The parents of a 13-year-old boy bring their son to the emergency department. He is rolling his head and is seemingly unaware of his surroundings. They say that he has a fever and is "acting strange."
The boy had been in his usual state of excellent health until 2 days ago, when he complained of a headache during a car trip back from a vacation. For most of the 4-hour drive, he slept restlessly in the back seat. The family, which consists of the boy, his parents, and two younger siblings, had enjoyed a 1-week vacation at an Indiana water park resort. They spent most of their time swimming in the artificial lake and hiking. A diving champion, the boy concentrated on perfecting his diving technique in the lake; he also went snorkeling.
The family members all used insect repellent and sunscreen while outdoors. They also checked each other for ticks. They always ate at the resort's four-star restaurant. As far as the parents know, no diners became ill. No other family member is currently ill. They have no pets at home and have not had any exposure to feral or domesticated animals.
Yesterday, the boy lay quietly on the couch and watched
television. He had a headache and was also nauseated. His mother reports that
he felt warm to the touch just before he went to bed, and she gave him
ibuprofen. In the morning, hearing "funny noises," his parents
entered his bedroom. He was lethargic and incoherent. Yellow vomitus and urine
colored the bedsheets. They immediately wrapped him up and brought him to the
emergency department by car.
The patient's temperature is 102.6 °F (39.2 °C); heart rate is 113 beats/minute; respiration rate is 12 breaths/minute with shallow breaths; blood pressure is 102/54 mm Hg; and oxygen saturation is 93% (fraction of inspired oxygen, 2 L/minute by nasal cannula). His score on the Glasgow Coma Scale is 9-10. Nuchal rigidity is present. No rashes are observed, and no evidence of trauma is noted. Airway, breathing, and circulation stabilization is achieved with advanced resuscitative techniques. Broad-spectrum antimicrobial medications are administered.
Results of a CT scan of the brain and other radiologic imaging studies are interpreted as normal. The results of the initial laboratory studies are remarkable for a white blood cell (WBC) count of 16,000/µL (reference range, 4500-11,000/µL), with a left shift, and elevated levels of inflammatory biomarkers.
A lumbar puncture reveals these findings:
Opening pressure: 36 cm H2O (reference range, 10-20 cm H2O)
WBC count: 3690/µL (75% neutrophils) (reference range, 0-5/µL [< 2 polymorphonucleocytes])
Red blood cell (RBC) count: 423/µL (reference range, 0-10/µL)
Protein level: 425 mg/dL (reference range, 20-40 mg/dL)
Glucose level: < 10 mg/dL (reference range, 45-80 mg/dL)
The results of Gram staining are negative. Blood, urine, and
cerebrospinal fluid (CSF) cultures are ordered. A more thorough analysis of the
history prompts a request for a wet preparation of the CSF. The results point
toward the presumptive diagnosis...
A more in-depth analysis of the history of the boy's diving
and snorkeling in a warm freshwater lake prompted additional CSF testing. A wet
preparation of the CSF revealed amebic microorganisms. Giemsa and trichrome
staining of wet samples may show the organisms in real time. Polymerase chain
reaction testing can confirm the initial findings. Results of a CT scan may be
normal early in the course of the disease, as it was in this case.
Within the plethora of conditions in the differential diagnosis of fever and altered sensorium, PAM [primary amebic meningoencephalitis] should be entertained. This is particularly true in light of the impact climate change has had in extending the geographic boundaries of certain emerging and re-emerging infectious diseases. PAM was once considered a disease of the southern United States; however, recent case reports have noted that it is now found as far north as Minnesota. Nevertheless, between 2010 and 2020, most cases (approximately 17) occurred in Texas and Florida.
The cause of PAM is N fowleri, a pathogenic free-living
thermophilic ameba. It thrives in temperatures as high as 114.4 °F (45.8 °C).
Other amebic genera can cause disease, such as Acanthamoeba and Balamuthia, but
N fowleri, of the amoeboflagellated genus, Naegleria, is the most pathogenic
N fowleri is ubiquitous; it is found in both the fresh waters and the soils of six of the seven continents.
Infection with N fowleri typically occurs as contaminated
fresh water is introduced into the nose, along the nasal mucosa, through the
cribriform plate, and onto the olfactory bulbs of the central nervous system.
The organism's cytoxic effects then proceed to destroy nerve cells. The
inflammatory response causes neuronal demyelination and lysis of erythrocytes
and nerve cells. The end result is a hemorrhagic necrotizing
Patients most commonly acquire the ameba by swimming and diving in warm freshwater lakes, hot springs, ponds, and spas. Another source of infection is the use of contaminated water for religious/cultural nasal ablutions and sinus-cleansing nasal irrigations. Even poorly chlorinated tap water can be unsafe if it is contaminated by the ameba. Infections and deaths related to PAM have also resulted from exposure to contaminated water from backyard water slides, artificial whitewater rafting, and water skiing.
Despite the global habitat of N fowleri, PAM is rarely reported. The first case was discovered in Australia and described by Fowler and Carter in 1965. Several hundred more cases have been recorded around the world, and from 1962 through 2018, 145 cases have been reported in the United States. On average, three cases of PAM are reported each year in the United States.
This rarity is not the only factor that makes PAM a
diagnostic challenge. The initial symptoms are fairly general in nature. As the
manifestations worsen, they and the usual test results seem to point to a
diagnosis of bacterial meningoencephalitis. Therefore, it is not surprising
that in 75% of cases, the correct diagnosis is made at autopsy. It is
hypothesized that the number of N fowleri cases worldwide is grossly underestimated,
owing to a lack of recognition and a dearth of laboratory resources.
After a mean incubation period of 5 days (range, 3-8 days),
patients with PAM may present innocuously with nausea, vomiting, headache, and
fever early in the course of the disease. If the patient delays seeking medical
care, neurologic manifestations will develop and progress ominously similarly
to a case of bacterial meningitis.
N fowleri meningoencephalitis has a death rate of as much as 97%. Only three survivors have been reported in the United States. The sole chance a patient has for survival is an early diagnosis and initiation of the proper therapy. The usual outcome, death within 6-17 days, is typically related to increased intracranial pressure and brain herniation.
Delay of the patient in seeking medical attention and delay in making the correct diagnosis explain, in part, why the mortality rate is so high. Without an in-depth questioning of the patient and/or the family, the historical clue of nasal exposure to warm, untreated fresh water will be overlooked. Similarly, when the results of a lumbar puncture demonstrate cloudy fluid with an elevated CSF WBC count, a high CSF protein value, and a low CSF glucose value, the logical diagnosis will be a bacterial meningitis despite a negative Gram stain result.
However, in this case, an elevated index of suspicion for N fowleri meningoencephalitis, in addition to the ordering of appropriate testing, allowed for an early, accurate diagnosis. This led to the activation of the pipeline of therapeutics that have been deemed essential for any hope of survival. The drug regimen recommended by the Centers for Disease Control and Prevention includes amphotericin B, intravenously and intrathecally; azithromycin; fluconazole; rifampin; miltefosine; and dexamethasone. It may be difficult to acquire some of these medications, so making an early, accurate diagnosis is even more critical in order to obtain the drugs as quickly as possible. Other interventions that have been reported in the literature include inducing therapeutic hypothermia (89.6 °F [32 °C] to 93.2 °F [34 °C]) and stabilizing intracranial pressures (eg, with hyperventilation, hyperosmolar therapy, and phenobarbital-induced coma).
Amazingly, through the aggressive use of induced
hypothermia, invasive monitoring of intracranial pressures, and a medley of
pharmaceutical measures, this patient made a virtually complete recovery
following a week in the intensive care unit and 1 month in a rehabilitation
center. The key to success was the timely diagnosis.