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2024年5月23日，《美國(guó)醫(yī)學(xué)會(huì)雜志》腫瘤學(xué)分冊(cè)在線發(fā)表日本靜岡紅十字醫(yī)院疑難病例分析。 患者女性，70歲，患有高血壓和血脂異常，右側(cè)乳腺癌手術(shù)（pT2N2aM0，IIIA期）輔助化療（多西他賽＋環(huán)磷酰胺）6個(gè)療程之后90天出現(xiàn)語(yǔ)言緩慢和行走困難。1周前由于厭食住院，入院后進(jìn)食良好，1天前出院。術(shù)后化療第3個(gè)療程后，出現(xiàn)嚴(yán)重惡心，導(dǎo)致食物攝入不足，隨后6個(gè)月內(nèi)體重減輕28%。未飲酒或服用非法藥物。就診時(shí)，未發(fā)熱，血壓102/64 mmHg，面無(wú)表情，神志不清，反應(yīng)遲緩，準(zhǔn)確評(píng)定記憶障礙較為困難。未觀察到失語(yǔ)。目光能夠移動(dòng)，但是向左凝視時(shí)出現(xiàn)眼球震顫。上下肢不能順利活動(dòng)，步態(tài)共濟(jì)失調(diào)。手動(dòng)肌肉測(cè)試結(jié)果正常。未觀察到頸部僵硬或不自主運(yùn)動(dòng)。體格檢查未發(fā)現(xiàn)腦膜刺激跡象。- 白細(xì)胞計(jì)數(shù)：14580/μL（14.58×109/L）
- C反應(yīng)蛋白：7.81mg/dL（70.81mg/L）
- 無(wú)機(jī)磷：4.0mg/dL（1.292mmol/L）
肌酐水平以及肝臟、甲狀腺和腎上腺功能正常。尿液分析提示尿路感染。磁共振成像如下圖所示。彌散加權(quán)成像（DWI）顯示內(nèi)側(cè)丘腦（A）彌散受限，液體衰減反轉(zhuǎn)恢復(fù)（FLAIR）磁共振成像顯示內(nèi)側(cè)丘腦（B）雙側(cè)高信號(hào)區(qū)域。 JAMA Oncol. 2024 May 23. IF: 28.4 A Patient With Slow Communication and Difficulty Walking. Matsushima H, Kikuchi M, Shintani T. Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan. Case A 70-year-old woman with hypertension and dyslipidemia presented with slow communication and difficulty walking 90 days after 6 courses of postoperative chemotherapy (docetaxel plus cyclophosphamide) following right breast cancer surgery (pT2N2aM0, stage IIIA). She had been hospitalized for anorexia 1 week before, had good oral intake after admission, and was discharged the day prior. After the third course of postoperative chemotherapy, she experienced severe nausea, leading to poor food intake and 28% loss of body weight over the following 6 months. She did not consume alcohol or illegal drugs. At presentation, she was fever free with a blood pressure of 102/64 mm Hg, was expressionless and disoriented, and had delayed responses, which made the accurate assessment of memory impairment difficult. Aphasia was not observed. She was able to follow her gaze but had nystagmus during the left gaze. She could not move her upper and lower extremities smoothly and had an ataxic gait. Results of a manual muscle test were normal. No stiff neck or involuntary movements were observed. Physical examination revealed no signs of meningeal irritation. Blood test results showed a white blood cell count of 14580/μL (to convert to ×109/L, multiply by 0.001), C-reactive protein of 7.81 mg/dL (to convert to mg/L, multiply by 10), sodium of 129 mEq/L (to convert to mmol/L, multiply by 1), potassium of 3.4 mEq/L (to convert to mmol/L, multiply by 1), calcium of 8.9 mg/dL (to convert to mmol/L, multiply by 0.25), inorganic phosphorus of 4.0 mg/dL (to convert to mmol/L, multiply by 0.323), and magnesium of 1.4 mg/dL (to convert to mmol/L, multiply by 0.4114). Creatinine level and liver, thyroid, and adrenal function were normal. Urinalysis suggested a urinary tract infection. Magnetic resonance imaging (MRI) was performed. Diffusion-weighted imaging (DWI) demonstrated diffusion restriction in the medial thalamus (A), and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) showed high bilateral signal areas in the medial thalamus (B). What Is Your Diagnosis? A. Encephalitis B. Meningitis C. Nonalcoholic Wernicke encephalopathy D. Paraneoplastic syndrome 診斷關(guān)鍵為患者早期乳腺癌術(shù)后化療期間出現(xiàn)厭食，并且意識(shí)障礙（反應(yīng)遲鈍）、眼球震顫和共濟(jì)失調(diào)步態(tài)的體征為非酒精性韋尼克腦病特征。此外，磁共振成像結(jié)果提示韋尼克腦病。因此，建議測(cè)定維生素B1。雖然觀察到炎癥反應(yīng)升高，但是未發(fā)熱或頸部僵硬，因此腦膜炎可能性不大。當(dāng)出現(xiàn)腦膜炎3個(gè)癥狀（發(fā)熱、意識(shí)障礙和頸部僵硬）時(shí)或者當(dāng)體檢發(fā)現(xiàn)腦膜刺激癥狀時(shí)，腰椎穿刺是必要的，對(duì)于異常行為或認(rèn)知能力突然下降相關(guān)疑似腦炎病例也很有用。此外，由于患者接受過(guò)乳腺癌手術(shù)，并且沒(méi)有遠(yuǎn)處轉(zhuǎn)移的證據(jù)，因此腦膜轉(zhuǎn)移和副腫瘤綜合征可能性不大。 韋尼克腦病為急性神經(jīng)系統(tǒng)疾病，由維生素B1（硫胺素）缺乏引起，需要早期診斷，因?yàn)殚L(zhǎng)期可能導(dǎo)致科薩科夫綜合征（醫(yī)療緊急情況）。硫胺素作為有機(jī)代謝輔助因子，對(duì)腦能量代謝發(fā)揮重要作用。硫胺素缺乏可導(dǎo)致氧化應(yīng)激，導(dǎo)致神經(jīng)元死亡，可以損害中腦、內(nèi)側(cè)丘腦和中樞神經(jīng)系統(tǒng)乳頭體導(dǎo)水管周圍灰質(zhì)。 惡性腫瘤是韋尼克腦病的風(fēng)險(xiǎn)因素。惡性腫瘤患者缺乏硫胺素的原因是腫瘤快速生長(zhǎng)導(dǎo)致硫胺素消耗增加、惡心所致食物攝入減少、嚴(yán)重吸收不良以及氟嘧啶類化療藥物（導(dǎo)致硫胺素代謝增加）。大多數(shù)韋尼克腦病病例相關(guān)腫瘤為胃腸或血液腫瘤。乳腺癌術(shù)后化療期間發(fā)生韋尼克腦病的報(bào)道極少。 韋尼克腦病通常與精神狀態(tài)改變、眼球震顫等眼球功能障礙和步態(tài)不穩(wěn)有關(guān)，這些癥狀僅出現(xiàn)于16%的患者。磁共振成像用于診斷韋尼克腦病，特異性高達(dá)93%，但是敏感性低達(dá)53%。韋尼克腦病還可引起科爾薩科夫綜合征并且造成嚴(yán)重后果。無(wú)酗酒史與有酗酒史的患者相比，預(yù)后較好，殘留記憶功能障礙的病例較少，但是癥狀發(fā)作較嚴(yán)重。因此，應(yīng)該綜合病史、體格檢查和磁共振成像檢查結(jié)果懷疑韋尼克腦病，并且應(yīng)該給受影響的患者補(bǔ)充硫胺素。 葡萄糖攝入可增加硫胺素需求，這可能導(dǎo)致硫胺素缺乏。其中，患者由于厭食入院，能夠進(jìn)食，可能導(dǎo)致進(jìn)行性硫胺素缺乏，出院后出現(xiàn)韋尼克腦病癥狀。因此，如果懷疑韋尼克腦病，在給予葡萄糖之前必須補(bǔ)充硫胺素。- 維生素B1：9μg/dL（266.4nmol/L）
- 維生素B2：64μg/dL（1702.4nmol/L）
- 維生素B12：大于1500pg/mL（1106.7pmol/L）
腰椎穿刺顯示脊髓液清澈無(wú)色，脊髓液細(xì)胞數(shù)量或蛋白質(zhì)濃度未增加，糖濃度未降低。靜脈注射硫胺素500mg，每天3次，連續(xù)4天。不久之后，患者完全康復(fù)，能夠正常交流和行走。出院后，營(yíng)養(yǎng)師在門(mén)診提供營(yíng)養(yǎng)管理，以防止韋尼克腦病復(fù)發(fā)。C. Nonalcoholic Wernicke encephalopathyThe key to the diagnosis was the patient's background of anorexia during adjuvant chemotherapy for early-stage breast cancer and recognition that the physical findings of impaired consciousness (delayed response), nystagmus, and ataxic gait were characteristic of nonalcoholic Wernicke encephalopathy. Furthermore, MRI findings were suggestive of Wernicke encephalopathy. Therefore, vitamin B1 measurements were recommended. Although an elevated inflammatory response was observed, there was no fever or neck stiffness; therefore, meningitis was unlikely. Lumbar puncture is essential when the 3 signs of meningitis are fever, impaired consciousness, and stiff neck, or when physical examination reveals signs of meningeal irritation. It is also useful in cases of suspected encephalitis associated with abnormal behavior or sudden cognitive decline. Furthermore, because the patient had undergone breast cancer surgery and there was no evidence of distant metastasis, meningeal carcinomatosis and paraneoplastic syndrome were unlikely.Wernicke encephalopathy, an acute neurological disorder, results from vitamin B1 (thiamine) deficiency. Early diagnosis is required because prolonged exposure can lead to Korsakoff syndrome, a medical emergency. Thiamine functions as a cofactor in organic pathways and plays an essential role in brain energy metabolism. Thiamine deficiency causes oxidative stress, leading to neuronal death. It can damage the periaqueductal gray matter of the midbrain, medial thalamus, and mammillary bodies of the central nervous system.Malignant tumors are a risk factor for Wernicke encephalopathy. Thiamine deficiency in patients with malignant tumors is attributed to increased thiamine consumption by rapidly growing cancers, decreased food intake associated with nausea, substantial malabsorption, and use of fluoropyrimidine chemotherapeutic agents (which induce increased thiamine metabolism). Most cancers associated with Wernicke encephalopathy cases are gastrointestinal or hematologic cancers. There are few reports of Wernicke encephalopathy occurring during postoperative chemotherapy after breast cancer surgery.Wernicke encephalopathy is often associated with altered mental status, ocular dysfunction such as nystagmus, and unstable gait, which are present in only 16% of patients. MRI is used to diagnose Wernicke encephalopathy with high specificity (93%) but low sensitivity (53%). Wernicke encephalopathy can also cause Korsakoff syndrome with severe outcomes. Patients without alcohol use disorder have a better prognosis than patients with alcohol use disorder, with fewer cases of residual memory dysfunction, but symptom onset is more acute in patients without alcohol use disorder than those with it. Therefore, Wernicke encephalopathy should be suspected based on a comprehensive history, physical examination, and MRI findings, and affected patients should be given thiamine as a supplement.Glucose intake increases thiamine demand, which may lead to thiamine deficiency. Herein, the patient was hospitalized for anorexia and was able to eat, which may have led to progressive thiamine deficiency, resulting in symptoms of Wernicke encephalopathy after discharge. Therefore, if Wernicke encephalopathy is suspected, it is imperative to supplement with thiamine before administering glucose.Results of the patient's blood tests revealed levels of vitamin B1 at 9 μg/dL (to convert to nmol/L, multiply by 29.6), vitamin B2 at 64 μg/dL (to convert to nmol/L, multiply by 26.6), vitamin B12 at greater than 1500 pg/mL (to convert to pmol/L, multiply by 0.7378), folic acid at 4.2 ng/mL (to convert to nmol/L, multiply by 2.266), copper at 81 μg/dL (to convert to μmol/L, multiply by 0.157), and zinc at 50 μg/dL (to convert to μmol/L, multiply by 0.153). A lumbar puncture was also performed. The spinal fluid was clear and colorless, and there was no increase in the number of cells or protein concentration in the spinal fluid or any decrease in sugar concentration. Thiamine, 500 mg, was administered intravenously 3 times daily for 4 days. Immediately after, the patient recovered completely and was able to communicate and walk normally. After discharge, nutritional management by a dietitian was provided on an outpatient basis to prevent recurrence of Wernicke encephalopathy.DOI: 10.1001/jamaoncol.2024.0978原文共享
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