ABOUT AUTHOR:
Akshay Rajgaria
Kanak Manjari Institute of Pharmaceutical Sciences
Rourkela, Orissa
akshaykrish2007@gmail.com
ABSTRACT:
Primary amoebic meningoencephalitis (PAM) caused by free-living amoebae Naegleria fowleri is a rare and fatal condition.
REFERENCE ID: PHARMATUTOR-ART-2047
INTRODUCTION:
Primary amoebic meningoencephalitis (PAM or PAME) is a disease of the central nervous system caused by infection from the amoeboid excavate Naegleria fowleri. Typically, N fowleri produces primary amebic meningoencephalitis (PAM), which is clinically indistinguishable from acute bacterial meningitis. The other amoebae cause granulomatous amebic encephalitis (GAE), which is a more subacute or chronic infection. The presentation of GAE can mimic a brain abscess, aseptic or chronic meningitis, or CNS malignancy.
CAUSES:
Naegleria fowleri is a parasite commonly referred to as an amoeba, but is more precisely an excavate that is ubiquitous in soils and warm waters. Infection typically occurs during the summer months and patients typically have a history of exposure to a natural body of water. The organism specifically prefers temperatures above 32 °C, as might be found in a tropical climate or in water heated by geothermal activity. The organism is extremely sensitive to chlorine (<0.5 ppm). Exposure to the organism is extremely common due to its wide distribution in nature, but thus far lacks the ability to infect the body through any method other than direct contact with the olfactory nerve, which is exposed only at the extreme vertical terminus of the paranasal sinuses; the contaminated water must be deeply insufflated into the sinus cavities for transmission to occur.
Michael Beach, a recreational waterborne illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that the wearing of nose-clips to prevent insufflations of contaminated water would be an effective protection against contracting PAM, noting that "You'd have to have water going way up in your nose to begin with".
SYMPTOM:
The following symptoms usually develop within three to seven days of infection:
- high fever
- severe and persistent headache
- neck stiffness
- confusion, hallucinations
- sleepiness
- sore throat
- nausea and vomiting
- disturbances of taste and smell
- Seizures (fitting).
PATHOPHYSIOLOGY:
Inflammation and Purulent Exudates: Inflammation is one of three main features that underlie the path physiology of PAM.
Inflammation initiates in the olfactory bulbs, and eventually spreads to other areas of the brain and meninges. According to one study, the inflammation is limited only to the frontal regions of the brain. The current understanding regarding the N. fowleri-induced inflammatory process initially involves two types of cell-cell interactions. The first involves N. fowleri-astroglial cell interactions and the activation of Interleukin-8 (IL-8) genes through the ERK-1/2 signaling pathway . N. fowleri stimulates the activity of (1) extracellular signal-regulated kinases (ERKs) and the (2) DNA binding activity of activator protein-1 (AP-1) to upregulate the expression of IL-8 genes in human astroglial cells. The IL-8 genes producecytokines that play a key role in the development of the inflammatory response against the trophozoite . N. Fowler-microglial cell interactions are also implicated in the process of inflammation. Pro-inflammatory cytokines, such as interleukin-6, IL1-beta, and tumor necrosis factor-alpha, are released when N. fowleri interacts with microglia . Purulent exudate is typically associated with the inflammatory process. The exudates accumulate within the base of the brain, olfactory bulbs, brainstem, cerebellum, and in between sulci, causing congestion and hyperemia.
Brain Hemorrhaging and Necrosis:
The hemorrhagic and necrotic events are mediated by N. fowleri-host cell interactions. A series of studies examining the interaction between N. fowleri and mammalian cells have shown that various proteins are involved. The trophozoite induces necrotic hemorrhaging by releasing cytolytic proteins and by trogocytosis. These mechanisms are used to destroy neurons and other cell types for easy digestion. The mechanism selected by the trophozoite depends on its pathogenic strength, at least in vitro. For example, weakly pathogenic trophozoites use trogocytosis, a mechanism involving the ingestion of mammalian cells, such as neurons, with a 'food-cup' structure located on the surface of the trophozoite. In contrast, highly pathogenic trophozoites consume mammalian cells after releasing cytolytic proteins .
N. fowleri secretes enzymes that degrade a wide variety of connective tissue and structural proteins. For instance, N. Fowleri degrades sphingomyelin by releasing proteases, acid hydrolases, phospholipases, and phospholipolytic enzymes. In addition, the trophozoite secretes neuraminidases and elastase. These enzymes are responsible for degrading collagen and proteoglycans, and for altering glycolipid and phospholipids’ composition to induce demyelization, respectively. Since the cytopathology of PAM is poorly understood, the proteins aforementioned are by no means an exhaustive list and the exact determinants of the pathogenicity remain unclear .Neuronal lysis by the trophozoite triggers an inflammatory response, which ultimately leads to the destruction of brain tissue. The inflammatory response is associated with necrotic hemorrhaging, resulting in widespread lesions through the cortex and spinal cord. The areas of the CNS most susceptible to the hemorrhaging include the base of the brain, olfactory bulbs, temporal and orbitofrontal lobes, hypothalamus, brainstem, and cervical portion of the spinal cord.
TREATMENT:
The current standard treatment is prompt intravenous administration of heroic doses of Amphotericin B, a systemic antifungal that is one of the few effective treatments for systemic infections of protozoan parasitic diseases (such as leishmaniasis and toxoplasmosis).
The success rate in treating PAM is usually quite poor, since by the time of definitive diagnosis most patients have already manifested signs of terminal cerebral necrosis. Even if definitive diagnosis is affected early enough to allow for a course of medication, Amphotericin B also causes significant and permanent nephrotoxicity in the doses necessary to quickly halt the progress of the amoebae through the brain.
Rifampicin has also been used with amphotericin B in successful treatment. However, there is some evidence that it does not effectively inhibit Naegleria growth.
Two cases of similar amoebic infections (caused by Balamuthia mandrillaris) were successfully treated for amoebic encephalitis and recovered, including a 5-year-old girl and a 64-year-old man. The successful use of a combination regimen that includes one amebicidal drug (miltefosine) along with two amebistatic drugs capable of crossing the brain-blood barrier (fluconazole and albendazole) provides hope for attaining clinical cure for an otherwise lethal condition.
There is preclinical evidence that the relatively safe, inexpensive, and widely available phenothiazine antipsychotic chlorpromazine is a highly efficacious amebicide against N. fowleri, with laboratory animal survival rates nearly double those receiving treatment with amphotericin B. The mechanism of action is possibly the inhibition of the nfa1 and Mp2CL5 genes, found only in pathogenic strains of N. fowleri, which are involved in amoebic phagocytosis and regulation of cellular growth, respectively.
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