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2024年5月23日，《美国医学会杂志》肿瘤学分册在线发表日本静冈红十字医院疑难病例分析。 患者女性，70岁，患有高血压和血脂异常，右侧乳腺癌手术（pT2N2aM0，IIIA期）辅助化疗（多西他赛＋环磷酰胺）6个疗程之后90天出现语言缓慢和行走困难。1周前由于厌食住院，入院后进食良好，1天前出院。术后化疗第3个疗程后，出现严重恶心，导致食物摄入不足，随后6个月内体重减轻28%。未饮酒或服用非法药物。就诊时，未发热，血压102/64 mmHg，面无表情，神志不清，反应迟缓，准确评定记忆障碍较为困难。未观察到失语。目光能够移动，但是向左凝视时出现眼球震颤。上下肢不能顺利活动，步态共济失调。手动肌肉测试结果正常。未观察到颈部僵硬或不自主运动。体格检查未发现脑膜刺激迹象。- 白细胞计数：14580/μL（14.58×109/L）
- C反应蛋白：7.81mg/dL（70.81mg/L）
- 无机磷：4.0mg/dL（1.292mmol/L）
肌酐水平以及肝脏、甲状腺和肾上腺功能正常。尿液分析提示尿路感染。磁共振成像如下图所示。弥散加权成像（DWI）显示内侧丘脑（A）弥散受限，液体衰减反转恢复（FLAIR）磁共振成像显示内侧丘脑（B）双侧高信号区域。 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 诊断关键为患者早期乳腺癌术后化疗期间出现厌食，并且意识障碍（反应迟钝）、眼球震颤和共济失调步态的体征为非酒精性韦尼克脑病特征。此外，磁共振成像结果提示韦尼克脑病。因此，建议测定维生素B1。虽然观察到炎症反应升高，但是未发热或颈部僵硬，因此脑膜炎可能性不大。当出现脑膜炎3个症状（发热、意识障碍和颈部僵硬）时或者当体检发现脑膜刺激症状时，腰椎穿刺是必要的，对于异常行为或认知能力突然下降相关疑似脑炎病例也很有用。此外，由于患者接受过乳腺癌手术，并且没有远处转移的证据，因此脑膜转移和副肿瘤综合征可能性不大。 韦尼克脑病为急性神经系统疾病，由维生素B1（硫胺素）缺乏引起，需要早期诊断，因为长期可能导致科萨科夫综合征（医疗紧急情况）。硫胺素作为有机代谢辅助因子，对脑能量代谢发挥重要作用。硫胺素缺乏可导致氧化应激，导致神经元死亡，可以损害中脑、内侧丘脑和中枢神经系统乳头体导水管周围灰质。 恶性肿瘤是韦尼克脑病的风险因素。恶性肿瘤患者缺乏硫胺素的原因是肿瘤快速生长导致硫胺素消耗增加、恶心所致食物摄入减少、严重吸收不良以及氟嘧啶类化疗药物（导致硫胺素代谢增加）。大多数韦尼克脑病病例相关肿瘤为胃肠或血液肿瘤。乳腺癌术后化疗期间发生韦尼克脑病的报道极少。 韦尼克脑病通常与精神状态改变、眼球震颤等眼球功能障碍和步态不稳有关，这些症状仅出现于16%的患者。磁共振成像用于诊断韦尼克脑病，特异性高达93%，但是敏感性低达53%。韦尼克脑病还可引起科尔萨科夫综合征并且造成严重后果。无酗酒史与有酗酒史的患者相比，预后较好，残留记忆功能障碍的病例较少，但是症状发作较严重。因此，应该综合病史、体格检查和磁共振成像检查结果怀疑韦尼克脑病，并且应该给受影响的患者补充硫胺素。 葡萄糖摄入可增加硫胺素需求，这可能导致硫胺素缺乏。其中，患者由于厌食入院，能够进食，可能导致进行性硫胺素缺乏，出院后出现韦尼克脑病症状。因此，如果怀疑韦尼克脑病，在给予葡萄糖之前必须补充硫胺素。- 维生素B1：9μg/dL（266.4nmol/L）
- 维生素B2：64μg/dL（1702.4nmol/L）
- 维生素B12：大于1500pg/mL（1106.7pmol/L）
腰椎穿刺显示脊髓液清澈无色，脊髓液细胞数量或蛋白质浓度未增加，糖浓度未降低。静脉注射硫胺素500mg，每天3次，连续4天。不久之后，患者完全康复，能够正常交流和行走。出院后，营养师在门诊提供营养管理，以防止韦尼克脑病复发。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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