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An 80-year-old right-handed man was accompanied by his wife to the neurology clinic for difficulties in performing activities of daily living. He was reported to struggle using cutlery and remembering how to dial a phone number. His wife had noticed changes in his speech, which had become incomprehensible. Symptom onset was insidious, with progressive worsening over a couple of weeks. The patient himself had no complaint. His medical history included an episode of transient vertical diplopia 2 months prior to admission, diagnosed as a TIA in the midbrain. Brain MRI at the time of TIA showed no acute lesion but moderate vascular white matter disease (WMD), related to arterial hypertension and type II diabetes, and 11 lobar microbleeds (bilateral temporal, parietal, and frontal).

一名80歲的右利手男性，因日常生活中遇到困難在妻子的陪同下前往神經(jīng)科診所。據(jù)描述，他不會(huì)使用餐具，不知道如何撥打電話號碼。他的妻子注意到他講話讓人難以理解。癥狀起初隱匿，數(shù)周后加重?；颊弑救藷o不適主訴。患者既往史包括入院前2個(gè)月出現(xiàn)短暫性垂直復(fù)視，被診斷為中腦短暫性腦缺血發(fā)作。短暫性腦缺血發(fā)作時(shí)的腦MRI未見急性病變，但有中度血管性白質(zhì)病變（WMD），與高血壓和II型糖尿病有關(guān)，11個(gè)腦葉微出血（雙側(cè)顳葉、頂葉和額葉）。

Neurologic examination at the time of the current admission revealed right homonymous hemianopia, production of jargon and impaired comprehension suggestive of Wernicke aphasia, ideational apraxia, executive dysfunction, and anosognosia. The rest of the physical examination was normal. Episodes of paroxysmal atrial fibrillation were detected during the patient’s hospital stay.

入院時(shí)的神經(jīng)系統(tǒng)查體：右同向偏盲，語言理解障礙提示韋尼克失語，觀念性失用，執(zhí)行功能障礙和失認(rèn)。其余體征正常。在患者住院期間檢測到陣發(fā)性房顫。

Both Wernicke aphasia and ideational apraxia suggest a dysfunction in the left posterior hemisphere; more specifically in temporoparietal associative cortices for the Wernicke aphasia and in the supramarginal gyrus for ideational apraxia. Right homonymous hemianopia indicates involvement of the left visual pathways. Although executive functions are widely distributed throughout the brain, executive dysfunction is classically associated with pathologies of prefrontal brain regions. Anosognosia is the result of a lesion in the right temporoparietal lobe. The symptoms and signs suggest widespread bihemispheric dysfunction predominantly affecting the posterior part of the left hemisphere.

韋尼克失語和觀念性失用都提示左后大腦半球功能障礙；更具體地說，韋尼克失語的顳頂葉皮質(zhì)和觀念性失用的緣上回出現(xiàn)功能障礙。右側(cè)同向偏盲顯示左側(cè)視覺通路受累。盡管執(zhí)行功能廣泛分布于整個(gè)大腦，但傳統(tǒng)上執(zhí)行功能紊亂與額葉前部腦功能區(qū)的病變相關(guān)。失認(rèn)是右顳頂葉病變的結(jié)果?；颊甙Y狀和體征表明雙側(cè)大腦半球廣泛的功能障礙，主要累及左側(cè)大腦半球后部。

In our patient, the rapidly progressive evolution of cognitive decline points towards several etiologies including vascular, infectious, and inflammatory processes. Vascular causes should be considered because of the history of chronic arterial hypertension, possible TIA, and WMD. However, the absence of an acute or stepwise evolution does not favor a vascular etiology. Among infectious causes, herpes simplex virus encephalitis was ruled out because of the subacute evolution of the disease and the absence of fever or seizures. Neurosyphilis and HIV dementia have a more indolent evolution, and the patient had no sexual risk factors. There was no tick bite or erythema migrans history to support Lyme disease. Voltagegated potassium channel (VGKC), NMDA receptor, and other antibody-related autoimmune encephalitis are frequently associated with myoclonus or seizures. Paraneoplastic autoimmune encephalitis may also cause rapidly progressive cognitive and neuropsychiatric symptoms. Other inflammatory causes include cerebral vasculitis, which could present with subacute cognitive impairment. Inflammatory cerebral amyloid angiopathy is a rare and newly recognized entity that may cause subacute dementia in predominantly older patients. Creutzfeldt-Jacob disease can present with rapid cognitive decline, sometimes associated with visual field defects, myoclonus, or seizures. In the absence of preexisting cognitive decline reported by the family, Alzheimer disease and frontotemporal disease were considered less likely. As for tumor-related pathologies, lymphoma typically presents with progressive cognitive decline, and brain metastases can cause rapidly progressive cognitive symptoms.

對于該患者，認(rèn)知功能快速減退的的病因包括血管性、感染和炎癥。因患者有慢性高血壓病史，血管原因如TIA和WMD應(yīng)被考慮。但是，非急性起病和漸進(jìn)性加重不支持血管性病因。在感染原因中，因?yàn)榛颊咂鸩〕蕘喖毙?，無發(fā)燒或癲癇發(fā)作，單純皰疹病毒性腦炎被排除。神經(jīng)梅毒和艾滋病性癡呆起病更緩慢，該患者無冶游史。無蜱蟲叮咬史或游走性紅斑病史，故不支持萊姆病。電壓門控鉀通道（VGKC）、NMDA受體和其他抗體相關(guān)的自身免疫性腦炎通常與肌陣攣或癲癇發(fā)作有關(guān)。副腫瘤性自身免疫性腦炎也可能導(dǎo)致快速進(jìn)展性認(rèn)知障礙和神經(jīng)精神癥狀。其他炎癥原因如腦動(dòng)脈炎，可能出現(xiàn)亞急性認(rèn)知障礙。炎癥性腦淀粉樣血管病是一種罕見的新認(rèn)識的疾病，可能導(dǎo)致亞急性癡呆，主要是老年患者。CJD可表現(xiàn)為認(rèn)知能力迅速下降，有時(shí)與視野缺損、肌陣攣或癲癇發(fā)作有關(guān)。在無家族史的情況下，阿爾茨海默病和額顳葉癡呆被認(rèn)為不太可能發(fā)生。至于腫瘤相關(guān)的疾病，淋巴瘤通常表現(xiàn)為進(jìn)行性認(rèn)知功能下降，腦轉(zhuǎn)移可導(dǎo)致快速進(jìn)展性認(rèn)知障礙。

Brain MRI, FSE T2-weighted sequence, showed bilateral and asymmetric cortical and subcortical hyperintense lesions in the left parietal, temporal, and occipital lobes with a discrete mass effect on adjacent structures (figure 1). Axial T2*- weighted images showed the same lobar microbleeds as described previously. There was no superficial hemosiderosis or signs of past intracerebral hemorrhage. Gadolinium-enhanced T1-weighted sequence showed no parenchymal or meningeal enhancement. Magnetic resonance spectroscopy revealed a decrease of the N-acetylaspartate/choline ratio, but no characteristic pattern of brain tumor.

腦MRI，F(xiàn)SE-T2加權(quán)序列，顯示雙側(cè)不對稱的皮質(zhì)和皮質(zhì)下高信號病變，左頂葉、顳葉和雙側(cè)枕葉的病灶對鄰近腦組織有占位效應(yīng)（圖1）。軸位T2*加權(quán)圖像顯示上述部位的微出血。無淺表性含鐵血黃素沉著或既往腦出血的跡象。釓增強(qiáng)T1加權(quán)序列無腦實(shí)質(zhì)或腦膜強(qiáng)化。磁共振波譜顯示N-乙酰天門冬氨酸/膽堿比值降低，但腦腫瘤無此特征性表現(xiàn)。

圖1 入院前、入院時(shí)和隨訪期間的腦MRI

（A）入院前2個(gè)月，短暫腦缺血發(fā)作后，軸向快速自旋回波（FSE）T2加權(quán)成像序列無病灶。（B）入院時(shí)MRI軸位FSE-T2像顯示枕頂葉高信號（箭頭）和（C）軸位T2*加權(quán)序列顯示數(shù)個(gè)點(diǎn)狀微出血（箭頭）。（D）軸向釓增強(qiáng)T1加權(quán)序列未見增強(qiáng)。（E）發(fā)病4個(gè)月時(shí)隨訪MRI，彌散加權(quán)成像（箭頭）顯示額葉皮質(zhì)下小灶性缺血病變。（F）隨訪MRI軸位FSE-T2顯示高信號較前減輕（箭頭）。

Laboratory investigations, including blood electrolytes, C-reactive protein, erythrocyte sedimentation rate, liver function, and blood cell count (particularly white blood cells, 5.9 g/L, normal 4–11), were normal. HIV, Treponema pallidum hemagglutination, and Lyme disease screening was negative. VGKC and NMDA antibodies, antinuclear antibodies, and anti-double-stranded DNA antibodies were also negative. Characterization of APOE gene showed a heterozygous APOE with e4/e3 alleles. Finally, CSF examination revealed increased protein concentration (1.45 g/L, normal <0.45), normal cell count (<1 M/L, normal 0–5), normal glucose level (4.0 mmol/L, normal 2.8–4.0), no oligoclonal bands, and no abnormal cells. The subacute evolution of the clinical picture and apraxia should prompt a thorough assessment for Creutzfeldt-Jacob disease. However, the MRI did not support this hypothesis.

實(shí)驗(yàn)室檢查，包括血電解質(zhì)、C反應(yīng)蛋白、紅細(xì)胞沉降率、肝功能和血細(xì)胞計(jì)數(shù)（特別是白細(xì)胞，5.9 g/L，正常4-11）均正常。HIV、梅毒螺旋體和萊姆病篩查均為陰性。VGKC和NMDA抗體、抗核抗體和抗雙鏈DNA抗體均呈陰性。APOE基因的特征表明，APOE與e4/e3等位基因雜合。CSF檢查示蛋白濃度增加（1.45g/L，正常<0.45），細(xì)胞計(jì)數(shù)正常（<1 M/L，正常0-5），糖水平正常（4.0mmol/L，正常2.8-4.0），寡克隆帶陰性，未見異常細(xì)胞?；颊吲R床癥狀的亞急性進(jìn)展和失用癥應(yīng)考慮到CJD，但MRI成像并不支持這一假設(shè)。

The clinical picture, imaging, CSF, and blood workup are suggestive of inflammatory cerebral amyloid angiopathy (CAA-I). The patient also carried the APOE e4 allele, which increases the risks of β-amyloid peptide deposition and CAA related hemorrhage compared to carriers of the common e3 alleles.

臨床表現(xiàn)、影像、腦脊液和血液檢查均提示有炎性腦淀粉樣血管病（CAA-I）。與普通e3等位基因攜帶者相比，患者還攜帶APOE e4等位基因，這增加了β-淀粉樣肽沉積和CAA相關(guān)出血的風(fēng)險(xiǎn)。

To confirm the diagnosis, we performed a brain biopsy in the left posterior parietal lobe including cortical and subcortical brain tissue. Cerebral biopsy showed transmural inflammatory infiltrates and amyloid deposition within vessels, and perivascular inflammatory infiltrates with reactive astrogliosis and microglial activation (figure 2). This provides evidence for 2 variants of CAA-I. The transmural inflammatory infiltrate is a destructive vasculitic process that characterizes Aβ-related angiitis (ABRA), and perivascular inflammatory infiltrates are characteristic of CAA-related inflammation (CAA-ri). Both subtypes can coexist in patients with CAA-I3 and respond to immunosuppressive treatment, but it is not established whether such pathologic subtypes translate into separate entities that require different therapeutic management.

為明確診斷，我們對左后頂葉皮質(zhì)和皮質(zhì)下腦組織進(jìn)行了活檢。腦活檢顯示血管透壁炎癥浸潤和淀粉樣蛋白沉積，血管周圍炎癥浸潤伴有反應(yīng)性星形膠質(zhì)細(xì)胞增生和小膠質(zhì)細(xì)胞活化（圖2）。上述證據(jù)支持CAA-I的2種變異型。透壁炎性浸潤是一種破壞性血管炎過程，提示Aβ相關(guān)血管炎（ABRA）。血管周圍炎性浸潤是CAA相關(guān)炎癥（CAA ri）的特征。這兩種亞型都能在CAA-I患者中共存并對免疫抑制治療反應(yīng)良好，但還不能確定這些病理亞型是否為獨(dú)立的疾病，是否需要不同的治療策略。

圖2 左頂葉皮質(zhì)腦活檢

（A）NeuN免疫染色顯示皮質(zhì)水腫和神經(jīng)元丟失（放大×100）。（B）蘇木精&伊紅染色顯示皮層血管壁內(nèi)有嗜酸性細(xì)胞沉積、管腔狹窄和血管周圍炎性浸潤（放大×400）。（C）剛果紅染色顯示大腦和腦膜血管壁內(nèi)淀粉樣沉積物（放大×40）。（D）β-淀粉樣蛋白免疫染色顯示皮層血管壁內(nèi)有Aβ沉積（放大×400）。

We initiated immunosuppressive treatment, consisting of oral prednisone, 1 mg/kg a day, tapered over 3 months, with a good initial clinical and radiologic evolution. However, 1 month after the end of immunosuppression (i.e., 4 months after diagnosis of CAA-I), the patient experienced rapid worsening of cognitive functions. MRI at the time showed the recurrence of the same initial hyperintensity at the same location, and an acute, asymptomatic diffusion-weighted imaging (DWI) punctiform ischemia in the right subcortical parietal lobe. We reinitiated oral prednisone and introduced oral azathioprine with a favorable clinical evolution. Follow-up MRI did not show recurrence of the inflammatory findings of CAA, but 6 new lobar microbleeds were reported over the 36-month follow-up.

我們給予該患者口服強(qiáng)的松免疫抑制治療，1mg/kg/d，逐漸減量3個(gè)月，臨床癥狀和影像均有好轉(zhuǎn)。但是在免疫抑制治療結(jié)束后1個(gè)月（即診斷出CAA-I后4個(gè)月），患者的認(rèn)知功能迅速惡化。復(fù)查MRI示相同部位高信號再次復(fù)發(fā)，右頂葉皮層下彌散加權(quán)成像（DWI）示急性無癥狀點(diǎn)狀缺血。再次給予患者口服強(qiáng)的松，聯(lián)合硫唑嘌呤，臨床恢復(fù)良好。隨訪MRI未見CAA炎性病變復(fù)發(fā)，但在36個(gè)月的隨訪中患者新發(fā)出現(xiàn)6個(gè)腦葉微出血灶。

Regarding the episode of regressive vertical diplopia presented by our patient 2 months prior to admission, several hypotheses may exist. Transient focal neurological episodes or “amyloid spells,” defined as short, recurrent, stereotyped, spreading neurologic symptoms, are frequently reported in patients with CAA and are often related to superficial hemosiderosis or subarachnoid hemorrhage. A TIA is also possible given the age, cardiovascular risk factors, and detection of episodes of atrial fibrillation. Interestingly, small asymptomatic DWI ischemic lesions have been described recently in patients with CAA over the course of the disease.

對于患者住院前2個(gè)月出現(xiàn)的短暫性垂直復(fù)視，存在幾個(gè)可能的假設(shè)。短暫的局灶性腦缺血發(fā)作或“淀粉樣變”，定義為短暫的、復(fù)發(fā)的、刻板的、擴(kuò)散的神經(jīng)癥狀，在CAA患者中經(jīng)常報(bào)告，并且通常與淺表性含鐵血黃素沉著或蛛網(wǎng)膜下腔出血有關(guān)。當(dāng)患者高齡、具備心血管危險(xiǎn)因素和房顫發(fā)作時(shí)，短暫性腦缺血發(fā)作要考慮。有趣的是，最近有人在CAA患者的病程中描述了無癥狀的小DWI缺血性病變。

The diagnosis of CAA-I was established based on (1) cerebral MRI showing rapid onset leukoencephalopathy and edema; (2) CSF analysis displaying mildly elevated protein concentration, but no pleiocytosis； and (3) neuropathology demonstrating perivascular inflammation associated with amyloid deposits in cortical vessels and transmural and perivascular inflammation. Before confirmation with cerebral biopsy, our patient met the diagnostic criteria of probable CAA-I: (1) age >40 years; (2) clinical symptoms, such as headaches or cognitive disturbances, not directly attributable to intracerebral hemorrhage; (3) asymmetric WMD patterns that extend to the immediately subcortical area; and (4) presence of cortico–subcortical hemorrhagic lesions.

CAA-I的診斷是基于：（1）腦MRI顯示快速進(jìn)展的白質(zhì)腦病和水腫；（2）CSF示蛋白濃度輕度升高，但無細(xì)胞增多；（3）神經(jīng)病理學(xué)顯示與皮層血管淀粉樣蛋白沉積相關(guān)的血管透壁及周圍炎癥。在確認(rèn)腦活檢前，該患者符合可能的CAA-I診斷標(biāo)準(zhǔn)：（1）年齡>40歲；（2）不能歸因于腦出血的臨床癥狀，如頭痛或認(rèn)知障礙；（3）延伸至皮質(zhì)下區(qū)域的不對稱WMD病變；（4）存在皮層-皮層下出血性病變。

The inflammatory variants of CAA have gained a great amount of interest lately because of their increased incidence in the elderly population. Unlike classical CAA, inflammatory variants do not usually present with intracerebral hemorrhage, and the symptoms may be reversed by immunomodulatory therapy. However, CAA without inflammation can also exhibit infiltrative white matter processes. In order to avoid undue immunosuppressive treatment and the side effects thereof, we carried out a brain biopsy to look for vascular inflammation that characterizes CAA-I. An interesting point raised by this case is the speed of the clinical and radiologic course. The fact that lobar microbleeds were present before the onset of CAA-I supports the preexistence of CAA. The subsequent cognitive symptoms were more likely linked to the CAA-I, as supported by the clinical and radiologic features that progressed rapidly over 2 months. Based on repetitive MRIs and cerebral biopsy findings, our case illustrates that the course of CAA-I may be subacute and clearly distinct from the more progressive evolution of the noninflammatory form of CAA.   

近年來，由于CAA在老年人群中的發(fā)病率增加，其炎癥變異型引起了人們的極大興趣。與經(jīng)典的CAA不同，炎癥變異型通常不與腦出血同時(shí)出現(xiàn)，并且這些癥狀可以通過免疫調(diào)節(jié)療法逆轉(zhuǎn)。然而，非炎癥的CAA也可以表現(xiàn)出白質(zhì)浸潤過程。為避免過度應(yīng)用免疫抑制治療及其副作用，我們進(jìn)行了腦部活檢，以尋找CAA-I特異性的血管炎癥。該病例提出的一個(gè)有趣的觀點(diǎn)是臨床和影像的快速進(jìn)展。事實(shí)上，在CAA-I發(fā)病之前就存在腦葉微出血，這支持了CAA的存在。隨后的認(rèn)知障礙更可能與CAA-I有關(guān)，因?yàn)榕R床和影像學(xué)特征在2個(gè)月內(nèi)進(jìn)展迅速。基于重復(fù)的MRI和腦活檢結(jié)果，該病例表明CAA-I的病程可能是亞急性的，并且明顯不同于CAA的非炎癥形式的進(jìn)展。

A second interesting point is the management of transient neurologic symptoms and the ischemic lesion on DWI attributed to CAA. Our patient had CAA, but also cardiovascular disease risks factors (diabetes, hypertension) and episodes of atrial fibrillation. The presence of ≥5 cerebral microbleeds carries a major risk of intracerebral hemorrhage with anticoagulant use (odds ratio 5.50 or 2.8%/y). Therefore, we opted for a percutaneous left atrial appendage closure, although it is not known if the bleeding risk is increased to the same extent in the inflammatory form of CAA.

第二個(gè)有趣的觀點(diǎn)是短暫性腦缺血的治療和由CAA引起的DWI的缺血性損傷。該患者有CAA，但也有心血管疾病危險(xiǎn)因素（糖尿病、高血壓）和房顫發(fā)作。使用抗凝劑時(shí)，出現(xiàn)≥5個(gè)腦微出血即可增加腦出血的風(fēng)險(xiǎn)（比值比5.50或2.8%/y）。由于不知道炎癥性CAA出血風(fēng)險(xiǎn)是否和其他CAA一樣，因此，該患者接受了經(jīng)皮左心耳封堵術(shù)。

編輯：李會(huì)琪