Naegleria fowleri: An Amoeba That Eats your Brain

Shinde Siddhi Suhas¹*, Anuradha Prajapati², Sachin B. Narkhede², Shailesh Luhar²

¹Smt. B.N.B Swaminarayan Pharmacy College, Salvav - Vapi, Gujarat.

²Department of Pharmaceutics, Smt. BNB Swaminarayan Pharmacy College,

Gujarat Technological University, Salvav, Vapi, Gujarat, India, 396191.

*Corresponding Author E-mail: anuradha@ssgsalvav.in

ABSTRACT:

This comprehensive review aims to alert and educate physicians, pharmacists, healthcare professionals, and the general public to the emerging threat of Primary amoebic meningoencephalitis (PAM) that is a rare but potentially fatal neurological disease caused by the free-living amoeba Naegleria fowleri. Thermophilic amoeba Naegleria fowleri is a serious hazard to human health. Swimming in freshwater bodies or rinsing one's nose with contaminated water may lead to exposure to N. fowleri-infected water, which can cause primary amoebic meningoencephalitis. PAM causes total brain tissue damage, which puts the patient in a coma and ultimately results in death. An extensive summary of the biology, epidemiology, symptoms, diagnosis, and available treatments for N. fowleri is given in this review article.

KEYWORDS: N. Fowleri, Naegleria, Amoeba, Primary Amoebic Meningoencephalitis, Nasal.

INTRODUCTION:

In the world's poorest nations, infectious illnesses remains a leading source of sickness and mortality. The three major causative agents responsible for infections are: bacteria, viruses and parasites. Many amoeba are responsible for infections.² Amoebic encephalitis is an extremely rare but frequently fatal infection of the central nervous system produced by free-living amoeba.

Human disease transmission is attributed to four main genera of amoebae: Acanthamoeba, Sappinia, Balamuthia and Naegleria.¹

Primary amoebic meningoencephalitis (PAM) is one of the most well-known cases of amoebic encephalitis. Naegleria fowleri, commonly referred to as brain-eating amoeba, is the causative agent. PAM is marked by an infection that spreads quickly throughout the central nervous system, causing a substantial amount of brain oedema and brain tissue loss.¹ This condition though rare, is fatal and 97% of the patients don’t survive.

Malcolm Fowler, who reported the first PAM infection in Australia, inspired the naming of N. fowleri^.1 Inhaling water contaminated with N. fowleri through the nose is the most common way that leads to infection. Being thermophilic, the organism prefers warm, watery environments. After nasal exposure of N. fowleri flagellates, symptoms occur within 1-12 days.

Since primary amoebic meningoenecephalitis (PAM) is an uncommon and deadly illness, having thorough knowledge about its diagnosis and available treatments can significantly improve the prognosis for N. fowleri infections.

LIFE CYCLE OF N. fowleri:³

There are three morphological forms for N. fowleri:

· A stage of feeding trophozoites

· A stage of dormant cyst

· A flagellate state in transition.

Figure 1: Life cycle of N. fowleri⁴

Cyst Stage:

Trophozoites give rise to microbial cysts, which provide the amoeba the ability to endure extreme environmental conditions. The amoeba may emerge via the cyst's central ostiole or pore when circumstances improve. N. fowleri has been seen to encyst at temperatures lower than 10°C (50°F).

Trophozoite stage:

The trophozoite stage is the human infecting stage wherein the organism is able to actively feed and reproduce. When trophozoites are free-living, they consume bacteria. Within tissues, the appear to phagocytise red blood cells resulting in tissue damage. Naegleria fowleri are trophozoites that can generate one to twelve amoebastomes (amorphous cytostomes) on their membrane that help them in feeding.

Flagellate Stage:

In Naegleria fowleri, the flagellate stage is biflagellate and pear-shaped. It is possible to breathe this stage into the nasal cavity, usually when diving or swimming. The flagellated stage becomes a trophozoite a few hours after it enters the nasal canal.

EPIDEMIOLOGY:

The first place this organism was discovered was Australia; other reports of invasive human infections have come from New Zealand, Europe, Africa, Asia, and Latin America. Annually, approximately 400 instances are documented in the literature (381 PAM cases in 2018). 16 cases were discovered in US in 2018, including 8 males and 8 females and all these cases were fatal in nature. There were 157 cases reported in the USA between 1962 and 2022.²

Recently there have been several reports of cases in countries such as Bangladesh, India, Taiwan, Pakistan, Turkey, Zambia and China.⁸ Some cases of primary amoebic meningoencephalitis (PAM) are as follows:

Author	Country	Age	Gender	Survival
Chen et al., 2019 ^9	China	43	Male	Death
Ravinder et al., 2016 ^10	India	15	Male	Survive at point of time
Cope et al., 2018 ^11	USA	18	Female	Death
Yadav et al., 2013 ^12	India	25 days old	Male	survival
Dunn et al., 2016 ^13	USA	12	female	survival

PATHOPHYSIOLOGY:

N. fowleri infections are caused by inhalation of contaminated water present in lakes, rivers, ponds through nose. In rare cases, employing contaminated water in neti pot or other nasal rinsing devices that help to rinse the sinuses or nasal cavity has resulted in infection. It does not occur due to swallowing of contaminated water and neither does it spread from person to person.

First, the organism attaches itself to the nasal mucosa. It then travels down the olfactory nerve and cribriform plate before arriving at the CNS's olfactory bulb. When N. fowleri enters the olfactory bulb, it triggers the innate immune system, which causes an immunological reaction. As a trophozoite, it enters the human body.⁵ Food cups present on trophozoites enable N. fowleri to feed on bacteria, human tissue etc. Additionally, cytolytic substances such as phospholipase and acid hydrolases are produced, which are responsible for death of host cell and nerves. Both this situation results serious nerve injury and CNS tissue destruction.

Ultimately, the illness causes a rapid deterioration in mental state, severe intracranial hypertension, a hernia, and eventually death of the person occurs.

Signs and Symptoms:

Once N. fowleri enters human body, it causes primary amoebic meningoencephalitis (PAM). The onset of disease starts rapidly after entry of parasite in the body. The first symptoms appear between 3-7 days after exposure.

The symptoms occur in 2 stages.⁶ During the initial stage symptoms like severe nausea and vomiting, fever, headache, and stiffness in the neck. With the progress of the disease further, tissues of brain are affected more severely thus neurological problems develop which includes altered mental state, photophobia, seizures hallucinations, confusion, loss of balance etc. In certain instances, heart rhythm problems and myocardial necrosis are also been observed.⁵

All these symptoms eventually lead to coma and ultimately in majority of cases, death of the patient occurs within one week after onset of symptoms.

Diagnosis:

Diagnosis of primary amoebic meningoencephalitits (PAM) is challenging as the symptoms resemble to that of bacterial and viral meningitis. Studying history of exposure to freshwater can help to achieve the right diagnosis. Further analysis of cerebrospinal fluid (CSF) by PCR analysis leads to accurate diagnosis. Use of MRI and CT scan improves the visualization of the affected parts of brain. A 600mm H2O cerebral spinal fluid pressure is noted in N. fowleri-infected patients.⁵

Increase in polymorphonuclear cell concentrations as high as 26000mm³ and also the presence of trophozoites in CSF is observed.⁵ Microscopic examination of the patient’s CSF is done and PAM turns out to be positive when N. fowleri sporozoites are observed moving quickly. A distinctive feature of N. fowleri is its capacity of cell differentiation. In presence of hypotonic water, N. fowleri converts into its flagellate stage in span of 2 hours thus easily diagnosed as other pathogens are not able to do so.²

Prevention:

Considering the increasing mortality of people due to primary amoebic meningoencephalitits (PAM) It is necessary to implement public health precautions. Health awareness campaigns are helpful to educate the public about this illness. Some preventive measures include:¹

· Avoid swimming in warm, still water, particularly if it's shallow.

· While swimming in freshwater and other untreated water bodies keep head above the water level.

· Avoid jumping and diving in untreated water bodies.

· While engaging in water related activities always wear a nasal clip.

· Chlorination of water can help to reduce risk of infection as N. fowleri cannot survive in such conditions.

· Rinsing of nasal passages and nose with help of clean and distilled water subsequent to swimming in fresh water bodies is recommended to reduce risk of infection.¹

Treatment:

Due to rare occurrence of the condition a specific treatment regimen is not available for PAM. Information about efficacy of medicines is based on case reports and invitro studies. Amphotericin B is the medication most commonly used for therapy. Other medications include: miltefosine, fluconazole, miconazole, azithromycin, rifampin etc.⁵

· Amphotericin B: For treatment against N. fowleri, amphotericin B should be administered either intravenously or intrathecally. Adults should receive intravenous doses of amphotericin B between 0.25 and 1.5mg/kg/day, whereas paediatric patients should get dosages between 0.5 and 0.7mg/kg/day. Treatment takes about ten days to complete.⁵ Although it is a primary choice of drug for PAM it includes side effects like liver and kidney toxicity.

· Miltefosine: The CDC began promoting miltefosine as a therapy for N. fowleri in 2013.

An invitro study was conducted between amphotericin B and miltefosine which showed MIC of amphotericin B and miltefosine as 0.78 and 0.25µg/ml respectively survival rates were also higher for miltefosine. According to the CDC, oral administration of 50 mg miltefosine should be taken two to three times a day (based on body weight), with a maximum dose of 1.5 mg/kg/day for a duration of 28 days.⁶

· Fluconazole: It is recommended in conjugation with amphotericin B in treatment of some cases of N. fowleri because of its ability to penetrate the CNS. Both these drugs show synergistic effect against N.fowleri. The CDC advises administering intravenous fluconazole once a day with dose of 10 mg/kg (maximum dose: 600 mg/day) for a total of 28 days.⁵

REFERENCES:

1. Ahmad Zamzuri, M.‘A.I.; Abd Majid, F.N.; Mihat, M.; Ibrahim, S.S.; Ismail, M.; Abd Aziz, S.; Mohamed, Z.; Rejali, L.; Yahaya, H.; Abdullah, Z.; et al. Systematic Review of Brain-Eating Amoeba: A Decade Update. Int. J. Environ. Res. Public Health 2023; 20: 3021. https://doi.org/10.3390/ijerph20043021n

2. Borkens, Y. The Pathology of the Brain Eating Amoeba Naegleria fowleri. Indian J Microbiol. 2024; 64: 1384–1394. https://doi.org/10.1007/s12088-024-01218-5

3. Marciano-Cabral F. Biology of Naegleria spp. Microbiol Rev. 1988 Mar; 52(1): 114-33. doi: 10.1128/mr.52.1.114-133.1988. PMID: 3280964; PMCID: PMC372708.

4. Ismail N, Yusof H. Occurance of the pathogenic Amoeba Naegleria fowleri, pathogenesis, diagnosis, and treatment options. Mal J Med Health Sci. 2021; 17(4): 285-295

5. Grace E, Asbill S, Virga K. Naegleria fowleri: pathogenesis, diagnosis, and treatment options. Antimicrob Agents Chemother. 2015 Nov; 59(11): 6677-81. doi: 10.1128/AAC.01293-15. Epub 2015 Aug 10. PMID: 26259797; PMCID: PMC4604384.

6. Alli A, Ortiz JF, Morillo Cox Á, Armas M, Orellana VA. Miltefosine: A Miracle Drug for Meningoencephalitis Caused by Free-Living Amoebas. Cureus. 2021 Mar 4; 13(3): e13698. doi: 10.7759/cureus.13698. PMID: 33833918; PMCID: PMC8020194.

7. Ruqaiyyah Siddiqui, David Lloyd, Ahmad M. Alharbi and Naveed Ahmed Khan. Emerging therapies against Naegleria fowleri, Expert Opinion on Orphan Drugs. 2024; 12(1): 41-49, DOI: 10.1080/21678707.2024.2383173

8. Pervin N, Sundareshan V. Naegleria. [Updated 2022 Sep 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535447/

9. Chen, M.; Ruan, W.; Zhang, L.; Hu, B.; Yang, X. Primary amebic meningoencephalitis: A case report. Korean J. Parasitol. 2019; 57: 291–294.  

10. Ravinder, K.; Uppal, B.; Aggarwal, P.; Mehra, B.; Hasan, F.; Mridul Daga, K. Co-infection of central nervous system by M. Tuberculosis, Cryptococcus and possibly Naegleria fowleri. Trop. Biomed. 2016; 33: 387–392

11. Cope, J.R.; Murphy, J.; Kahler, A.; Gorbett, D.G.; Ali, I.; Taylor, B.; Corbitt, L.; Roy, S.; Lee, N.; Roellig, D.; et al. Primary Amebic Meningoencephalitis Associated with Rafting on an Artificial Whitewater River: Case Report and Environmental Investigation. Clin. Infect. Dis. 2018; 66: 548–553.

12. Yadav, D.; Aneja, S.; Dutta, R.; Maheshwari, A.; Seth, A. Youngest survivor of Naegleria meningitis. Indian J. Pediatr. 2013; 80: 253–254.  

13. Dunn, A.L.; Reed, T.; Stewart, C.; Levy, R.A. Naegleria fowleri that induces primary amoebic meningoencephalitis: Rapid diagnosis and rare case of survival in a 12-year-old Caucasian girl. Lab. Med. 2016; 47: 149–154.  

14. Senthil kumar K, Manoj Varma G, Vudaykiran A, R Arun Kumar and B Sudhakar. Nasal Drug Delivery System - An Overview. International Journal of Pharmaceutical and Chemical Sciences. 2012; 1(3): 1358-1367.

15.  Muhammad U. Ghori, Mohammed H. Mahdi, Alan M. Smith, Barbara R. Conway. Nasal Drug Delivery Systems: An Overview. American Journal of Pharmacological Sciences. 2015; 3: 110.

16. Article on Nasal drug delivery: An approach of drug delivery through nasal route by Sanjay Dey, Beduin Mahanti, Bhaskar Mazumder, Ananaya Malgope, Sandeepan Desgupata. Published by Pelagia Research Library. 2014; 1.

17.  Pagar Swati Appasaheb, Shinkar Dattatraya Manohar, Saudagar Ravindra Bhanudas. A Review on Intranasal Drug Delivery System. Journal of Advanced Pharmacy Education and Research. 2013; 3(4): 334-340.

18. Prajapati M., Mandloi R., Pillai S, Birla N. The Review on The Nasal Drug Delivery. Asian J. Pharm. Res. 2020; 10(2):110-116. doi: 10.5958/2231-5691.2020.00021.0

Received on 08.10.2024      Revised on 06.12.2024

Accepted on 16.01.2025 Published on 03.03.2025

Available online from March 10, 2025

Res.  J. Pharma. Dosage Forms and Tech.2025; 17(1):37-40.

DOI: 10.52711/0975-4377.2025.00006

©AandV Publications All Right Reserved

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.