Fatal Primary Amebic Meningoencephalitis due to Naegleria fowleri: The First Imported Case in Korea

Primary amebic meningoencephalitis (PAM) is a rare, but almost always fatal, central nervous system (CNS) infection caused by the free-living amoeba (FLA) Naegleria fowleri. N. fowleri infects humans through nasal inhalation and invades the CNS via the olfactory nerves, resulting in extensive inflammation, cerebral edema, necrosis, hemorrhage, and ultimately death within a median duration of 5 days from symptom onset.1 It is pathogenetically characterized by human brain tissue destruction through food cups on trophozoites’ surface, release of cytolytic molecules, and elicitation of intense host immune responses. From 1962 to 2018, 381 PAM cases were reported in 33 countries, with a 96% mortality rate among 182 confirmed cases.1 We report the first case of PAM caused by N. fowleri detected in South Korea, probably imported from Thailand. Informed consent was obtained from the patient’s wife for the publication of clinical data.

A 52-year-old male presented to the emergency room on December 11, 2022, with a 3-day history of headache and fever. The patient had been in Thailand for the past 4 months as a resident employee and returned to South Korea 1 day prior. Physical examination revealed neck stiffness and positive Kernig signs; moreover, the patient had an alert mental status. Brain computed tomography (CT) findings were unremarkable (Fig. 1A). Blood test results showed an elevated white blood cell (WBC) count (13070 cells/mm³) with neutrophil predominance (93.2%), an elevated C-reactive protein of 54.1 mg/L (reference range 0 to 5 mg/L) and procalcitonin level of 0.23 ng/mL (reference range 0 to 0.05 ng/mL). Cerebrospinal fluid (CSF) examination revealed a turbid-yellowish appearance with elevated opening pressure of 26 cm H₂O, WBC count of >1000/mm³ (reference range 0 to 5 cells/mm³) [polymorphonuclear leukocytes (PMNs) 94%], red blood cell (RBC) count of 3168/mm³ (reference range 0 cells/mm³), protein level of 1536.6 mg/dL (reference range 15 to 60 mg/dL), and glucose level of 1 mg/dL (reference range 40 to 80 mg/dL) (Fig. 2A).

Fig. 1
Brain computed tomography. (A) Well-preserved ventricle and cisternal space on hospital day 1. (B) Diffuse subarachnoid hemorrhage with brain edema on hospital day 6. (C) Severe brain edema on hospital day 9.

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Fig. 2
The appearance of cerebrospinal fluid. (A) Turbid-yellowish color on hospital day 1. (B) Hemorrhagic appearance on hospital day 4. (C) More bloody color on hospital day 11.

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The patient was started on empirical treatment with vancomycin, ceftriaxone, and ampicillin. However, his condition rapidly worsened to stuporous mental status after 8 hour and required mechanical ventilation after 10 hour due to apnea and fixed pupils. After resuscitation from cardiac arrest on hospital day 3, the patient underwent venoarterial extracorporeal membrane oxygenation. Follow-up CSF analyses on day 4 revealed 110620/mm³ WBCs (PMNs 88%), 59000/mm³ RBCs, 3586.9 mg/dL protein, and 2 mg/dL glucose (Fig. 2B). CSF polymerase chain reaction (PCR) test for N. fowleri from the Korea Disease Control and Prevention Agency (KDCA) was requested on hospital day 5; empirical treatment initiated for N. fowleri infection with intravenous liposomal amphotericin B (AmB), fluconazole, azithromycin, and oral rifampin. On day 6, brain CT examination revealed severe brain edema with diffuse subarachnoid hemorrhage (Fig. 1B). On day 8, the CSF PCR test for N. fowleri came back positive; additionally, 18S rRNA internal transcribed spacer sequencing (GenBank accession number OR237809) showed 99.64% similarity with N. fowleri strain KT375442, which was isolated from the CSF of a Norwegian returning from Thailand. On day 9, electroencephalography and non-enhanced brain CT revealed diffuse cerebral dysfunction and severe brain edema with diffuse subarachnoid hemorrhage, respectively (Fig. 1C). Follow-up CSF analyses after 6 days of PAM-specific treatment revealed persistent pleocytosis with 150670/mm³ WBCs, a slightly decreased proportion of PMNs (58%) and protein level (1428.6 mg/dL) (Fig. 2C). The patient’s condition deteriorated despite specific combination treatment for PAM, and he died 13 days after symptom onset.

Since amoeba molecular identification from the CSF cannot be performed in the usual hospital settings in South Korea, PAM cannot be diagnosed unless early recognition and specific molecular tests for N. fowleri are conducted at the KDCA. PAM-specific treatment was initiated, and the diagnosis was confirmed on hospital days 5 and 8, respectively. Since delayed PAM diagnosis and treatment increase mortality risk, improving clinicians’ awareness of this rare but fatal illness is important.

In 2017, viable N. fowleri surveillance in tap water sources in South Korea detected it in 11.5% of water samples, which suggested a possible distribution in the Korean aquatic environment.2 Given the accelerated climate change, further surveillance in Korean aquatic environments during summer might be necessary. The countries with the highest number of PAM are the United States (41%) and Pakistan (11%), mainly associated with swimming in freshwater bodies.1 In 2019, 28.7 million Koreans went abroad, of whom 11% and 17.7% reported experience of outdoor activities and hot springs at their travel destinations, respectively.3 Clinicians should include PAM as a differential diagnosis in patients with rapidly progressive meningoencephalitis.

With PAM’s rapid progression, prompt and efficient medical interventions, including effective antiamebic treatment and management of elevated intracranial pressure, are critical. However, no established effective antimicrobial treatment options for PAM currently exist.4 Seven confirmed PAM survivors have been treated with intravenous and intrathecal AmB, with or without other agents (azoles, azithromycin, miltefosine, rifampin, and dexamethasone) (Table 1).1, 5 AmB exerts inhibitory effects on N. fowleri in vitro and in vivo and induces amoebic ultrastructural abnormalities.6, 7 Conventional deoxycholate AmB is preferred, given its lower minimum inhibitory concentration than liposomal AmB despite having worse CSF penetration and more adverse effects.8 However, our patient was treated with liposomal AmB since deoxycholate AmB was unavailable in stock. Azole compounds have been used, given their potential activity against ergosterol in FLA’s plasma membrane.9 Miltefosine is an FDA-approved antileishmanial agent with in vitro and in vivo activity against FLA.4, 10, 11 The Centers for Disease Control and Prevention suggested that miltefosine can be used as an anti-Naegleria agent under an expanded-access investigational drug protocol.12 Azithromycin has a long half-life, high brain penetration, relatively low toxicity, and potential synergistic effects combined with AmB.8, 13

Table 1
Detailed Treatment Regimens Used in Seven Well-Documented Cases of Primary Amebic Meningoencephalitis Survivors

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Further investigations of effective antiamebic compounds with high CNS penetration are warranted. Additionally, improving access to therapeutics and establishing an expeditious process for PCR testing for N. fowleri should be implemented comprehensively. Finally, it is crucial to improve clinicians’ awareness of PAM and include it as a differential diagnosis for patients with rapidly progressive meningoencephalitis within 14 days of water exposure, especially for returning travelers from tropical regions.