A 72-year-old man presented with cognitive decline and unilateral muscle jerks. Three months prior to presentation, the patient suddenly developed violent muscle jerks involving the right side of his body and face that impaired his gait and balance. Approximately 1 week later, he acutely developed confusion and memory loss. Over the following weeks, he experienced fluctuating symptoms of confusion, memory impairment, insomnia, and paranoid delusions. His muscle jerks and unstable gait were intermittent with return to baseline in between attacks, but they increased in frequency and occurred many times throughout the day. He was found to be mildly hyponatremic and was eventually admitted to a psychiatric ward for treatment of acute psychosis.
72歲男性，表現為認知功能衰退和單側肌肉抽搐。發病前三個月，患者突發右側肢體和面部劇烈的肌肉抽搐，導致步態不穩，平衡失調。大約1周后，病情急性進展，出現意識模糊和記憶喪失。在接下來的數周內，表現為意識模糊、記憶障礙、失眠和偏執性妄想，癥狀呈波動性。肌肉抽搐和步態不穩間斷發作，發作間期恢復到基線狀態，但是，發作頻率增加，每日數次。檢驗結果示輕度低鈉血癥，最終被送往精神科治療急性精神病。
The patient’s medical history was significant for hypertension, well-controlled diabetes, and a myocardial infarction 22 years previously. He was a retired mechanical engineer and was physically active prior to the onset of symptoms.
患者重要的既往史是高血壓病，糖尿病，血糖控制良好，22年前患心肌梗死。是一名退休的機械工程師，癥狀發作前身體狀況良好。
On neurologic examination, the patient was alert and oriented to person only. He registered 3 items but was unable to recall them at 5 minutes and was unable to complete serial 7s. He had no language deficits and could follow 3-step commands without difficulty. His cranial nerve, motor, and sensory examination results were normal. He had a wide-based gait with prominent right lateral pulsion and retropulsion, without any observed muscle jerks during gait examination. Occasional myoclonus involving the right side of his face and right upper extremity were observed, which were associated with loss of awareness and dystonic posturing of the right arm.
神經系統查體：患者神志清晰，人物定向準確。他記住了3個項目，但5分鐘后不能想起。無法完成連續減7測試。沒有語言障礙，輕松完成三步指令動作。顱神經、運動和感覺檢查結果正常。寬基底步態，明顯向右側和后方傾倒，步態檢查過程中沒有看到任何的肌肉抽搐，可以觀察到右側面部和右上肢偶發的肌陣攣，這與意識喪失和右臂的肌張力障礙有關。
The patient was admitted to the general neurology ward and an MRI of the brain was performed(figure).
患者入住普通神經科病房，并進行腦MRI檢查（圖）。
圖 MRI腦
FLAIR序列顯示雙側海馬和杏仁核（A）和左尾狀核和殼核（B）高信號。
Questions for consideration:
1. Based on the history and physical examination, what is the differential diagnosis? How does the MRI narrow the differential?
2. What further workup would you order at this time?
思考問題：
1.根據病史和體格檢查，鑒別診斷是什么？ MRI結果如何縮小鑒別診斷的范圍？
2.此時，你會安排哪些進一步的檢查？
This patient presents with a subacute encephalopathy of fluctuating intensity, with myoclonus and gait abnormalities preceding the development of cognitive symptoms. Though the right-sided myoclonus may be cortical or subcortical, the localization can be narrowed based on other findings. Retropulsion is an extrapyramidal sign often due to loss of postural reflexes and is seen in disorders that involve the basal ganglia; the asymmetric right lateral pulsion localizes this to the left basal ganglia. The patient also displays cognitive deficits in orientation, memory, and attention, which indicate that there might be further cortical or subcortical involvement. The differential diagnosis should consider subacute encephalopathies that present with this constellation of findings.
患者表現為程度波動性的亞急性腦病，在認知癥狀進展之前，表現肌陣攣和步態異常。雖然右側肌陣攣可定位于皮層或皮層下，但是，可以結合其他發現來縮小病變范圍。向后傾倒是一種錐體外系體征，通常由于姿勢反射喪失所致，見于基底神經節病變; 非對稱的向右側傾倒定位于左側基底神經節。患者還在定向力、記憶和注意力方面存在認知缺陷，這表明可能進一步累及到皮層或皮層下。鑒別診斷應該考慮表現為這一系列異常的亞急性腦病。
The patient’s rapid cognitive decline, myoclonus, and gait instability raise concern for Creutzfeldt-Jakob disease (CJD) and other prion diseases; other neurodegenerative conditions are common in this age group but less likely given the rapid clinical progression. Limbic encephalitis can mimic CJD and may result from a paraneoplastic syndrome or autoantibodies in the absence of cancer. Additional diagnostic categories to consider are autoimmune conditions (e.g., Sj?gren syndrome, lupus, Hashimoto encephalopathy, sarcoidosis, CNS vasculitis), infections (tuberculosis, Lyme disease, Listeria, Whipple disease, Cryptococcus, toxoplasmosis), and neoplasms. Potentially reversible causes of encephalopathy can be ruled out with simple blood tests, including complete blood count (CBC), general chemistries, thyroid-stimulatinghormone(TSH),vitamin B12, and rapid plasma reagin, and an EEG can be performed to rule out seizures.
對于快速認知衰退、肌陣攣和步態不穩的患者，要重點關注Creutzfeldt-Jakob病（CJD）和其他朊蛋白病; 雖然其他神經變性病在這個年齡組中很常見，但是，臨床出現快速進展的可能性較小。邊緣葉腦炎可以酷似CJD，并且可以在不存在癌癥的情況下引起副腫瘤綜合征或產生自身抗體。其他的診斷需要考慮自身免疫性疾病（例如，干燥綜合征，狼瘡，橋本腦病，結節病，CNS血管炎），感染（結核病，萊姆病，李斯特菌，Whipple病，隱球菌，弓形體病）和腫瘤。通過簡單的血液檢查，包括全血細胞計數（CBC），生化全項，促甲狀腺激素（TSH），維生素B12和快速血漿反應素檢測，排除腦病潛在的可逆性的病因，并行EEG檢查以排除癲癇。
The MRI showed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in bilateral hippocampi and amygdalae, with FLAIR hyperintensity and postcontrast enhancement in the left caudate and putamen. There was no cortical ribboning or diffusion restriction on diffusion-weighted imaging, making CJD less likely. The MRI confirms the suspected basal ganglia involvement, and the hyperintensities in the limbic region may explain the patient’s cognitive symptoms. These findings are consistent with limbic encephalitis; however, other autoimmune and infectious etiologies should be ruled out.
MRI顯示雙側海馬和杏仁核T2 / FLAIR高信號，左側尾狀核和殼核FLAIR高信號強化病灶。DWI未見皮層飄帶征或彌散受限，CJD的可能性很小。MRI結果證實了基底神經節病變，并且邊緣系統的高信號可以解釋患者的認知癥狀，這些發現符合邊緣性腦炎; 然而，應該排除其他自身免疫性和感染性病因。
Plasma sodium level on admission was 132 mM (normal range 135–145 mM) with a nadir of 122 mM during his hospitalization; otherwise his CBC and chemistry panel were unremarkable. TSH and vitaminB12 were normal. CSF studies showed a mildly elevated protein of 69 mg/dL (normal range 15–40 mg/dL) but were otherwise unremarkable, including immunoglobulin G synthesis rate and index with no inflammatory cells or oligoclonal bands. Serum autoimmune and inflammatory workup including erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, rheumatoid factor, Sj?gren syndrome A/ Sj?grensyndrome B, angiotensin-converting enzyme, antithyroid peroxidase, and antithyroglobulin were unremarkable. Infectious workup was negative for herpes simplex virus, HIV, syphilis, and a meningoencephalitis panel. A paraneoplastic antibody panel (table e-1 on the Neurology? Web site at Neurology.org) of the serum and CSF was pending, although anti-Hu and anti-NMDA receptor were negative by outside records. A 16-hour continuous EEG showed diffuse slowing and was negative for epileptiform discharges. Whole-body PET/CT scan, a serum lymphoma panel, and a scrotal ultrasound were all negative for neoplasm.
入院時血鈉水平為132mM（正常范圍135-145mM），住院期間最低值為122mM; CBC和生化結果未見異常； TSH和維生素B12正常； CSF檢查顯示輕度蛋白升高，為69mg / dL（正常范圍15-40mg / dL），但是除此以外無明顯異常，包括免疫球蛋白G合成率和IgG指數，未見炎性細胞或寡克隆帶；血清自身免疫性和炎癥性指標檢查，包括紅細胞沉降率、C-反應蛋白、抗核抗體、類風濕因子、Sj?gren綜合征A /Sj?gren綜合征B、血管緊張素轉換酶、抗甲狀腺過氧化物酶和抗甲狀腺球蛋白，結果均未見明顯異常；感染性指標檢查結果陰性，包括單純皰疹病毒、艾滋病毒、梅毒和腦膜腦炎系列。雖然外院抗-Hu和抗-NMDA受體抗體結果是陰性，但是，血清和CSF的副腫瘤抗體系列（表e-1，Neurology?Web site at Neurology.org）結果待回報；16小時動態EEG顯示彌漫性慢波，未見癲癇樣放電；全身PET / CT掃描、血清淋巴瘤系列和陰囊超聲檢查未發現腫瘤。
Questions for consideration:
1. Can a diagnosis of paraneoplastic limbic encephalitis be made in the absence of cancer or a paraneoplastic antibody?
2. Would you initiate presumptive treatment at this point, or wait for more results?
思考問題：
1.在沒有癌癥或副腫瘤抗體支持的情況下，可以診斷副腫瘤性邊緣葉腦炎嗎？
2.此時你會開始預防性治療嗎？還是等待更多的檢查結果？
According to an international guideline developed in 2004, this patient meets the definition of probable (rather than definite) paraneoplastic neurologic syndrome (PNS) given a classic neurologic syndrome (limbic encephalitis) in the absence of antibodies or cancer.1 If a paraneoplastic antibody is identified and initial cancer screening is negative, the European Federation of Neurological Societies Task Force recommends repeat cancer screening (targeting cancers associated with the identified antibody) at 3–6 months and then every 6 months up to 4 years.2 Starting treatment for probable PNS is reasonable while awaiting the identification of an antibody or tumor because of the potential for rapid, often irreversible neurologic decline.
根據2004年制定的國際指南，本例患者表現為一個經典的神經綜合征(邊緣葉腦炎），而又沒有抗體或癌癥的證據，符合可能的（而不是確診的）副腫瘤性神經綜合癥（PNS）的定義。如果副腫瘤抗體是陽性，癌癥初查結果陰性，歐洲神經病協會聯盟工作組推薦，在3-6個月內復查（與已知抗體相關的靶向癌癥），于4年內每6個月復查一次。由于存在潛在的快速、通常不可逆的神經功能下降的可能性，所以，在等待抗體或腫瘤結果的同時，開始治療可能的PNS是合理的。
The patient received 5 days of plasma exchange and was discharged. Corticosteroids were not given at this time due to his diabetes, psychiatric symptoms, and availability of plasma exchange. The myoclonic jerks resumed at home, and his other symptoms persisted. During a follow-up visit, the patient was initially alert but became progressively drowsy and unresponsive. Right-sided myoclonic jerks were apparent in his face, arm, and leg. He was readmitted to the hospital, with concern for status epilepticus or worsening of his underlying condition.
患者接受了5天的血漿交換治療后出院。由于糖尿病、精神癥狀和血漿交換治療有效，此時未給予皮質類固醇。肌陣攣性抽搐在家中恢復，其他癥狀持續存在。隨訪期間，患者最初意識清晰，但逐漸進展為昏睡和無反應狀態。右側面部、手臂和腿部出現明顯的肌陣攣性抽搐。他再次住院，著重解決癲癇持續狀態或其潛在的病情惡化。
An EEG and MRI showed no changes from previous studies. The paraneoplastic panel returned positive for voltage-gated potassium channel (VGKC) antibodies with a level of 190 pM. The patient finished 3 days of IV immunoglobulin (IVIg) treatment and then received 1 g of IV methylprednisolone for 4 days. He was discharged home with a diagnosis of limbic encephalitis associated with VGKC complex antibodies. He received 1 g of IV methylprednisolone weekly, with an additional course of plasma exchange, and started 500 mg of mycophenolate twice daily, which was up titrated to 1,000mg twice daily. He also received levetiracetam, which required uptitration to 1,500 mg twice daily to achieve control of the myoclonus. Four months after his discharge from the hospital, he experienced almost complete resolution of symptoms, with only sporadic myoclonus associated with insomnia.
EEG和MRI同前比較沒有變化。副腫瘤性標志物檢測結果回報：電壓門控鉀通道（VGKC）抗體在190pM水平陽性表達。患者給予3天的靜脈注射免疫球蛋白（IVIg）治療，然后甲基強的松龍1g，連用4天。診斷VGKC復合物抗體相關的邊緣性腦炎，出院回家。每周接受1g甲基強的松龍靜脈注射，一療程血漿置換，麥考酚酸酯500mg，每日2次，逐漸增加劑量至1,000mg，每日2次。同時口服左乙拉西坦，增量至1,500mg，每日2 次，肌陣攣得以控制。出院后四個月，癥狀接近完全消失，只有偶發的肌陣攣伴失眠。
Question for consideration:
1. What prognosis does this diagnosis carry?
思考問題：
1. 該病預后如何？
Limbic encephalitis is an autoimmune process affecting the medial temporal lobes or limbic structures that can present either acutely or subacutely with symptoms of confusion, memory impairment, sleep disturbance, seizures, and psychiatric disturbance.1 The cause may be paraneoplastic or nonparaneoplastic, and the diagnosis is usually made with neuroimaging and identificationof the associated antibody. CSF studies are typically normal or have a mildly elevated protein level.3 In general, the well-characterized paraneoplastic antibodies (e.g., anti-Hu, anti-Yo) are directed at intracellular antigens, affect older individuals, are more often associated with cancer, and have a poor response to immunotherapy; antibodies targeting cell surface antigens (e.g., VGKC, NMDA receptor) can affect all ages, are less likely to be associated with cancer, and often respond well to immunotherapy.4 VGKC antibodies identified on radioimmunoassay have antigenic targets other than the VGKC itself and are therefore more accurately referred to as VGKC complex antibodies.4 At least 2 targets are well described: leucine-rich gliomain activated1(LGI1) and contact in associated protein related 2 (Caspr2). LGI1 antibodies typically produce limbic encephalitis, hyponatremia, and myoclonic-like movements, whereas Caspr2 antibodies can produce encephalitis, Morvan syndrome, painful neuropathy, or neuromyotonia.4
邊緣葉腦炎是影響顳葉內側或邊緣系統結構的自身免疫性疾病，急性或亞急性起病，表現意識模糊、記憶損害、睡眠障礙、癲癇發作和精神癥狀。病因可能是副腫瘤或非副腫瘤性，并且通常通過神經影像和相關抗體的檢測進行診斷。CSF通常正常或蛋白輕度升高。一般來說，針對細胞內抗原的特征性副腫瘤抗體（例如抗-Hu，抗-Yo），多見于老年人群，常與癌癥相關，對免疫治療反應差；針對細胞表面抗原的抗體（例如，VGKC，NMDA受體）可以見于所有年齡段，很少與癌癥相關，通常對免疫治療反應良好。通過放免法測定的VGKC抗體，除VGKC本身之外還有靶抗原，因此更準確地稱為VGKC復合物抗體。目前至少詳細描述了2種：富亮氨酸膠質瘤失活1蛋白（LGI1）和接觸蛋白相關樣蛋白-2（Caspr2 ）。LGI1抗體通常導致邊緣葉腦炎、低鈉血癥和肌陣攣樣運動，而Caspr2抗體可導致腦炎、Morvan綜合征、疼痛性神經病或神經性肌強直。
Our patient presented with limbic encephalitis, hyponatremia, and myoclonic jerks and was found to be VGKC complex antibody–positive, likely LGI1. The myoclonic jerks are termed faciobrachial dystonic seizures (FBDS), which are highly associated with LGI1 antibodies and can precede cognitive symptoms.5,6 Although only a minority of patients with FBDS show basal ganglia involvement on MRI, abnormalities are commonly seen on PET.5 FBDS typically show a poor response to standard antiepileptic drugs but may respond to early immunotherapy.5,6 A recent prospective study suggests that early recognition of FBDS and treatment with immunotherapy may reduce the frequency of FBDS attacks and prevent the development of cognitive symptoms.6
本例患者表現為邊緣葉腦炎、低鈉血癥和肌陣攣，VGKC復合抗體陽性，可能是LGI1。把肌陣攣性抽搐稱為面-臂肌張力障礙（FBDS），其與LGI1抗體高度相關，并且可以發生在認知癥狀出現之前。雖然只有少數FBDS患者在MRI上顯示基底節受累，但是，PET異常更常見。FBDS通常對標準抗癲癇藥反應差，但可能對早期免疫治療顯現療效。最近的一項前瞻性研究表明，早期識別FBDS和免疫治療可減少FBDS發作的頻率，并能預防認知癥狀的進展。
Prognosis is generally favorable, as 80% of patients respond to immunotherapy with improvement in memory and executive functions.7,8 Cancer is rarely reported with LGI1 antibodies, and a series of 55 patients with confirmed LGI1 antibodies revealed no cancer after a median follow-up of 3 years9; therefore, the utility of cancer screening in these patients is questionable. Though evidence is limited as to the optimal treatment regimen, most patients respond well to initial treatment with corticosteroids, plasma exchange, or IVIg, with maintenance options including corticosteroids or steroid-sparing agentssuch as mycophenolate, rituximab, or cyclophosphamide.6,7,10
由于80％的患者對免疫治療有效，記憶和執行功能得到改善，多數患者預后良好。LGI1抗體很少有癌癥的報道，55例確診的LGI1抗體陽性的患者在中位隨訪3年后沒有發現癌癥。因此，在這類患者中癌癥篩查的作用是值得質疑的。盡管最佳的治療方案證據有限，但是大多數患者對皮質類固醇、血漿交換或IVIg的初始治療反應良好，維持治療包括皮質類固醇或非甾體類藥物，如：麥考酚酸酯、利妥昔單抗或環磷酰胺。
（全文終）
詩句賞析
Life is like a theatre. Everyone is the protagonist of his own drama.
生活就像一個劇本，每個人都是自己戲劇主角
編輯：李會琪
：李神經群招賢榜--招募病歷討論總結員，公眾號編輯的通知【公告】
