真菌性脑膜炎可伪装成缺血性卒中

《美国医学会杂志-神经病学》(JAMA Neurology)7月22日在线发表的一篇报告显示，由脊髓注射受污染的甲基强的松龙引起的真菌性脑膜炎可表现为缺血性卒中(JAMA Neurol. 2013 July 22 [doi: 10.1001/jamaneurol.2013.3586])。

在这篇报告中，田纳西州纳什维尔范德比尔特大学医学中心的Kirk Kleinfeld医生及其同事介绍了3例此类患者。这3例患者接受甲基强的松龙注射的地点，均已被美国疾病预防控制中心(CDC)证实为甲基强的松龙污染批次接收单位。

第1例，男性，78岁，发生急性左侧无力和构音障碍，无发热且无脑膜刺激征，实验室检查仅显示轻度白细胞增多。患者合并高脂血症、高血压和房颤。MRI扫描显示右脑桥前上部/中脑下部存在小血管缺血性梗死。给予标准卒中后治疗，但未见改善。在第3天左侧无力加重时进行另一次MRI，结果显示梗死扩大，并且右丘脑有新的梗死形成。第4天，患者丧失反应，重复影像学检查显示这些梗死扩大和进展，并且右小脑上动脉闭塞形成。患者在第6天死亡。患者在2周前曾接受硬膜外类固醇注射治疗腰痛。对其进行尸检，结果显示存在小范围的局灶性皮质和脑桥蛛网膜下腔出血，以及真菌性脑血管炎和动脉瘤形成。证实突脐孢属真菌感染。

第2例，女性，78岁，发生亚急性眩晕、恶心和头痛，检查发现存在单侧辨距不良和轻度共济失调。病史包括高血压、高脂血症和冠心病，初步实验室检查示2型糖尿病。MRI扫描显示左脑桥外侧、小脑脚上部和小脑上部存在大血管(小脑上动脉)病因的缺血性梗死。高凝检查示狼疮抗凝物和抗磷脂蛋白抗体增高。予抗凝治疗。患者未获改善，第4天发生低热和轻度脑病。重复MRI示新的缺血性脑桥卒中。患者的精神状态未见改善，患者在2周前曾接受硬膜外类固醇注射治疗腰痛。进行腰穿以确定是否存在真菌感染，第15天开始予静脉抗生素和伏立康唑治疗，但患者在第50天死亡。尸检显示左小脑上动脉真菌性动脉瘤及菌丝型真菌浸润动脉壁。聚合酶链反应显示真菌为突脐孢属。

第3例，女性，70岁，发生头痛、平衡困难、颈背强直和低热。患者具有高脂血症，体检示轻度构音障碍和双侧辨距不良。MRI扫描示右丘脑和内囊存在急性小血管卒中。由于患者具有慢性腰痛及临床医生怀疑真菌性脑膜炎，发现患者1个月前曾接受硬膜外类固醇注射。进行腰穿确定是否存在真菌性感染，给予静脉抗生素和伏立康唑治疗。患者在第7天发生脑病，重复MRI显示存在累及左内囊的新的小血管卒中。在继续进行伏立康唑治疗的情况下，患者的精神状态和脑脊液细胞数缓慢改善。患者存活并在37天后出院。Kleinfeld医生认为早期抗真菌治疗终止了该患者感染的进一步血管进展。

这些病例表明，临床医生应在观察到小血管梗死局部扩大或在相同血管区域观察到新的梗死形成时考虑非典型的发病机制。此外，这些病例表明突脐孢属等一些真菌属具有血管浸润性，可导致进行性血管闭塞。

研究者声明无相关经济利益冲突。

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By: MARY ANN MOON, Cardiology News Digital Network

The recent outbreak of fungal meningitis caused by spinal injections of contaminated methylprednisolone illustrates that the disease can present as ischemic stroke, according to a report published online July 22 in JAMA Neurology.

Three such cases occurred in elderly patients who had clear risk factors for stroke and no fever or meningeal signs; whose exposure to the contaminated injection was as remote as 4 weeks earlier; and whose early MRI scans indicated stroke rather than infection, said Dr. Kirk Kleinfeld and his associates at Vanderbilt University Medical Center, Nashville, Tenn.

The investigators described these cases in detail so as to alert clinicians to this confusing presentation, which would enable them to initiate antifungal therapy as soon as possible. In two of these cases, the diagnosis was delayed and the patients died. In the third case, once clinical suspicion of fungal meningitis had been aroused, empiric antifungal therapy appears to have saved the patient’s life, they noted.

"An awareness of the presentation and vascular sequelae of fungal meningitis in immunocompetent patients should lead to earlier treatment and improved outcomes prior to a definitive diagnosis," Dr. Kleinfeld and his colleagues wrote.

In the first case, a 78-year-old man presented with acute-onset, left-sided weakness and dysarthria. He was afebrile and had no meningeal signs, and his laboratory workup showed only mild leukocytosis. He had hyperlipidemia, hypertension, and atrial fibrillation, and an MRI scan showed a small-vessel ischemic infarct of the right anterior superior pons/lower midbrain.

The patient failed to improve with standard poststroke care. When his left-sided weakness worsened on day 3, another MRI showed that the infarct had extended and a new one had formed in the right thalamus. The next day he became unresponsive, and repeated imaging showed enlargement and evolution of those infarcts plus formation of an occlusion of the right superior cerebellar artery. The patient died on day 6.

An autopsy was performed when it was noted that the patient had received an epidural steroid injection 2 weeks earlier to treat low-back pain. It "revealed small areas of focal cortical and pontine subarachnoid hemorrhage, as well as fungal cerebral vasculitis with aneurysm formation." Infection with Exserohilum species was identified, the investigators reported (JAMA Neurol. 2013 July 22 [doi: 10.1001/jamaneurol.2013.3586]).

In the second case, a 78-year-old woman presented with subacute vertigo, nausea, and headache, and was found on examination to have one-sided dysmetria and mild ataxia. Her medical history included hypertension, hyperlipidemia, and coronary artery disease, and the initial laboratory workup revealed type 2 diabetes. The authors noted that an MRI scan showed "ischemic infarcts of the left lateral pons, superior cerebellar peduncle, and superior cerebellum suggestive of a large-vessel (superior cerebellar artery) etiology."

A hypercoagulable panel revealed lupus anticoagulant and elevated antiphospholipid protein antibodies. Anticoagulation therapy was given. The patient failed to improve, and on day 4 she developed a low-grade fever and mild encephalopathy. A repeat MRI showed a new ischemic pontine stroke.

The patient’s mental status failed to improve, and it was noted that she had received an epidural steroid injection 2 weeks earlier to treat low-back pain. The patient underwent lumbar puncture to identify any fungal infection, and intravenous antibiotics and voriconazole were administered beginning on day 15. However, the patient died on day 50.

"An autopsy revealed a left superior cerebellar artery mycotic aneurysm with vascular infiltration of the arterial wall by hyphal fungal forms," which were thought to represent Exserohilum species based on polymerase chain reaction studies, the investigators reported.

In the third case, a 70-year-old woman presented with headache, difficulty balancing, nuchal rigidity, and mild fever. She had hyperlipidemia, and physical examination showed mild dysarthria and bilateral dysmetria. An MRI scan revealed acute small-vessel strokes in the right thalamus and internal capsule.

Because the patient had chronic back pain and the clinicians’ suspicions were raised regarding fungal meningitis, it was found that she had undergone an epidural steroid injection 1 month earlier. A lumbar puncture was performed to identify possible fungal infection, and treatment with intravenous antibiotics and voriconazole was initiated.

The patient became encephalopathic on day 7, and a repeat MRI showed a new small-vessel stroke involving the left internal capsule. With continued voriconazole therapy, the patient’s mental status and her cerebrospinal fluid cell counts slowly improved. She survived and was discharged 37 days later.

"We suspect that [the early antifungal treatment] halted the further vascular progression of her infection," Dr. Kleinfeld and his associates wrote.

All three patients received methylprednisolone from contaminated lots at medical facilities that were identified by the Centers for Disease Control and Prevention as recipients of contaminated lots.

These cases show that clinicians should consider an atypical pathogenesis when small-vessel infarctions expand locally or when new infarctions develop in the same vascular territory. They also demonstrate the angioinvasive nature of some fungal species such as Exserohilum, which can lead to progressive vascular occlusion, the investigators said.

No relevant financial conflicts of interest were reported.