Handbook of Clinical Neurology, Vol. 114 (3rd series)Neuroparasitology and Tropical NeurologyH.H. Garcia, H.B. Tanowitz, and O.H. Del Brutto, Editors© 2013 Elsevier B.V. All rights reserved

Chapter 18

Neurological manifestations of filarial infections

DEVENDER BHALLA1,2,3, MICHEL DUMAS1,2, AND PIERRE-MARIE PREUX1,2,3*

1INSERM UMR 1094, Tropical Neuroepidemiology, Limoges, France2University of Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology,

CNRS FR 3503 GEIST, Limoges, France3Centre Hospitalier Universitaire, Limoges, France

INTRODUCTION

Filarial infections are disorders that have remained “sci-entifically silent” for a long time, perhaps because oftheir absence in western countries. Together howeverthey constitute a huge burden in endemic countries;nearly two billion people are at risk of infection fromfilariasis resulting in at least 534000 deaths per year.Huge economic losses are evident in many African(Baker et al., 2007) and Asian countries (Ramaiahet al., 2000). As an example economic losses per yearin India are estimated to be nearly 1 bn US $ (Ramaiahet al., 2000). Filarial infections affect humans and ani-mals equally and are caused by nematode parasites ofthe order Filariidae, commonly called filariae. Accordingto the location of the adult worms in the vertebral host,they are categorized into the cutaneous group, whichincludes Loa loa, Onchocerca volvulus andMansonellastreptocerca, the lymphatic group, which includesWuchereria bancrofti,Brugiamalayi andBrugia timori,or the body-cavity group, which includes Mansonellaperstans and Mansonella ozzardi. Only eight speciescause natural infections in humans; other species areunable to reach adult maturity in human hosts and there-fore cannot produce microfilaria (e.g.,Dirofilaria immi-tis (dog heartworm), Dirofilaria [Nochtiella] repens,and Dirofilaria tenuis (raccoon heartworm)), althoughinvasion of cerebrospinal fluid (CSF) and human menin-goencephalitis due tomicrofilaria ofD. repens are noted(Poppert et al., 2009).

The filariae have a defined geographical distribution,for instance, W. bancrofti is found in sub-SaharanAfrica, Southeast Asia, India, and the Pacific Islands,

*Correspondence to: Prof. Pierre-Marie Preux, M.D., Ph.D., InstiFaculte de Medecine, 2, rue du Dr Marcland, 87025 Limoges, Ced

preux@unilim.fr

whileB.malayi is not found in sub-SaharanAfrica. Theirtransmission is confined to warm climates, a high tem-perature being necessary for the parasites to developin the vectors. Like all nematodes, they have five devel-opmental or larval stages in a vertebral host and anarthropod intermediate host and a vector. The life cyclesfor filariae may differ depending upon the body locationof adult worms, the microfilariae present, and thearthropod intermediate hosts and vectors.

These filariae may invade any location in the humanbody (Table 18.1). Neurological manifestations of filarialinfections are thought to be less common than systemicones. However, despite the large size of infected or at-risk population, no to little systematic attempt, exceptcase reports (Kenney and Hewitt, 1950; Deodhar et al.,1971; Bada et al., 1976), has actually been made in defin-ing microbiological, pathophysiological, clinical, andneurological mechanisms in causing neurological symp-toms. Their neurological manifestations may, however,depend upon many factors such as quantity of accumu-lating adult worm antigen or duration and level of expo-sure or number of secondary bacterial and fungalinfections or degree of host immune response (King,2001; Baird et al., 2002). Pathogenesis of neurologicalmanifestations of these infections is complex; however,they may cause pathogenic reactions by mechanicaldisruption as they migrate through or disrupt tissuesor vascular lesion or vascular block of cerebral vessels,or via immune response to infection (Bada et al., 1976).Degeneration is often followed by granulomas, whichcan cause fibrosis or mass effects on other tissues orinduce disordered inflammatory responses resulting in

tut de Neuroepidemiologie et Neurologie Tropicale (EA3174),ex, France. Tel: 33 5 55 43 58 20, Fax: 33 5 55 43 58 21, E-mail:

Table 18.1

Possible neurological complications of various filariae

Filariae Microfilariae Location of adult filariae Neurological complications

Dracunculiasis medinensis Subcutaneous Subcutaneous Medullar compressionLoa loa Blood Subcutaneous Epilepsy, meningitisOnchocerca volvulus Skin Subcutaneous Epilepsy

Wuchereria bancrofti Blood Lymphatic vessels EncephalitisDipetalonema perstans Blood Peritoneal Headache

236 D. BHALLA ET AL.

meningitis, encephalitis, or localized inflammatory respo-nses. Some species may secrete cytokine homologs. It isoften the death of helminths within the body that causespathology. The infecting organism must first gain entryto the brain tissues–common routes include hematoge-nous spread via arterial blood and direct infection fromanother site of infection. Once invasion is achieved, it mustsubvert the local host defense system to survive and repro-duce. This local host defense mechanism invokes a moresystemic response. These defensive responses are intendedto clear the infection but their effect is often deleterious tothe nervous system itself, because many signs and symp-toms are often a consequence of inflammatory responses.Because all filariae reproduce sexually, and larvae requirepassage through the intermediate host, or vector, anyincrease in adult worm burden necessarily implies re-exposure to infective third-stage larvae.

From the public health point of view, these filarialinfections are very important. This review focuses oninfections caused by five major filariae, namely, dracun-culiasis, lymphatic filariasis, onchocerciasis, lymphaticfilariasis, and M. perstans.

DRACUNCULIASIS

Dracunculiasis is a nematode infection caused by Dra-cunculus medinensis. It has been known since biblicaltimes, and was reported in the Bible in relation to theIsraelites on their journey back from Egypt. Extensivecontrol programs have led to its optimal control anderadication from many previously endemic countries.In 2009, 1929 cases were reported worldwide as com-pared to 10074 cases in 2006 (WHO, 2009). Currentlyit is observed mostly in two regions of Southern Sudan,which host about 60% of all reported cases (Greenaway,2004). Despite its near eradication, little is known aboutits pathogenic mechanisms and manifestations outsidethe more common locations. About 90% of these wormsoccupy the deep connective and subcutaneous tissues ofthe skin (of the lower limbs in 90% of cases); however,the worms can be located almost anywhere in thebody including the central nervous system (CNS).

Manifestations in the lower extremities are frequentlyreported for the simple reason that this is the body areawhich more often is in contact with infected waterbasins, which are the major source of infection. How-ever, it can be expected that those individuals who carrywater or basins of wet bricks or sand on their head mayhave greater chances of acquiring manifestationsaround the head region. CNS manifestations are rarelyreported. A few old reports show infrequent paraplegiadue to extradural abscess caused by guinea-worms(Mitra and Haddock, 1970). These worms cause a localcompression that usually forms an abscess. No directinstances of epilepsy or seizures are known in these casesalthough secondary bacterial infections (abscess, celluli-tis, or ulceration), systemic sepsis, or tetanus may indi-rectly lead to neurological manifestations or these mayalso result from the “metastatic seeding” which is com-mon with bacterial infections. Generally male wormsrarely calcify but immature female worms may getencysted and calcify after dying or rupture and may con-sequently get lodged in the CNS, although no attempts toprove or disprove this fact were found in the literature.The chances of having neurological manifestations mayalso depend upon the frequency and “heaviness” of infec-tion over a lifetime, for instance a person can have dra-cunculiasis several times during the course of their life(Greenaway, 2004). The possibility for neurological man-ifestations may also occur as a result of immunosuppres-sive substances such as morphine produced by theseworms (Zhu et al., 2002). Immunosuppressive agentscan cause subtle seizures (Bertran et al., 2000) whichmay become frequent or more obvious with frequent or“heavy” infection. No instances of other neurological dis-orders in relation to this infection are found in the litera-ture. Lastly, in this case, immunological pathways aremore likely for neurological manifestations rather thandevelopment of mechanical epileptogenic lesions.

ONCHOCERCIASIS

Onchocerciasis, also known as river blindness or filarialblindness, is caused by the filarial nematodeO. volvulus.

Onchocercavolvulus

Prevalence ofinfection

20 to 30 (1)10 to 20 (6)5 to 10 (4)0 to 5 (23)

Fig. 18.1. Distribution of onchocerciasis.

Fig. 18.2. Subcutaneous nodule due to onchocerciasis.

NEUROLOGICAL MANIFESTATIONS OF FILARIAL INFECTIONS 237

Currently, it is one of the most common and debilitatingfilarial infections in humans with at least 87 million per-sons at risk (Amazigo et al., 2006) and about 18 millionof them are currently infected (Fig. 18.1). Subcutaneousnodules are often present (Fig. 18.2). In about 99% ofcases, the focus of infection is in sub-Saharan Africaand some pockets of Yemen, and South and CentralAmerica particularly Mexico, Guatemala, Venezuelaand Colombia (Amazigo et al., 2006). Ocular manifesta-tions are far more frequent (Hoerauf et al., 2003). Neu-rological manifestations are observed althoughconflicting reports also exist. Old data shows the pres-ence of microfilariae in the CSF of “heavily infected”onchocerciasis patients causing severe vertigo (Dukeet al., 1976). Onchocerca-related spinal compressionand axonopathy in horses were reported (Hestviket al., 2006). A relationship between onchocerciasisand syphilis in the Sudan was also reported (Haussyet al., 1957). Reports of associated epilepsy have beenaround for some time (Jilek-Aall, 2004) but have onlyjust started to be appreciated (Table 18.2). Reportsshowed conflicting results in the relationship between

onchocerciasis and epilepsy in West, Central and EastAfrica (Kabore et al., 1996; Pion et al., 2009), and LatinAmerica (Jilek-Aall, 2004) as well as the role of oncho-cerciasis in epileptogenesis (Winkler et al., 2008). Headnodding syndrome and the presence of mechanicalepileptogenic lesions such as calcification are reportedto be linked with onchocerciasis (Van der Walls et al.,1983). Studies indicated a low frequency of neurocysti-cercosis, which could have been a confounding etiology,in epilepsy cases in onchocerciasis-endemic areas(Newell et al., 1997). Studies also showed the role ofonchocerciasis in impaired psychological functioning(Ovuga et al., 1992).

The presence of microfilariae in brain tissues is likelysince some studies show a decline in seizure frequencywith ivermectin, which may in turn indicate that seizureimprovement after ivermectin is due to elimination ofmicrofilariae from brain tissues (Kipp et al., 1992).Another study showed that microfilaria load and thechance of neurological involvement increased with treat-ment with diethylcarbamazine citrate in onchocerciasispatients (Duke et al., 1976). This may be corroboratedby a study that showed high mortality in patients withonchocerciasis-associated epilepsy despite regular anti-epilepsy treatment (Kaiser et al., 2007). Risk of havingneurological manifestations may in fact depend uponthe severity of infection or presence of large numbersof microfilariae (Kaiser et al., 2011). Adult wormsremain in subcutaneous nodules, limiting access to thehost’s immune system, while microfilariae are able ofinducing intense inflammatory responses, especiallyupon their death. Some studies suggest that absent orfunctional deficiency of P-glycoprotein may result inreduced extracellular efflux and enhanced neurotoxicity(Edwards, 2003) and may thus lead to neurological man-ifestations. Also, dying microfilariae releaseWolbachiasurface protein that activates TLR2 and TLR4 (Baldoet al., 2010), which play different roles in acute cerebral

Table 18.2

Relation between onchocerciasis and epilepsy

Study No. of subjects

Epilepsy

onchocerciasisþ

Prevalence (%)Onchoþepilepsy

Nonepilepsy

Onchoþ

Prevalence (%)OnchoþNonepilepsy

Uganda 231 112 74.7 72 88.9

Uganda 985 32 82.1 364 38.5Benin 530 9 69.2 242 46.8Tanzania 414 30 88.2 259 68.2Burkina Faso 2040 4 14.3 275 13.7

Burundi 192 90 81.8 56 68.3Central AfricanRepublic

561 74 39.6 134 35.8

Mali 196 15 22.4 28 21.7Cameroon 144 71 98.6 68 94.4

Oncho: onchocerciasis; þ: positive.

238 D. BHALLA ET AL.

ischemic/reperfusion injuries. TLR4 contributes to cere-bral ischemic/reperfusion injury while TLR2 appears tobe neuroprotective by enhancing the activation ofprotective signaling in response to cerebral ischemic/reperfusion (Hua et al., 2009). Thus an imbalance inTLR2 and TLR4 functionalitymay lead to cerebral ische-mic manifestations. Studies show that TLR2 and TLR4are upregulated in response to ischemia; thus they playimportant roles in ischemic tissue injury (Dybdahlet al., 2002; Kim et al., 2005) and pathogenesis of stroke(Okun et al., 2011).

LOA LOA

The infection, also known as tropical eye worm infec-tion, is caused by the filarial parasite called Loa loaand is mainly confined to parts of West and CentralAfrica, particularly rainforest areas of low socioeco-nomic status and in some savannah regions (Padgettand Jacobsen, 2008) where 30 million people are at risk.In some regions it is the second or third most commonreason for medical consultation after malaria and pul-monary diseases (Pinder, 1988). Clinical signs that aremore frequent include subcutaneous swellings on theextremities, localized pain, pruritus, and urticaria.Microfilaremia tends to be asymptomatic; however,invasion of CNS and coma in individuals with a high levelof micro-filaremia who receive anti-filarial therapy hasbeen reported (Gardon et al., 1997). Presence ofmicrofilar-iae in CNS has been reported (Ducorps, 1955) and antifilar-ial drugs can provoke the passage of Loa loamicrofilariaeinto CSF (Ducorps, 1955). Efforts describing direct CNSinvolvement due to this infection are limited. Few reportssuggest direct CNS involvement such as meningoencepha-litis (Taiwo and Tamiowo, 2007) and encephalitis (Van

Bogaert et al., 1955) from Loa loa infection. Such casesare reported to have higher mortality when CNS is directlyinvolved. Loa loa infection when left untreated may pro-gress to causeunconsciouness and/or coma in suchpatients(Bonnet, 1943; Negesse et al., 1985) or those without prob-lems of consciousness such as headaches, asthenia, somno-lence, motor deficits, troubles of sensation, and cerebellar,vestibular, or psychiatric disorders (Dumas and Girard,1978). Thus invasionof brain tissues byLoa loa is likely alsoa coinfectionwith a female fourth stage larva ofMeningo-nema peruzzii in the CSF of Loa loa patients, but withoutany neurological signs (Boussinesq et al., 1995). Neurolog-icalmanifestationsmay also develop as a result of coinfec-tion with Plasmodium falciparum or other parasites thatsometimesmanifest as encephalopathic illnesses and couldincrease susceptibility to develop Loa loa encephalopathyfollowing ivermectin treatment. Some cases of peripheralneuropathy which disappeared after treatment with alben-dazole and ivermectin are also seen (Gobbi et al., 2011).

There has also been a lot of focus on indirect neuro-logical manifestations that have been reported (Twum-Danso, 2003) especially affecting those harboring Loaloa microfilaremia> 30000 microfilariae/per mL ofblood (Gardon et al., 1997). Co-endemicity with oncho-cerciasis is common and is particularly observed inAngola, Cameroon, and DRC thus represent the highestrisk areas for serious adverse events during mass drugadministration with ivermectin (Boussinesq, 2006).The mechanisms associated with the neurologicaladverse events are poorly understood but these neuro-logical manifestations are often associated with retinalhemorrhage and exudates evocative of an obstructiveprocess (Kivits, 1952). In autopsy reports of post-ivermectin Loa loa encephalopathy, presence of co-conditions is more likely to weaken the blood–brain

IO

barrier (BBB) resulting in encephalopathies. Such condi-tions include trypanosomiasis (Bonnet, 1943; Negesseet al., 1985), syphilis (Bonnet, 1943; Negesse et al.,1985), acute encephalitis (Kivits, 1952), or Plasmodiuminfection (Lukiana et al., 2006). Loa loa infection mayalso lead to changes in the walls of cerebral vessels caus-ing obstruction of microcirculation–thickening of thebasement membrane, disruption of the integrity of thevessel wall, etc. – that may bring changes at the blood–brain level and facilitate development of neuropatholog-ical conditions. Also, reports demonstrate microfilarialpresence in brain tissue post-ivermectin treatment(Kamgno et al., 2008).

NEUROLOGICAL MANIFESTAT

LYMPHATIC FILARIASIS

About 120 million are infected with lymphatic filariasis(LF) and about 40 million people have clinical disease,making it the second largest cause of permanent andlong-term disability worldwide (Gyapong et al., 2005).Huge economic losses are evident in many African(Baker et al., 2007) and Asian countries (Ramaiahet al., 2000). As an example economic losses per yearin India are estimated to be nearly 1 bn US $ (Ramaiahet al., 2000). For instance, LF is prevalent in 85% ofHaiti’s communes. It is caused by W. bancrofti (>90%of cases), B. malayi, and B. timori (Fig. 18.3). Like otherhelminths, the neurological manifestations have notbeen explored systematically or in detail, although exist-ing reports suggest that microfilariae ofW. bancrofti areseen in intracranial lesions in meningioma and cerebel-lum hemangioblastoma (Agarwal et al., 1982) and tumorcyst fluid of craniopharyngioma (Aron et al., 2002).They have not been documented in CSF. Acute dissem-inated encephalomyelitis has been reported (Paliwalet al., 2012). Microfilariae of W. bancrofti have alsobeen demonstrated in cyst fluid of astrocytomas andcraniopharyngioma (Aron et al., 2002) and bone

Fig. 18.3. Microfilariae ofW. bancrofti in thick blood smears stain

Health Laboratory and Centers for Disease Control and Preventio

marrow aspirates (Pradhan et al., 1976). The presenceof W. bancrofti microfilariae in the brain has also beenshown (Rowlands, 1956). A study on African epilepsydid not find any cases resulting fromW. bancrofti infec-tion but reported cases due to M. perstans, O. volvulus,and Loa loa; however, a case of epileptic seizure associ-ated with multiple filariasis is known (Adamolekunet al., 1993). Cerebromeningeal complications due toW. bancrofti has also been observed in the Far East(Carayon et al., 1954).

Diversity in immune response presumably may leadtomyriad clinical presentations, such as overt chronic fil-ariasis, occult filariasis with atypical systemic manifes-tations, and asymptomatic microfilariae carrier state.Anticipated oxidative stress during inflammatoryresponse to infective conditions might complicate theimmune response and thus might alter the disease out-come (Pal et al., 2006). Coinfection with other parasitesand infectious diseases is a common occurrence inhuman filariasis, and the suppressive immunomodula-torymechanisms induced by filaria canmodulate protec-tive immune responses for malaria and tuberculosis(Babu et al., 2009). Neurological manifestations suchas seizures (Bachli et al., 2004), precipitated by toxocar-iasis and onchocerciasis, may also result from cerebraldamage from tropical eosinophilia, a distinct immuno-logical reaction to W. bancrofti or B. malayi (Ottesenand Nutman, 1992) that develops in< 0.5% of thesepatients. The relationship with the nature of local soilcan also be important (Price, 1974). Coinfection withmalaria has been known for a long time. A studyshowed significantly higher numbers of W. bancroftiin Plasmodium-infected Anopheles mosquitoes com-pared with uninfected ones (Bockarie et al., 2002) andhad a higher mortality among those carrying both infec-tions. From these studies, it was evident that the mostprevalent malaria parasite in an area was the one thatco-occurred more often with W. bancrofti suggesting

NS OF FILARIAL INFECTIONS 239

ed with Giemsa. (Images courtesy of the Oregon State Public

n.)

LA ET AL.

that filarial parasites may enhance malaria infectionsand result in neurological manifestations. In humans,studies in India show a prevalence of 1% of coinfectionof malaria and filariasis (Ghosh and Yadav, 1995).

MANSONELLA PERSTANS

Mansonella perstans is a vector-borne human filarialnematode, transmitted by tiny blood-sucking flies calledmidges (Al-Mously, 1998) and is widespread in manyparts of sub-Saharan Africa, parts of Central and SouthAmerica, and the Caribbean (Al-Mously, 1998). Com-pared to other filarial manifestations, this infection isrelatively mild. Neurological manifestations have notbeen reported except headache without any change inconsciousness (Al-Mously, 1998); a high degree of trop-ical eosinophilia is also reported to be common andmay contribute to cerebral damage and may indicate adistinct immunological reaction as in W. bancrofti orB. malayi (Ottesen and Nutman, 1992). Coinfection withother filarial infections may also be a factor for develop-ing neurological manifestations (Keiser et al., 2003).

CONCLUSIONS

There is insufficient data with no systematic evaluationof the association of neurological manifestations withdifferent filarial infections. However, these manifesta-tions are increasingly recognized, especially in casesof onchocerciasis or in the presence of other infectionssuch as malaria. Neurological symptoms should raise thequestion of filarial infection in countries where theseinfections are endemic. These infections should no lon-ger be considered a disease of the more commonlyaffected areas, but one that may produce systemiceffects or other manifestations.

REFERENCES

Adamolekun B, Akinsola AA, Onayemi O (1993). Seizures

associated with filariasis. Cent Afr J Med 39: 264–265.Agarwal PK, Srivastava AN, Agarwal N (1982). Microfilariae

in association with neoplasms. Report of six cases. Acta

Cytol 26: 488–490.Al-MouslyN (1998).Microfilaria. [Online].Available at: http://

www.ncbi.nlm.nih.gov/pubmed/9524864. (Accessed 25

June 2011).

Amazigo U, NomaM, Bump J et al. (2006). Onchocerciasis. In:

DT Jamison, RG Feachem, MW Makgoba, ER Bos,

FK Baingana, KJ Hofman, KO Rogo (Eds.), Disease and

Mortality in Sub-Saharan Africa. 2nd edn. Washington

(DC): World Bank.

Aron M, Kapila K, Sarkar C et al. (2002). Microfilariae of

Wuchereria bancrofti in cyst fluid of tumors of the brain:

a report of three cases. Diagn Cytopathol 26: 158–162.

BabuS, Bhat SQ,KumarNP et al. (2009).Human type 1 and 17

responses in latent tuberculosis aremodulatedbycoincident

240 D. BHAL

filarial infection through cytotoxic T lymphocyte antigen-4

and programmed death-1. J Infect Dis 200: 288–298.Bachli H, Minet JC, Gratzl O (2004). Cerebral toxocariasis: a

possible cause of epileptic seizure in children. Childs Nerv

Syst 20: 468–472.Bada JL, Fernandez-Nogues F, Cerda E et al. (1976).

Neurological manifestations in a patient with filariasis.

Br Med J 2: 978–979.Baird JB, Charles JL, Streit TG et al. (2002). Reactivity to

bacterial, fungal, and parasite antigens in patients with

lymphedema and elephantiasis. Am J Trop Med Hyg 66:163–169.

Baker MC, McFarland DA, Gonzales M et al. (2007). The

impact of integrating the elimination programme for lym-

phatic filariasis into primary health care in the Dominican

Republic. Int J Health Plann Manage 22: 337–352.Baldo L, Desjardins CA, Russell JA et al. (2010). Accelerated

microevolution in an outer membrane protein (OMP) of the

intracellular bacteria Wolbachia. BMC Evol Biol 10: 48.Bertran F, Denise P, Letellier P (2000). Nonconvulsive status

epilepticus: the role of morphine and its antagonist.

Neurophysiol Clin 30: 109–112.Bockarie MJ, Tavul L, Kastens W et al. (2002). Impact of

untreated bednets on prevalence of Wuchereria bancroftitransmitted by Anopheles farauti in Papua New Guinea.

Med Vet Entomol 16: 116–119.Bonnet M (1943). Reflexions sur un cas de meningite aigue a

Microfilaria loa. Medecine Tropicale 3: 273–277.Boussinesq M (2006). Loiasis. Ann Trop Med Parasitol 100:

715–731.

Boussinesq M, Bain O, Chabaud AG et al. (1995). A new zoo-

nosis of the cerebrospinal fluid of man probably caused by

Meningonema peruzzii, a filaria of the central nervous

system of Cercopithecidae. Parasite 2: 173–176.CarayonA,SankaleM,WillmAetal. (1954).Cerebro-meningeal

complicationsof filariasis; a case due toWuchereria bancroftiin the Far East. Med Trop (Mars) 14: 678–688.

Deodhar LP, Deshpande CK, Anand RK et al. (1971). Acute

microfilarial encephalopathy: a case report. J Postgrad

Med 17: 35–36.

DucorpsM (1955). Effets secondaires du traitement de la loase

hypermicrofilaremique par l’ivermectine. Bull Soc Pathol

Exot 88: 105–112.

Duke BO, Vincelette J, Moore PJ (1976). Microfilariae in the

cerebrospinal fluid, and neurological complications, during

treatment of onchocerciasis with diethylcarbamazine.

Tropenmed Parasitol 27: 123–132.Dumas M, Girard PL (1978). Filariasis of the nervous system.

In: PJ Vinken, GW Bruyn (Eds.), Handbook of Clinical

Neurology. Infections of the Nervous System. Part III.

35. North-Holland Publishing Company Amsterdam, NewYork and Oxford, pp. 161–173.

Dybdahl B, Wahba A, Lien E et al. (2002). Inflammatory

response after open heart surgery: release of heat-shock

protein 70 and signaling through toll-like receptor-4.

Circulation 105: 685–690.

EdwardsG (2003). Ivermectin: does P-glycoprotein play a role

in neurotoxicity? Filaria J 2: S8.

NEUROLOGICAL MANIFESTATIONS OF FILARIAL INFECTIONS 241

Gardon J, Gardon-Wendel N, Demanga-Ngangue et al. (1997).

Serious reactions after mass treatment of onchocerciasis

with ivermectin in an area endemic for Loa loa infection.

Lancet 350: 18–22.Ghosh SK, Yadav RS (1995). Naturally acquired concomitant

infections of bancroftian filariasis and human plasmodia in

Orissa. Indian J Malariol 32: 32–36.

Gobbi F, Boussinesq M, Mascarello M et al. (2011). Case

report: loiasis with peripheral nerve involvement and

spleen lesions. Am J Trop Med Hyg 84: 733–737.

Greenaway C (2004). Dracunculiasis (guinea worm disease).

CMAJ 170: 495–500.Gyapong JO, Kumaraswami V, Biswas G et al. (2005).

Treatment strategies underpinning the global programme

to eliminate lymphatic filariasis. Expert Opin

Pharmacother 6: 179–200.Haussy RD, Pfister R, Rit JM et al. (1957). Relation of onch-

oceriasis and syphilis in Sudan. Bull Soc Pathol Exot

Filiales 50: 314–321.Hestvik G, Ekman S, Lindberg R (2006). Onchocercosis of an

intervertebral joint capsule causing cervical vertebral ste-

noticmyelopathy in a horse. J Vet Diagn Invest 18: 307–310.Hoerauf A, Buttner DW,Adjei O et al. (2003). Onchocerciasis.

BMJ 326: 207–210.Hua F,Ma J, HAT et al. (2009). Differential roles of TLR2 and

TLR4 in acute focal cerebral ischemia/reperfusion injury in

mice. Brain Res 1262: 100–108.

Jilek-Aall L (2004). Epilepsy and onchocerciasis: pionnering

work of Mexican researcher vindicated. Investigacion en

Salud 6: 22–27.

Kabore JK, Cabore JW, Melaku Z et al. (1996). Epilepsy

in a focus of onchocerciasis in Burkina Faso. Lancet

347: 836.

Kaiser C, Asaba G, Kasoro S et al. (2007). Mortality from epi-

lepsy in an onchocerciasis-endemic area in West Uganda.

Trans R Soc Trop Med Hyg 101: 48–55.

Kaiser C, Rubaale T, Tukesiga E et al. (2011). Association

between onchocerciasis and epilepsy in the itwara hyperen-

demic focus, west Uganda: controlling for time and inten-

sity of exposure. Am J Trop Med Hyg 85: 225–228.

Kamgno J, Boussinesq M, Labrousse F et al. (2008).

Encephalopathy after ivermectin treatment in a patient

infected with Loa loa and Plasmodium spp. Am J Trop

Med Hyg 78: 546–551.Keiser PB, Coulibaly YI, Keita F et al. (2003). Clinical

characteristics of post-treatment reactions to ivermectin/

albendazole for Wuchereria bancrofti in a region co-

endemic for Mansonella perstans. Am J Trop Med Hyg

69: 331–335.Kenney M, Hewitt R (1950). Psychoneurotic disturbances in

filariasis, and their relief by removal of adult worms or

treatment with hetrazan. Am J Trop Med Hyg 30: 895–899.Kim BS, Lim SW, Li C et al. (2005). Ischemia-reperfusion

injury activates innate immunity in rat kidneys.

Transplantation 79: 1370–1377.King CL (2001). Transmission intensity and human immune

responses to lymphatic filariasis. Parasite Immunol 23:363–371.

Kipp W, Burnham G, Kamugisha J (1992). Improvement in

seizures after ivermectin. Lancet 340: 789–790.Kivits M (1952). Quatre cas d’encephalite mortelle avec inva-

sion du liquide cephalo-rachidien par Microfilaria loa. Ann

Soc Belg Med Trop 32: 235–242.Lukiana T, Mandina M, Situakibanza NH et al. (2006). A pos-

sible case of spontaneous Loa loa encephalopathy associ-

ated with a glomerulopathy. Filaria J 5: 6.Mitra AK, Haddock DR (1970). Paraplegia due to guinea-

worm infection. Trans R Soc Trop Med Hyg 64: 102–106.

Negesse Y, Lanoie LO, Neafie RC et al. (1985). Loiasis:

“Calabar” swellings and involvement of deep organs.

Am J Trop Med Hyg 34: 537–546.Newell ED, Vyungimana F, Bradley JE (1997). Epilepsy,

retarded growth and onchocerciasis, in two areas of differ-

ent endemicity of onchocerciasis in Burundi. Trans R Soc

Trop Med Hyg 91: 525–527.

Okun E, Griffioen KJ, Mattson MP (2011). Toll-like receptor

signaling in neural plasticity and disease. Trends Neurosci

34: 269–281.

Ottesen EA, Nutman TB (1992). Tropical pulmonary eosino-

philia. Annu Rev Med 43: 417–424.Ovuga E, Kipp W, Mungherera M et al. (1992). Epilepsy and

retarded growth in a hyperendemic focus of onchocerciasis

in rural western Uganda. East Afr Med J 69: 554–556.Padgett JJ, Jacobsen KH (2008). Loiasis: African eye worm.

Trans R Soc Trop Med Hyg 102: 983–989.

Pal BK, Kulkarni S, Bhandari Y et al. (2006). Lymphatic fil-

ariasis: possible pathophysiological nexus with oxidative

stress. Trans R Soc Trop Med Hyg 100: 650–655.

Paliwal VK,Goel G, VemaR et al. (2012). Acute disseminated

encephalomyelitis following filarial infection. J Neurol

Neurosurg Psychiatry 83: 347–349.

Pinder M (1988). Loa loa: a neglected filaria. Parasitol Today4: 279–284.

Pion SD, Kaiser C, Boutros-Toni F et al. (2009). Epilepsy in

onchocerciasis endemic areas: systematic review and

meta-analysis of population-based surveys. PLoS Negl

Trop Dis 3: e461.Poppert S, Hodapp M, Krueger A et al. (2009). Dirofilaria

repens infection and concomitant meningoencephalitis.

Emerg Infect Dis 15: 1844–1846.Pradhan S, Lahiri VL, Elhence BR et al. (1976).Microfilaria of

Wuchereria bancrofti in bone marrow smear. Am J Trop

Med Hyg 25: 199–200.Price EW (1974). The relationship between endemic elephan-

tiasis of the lower legs and the local soils and climate. Trop

Geogr Med 26: 225–230.Ramaiah KD, Das PK, Michael E et al. (2000). The economic

burden of lymphatic filariasis in India. Parasitol Today 16:

251–253.Rowlands A (1956). The distribution of microfilariae of

Wuchereria bancrofti in human organs. Trans R Soc

Trop Med Hyg 50: 563–564.Taiwo SS, TamiowoMO (2007). Loa loameningoencephalitis

in Southwestern Nigeria. West Afr J Med 26: 156–159.

Twum-Danso NA (2003). Loa loa encephalopathy temporally

related to ivermectin administration reported from

242 D. BHALLA ET AL.

onchocerciasis mass treatment programs from 1989 to

2001: implications for the future. Filaria J 2: S7.Van Bogaert L, Dubois A, Janssens PG et al. (1955).

Encephalitis in loa-loa filariasis. J Neurol Neurosurg

Psychiatry 18: 103–119.Van DerWalls FW, Goudsmit J, Gajdusek DC (1983). See-ee:

clinical characteristics of highly prevalent seizure disorders

in the Gbawein and Wroughbarh clan region of Grand

Bassa County, Liberia. Neuroepidemiology 2: 35–44.

WHO (2009). Monthly report on dracunculiasis cases,

January–July 2009. Wkly Epidemiol Rec 84: 371–372.Winkler AS, Friedrich K, Konig R et al. (2008). The head nod-

ding syndrome: clinical classification and possible causes.

Epilepsia 49: 2008–2015.Zhu W, Baggerman G, Secor WE et al. (2002). Dracunculus

medinensis and Schistosoma mansoni contain opiate alka-

loids. Ann Trop Med Parasitol 96: 309–316.