease. Case 4 had neuropathy. The major lesson from a review of these four cases is that a diagnosis MSA requires the exclusion of alternative etiologies for both autonomic and extrapyramidal signs before applying the consensus criteria. We suggest that the presence of multiple vascular risk factors supported by cerebrovascular pathology in the subcortical gray matter on neuroimaging studies should be considered evidence for possible vascular parkinsonism and “red flags” against a diagnosis of MSA.

Autonomic dysfunction in vascular parkinsonism is a challenge [10, 21]. A previous study of pathologically confirmed vascular parkinsonism found urinary incontinence and constipation in about half the patients, while 25% had orthostatic hypotension [10]. Several studies demonstrate that lesions in brainstem autonomic centers, including ventrolateral medulla and solitary nucleus, periaqueductal gray matter in the midbrain, hypothalamus, amygdala, and insular cortex may all play a role in autonomic dysfunction [22–25]. In the present study, however, the medulla, midbrain, hypothalamus, and amygdala were not consistently affected. Bladder dysfunction is a common non-motor symptom of Parkinson’s disease and thought to be related to altered dopamine-basal ganglia circuitry, which normally suppresses the micturition reflex [26]. The basal ganglia are usually affected in vascular parkinsonism, and there was gross or microscopic evidence of basal ganglia pathology in all four patients.

The correlation between cerebrovascular pathology and clinical presentation of MSA should be interpreted cautiously. Given the fact that all patients had infarcts in subcortical and perivascular white matter, white matter damage may be associated with the clinical presentation of MSA. All patients had striatal lesions, which can be associated with parkinsonism. In contrast, Case 4 was considered to have cerebellar ataxia, but no apparent infarct was found in the cerebellum and related structures on the side of the brain eval‎uated. Given that the patient had significant neuropathy, sensory ataxia may have been misinterpreted as cerebellar ataxia [27]. The brain MRI of case 2 revealed ex vacuo ventricular enlargement, but there were no other radiographic findings to suggest normal pressure hydrocephalus (e.g., disproportionately enlarged subarachnoid space hydrocephalus). Gait abnormalities may have been related to the disruption of frontal subcortical systems by ischemic white matter pathology [28].

There are some limitations in our study. Given the retrospective nature of the study, the referral basis of the brain bank, limited clinical information in some cases (particularly Case 4 where medical records were not available between ages 46 and 56), it was not always possible to rigorously confirm‎ Gilman’s criteria. In addition, the diagnosis of MSA in Case 4 was not made by a movement disorder or autonomic disorder specialist. Another limitation is that only hemibrains were eval‎uated neuropathologically. Had the other side been eval‎uated additional cerebrovascular pathology might have been found. Assessment of peripheral nervous system and spinal cord was not possible, but would have been helpful to rule out sensory ataxia due to peripheral neuropathy and non-cerebellar causes of ataxia.

The strength of our study was post-mortem characterization of brain pathology linked with documentation of antemortem clinical syndromes. Previous studies have discussed clinicopathological correlates of vascular parkinsonism based on antemortem imaging studies; however, ischemic changes such as “white matter disease” or “leukoaraiosis” do not necessarily reflect cerebrovascular pathology at autopsy [29]. Histopathologic analysis is needed to clarify the correlation between vascular pathology and parkinsonism.

In summary, we identified four patients with cerebrovascular pathology as the likely pathologic substrate of antemortem clinical diagnoses of MSA. We did not, however, find convincing cerebrovascular pathology that might contribute to autonomic dysfunction, particularly orthostatic hypotension. Peripheral neuropathy, diabetes mellitus, and other etiologies might have been responsible for autonomic dysfunction [3, 30]. Cerebrovascular pathology itself, or a combination of cerebrovascular pathology and additional processes, such as peripheral neuropathy, might lead physicians to misdiagnose MSA. For this reason, the use of the term “vascular MSA” is imprecise in describing patients with this combination of clinical and pathologic findings. Our study demonstrates that even though uncommon, it is important to rule out cerebrovascular disease in patients with clinical features of MSA, especially if patients have multiple vascular risk factors and neuroimaging findings consistent with vascular parkinsonism.

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4. 논의

의뢰 뇌 은행을 기반으로 한 이 후향적 임상병리 연구에서 우리는 임상적으로 MSA로 진단된 환자 4명을 확인했는데, 이 환자들은 MSA의 병리학적인 기준을 충족하지 못했습니다. 대신 각 환자의 임상 증상에 대한 최선의 설명은 뇌혈관 병리였습니다. 여러 부검 연구에서 혈관성 파킨슨증이 MSA를 모방할 수 있다고 제안했지만, 뇌혈관 병리는 설명되지 않았습니다 [4, 6, 10]. 우리가 아는 한, 이것은 혈관성 MSA에 대한 가장 큰 임상병리학적 연구입니다.

이러한 경우 MSA의 무증상은 합리적이지만, MSA에 대한 '위험 신호'를 고려했다면 진단 정확도를 높일 수 있었을 것입니다. 자율 신경 병증을 동반한 당뇨병과 같이 기립성 저혈압을 유발하는 것으로 알려진 다른 질환은 배제하거나 최소한 고려해야 한다는 자율 신경 장애에 대한 주의 사항이 기준에 명시되어 있습니다[1]. 반면에 혈관 및 약물 유발 기전은 파킨슨병의 가능한 원인으로 구체적으로 언급되지 않았습니다 [1, 3].

사례 1은

신경병증, 망막병증, 신장병증의 당뇨병성 삼중증과 전신적인 자율신경 기능 부전을 동반했습니다. 이 환자의 모든 자율신경 이상은 당뇨병성 자율신경병증에 더 잘 기인합니다. 이 소견과 뇌혈관 병리에 대한 MRI 증거는 당뇨병성 자율신경병증을 동반한 혈관성 파킨슨증 진단으로 이어졌어야 합니다.

사례 2는 MSA에 대한 여러 가지 "위험 신호"가 있었습니다. 환자는 발병 당시 85세였고, 정서적 증상과 지속적인 환각이 있었으며, 이는 MSA 이외의 진단을 시사합니다. 또한 파킨슨병의 발병은 할로페리돌 투여 후에야 발견되었습니다. 그는 상대적으로 낮은 CASS와 혈관 질환에서 나타나는 전형적인 MRI 변화를 보였습니다.

사례 3은 인지 및 정서적 불만이 지배적인 임상 표현형과 혈관 질환을 뒷받침하는 여러 혈관 위험 인자 및 CT 소견을 보였습니다.

사례 4는 신경병증이 있었습니다.

이 네 가지 사례의 검토를 통해 얻은 주요 교훈은

합의 기준을 적용하기 전에

자율신경계 및 추체외로 징후에 대한 대체 원인을

모두 배제해야 MSA를 진단할 수 있다는 것입니다.

저희는 신경 영상 연구에서 피질하 회백질에서 뇌혈관 병리로 뒷받침되는 여러 혈관 위험 요인의 존재를 혈관성 파킨슨증 가능성에 대한 증거 및 MSA 진단에 대한 "위험 신호"로 간주해야 한다고 제안합니다.

혈관성 파킨슨병의 자율 기능 장애는 어려운 과제입니다 [10, 21].

병리학적으로 확인된 혈관성 파킨슨병에 대한 이전 연구에서는

환자의 약 절반에서 요실금과 변비가 발견되었고,

25%는 기립성 저혈압이 있었습니다 [10].

여러 연구에 따르면 복측 수질 및 단독 핵, 중뇌의 뇌실질 주위 회백질, 시상하부, 편도체, 섬 피질을 포함한 뇌간 자율 중추의 병변이 모두 자율 기능 장애에 영향을 미칠 수 있습니다 [22-25]. 그러나 본 연구에서는 수질, 중뇌, 시상하부, 편도체는 일관되게 영향을 받지 않았습니다. 방광 기능 장애는 파킨슨병의 흔한 비운동 증상이며 일반적으로 배뇨 반사를 억제하는 도파민 기저핵 회로 변경과 관련이 있는 것으로 생각됩니다 [26]. 기저핵은 일반적으로 혈관성 파킨슨병에서 영향을 받으며, 네 명의 환자 모두에서 기저핵 병리의 총체적 또는 현미경적 증거가 있었습니다.

뇌혈관 병리와 MSA의 임상 증상 간의 상관관계는 신중하게 해석해야 합니다. 모든 환자가 피질하 및 혈관 주위 백질에 경색이 있었다는 사실을 고려할 때 백질 손상은 MSA의 임상 증상과 관련이 있을 수 있습니다. 모든 환자는 선조체 병변이 있었으며, 이는 파킨슨병과 관련이 있을 수 있습니다. 대조적으로, 사례 4는 소뇌 운동 실조증으로 간주되었지만 평가된 뇌 측면의 소뇌 및 관련 구조에서 명백한 경색이 발견되지 않았습니다. 환자에게 심각한 신경 병증이 있었기 때문에 감각 실조증이 소뇌 운동 실조증으로 잘못 해석되었을 수 있습니다 [27]. 사례 2의 뇌 MRI에서 뇌실 외 뇌실 비대가 확인되었지만 정상압 수두증(예: 불균형하게 확대된 지주막하 공간 수두증)을 시사하는 다른 방사선학적 소견은 없었습니다. 보행 이상은 허혈성 백질 병리에 의한 전두엽 피질 시스템의 파괴와 관련이 있을 수 있습니다 [28].

이 연구에는 몇 가지 한계가 있습니다. 연구의 후향적 성격, 뇌 은행의 의뢰 근거, 일부 사례의 제한된 임상 정보(특히 46세에서 56세 사이에 의료 기록을 이용할 수 없었던 사례 4)를 고려할 때 길만의 기준을 엄격하게 확인하는 것이 항상 가능하지 않았습니다. 또한 사례 4의 경우 운동 장애 또는 자율신경계 장애 전문가가 MSA를 진단한 것이 아니었습니다. 또 다른 한계는 반뇌만 신경 병리학적으로 평가되었다는 것입니다. 반대쪽을 평가했다면 추가적인 뇌혈관 병리가 발견되었을 수도 있습니다. 말초 신경계와 척수에 대한 평가는 불가능했지만 말초 신경 병증으로 인한 감각 실조증과 비소뇌 운동 실조증의 원인을 배제하는 데 도움이 되었을 것입니다.

우리 연구의 강점은 사후 임상 증후군의 문서화와 관련된 뇌 병리의 사후 특성화였습니다. 이전 연구에서는 사후 영상 연구를 기반으로 혈관성 파킨슨병의 임상병리학적 상관관계를 논의했지만, 부검 시 '백질 질환' 또는 '백질 경화증'과 같은 허혈성 변화가 반드시 뇌혈관 병리를 반영하지는 않습니다[29]. 혈관 병리와 파킨슨병의 상관관계를 명확히 밝히기 위해서는 조직 병리학적인 분석이 필요합니다.

요약하면, 우리는 뇌혈관 병리를 가진 4명의 환자를 MSA의 사후 임상 진단의 병리학적인 기질로 확인했습니다. 그러나 자율 기능 장애, 특히 기립성 저혈압을 유발할 수 있는 뇌혈관 병리는 발견하지 못했습니다. 말초 신경병증, 당뇨병 및 기타 원인이 자율신경 기능 장애의 원인이 되었을 수 있습니다[3, 30]. 뇌혈관 병리 자체 또는 뇌혈관 병리와 말초 신경병증과 같은 추가 과정의 조합으로 인해 의사가 MSA를 오진할 수 있습니다. 이러한 이유로 임상 및 병리학적 소견이 복합적으로 나타나는 환자를 설명할 때 '혈관성 다발성 경화증'이라는 용어를 사용하는 것은 정확하지 않습니다. 이번 연구는 흔하지는 않지만, 특히 혈관성 파킨슨병과 일치하는 여러 혈관 위험 인자와 신경 영상 소견이 있는 환자에서 MSA의 임상적 특징을 가진 환자의 경우 뇌혈관 질환을 배제하는 것이 중요하다는 것을 보여줍니다.

하이라이트:

• 다발성 시스템 위축(MSA)과 함께 뇌혈관 병리가 나타나는 경우는 드뭅니다.
• 뇌실 주위 백질과 기저핵의 다발성 경색이 관련됨
• MSA를 진단하려면 다른 원인을 배제해야 합니다.

Acknowledgements

We would like to thank the patients and their families who donated brains to help further the scientific understanding of MSA. The authors would also like to acknowledge Virginia Phillips and Ariston L. Librero (Mayo Clinic, Jacksonville) for histologic support, and Monica Castanedes-Casey (Mayo Clinic, Jacksonville) for immunohistochemistry support.

Funding

This work is supported by NIH grants, CurePSP, Rainwater Charitable Foundation, Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research, and Karin & Sten Mortstedt CBD Solutions research grant.

Financial Disclosures of all authors

Dr. Koga receives support from a Karin & Sten Mortstedt CBD Solutions research grant.

Dr. Roemer reports no disclosures.

Dr. Tipton reports no disclosures.

Dr. Low receives support from NIH (R01NS065736, U54NSO65736, P50 NS44233) and FDA (R01 FD004789). He is Clinical Editor of Clinical Autonomic Research and is on editorial board of a number of scientific journals.

Dr. Josephs receives research support from the NIH (R01-DC010367, R01-DC012519 & R01AG037491) and the Alzheimer’s Association. Dr. Josephs is an editorial board member of Acta Neuropathologica, Journal of Neurology, and Parkinsonism and Related Disorders.

Dr. Dickson receives support from the NIH (U54-NS110435, P30 AG062677, UG3 NS104095).

Dr. Dickson is an editorial board member of Acta Neuropathologica, Annals of Neurology, Brain, Brain Pathology, and Neuropathology, and he is editor in chief of American Journal of Neurodegenerative Disease, and International Journal of Clinical and Experimental Pathology.

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Footnotes

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References

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