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S. Venugopal
free-living amoeba; there are over 40 species of Naegleria, but only Naegleria fowl-
eri infection results in primary amoebic meningoencephalitis. The incubation period
varies anywhere from 2 to 15days [1–3].
In most cases, death happens around 3 to 7 days from the onset of symptoms.
Naegleria fowleri, upon entering the central nervous system, causes cerebral edema,
necrosis, and herniation. The infection of Naegleria fowleri resembles that of acute
bacterial meningitis. The mortality rate is above 95%, with the highest number of
cases occurring in developed countries because cases occurring in developing countries go primarily undiagnosed. The signs and symptoms of primary amoebic
meningoencephalitis present in two stages, mild and severe. The risk factors for
primary amoebic meningoencephalitis are (1) geographic location, i.e., areas that
have been diagnosed, (2) summer seasons, and (3) sex. Primary amoebic meningoencephalitis has been promulgated widely around the globe, including America,
Australia, Thailand, Hong Kong, and Taiwan; about 300 cases in total have been
reported so far in 50years, since it was rst identied. Because of the limited availability of diagnostic testing and clinical expertise, the signs and symptoms of primary amoebic meningoencephalitis were misinterpreted as common neurological
infections such as bacterial and viral encephalitis. It is often misdiagnosed, as there
is no denitive variation in diagnosis that exists to discriminate primary amoebic
meningoencephalitis from bacterial meningoencephalitis. About <0.5% of diagnosed encephalitis deaths in the United States are because of primary amoebic
meningoencephalitis. There are about 0–8 cases per year that are laboratory conrmed [3, 4]. So far, there were about 151 conrmed primary amoebic meningoencephalitis cases from 1962 to 2020, with only 4 known survivors. These infections
are more prominent in 15 southern tier states of the United States, of which more
than half of the infections are concentrated in Texas and Florida [5]. About 1676
cases of undetermined neuroinfectious disease deaths are within 2–22years of age
during 1999–2010 in which 49% (826/1676) happened in the months of July to
September of each year, of which 23% (192/826) were reported in an included state
of the southern United States. Of which, 52% (100/192) were male, and 48%
(92/192) were female. Of the unspecied neuroinfectious deaths, an average of 16
(8 males and 8 females) suit the typical primary amoebic meningoencephalitis pattern of infection [3].
Apart from Antarctica, Naegleria fowleri was spotted in all the corners of the
world. Among identied 381 global primary amoebic meningoencephalitis cases,
this is believed to be an underestimation of the actual occurrence of primary amoebic meningoencephalitis cases worldwide. An approximation of about 16 cases per
year in the United States has been estimated in a previous study, of which only 0–8
cases are reported annually. The most favorable period for primary amoebic meningoencephalitis infections is the summer months, i.e., July, August, and September,
during which the water temperatures are high and water levels are low. In an environmental investigation of lakes and rivers where the patients swam, high water
temperature, algal bloom, and poor water clarity have been recorded, and samples
taken from this area were positive for Naegleria fowleri. In India, only 15 cases of
55 Primary Amoebic Meningoencephalitis Misdiagnosed asPyogenic Meningitis
397
amoebic encephalitis have been identied. Worldwide data estimates that around
133 cases were reported from 1992 to 2014, out of which 10 were from India; about
97% of the victims died because of infection resulting in very few survivors. Of the
identied 381 cases of primary amoebic meningoencephalitis from 1965 to 2016,
32 survived, and only 7 were laboratory-conrmed cases [6–9]. Of all those suffering from primary amoebic meningoencephalitis, most were previously healthy
young males exposed to warm recreational water more commonly in lakes, ponds,
and reservoirs in southern states of the United States during summer months.
Differing from other free-living amoeba like Acanthamoeba and Balamuthia that
affects the individuals who are immunocompromised, most of the Naegleria fowl-
eri infections were present in young and immunocompetent individuals. However,
in a place with high temperature like Africa, only less than ten cases of primary
amoebic meningoencephalitis have been recorded. Even though Naegleria fowleri
is a thermophilic organism, cases have also been identied in northern states of the
United States, such as Kansas and Indiana; this change in existence and epidemiology of primary amoebic meningoencephalitis would indicate climate change. The
change in geography, i.e., the reported cases outside of southern tier states, has
raised concern and debates that regardless of its geography, primary amoebic
meningoencephalitis should be made as a differential for meningitis [8, 10]
(Fig.55.1).
Fig. 55.1 Shows the data on the primary amoebic meningoencephalitis exposure places in the
United States [11]
398
S. Venugopal
Clinical Case Presentation
The patient is a 36-year-old male from the countryside who was admitted to
Dayanand Medical College & Hospital, Ludhiana, India, in a partially comatose
state. The patient had a severe frontal headache, neck stiffness, intermittent fever
with body pain, nausea, vomiting, and left hemiplegia. On reviewing the patient’s
history, it was known that he was a farmer with a history of opium use for the past
3 years and no signicant medical history. On further investigation, it was found
that the patient had a habit of taking bath in the village pond. The patient had an
episode of syncopal attack 2 months back but regained consciousness after a while.
There was signicant weight loss in the last 2 months. As per the patient’s medical
notes, he was complaining of sudden onset of left arm and leg weakness. A week
before admission, the patient was conscious, was responsive to command, and had
a regular appetite. At rst, he was admitted to a private nursing home, where his
condition started to deteriorate; he started losing his sensorium and stopped responding to commands. There he had two episodes of seizures, but it was controlled with
the help of medication. On physical examination, the patient’s temperature was
102F, blood pressure 130/80mmHg, and pulse rate of 88 and deeply comatose. The
patient’s pupils were constricted, and no papilledema was present. Computed
tomography scan was done after the lumbar puncture procedure; cerebrospinal uid
was slightly turbid, collected in a sterile vial and sent to the laboratory for
investigation.
On a computed tomography scan, it was revealed that there was a hypodensity in
the brain stem up to the hypothalamus without any enhancement. The fourth ventricle was normal; in the right parasellar region, sphenoid sinus, and prepontine
cistern, a soft tissue density was seen with evidence of erosion in the lateral wall of
sella and adjacent portion of the greater wing of sphenoid, with soft tissue mass
touching the basilar artery. The patient was diagnosed with a fungal infection of
sphenoid sinus involvement and brain stem infarct. On laboratory data a total leukocyte count was 6800/mm3 including 69% neutrophils, 25% lymphocytes, 2% eosinophils, and 4% monocytes, platelets were 210×109/L, and erythrocyte sedimentation
rate was 21mm/h. The patient’s hemoglobin concentration was 12.5g/dl. Peripheral
blood lm was negative for malarial parasites. A rapid test was negative for human
immunodeciency virus. The cerebrospinal uid was slightly turbid, and in biochemical analysis, glucose level was 36mg/dl, and proteins 110mg/dl. On cerebrospinal uid cytology, the presence of total white blood cell count was 90/mm3,
predominantly polymorphonuclear leukocytes. A provisional diagnosis of pyogenic
meningitis was given to the patient. Gram stain was negative for bacteria and fungus, and India ink was negative for Cryptococcus neoformans. Some organisms on
wet preparation of cerebrospinal uid resembled Naegleria fowleri in the trophozoite stage. On staining, this organism with Giemsa stains a sky-blue cytoplasm with
very pink nuclei and pseudopodia resembling Naegleria fowleri. There was no
growth of fungus or bacteria on the pyogenic culture of cerebrospinal uid done by
the BacT Alert system (Organon Teknika, USA). The cerebrospinal uid was
55 Primary Amoebic Meningoencephalitis Misdiagnosed asPyogenic Meningitis
Table 55.1 The patient’s laboratory results
Parameter Results Reference range
Total leukocyte count
Neutrophils—69%
Lymphocyte—25%
Eosinophils—2%
Monocytes—4%
Platelets 210×109
Erythrocyte sedimentation
rate
Hemoglobin concentration 12.5g/dl 13.2 to 16.6g/dl for men
Glucose level (CSF) 36mg/dl 50 to 80mg/100mL
Total leukocyte count (CSF) 90/mm
Proteins (CSF) 110mg/dl 18 to 58mg/dl
6800 cells/mm34000–11,000 cells/mm3 of blood
cells/L
21mm/h 0 to 22mm/h for men and 0 to 29mm/h for
3
150 to 400×109 cells/L
women
11.6 to 15g/dl for women
0–5 leukocytes/mm
3
399
negative for acid-fast bacilli or malignant cells. With the evidence of amoeba in
cerebrospinal uid, the patient was given a clinical diagnosis of primary amoebic
meningoencephalitis. The fully expanded organism had a signicantly consistent
limax shape; the organism was broader in the anterior part and narrower in the posterior portion. In the anterior end, there was a single pseudopod that was not clear in
agar culture preparation. The posterior end was narrow during motile, and sometimes a small number of intertwined debris was seen. Development of the uroid
process was observed and reported; rounded, dormant forms and binary ssion of
vegetative trophozoites were also noted. Binucleate and uninucleate amoebae were
also noted. Cerebrospinal uid/agar culture with the trophozoite forms was changed
to a test tube with 2.5ml of distilled sterile water and incubated at 37 C for about
16–20h. On microscopic observation of wet preparation, morphogenesis of amoeboid form to free swimming agellates was noted. Pear-shaped body with two agella helps the organism in forward motion. Some of the agellates changed back to
the amoeboid state after incubating for longer duration. In Table55.1 shows the test
results done in the patient.
Differential Diagnosis
1. Bacterial meningitis/encephalitis/pyogenic meningitis: Initially in our case, the
patient exhibited symptoms such as severe frontal headache, neck stiffness,
intermittent fever with body pain, nausea, and vomiting which are similar to the
most common symptoms of bacterial meningitis including fever, neck stiffness,
and headache; moreover on cerebrospinal uid cytology, the total leukocyte
count was 90/mm3, predominantly with polymorphonuclear leukocytes which
gave the provisional diagnosis of pyogenic meningitis [12].
400
2. Viral meningitis/encephalitis: In viral meningitis/encephalitis, there are common
symptoms such as fever, headache, nausea, vomiting, confusion, and altered
mental status and more severe symptoms such as seizure, weakness, and coma.
Some of these mild and severe symptoms are seen in our patients. Both viral and
bacterial meningitis are clinically overlapping making them difcult to distinguish. Since primary amoebic meningoencephalitis resembles both viral and
bacterial meningitis in symptoms, proper diagnostic technique and detailed history of the patient can help to distinguish [13].
3. Tuberculous meningitis: Tuberculous meningitis exhibits symptoms such as
malaise, fatigue, anorexia and vomiting, headache, and fever. It is almost
impossible for us to determine between tuberculous meningitis and bacterial
meningitis in acute presentation. Rarely a person with tuberculous meningitis
can show symptoms such as progressive dementia (change in one’s personality)
and social withdrawal [14].
S. Venugopal
What WasMisdiagnosed inThis Case andWhy?
The shortfall of knowledge on primary amoebic meningoencephalitis indicates that
there is almost limited or no awareness among the clinicians and laboratories,
regarding the infection leading to misdiagnosis of cases. Without a detailed history
of exposure, it is challenging to identify primary amoebic meningoencephalitis,
which presents as meningitis clinically. In our case, the preliminary diagnosis was
given as fungal infection with involvement of sphenoid sinus and brain stem infarct,
but later, based on the cerebrospinal uid cytology, a provisional diagnosis suggestive of pyogenic meningitis was made; as the wet preparation of cerebrospinal uid
revealed, trophozoites of Naegleria fowleri have pointed toward the nal diagnosis
of primary amoebic meningoencephalitis. Symptoms such as headache, high-grade
fever, photophobia, lethargy, confusion with an altered level of consciousness, and
seizures should raise a suspicion of primary amoebic meningoencephalitis infection; among these most of the symptoms were exhibited by our patient. Death in
most cases was due to increased intracranial pressure. Since the presentation of
primary amoebic meningoencephalitis is often identical to bacterial meningitis,
prompt identication is often too late, which increases the risk of death from infection due to cerebral edema [8, 10].
Discussion
In this, we have discussed a fatal case of primary amoebic meningoencephalitis, in
which the patient had a habit of bathing in the village pond. Naegleria fowleri can
be ingested into the nasal cavity by swimming or bathing in water contaminated
with the organism and via nasal irrigation as shown in Fig.55.2. The amoeba sticks
55 Primary Amoebic Meningoencephalitis Misdiagnosed asPyogenic Meningitis
Fig. 55.2 This gure shows the various activities leading to primary amoebic meningoencephalitis infection and route of entry for Naegleria fowleri
401
to the mucosa of the nasal cavity which enters the central nervous system via the
olfactory nerve and reaches the olfactory bulb through the cribriform plate [9]. The
signs and symptoms of the patient were frontal headache, neck stiffness, intermittent fever with body pain, nausea, vomiting, and left hemiplegia; the lesion will be
primarily concentrated in the orbitofrontal base, temporal lobe, base of the brain,
hypothalamus, midbrain, pons, medulla, and upper portion of the spinal cord. It is
evidenced in computed tomography that there is damage to cisternae around the
midbrain and subarachnoid space of the cerebral hemisphere. Fibropurulent leptomeningeal exudate with polymorphonuclear neutrophils, eosinophils, and a few
lymphocytes and macrophages was seen microscopically in the cerebral hemisphere, brain stem, cerebellum, and upper portion of the spinal cord. Amoebic trophozoites without polymorphonuclear neutrophils and tropic amoebae are visible in
necrotic neural tissue and Virchow-Robin spaces, respectively [15].
Diagnosing a case as primary amoebic encephalopathy increases the rate of mortality by more than 97% [8]. Primary amoebic meningoencephalitis has an acute
course of infection with median incubation period of 5 days; often death occurs
within 3 to 7 days from onset of symptoms [5]. In 1965 Fowler and Carter recorded
the rst case of primary amoebic meningoencephalitis; summer is the high point for
infection with amoeba, during which most of the recreational water activities are
recorded. Clinical symptoms seen with primary amoebic meningoencephalitis
infection are pretty indistinguishable from acute bacterial meningitis, such as headache, fever, nausea and vomiting, altered consciousness, and seizures [2]. Even a
402
few cases presented with anorexia/weight loss and hemiplegia, which is also found
in our case. In gross primarily young males are involved; these demographic groups
are indulging in high-risk activities. Other than recreational activities, the practice
of nasal irrigation among adults may result in Naegleria fowleri exposure [5].
Conrmed cases have a more rapid clinical course compared with suspect cases.
The portal of entry is the olfactory epithelium, in which the sustentacular cells
which line the olfactory neuroepithelium phagocytose the amoeba that enters the
victim’s nasal passage; they pass via porous cribriform plate into subarachnoid
space and reach the brain parenchyma. The period of incubation varies with the size
of inoculum and also with the virulence of infecting amoebic strain [8].
As proposed by the Centers for Disease Control and Prevention, the treatment for
primary amoebic meningoencephalitis includes high doses of intravenous and intrathecal amphotericin with rifampin, azithromycin, miltefosine, and miconazole.
Amphotericin and miltefosine were prescribed for the successful treatment of
Naegleria fowleri-related primary amoebic meningoencephalitis. Amphotericin is
an antifungal agent which also has an amoebicidal effect; it is used in the treatment
of primary amoebic meningoencephalitis, but the rate of recovery with amphotericin is less than 5%, i.e., 15 recoveries/300 cases worldwide. Miltefosine, which is
used in breast cancer and Leishmania infections, has now been suggested for primary amoebic meningoencephalitis infection. Timely diagnosis and triple regime
treatment with intravenous amphotericin, uconazole, and oral rifampin have been
seen to be effective in primary amoebic meningoencephalitis patients. Even amphotericin has limits due to its dose-dependent nephrotoxicity and is capable of inducing anemia, fever, chills, vomiting, and headache in a number of patients. In recent
research, it has been found that chlorpromazine has high potency and is faster- acting
than amphotericin and voriconazole in eliminating Naegleria fowleri trophozoites.
Another study revealed an effective, nontoxic drug called corifungin; it can kill both
the pathogenic Naegleria fowleri and nonpathogenic Naegleria gruberi. Naegleria
fowleri has a gene called nfa1 which is inuential in its pathogenicity; attempts
were made to develop a DNA (deoxyribonucleic acid) vaccine out of this gene using
lentiviral vector pCDH [2, 3, 10, 15–17].
S. Venugopal
Plan ofAction, thePoints Clinician Should Consider, Pitfalls
toAvoid, andPearls ofKnowledge toConsider
Initially he was admitted to a private nursing home, and then he was transferred to
another medical facility since his sensorium started to get worse to the extent that he
was not responsive to auditory stimuli. When admitted to another facility, computed
tomography of the brain was done which revealed hypodensity of the hypothalamus
and soft tissue density in parasellar region, sphenoid sinus, and prepontine cistern.
With the observed abnormality in computed tomography at rst, he was diagnosed
with fungal infection with involvement of sphenoid sinus and brain stem infarct and
was medicated with cefotaxime, dilantin, mannitol, and dexamethasone. After
55 Primary Amoebic Meningoencephalitis Misdiagnosed asPyogenic Meningitis
laboratory data of total leukocyte count, platelets, erythrocyte sedimentation rate,
and cerebrospinal uid cytology, a provisional diagnosis of pyogenic meningitis
was made. But no bacteria or fungi were visible in Gram smear and India ink preparation. Later, on a wet mount preparation of cerebrospinal uid, organisms resembling trophozoites of Naegleria fowleri were found, and on Giemsa stain sky-blue
cytoplasm and microscopic pink nuclei with pseudopodia similar to Naegleria fowl-
eri were visible, which conrmed the diagnosis of primary amoebic meningoencephalitis. After that, he started on amphotericin, 40mg for 6 hours with rifampicin
and ceftazidime. Even though he was treated, there was no signicant improvement
in his condition. He was discharged roughly after 10 days in declining state against
medical advice and died after a couple of days.
403
If Misdiagnosed, WasIt Realized Later? How
WasIt Rectied?
Even though our case was misdiagnosed initially, laboratory investigations helped
the physicians for a prompt and precise diagnosis, both of which are important in
case of infections like primary amoebic meningoencephalitis. In one of the case
studies, a new technique known as next-generation sequencing was used and played
a vital role in the precise diagnosis of Naegleria fowleri infection, but in that case,
the amoeba was absent in the culture. This should be taken as an example in the
future for the culture-negative cases to use the next-generation sequencing technique for diagnosing primary amoebic meningoencephalitis in time. Therefore
next-generation sequencing provides a rapid and accurate method for identifying
the pathogen and should be considered in diagnosing diseases with unknown causes
or cases with inadequate patient history. Diagnostic polymerase chain reaction,
immunohistochemistry, and indirect immunouorescence are methods that are
mainly available for diagnosis; but absence of these advanced techniques should not
delay the diagnosis. Rapid progression of meningoencephalitis in patients despite
starting on intravenous antibiotic therapy should raise an alarm of primary amoebic
meningoencephalitis. Molecular techniques like polymerase chain reaction and isothermal DNA amplication developed can be more helpful for specied spotting of
Naegleria fowleri clinically. Currently, polymerase chain reaction is considered the
gold standard for diagnosis and is even used by center of disease control for suspected primary amoebic meningoencephalitis cases [3, 8, 10].
Conclusion
Primary amoebic meningoencephalitis is a deadly infectious disease. This disease is
still an unexplored one for developing and underdeveloped countries. Proper disease surveillance needs to be enforced in the developing and underdeveloped countries to identify it in patients at an early phase of infection. Climatic change is one
404
S. Venugopal
of the affecting factors in controlling this condition, even though Naegleria fowleri
is a thermophilic organism; this disease is becoming prevalent even in cold temperate zones. Physicians at primary level and private medical practitioners should be
made familiar with this disease to identify primary amoebic meningoencephalitis
clinically and start treating them instead of waiting for laboratory results for conrmation; this will very much reduce the mortality of patients. Proper diagnostic criteria and guidelines should be formulated for better treatment and timely diagnosis.
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