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Acta Tropica 142 (2015) 86–88

Contents lists available at ScienceDirect

Acta Tropica

jo u r n al homep age: www.elsev ier .com/ locate /ac ta t ropica

eview

ackling infection owing to brain-eating amoeba

bdul Mannan Baig, Naveed Ahmed Khan ∗

epartment of Biological and Biomedical Sciences, Aga Khan University, Stadium Road, Karachi, Pakistan

r t i c l e i n f o

rticle history:eceived 24 July 2014eceived in revised form 31 October 2014ccepted 5 November 2014vailable online 13 November 2014

a b s t r a c t

In view of the devastating nature of primary amoebic meningoencephalitis caused by Naegleria fowleriand the problems associated with diagnostic delays and chemotherapeutic failures, here we proposea noninvasive diagnostic method using the ‘reverse transcribrial route device’, a novel strategy in themanagement of this life-threatening infection with a case fatality rate of more than 90%. The proposedrationale should stimulate interest in this emerging infection that almost always proves fatal.

© 2014 Elsevier B.V. All rights reserved.

eywords:aegleria fowleririmary amoebic meningoencephalitisrain-eating amoebaeiagnosisreatment anagement

ontents

1. Primary amoebic meningoencephalitis due to Naegleria fowleri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862. The current scenario . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863. The proposed diagnostic strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874. Recommendations in the management of PAM patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

. Primary amoebic meningoencephalitis due to Naegleriaowleri

N. fowleri is a free-living protozoan parasite and causativegent of a fulminating brain infection, primary amoebic menin-oencephalitis (PAM), which typically results in death (Visvesvara,010). N. fowleri cases have been reported in healthy individuals,ho had a history of swimming in fresh water, lakes or pools,

athing in hot spring spa, nasal irrigation, or ritual ablution. N.owleri invades the nervous system when contaminated water is

and supportive care; inadequate knowledge of the molecular mech-anisms involved in the pathogenesis of PAM, delayed diagnosis, anda lack of available effective therapeutic strategies are contributingfactors (da Rocha-Azevedo et al., 2009). Here, we discuss the cur-rent approach of PAM diagnosis and treatment, while proposingalternative strategies for PAM management. The proposed noveldiagnostic modality combined with effective drug delivery mayprovide a favorable outcome.

eeply inhaled into the nose, and ascends up into the brain tis-ue where it causes severe hemorrhage and inflammation (Yodert al., 2012). The mortality rate owing to PAM is distressing andemains over 95% despite advances in antimicrobial chemotherapy

∗ Corresponding author. Tel.: +92 021 3486 4540; fax: +92 021 3493 4294.E-mail address: naveed5438@gmail.com (N.A. Khan).

ttp://dx.doi.org/10.1016/j.actatropica.2014.11.004001-706X/© 2014 Elsevier B.V. All rights reserved.

2. The current scenario

Several lines of evidence suggest that early diagnosis is piv-otal in order to initiate appropriate antimicrobial chemotherapy(Visvesvara, 2010; Yoder et al., 2012; da Rocha-Azevedo et al.,

2009). The speed with which the infection establishes and causesneuronal damage – within a few days – and finally results indeath is alarming. Over the past 50 years, only three people havesurvived the attack of this merciless pathogen (CDC, 2013). PAM

A.M. Baig, N.A. Khan / Acta Tropica 142 (2015) 86–88 87

Fig. 1. Device for mucosal secretion collection for Naegleria fowleri diagnosis. The proposed device is made of three components, (A) nasal sliders, (B) two way insert cannula,and (C) an irrigation and collection component. Saline will be used to irrigate the upper nasal cavity in the region of the olfactory mucosa, and subsequently, secretions willbe collected passively back into the pump; the remaining secretions can be manually drawn using a suction syringe. The collected sample would be tested for the presenceof N. fowleri. To avoid aspiration into the lungs, posterior nasal packing could be used ahead of nasal irrigation.

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s difficult to differentiate from bacterial meningoencephalitis,eading to delays in correct diagnosis. PAM is suspected only iferebrospinal fluid (CSF) analysis indicates purulent meningitisithout bacteria (da Rocha-Azevedo et al., 2009). The majority

f patients have increased intracranial pressure, and under theseircumstances, drawing the CSF via lumbar puncture has its ownomplications such as herniation of the brain stem. In this case,he primary focus is to lower the intracranial pressure using drugsuch as Mannitol, which in the presence of intracranial hemor-hage complicates the management of the patient (Tilak et al.,008). Patients with PAM present with focal or general seizures,bnormal patterns of breathing, papilloedema, worsening levels ofonsciousness, state of shock, and hypertension (Visvesvara, 2010;oder et al., 2012; da Rocha-Azevedo et al., 2009; CDC, 2013). Underhese circumstances, performing the lumbar puncture is difficultrior to lowering intracranial pressure by drugs or via surgicalrocedure (Kneen et al., 2002). After obtaining CSF sample, lighticroscopy is used to confirm the presence of amoebae. Amoebae

an be identified using various stains, immunofluorescence assaysith anti-N. fowleri antibody, PCR-based assays using N. fowleri-

pecific primers, or simple culturing by plating on non-nutrientgar plates seeded with bacterial lawns (Visvesvara, 2010; daocha-Azevedo et al., 2009; CDC, 2013). A combination of drugs areiven intravenously after the infection gets established, includingmphotericin B, Rifampicin, Miconazole, and Phenytoin. Pheny-

oin and/or Diazepam is given intramuscularly or intravenously foreizures. Paraldehyde has been added in the past, if seizures recur,hile Mannitol is given to reduce intracranial pressure (Tilak et al.,

008). General anesthesia with induced coma has been attemptedo reduce cerebral edema with continued Amphotericin or Milte-osine therapy, which is currently recommended by the US Centersor disease control.

3. The proposed diagnostic strategy

The natural route of amoebal entry into the brain is the nasalcavity, followed by migration along the olfactory neuroepithelium.Amoebae subsequently enter the brain via the transcribial routethrough the cribrifom plate (Baig and Khan, 2014b). Owing to theproximity of the cribriform plate to the inferior surface of the frontallobe, this area is the first affected where trophozoites tend to pro-liferate prior to spreading throughout the central nervous system.Thus, secretions collected from the infracribrial part of the nasalcavity may serve as a valuable sample collection site to detectamoebae. For example, motile trophozoites were discovered innasal secretions of a PAM patient as well as in the CSF and iden-tified as N. fowleri by culturing the parasites (Singh et al., 1998).The finding of amoebae in the nasal samples and their culture issignificant. While the evidence that they were the same species asin the CSF was not pursued fully (e.g., results of an exflagellationtest on isolates from both sites), it is hypothesized that secretionscollected from the nasal cavity offers a valuable sample collec-tion site. In an attempt to effectively administer drugs from theinfracribrial region of the nasal cavity, we recently proposed a non-invasive device that reaches as high as the cribriform plate of theethmoid bone via the nose (Baig and Khan, 2014b). Unlike the pre-viously proposed device, here we propose to use a non-ball valvetip attached to a suction syringe of the device (Fig. 1). This devicewould initially flush the aforementioned region of the nasal cav-ity and collect secretions from the region around the cribriformplate. The wet preparation of the lavaged fluid can be examined to

detect N. fowleri using aforementioned methods. It is hypothesizedthat the possibility of obtaining the parasite from such a flushingis high because the olfactory mucosa and the bulb that overlies thecribriform bone is a natural route of the infection by N. fowleri. In

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Hill, V.R., Wilson, J.D., Linscott, A.J., Crager, R., Kozak, N.A., Sriram, R., Narayanan,J., Mull, B., Kahler, A.M., Schneeberger, C., da Silva, A.J., Poudel, M., Baumgarten,K.L., Xiao, L., Beach, M.J., 2012. Primary amebic meningoencephalitis deaths asso-

8 A.M. Baig, N.A. Khan / A

ddition, the proposed strategy would bypass the attendant com-lications of CSF collection via invasive lumbar puncture and delaysssociated with lowering intracranial pressure. Alternatively, bothumbar puncture and secretions via the transcribial route could beerformed to ensure early diagnosis of N. fowleri.

. Recommendations in the management of PAM patients

A recent study suggested that seizures and pain in Acanthamoebancephalitis patients should be managed with the alternativenesthetic agents Haloperidol and Loperamide, owing to theirnti-amoebic effects (Baig and Khan, 2014a); interestingly, bothhowed potent anti-N. fowleri effects (Baig et al., 2014). Givenhat PAM patients suffer repeated seizures and pain, we proposedding neuroleptanalgesia to the aforementioned drugs, whichould complement this therapy by exhibiting amoebicidal effects.f neuroleptanalgesia is administered by inhalation, some topicalffects are expected around the cribriform plate, olfactory bulb,nd frontal lobe of the brain because they would be en-route ofdministration to the CNS, thus effectively targeting the epicenterf trophozoite proliferation. In this regard, a ‘transcribrial route’evice could provide an effective route of delivery for the vapor-

zed drugs, including anesthetic agents as well as known anti-N.owleri compounds (Baig et al., 2014). The proposed delivery system

ould outweigh the current intra-ventricular, intra-thecal routeshat require surgical procedures and have their own attendant com-lications. Furthermore, the current drug delivery routes results

n dilution of the drugs in the plasma or CSF before reaching thenferior surface of the frontal lobe of the brain (Baig and Khan,014a,b). Even if drugs are injected into CSF, drainage into theenous blood by arachnoid villi would reduce the concentration

f the drug. In summary, it is hoped that the aforementioned diag-ostic, anesthetic, and treatment strategies would help improveatient compliance as well as the morbidity and mortality of thisevastating infection.

pica 142 (2015) 86–88

Conflict of interestNone to declare.

Acknowledgement

This work is supported by the Aga Khan University.

References

Baig, A.M., Khan, N.A., 2014a. Anesthesia with antiamoebic effects: can anesthe-sia choice affect the clinical outcome of granulomatous amoebic encephalitisdue to Acanthamoeba spp.? J. Neurosurg. Anesthesiol., http://dx.doi.org/10.1097/ANA.0000000000000036.

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Baig, A.M., Kulsoom, H., Khan, N.A., 2014. Primary amoebic meningoencephalitis:amoebicidal effects of clinically approved drugs against Naegleria fowleri. J. Med.Microbiol. 63, 760–762.

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