A scoping review on epidemiology and pathogenesis of death due to primary amoebic meningoencephalitis

INTRODUCTION

Primary amoebic meningoencephalitis (PAM) caused by the amoeba Naegleria fowleri, (N. fowleri) also known as ‘brain-eating amoeba’. It is a rare, lethal central nervous system disorder leading to oedema of brain. N. fowleri can live up to temperature of about 45.8°C while the other amoeba cannot. Hence, a temperature of 45°C is used to isolate N. fowleri species while it suppresses the growth of another amoeba. As the amoeba is heat- resistant it is most commonly seen in warm water sources and it cannot survive in salt water such as sea water.

Most of the infection occurs during summer. The infection spreads through contaminated water bodies and death occurs within 1-2 weeks.¹ Nose of humans are the only route of infection.^1-3 The infection occurs when water containing trophozoite is drawn through the nose. The pathogenesis depends on the site of the body where the trophozoites travel. In brain it leads to necrotising encephalitis leading to damage of brain parenchyma. The symptoms resemble those that of bacterial meningitis.

The amoeba is found in three morphological forms namely trophozoites, flagellates and cysts. Trophozoites are the infective form. The diagnosis is very rarely made before the death. The preventive measures include avoiding jumping or diving in to the stagnant water, using nose plugs while diving or swimming, keeping the head high during swimming and proper decontamination of water sources.^1,4

There are so many case reports published with cases of primary amoebic meningoencephalitis. Only few studies are conducted regarding the epidemiology and pathogenesis of death in PAM. A trial is made to record the epidemiology and pathogenesis of death due to PAM from 45 cases published in 22 articles dated 1978 to 2024.

A literature search was conducted using the words “death in primary amoebic meningoencephalitis”, “death due to primary amoebic meningoencephalitis”, “primary amoebic meningoencephalitis fatality,” “primary amoebic meningoencephalitis cases”, “death in naegleriasis”, “death due to naegleriasis”, “fatality in N.fowleri infection”, “Naegleriasis” from various databases of PubMed, Jama network, Springer nature and the Lancet. Google search engine was used to collect all relevant research articles and reports published till 2024. Twenty-two research articles were selected which includes the death cases due to PAM. Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) checklist is used for the review of these selected articles.

Number of patients

Data of 45 patients died due to PAM were analysed and summarized below.

Age

The age group of all the 45 cases were documented (Table 2).

Gender

The majority of cases belongs to male group. Of the 45 cases, 42 were males and 3 were females.

History of exposure

Out of 45 cases analysed, 4 cases had no history of exposure and in 10 cases history of exposure was not known (Table 3).

Duration from exposure to production of symptoms

The duration from exposure to production of symptoms in 17 patients were documented and it ranges from 3 days to 1-2 months. Out of 17, 5 had a duration of 5 days, 3 with duration of 6 days and others with duration of weeks and months.

Clinical symptoms

The symptoms produced by 41patients were documented as follows (Table 4).

Clinical examination findings

The examination findings of 24 documented cases were as follows (Figure 1).

Lab investigations

Laboratory findings of 17 cases were analysed and the cases with more leucocytes as well as neutrophils were also documented. Out of 17, 14 had elevated leucocytes, 13 had elevated neutrophils, 4 shows elevated CRP and 1 shows elevated lactate. Patients with number of elevated leucocytes is depicted in Table 5.

Findings in CSF analysis

CSF analysis of 30 documented cases were as follows and positive wet mount preparation was done in 28 patients (Table 6).

Radiological findings

Radiological findings of documented 17 cases were summarized in Table 7.

Other test

Other diagnostic test was done in some patients out of 45. 11 cases were diagnosed with polymerase chain reaction, 8 with next generation sequencing and 3 with metagenomic next generation sequencing

Associated diseases

Out of 45, 6 cases had other associated diseases. Thyromegaly, type II diabetes mellitus, acute leukaemic leukaemia, ebstein barr virus infection, extra pulmonary testicular TB and diabetes insipidus are the associated diseases with 1 patient in each.

Day of death from appearance of symptoms

The day of death from appearance of symptoms ranges from 3 to 64 days (Table 8).

Place from where cases were reported

Death cases due to PAM documented from 1978 to 2024 were analysed and 15 cases were reported from India (Table 9).

DISCUSSION

Details of 45 cases died from PAM were analysed and summarized. Out of 45 cases, 13 patients were between the age group 10 to 19 years. In a study reported in USA regarding the epidemiology of PAM in USA between 1962 and 2008, the median age of the cases was 12 years.27According to technical guidelines in diagnosis and prevention of PAM in Kerala, the most common age group suffering with PAM belongs to first three decades.1

Overall, the male to female ratio of PAM is 2:1.¹ In a epidemiological study conducted in USA, out of 111 cases males accounts for 88.⁵ In the present review, out of 45 cases,42 (93%) were males.

Out of 45 cases, history of exposure is not documented in 10 cases. 4 had no history of exposure. All others had history of exposure to water before the infection. The infection occurs once the person gets contact with water contaminated by amoeba through nasal mucosa.² Epidemiological studies in USA shows that amoeba proliferate in natural bodies of water.²⁷ A mini review on N. fowleri suggests that the infection is common among persons engaged in recreational water activities.⁴

According to the present review, the duration from exposure to production of symptoms ranges from 3 days to a maximum of 1-2 months. The persons will produce symptoms within 1-9 days after exposure to water.¹ A review on Pathology of brain eating amoeba reports that,not later than 14 days after exposure, the symptoms appear.²

Clinical symptoms of the 41 cases out of 45 cases had been documented and analysed. Out of which most common presentations were fever, headache, vomiting and altered sensorium. The change in host immune response due to affection of trophozoite leads to inflammatory response in brain parenchyma leading to necrosis and damage of brain parenchyma.¹

The most common presentations according to literature are severe headache, fever and chills, stiff neck with photophobia, nausea and vomiting, positive Brudzinski sign, positive Kernig sign, increased intracranial pressure and increased cerebrospinal fluid pressure has direct association with death.^4,29 Examination findings of 24 cases were analysed and presented with stiff neck, positive meningeal signs and other features which are in accordance with those in literature.

Regarding laboratory investigations, leukocytosis (300 to 26,000 cells/mm) with predominant polymorphonuclear cells, presence of red blood cells, elevated protein and low glucose during cerebrospinal fluid (CSF) examination are the characteristic finding in PAM. Fast moving N. fowleri trophozoites can be seen in wet mount preparation of CSF. PCR technique of CSF detects DNA of N. fowleri. Abnormalities in various structures of brain including subarachnoid space and midbrain can be identified in MRI of Brain.^1,4,29 Out of 17 patients having lab investigation, 14 had elevated leucocytes. In this article, 30 patients had CSF examination findings. Increased WBC count and increased protein were seen in 23 and 21 respectively. 13 patients presented with cerebral oedema in radiography. Postmortem finding of N. fowleri in brain tissue was found in 5 patients. Of the 45 patients, PCR was positive in 11, Next Generation Sequencing (NGS) in 8 and metagenomic next generation sequencing (mNGS) in 2 cases.

Regarding the day of death after appearance of symptoms, the range is from 3-64 days. Case fatality rate of PAM is more than 95% and death can occur in 3-7 days.³ According to the article on PAM in MSD manual, the death will occur within 10 days of infection.²⁸

The 45 death cases documented from 1978 to 2024 were included in the analysis. The demographic data, clinical symptoms, exposure, investigations and diagnosis were reviewed. As PAM is mostly a fatal disease and it mimics bacterial meningoencephalitis and difficult to diagnose, more extensive research should be carried out for generalization of results.

CONCLUSION

Out of 45 cases documented, most of the patients had contact with water contaminated by N. fowleri which shows the importance of decontamination of the water resources for preventing the spread of fatal disease. Late diagnosis of most of the cases due to resemblance of symptoms with bacterial meningitis is also a cause for lethality.

ACKNOWLEDGEMENTS

We would like to thank Dr. K. C. Muraleedharan, Officer in charge and Dr. R. Sitharthan, Principal of NHRIMH for their constant support and guidance in preparation of manuscript.

Funding: No funding sources

Conflict of interest: None declared

Ethical approval: Not required

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