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Neurologic manifestations of the neglected tropical diseases

  • Aaron L. Berkowitz
    Affiliations
    Brigham and Women's Hospital, Department of Neurology, Boston, MA, United States

    Harvard Medical School, Boston, MA, United States
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  • Pooja Raibagkar
    Affiliations
    Brigham and Women's Hospital, Department of Neurology, Boston, MA, United States

    Harvard Medical School, Boston, MA, United States

    Massachusetts General Hospital, Department of Neurology, Boston, MA, United States
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  • Bobbi S. Pritt
    Affiliations
    Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN, United States
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  • Farrah J. Mateen
    Correspondence
    Corresponding author at: Department of Neurology, 165 Cambridge Street, #627, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States. Tel.: +1 410 935 5181.
    Affiliations
    Harvard Medical School, Boston, MA, United States

    Massachusetts General Hospital, Department of Neurology, Boston, MA, United States
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Published:January 08, 2015DOI:https://doi.org/10.1016/j.jns.2015.01.001

      Highlights

      • We review the neurologic manifestations of the seventeen neglected tropical diseases (NTDs).
      • The NTDs have been reported to affect every level of the neuraxis.
      • NTDs may cause nervous system involvement through a variety of pathogenic mechanisms.
      • For most NTDs, only limited data is available on treatment of neurologic manifestations.

      Abstract

      Background

      The World Health Organization has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations. The neurologic aspects of many of these NTDs have received relatively little attention.

      Methods

      A review was performed in PubMed (MedLine) for each NTD by disease name, name of its causative organism, and neurology, neurosurgery, neurologist, brain, spinal cord, peripheral nerve, muscle, nervous system, encephalitis, meningitis, encephalopathy, stroke, neuropathy, and myopathy (1968-Sept. 2013). The Oxford Center for Evidence-based Medicine guidelines were used to determine the level of evidence of neurological involvement and treatment based on the reports identified.

      Results

      Neurologic manifestations were reported for all NTDs except yaws. Neurologic involvement was described in systematic reviews for four NTDs (Chagas disease, echinococcosis, rabies, cysticercosis) (levels 2a–3a), retrospective cohort studies for six (dengue, human African trypanosomiasis, leishmaniasis, leprosy, onchocerciasis, schistosomiasis) (levels 2b–3b), case series for one (foodborne trematodiasis) (level 4), and case reports for five (Buruli ulcer, dracunculiasis, filariasis, soil-transmitted helminthes, and trachoma). Level 1 evidence for treatment of neurologic manifestations of NTDs was found for human African trypanosomiasis, leprosy, and cysticercosis and level 2 evidence exists for treatment of neurologic involvement in Chagas disease. For the remaining NTDs, treatment of neurologic complications is described in case series and case reports only.

      Conclusions

      Neurologic manifestations of NTDs cause significant morbidity and mortality, although limited evidence exists on how best to treat these neurologic complications. Increased awareness of neurologic manifestations of the NTDs can increase their early identification and treatment, contributing to ongoing elimination and eradication campaigns.

      Keywords

      1. Introduction

      “Of the world's poorest 2.7 billion people (defined as those who live on less than US$ 2.00 a day), more than 1 billion are affected by one or more neglected tropical diseases. These diseases not only survive and spread in conditions of poverty, they also exacerbate and perpetuate the poverty of affected communities.” [
      • World Health Organization
      Working to overcome the impact of neglected tropical diseases.
      ]
      The World Health Organization (WHO) has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations (Table 1) [
      • World Health Organization
      Working to overcome the impact of neglected tropical diseases.
      ]. The NTDs cause significant disfigurement, morbidity, and mortality, accounting for 1% of the global burden of disability adjusted-life years (DALYs) lost in 2010 [
      • Murray C.J.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990—2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ], though this is likely to be an underestimate [
      • Hotez P.J.
      • Alvarado M.
      • Basanez M.
      • Bolliger I.
      • Bourne R.
      • Boussinesq M.
      • et al.
      The Global Burden of Disease Study 2010: Interpretation and Implications for the Neglected Tropical Diseases.
      ]. Notably, the NTDs can be controlled – and, in some cases, eliminated or eradicated – through low-cost, strategic interventions [
      • World Health Organization
      Working to overcome the impact of neglected tropical diseases.
      ]. Several international organizations advocate for the effective prevention and treatment of these illnesses, the impact of which has been deemed neglected compared to diseases such as HIV/AIDS, tuberculosis, and malaria [
      • World Health Organization
      Working to overcome the impact of neglected tropical diseases.
      ]. In 2011, the London Declaration affirmed the commitment of more than twenty stakeholders, including Ministries of Health, pharmaceutical companies, United Nations agencies, and non-governmental organizations, with the goal to eliminate or eradicate ten NTDs by 2020 [].
      Table 1Background characteristics of the neglected tropical diseases.
      NTDEstimated global prevalenceEndemic regionsCausative organismVector/intermediate hostMode of transmissionNon-neurologic manifestationsTreatmentControl, elimination, eradication, and prevention strategies
      Chagas disease7–8 millionLatin AmericaTrypanosoma cruziTriatomine bugInsect biteAcute phase: Skin lesions, lymphadenopathy, fevers

      Chronic phase: Organomegaly, cardiomyopathy
      Benznidazole and nifurtimoxVector control, house improvement, bed nets, food hygiene
      Human African trypanosomiasis30,000AfricaTrypanosoma brucei and brucei gambienseTsetse flyInsect biteFever, weakness, arthralgias, psychiatric symptomsPentamidine, suramin, melarsoprol and eflornithineEradication efforts target tsetse fly via traps, insecticide spraying
      Leishmaniasis1.3 millionAfrica, Middle East, Central and South Asia, South Europe, South AmericaLeishmania speciesSandflyInsect biteSkin ulcer, fever, weight loss, enlargement of the spleen and liver, anemia, leukopenia, thrombocytopenia.Pentavalent antimonials, liposomal amphotericin B, miltefosine, paromomycinElimination through vector management
      Taeniasis/Cysticercosis50 millionAfrica, Asia, Latin AmericaTaenia soliumPigs, humansUndercooked pork, contaminated soil/water/food, fecal-oralNo significant non-neurologic manifestationsPraziquantel, steroids, anti-epilepticsControl through improved pig husbandry
      Dracunculiasis148Chad, Ethiopia, Mali and South SudanDracunculus medinensis (guinea worm)Cyclops water fleaContaminated drinking waterPainful blister/ulcer, edema, fever, nausea/vomitingRemoval of worm by windingEradication through water treatment
      Echinococcosis1 millionEG: Regions of China, Russian Federation, continental Europe, North America

      EM: Central Europe, Russia, Turkey, Japan, China, Eastern France, North America
      Echinococcus granulosus (EG), Echinococcus multilocularis (EM)EG: Sheep, goats, cattle, pigs, yaks or other farm animals

      EM: Small mammals (rodents and lagomorphs)
      Ingestion of contaminated soil, water or food Contact with infected animalsAbdominal pain, nausea/vomiting, chronic cough, chest pain, and/or dyspneaSurgical or percutaneous intervention and albendazolePrevention and control through deworming of dogs, improved slaughterhouse hygiene, vaccination of livestock
      Foodborne trematodiasis:
       Clonorchiasis15,313,219
      • Reddy C.R.R.M.
      • Valli V.V.
      Extradural guinea worm abscess: report of two cases.
      China, Korea, Russia, VietnamClonorchis sinensisFreshwater snails, freshwater fish, fish-eating carnivoresRaw, undercooked freshwater fishCholangitis, cholecystitis, hepatitis, pancreatitis, cholangiocarcinomaPraziquantelControl and prevention through MDA
       Opisthorchiasis8,398,230
      • Reddy C.R.R.M.
      • Valli V.V.
      Extradural guinea worm abscess: report of two cases.
      Eastern Europe, Central and southeast AsiaOpisthorchis viverrini and felineusFreshwater snails, freshwater fish, fish-eating carnivoresRaw, undercooked freshwater fishCholangitis, cholecystitis, hepatitis, pancreatitis, cholangiocarcinomaPraziquantelControl and prevention through MDA
       Fascioliasis2,646,515
      • Reddy C.R.R.M.
      • Valli V.V.
      Extradural guinea worm abscess: report of two cases.
      South America, China, North Africa, Middle East, Western Europe, OceaniaFasciola hepatica and giganticaFreshwater snails, herbivoresAquatic plants (e.g., watercress)Cholangitis, pancreatitis, gall stonesTriclabendazoleControl and prevention through MDA
       Paragonimiasis23,155,105
      • Reddy C.R.R.M.
      • Valli V.V.
      Extradural guinea worm abscess: report of two cases.
      East and Southeast Asia, West and Central Africa, Central and South AmericaPagaronia westermani, heterotremus, philippinensi, Africanus, Uterobilateral, caliensis, kellicotti, and mexicanusFreshwater snails, crustacean-eating mammalsRaw, undercooked freshwater crustaceansCough, dyspnea, fever, bloody sputumTriclabendazole or PraziquantelControl and prevention through MDA
      Lymphatic filariasis120 millionSouth-east Asia and AfricaWuchereria bancrofti, Brugia malayi and Brugia timori.Mosquitos (Culex, Anopheles, Aedes, Mansoni)Mosquito biteLymphedema (elephantiasis), hydrocele, genital edemaDiethylcarbamazine citrate (DEC) or albendazole and ivermectinElimination by MDA
      Onchocerciasis26 millionAfrica, Yemen, Central/South AmericaOnchocerca volvulusBlackfly (Similium)Insect biteSkin lesions, blindnessIvermectinElimination by vector control via insecticides and MDA
      Schistosomiasis240 millionSub Saharan Africa, Latin America and AsiaSchistosoma japonicum, mansoni, and haematobiumFresh water snailContaminated fresh water with larval forms (cercaria)Hematuria, urogenital disease, abdominal pain, diarrhea, ascitesPraziquantelPrevention and control through MDA
      Soil transmitted helminthiasis1.5 billionCentral/South America, Africa, South/Southeast AsiaAscaris lumbricoides (roundworm), Trichuris trichiura (whipworm), Necator americanus and Ancylostoma duodenale (hookworms)(humans)Contaminated vegetable, water, soil; skin penetrationDiarrhea, malnutrition, intestinal obstruction, rectal prolapseAlbendazole mebendazole or levamisoleControl through MDA
      Dengue50–100 millionAfrica, Americas, Eastern Mediterranean, South-east Asia, Western PacificDengue virus (Flavivirus)Aedes aegyptiMosquito biteFever, myalgias, arthralgias, and rashSupportive careVector control
      Rabies60,000All continents (except Antarctica)Rabies virus (Lyssavirus)Wild carnivoresAnimal bites or scratchesNo significant non-neurologic manifestationsNo effective therapy; post-exposure prophylaxisElimination by vaccination of dogs
      Buruli ulcer5000Sub-Saharan Africa, Americas, Asia, Western PacificMycobacterium ulceransAquatic insects, adult mosquitoes, arthropodsExact mode of transmission unknownPainless necrotizing skin ulcerationRifampicin and streptomycin/amikacinElimination by treatment of affected patients
      Leprosy189,018Africa, South Asia, Southeast Asia, Brazil, ChinaMycobacterium lepraeArmadilloHuman–humanSingle or multiple skin lesionsRifampicine, clofazimine and dapsoneElimination by treatment of affected individuals
      Trachoma2.2 millionAfrica, Asia, Central and South America, Australia, Middle EastChlamydia trachomatisN/AHuman–human contact; eye-seeking fliesBlindness, genital infectionTetracycline eye ointmentElimination via surgery, antibiotics, improved facial cleanliness.
      Yaws460,000 in 1995; more recent data not availableAfrica, Asia, Western Pacific, Latin AmericaTreponema pallidum, subspecies PertenueN/AHuman-human contactSkin lesionsAzithromycin or benzathine penicillinElimination by treatment of affected patients
      All data obtained from the WHO websites on the individual diseases (see references in text) except where otherwise noted. MDA: mass drug administration (to at-risk individuals in endemic regions).
      Although several NTDs have well-known neurologic manifestations (e.g. Chagas disease, leprosy, cysticercosis, dengue, and rabies), the neurologic aspects of several other NTDs have received less attention. The neurologic complications of the NTDs are especially important to recognize and understand among vulnerable populations, travelers, and emigrants from endemic regions. Here, we review the neurologic manifestations of each of the 17 NTDs recognized by the WHO.

      2. Methods

      PubMed was searched for each of the NTDs (by common name and name of the causative organism) and the search terms (free text and/or MeSH when appropriate): neurology, neurosurgery, brain, spinal cord, peripheral nerve, muscle, nervous system, neurologist, encephalitis, meningitis, encephalopathy, stroke, neuropathy, and myopathy. We also reviewed the reference lists of acquired articles to obtain sources that may not be indexed in PubMed. Articles from January 1, 1968 to September 30, 2013 in English or French were reviewed. The level of evidence was determined based on the Oxford Center for Evidence-based Medicine guidelines [
      • Oxford Centre Ifor Evidence-Based Medicine
      Levels of Evidence.
      ]. For diseases for which the neurologic manifestations have been well-described in the literature (Chagas disease, cysticercosis, schistosomiasis, rabies, leprosy), mention is made of common and less common neurologic sequelae, but the reader is referred to recent reviews in the appropriate sections below.

      3. Results

      All NTDs are reported to affect one or more levels of the neuraxis, with the exception of yaws. Neurologic complications were reported by systematic reviews for four NTDs (Chagas disease, echinococcosis, rabies, cysticercosis) (levels 2a–3a), retrospective cohort studies for six (dengue, human African trypanosomiasis, leishmaniasis, leprosy, onchocerciasis, schistosomiasis) (levels 2b–3b), case series for one (foodborne trematodiasis) (level 4), and case reports for five (Buruli ulcer, dracunculiasis, filariasis, soil-transmitted helminthes, and trachoma). These levels of evidence may reflect both the incidence and strength of association of neurologic manifestations with particular NTDs. However, lack of access to neuroimaging, molecular diagnostics, and autopsy in endemic regions of many of the NTDs limits the ability to precisely diagnose these diseases and determine their association with neurologic complications. Level 1 evidence for the treatment of neurologic complications of NTDs exists for only three NTDs (human African trypanosomiasis, leprosy, cysticercosis), and level 2 evidence for only one NTD (Chagas disease). For the remaining NTDs, treatment of neurologic manifestations is described in case reports or case series.

      4. Reported neurologic manifestations of the NTDs

      The estimated global prevalence, endemic region, causative organism, vector/intermediate host, mode of transmission, non-neurologic manifestations, treatment, and control/elimination/eradication/prevention strategies for each of the NTDs are presented in Table 1. The reported neurologic manifestations are presented in Table 2. Fig. 1, Fig. 2 present neuropathological specimens from cases of parasitic infections of the nervous system. The neurologic complications of these infections have various mechanisms including direct infection of neurons (e.g., rabies), direct infection of brain tissue with provocation of local symptoms due to mass effect and local inflammatory reaction (e.g., human African trypanosomiasis, neurocysticercosis, leishmaniasis, dracunculiasis, echinococcosis, food borne trematodiasis neuroschistosomiasis), systemic inflammatory response to the pathogen at the time of infection or the time of treatment (e.g., filariasis, soil transmitted helminthiasis), increased risk of cerebrovascular disease (e.g., Chagas disease), and immune mediated nerve damage (e.g., leprosy). Some neglected tropical diseases cause neurologic disease through more than one of these mechanisms.
      Table 2Neurologic manifestations of the neglected tropical diseases.
      NTDLevel(s) of neuraxis affectedReported neurologic manifestationsReported mortality secondary to neurologic manifestations
      CNSPNSANSStrokeSpace-occupying lesionMeningo-encephalitisMyelopathyNeuropathy
      Chagas diseasexxxxxxxx
      Human African trypanosomiasisxxxxx
      Leishmaniaxxxx
      Taeniasis/Cysticercosisxxxxx
      Dracunculiasisxxxxx
      Echinococcusxxxxx
      Foodborne trematodiasis:
       Clonorchiasisx
       Opisthorchiasis
       Fascioliasisx
       Paragonimiasisxxxx
      Lymphatic filariasisxxxxx
      Onchocerciasisx
      Schistosomiasisxxxx
      Soil transmitted helminthiasisxxx
      Denguexxxx
      Rabiesxxxxxxx
      Buruli ulcerxx
      Leprosyxxxx
      Trachomaxx
      Figure thumbnail gr1
      Fig. 1Protozoal infections: Chagas, human African trypanosomiasis and leishmaniasis. (A) Low power view of Chagas disease in the brain. The dark regions (arrows) contain clusters of T. cruzi amastigotes (H&E, 100×); (B) higher magnification from the same case as (A) shows clusters of intracellular amastigotes in the cortex (arrows) with scattered plasma cells and lymphocytes (H&E, 400×). These must be differentiated from the similarly appearing cysts and free tachyzoites of toxoplasmosis; (C) T. cruzi amastigotes in cardiac muscle demonstrate characteristic pseudocysts (arrows) containing amastigotes (H&E, 400×). The inset shows the oval amastigote with a round nucleus and bar-like kinetoplast (H&E, 1000×); (D) The motile trypomastigotes of T. cruzi may be seen in the peripheral blood (Giemsa, 1000×). They characteristically have a “C” configuration and have a large kinetoplast (arrow); (E) human African trypanosomiasis (HAT) showing a central blood vessel with perivascular lymphocytic inflammation in the temporal cortex (H&E, 100×); (F) in cases of HAT, enlarged plasma cells containing numerous proteinaceous pink droplets (Mott cells) may be seen in the perivascular infiltrate (arrow, H&E, 1000×); (G) motile trypomastigotes of T. brucei may be seen in the peripheral blood (shown) and CSF in patients with HAT (Giemsa, 1000×). They have a similar appearance to the trypomastigotes of T. cruzi, but have a smaller kinetoplast (arrow); (H) Leishmania species amastigotes may be seen in the spleen, bone marrow, brain, and other infected organs and have a similar appearance to the amastigotes of T. cruzi. Touch preps are preferred for demonstrating intracellular (arrow) and extracellular (arrow heads) amastigotes (Giemsa, 1000×).
      Figure thumbnail gr2
      Fig. 2Helminth, bacterial, and viral infections. (A) Section of an intact cysticercus containing a larva with prominent suckers (arrow, H&E, 40×); (B) higher magnification of the cysticercus in (A) demonstrates sections through the refractile hooklets (H&E, 1000×); (C) Echinococcus daughter cyst containing a single larval form (H&E, 100×, inset 400×); (D) numerous bacilli of Mycobacterium leprae seen singly and in clusters (arrows) using a modified acid fast stain (Fite-Faraco, 1000×); (E) Cortical granuloma containing numerous Paragonimus westermani eggs (arrows) within a necrotic center (H&E, 100×); (F) higher magnification of the eggs in (E) reveal the characteristic features of Paragonimus eggs including a thin shell and shouldered operculum (arrow heads); (G) rabies virus eosinophilic cytoplasmic inclusions (Negri bodies) within Purkinje cells in the cerebellum (H&E, 1000×); (H) egg of Schistosoma japonicum with a small rudimentary spine (arrow, H&E, 400×).

      4.1 Protozoa

      4.1.1 Chagas disease (Trypanosoma cruzi)

      Chagas disease is transmitted by the reduviid bug, but since wild animals are a large reservoir for T. cruzi, Chagas disease cannot be readily eradicated, although elimination efforts are ongoing [
      • Coura J.R.
      Chagas disease: control, elimination and eradication. Is it possible?.
      ]. The neurologic manifestations of Chagas disease vary depending on the phase of the illness, immune status of the patient, and the presence of cardiac involvement.
      Acute Chagas disease can present with mild symptoms including malaise, headache, myalgia, and lymphadenopathy, or more severe illness with anasarca and/or respiratory difficulty. Neurologic complications such as meningoencephalitis, tumor-like Chagoma, and neuropathy occur in up to 10% of patients in the acute phase of the disease [
      • Pittella J.E.
      Central nervous system involvement in Chagas disease: a hundred-year-old history.
      ,
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ,
      • Benavente O.R.
      • Patino O.L.
      • Pena L.B.
      • Pena L.B.
      • Lugones H.
      • Kalala E.
      • et al.
      Motor unit involvement in human acute Chagas' disease.
      ]. Children and immunocompromised individuals may be more susceptible to severe neurologic involvement in acute Chagas disease [
      • Pittella J.E.
      Central nervous system involvement in Chagas disease: a hundred-year-old history.
      ,
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ]. Congenital Chagas disease due to maternal infection is characterized by newborn meningoencephalitis, microcephaly, and brain calcifications [
      • Córdova E1.
      • Maiolo E.
      • Corti M.
      • Orduña T.
      Neurological manifestations of Chagas' disease.
      ].
      Autonomic dysfunction and organomegaly are hallmarks of chronic Chagas disease. Any of the above neurologic manifestations of acute Chagas disease, in addition to ischemic stroke, may complicate the chronic phase of the infection. Chagas disease is considered an independent risk factor for ischemic stroke, likely due to associated dilated cardiomyopathy and resultant cardiac thrombus formation, as well as endothelial dysfunction leading to atherothrombosis in cerebral vessels [
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ,
      • Paixão L.C.
      • Ribeiro A.L.
      • Valacio R.A.
      • Teixeira A.L.
      Chagas disease: independent risk factor for stroke.
      ,
      • Oliveira-Filho J1.
      • Viana L.C.
      • Vieira-de-Melo R.M.
      • Faical F.
      • Torreao J.A.
      • Villar F.A.
      • et al.
      Chagas disease is an independent risk factor for stroke: baseline characteristics of a Chagas Disease cohort.
      ]. Although Chagas-related strokes are uncommon (1–3% of cases of Chagas disease) [
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ,
      • Nunes M.C1.
      • Barbosa M.M.
      • Ribeiro A.L.
      • Barbosa F.B.
      • Rocha M.O.
      Ischemic cerebrovascular events in patients with Chagas cardiomyopathy: a prospective follow-up study.
      ,
      • Sousa A.S1.
      • Xavier S.S.
      • Freitas G.R.
      • Hasslocher-Moreno A.
      Prevention strategies of cardioembolic ischemic stroke in Chagas' disease.
      ,
      • Lima-Costa M.F1.
      • Matos D.L.
      • Ribeiro A.L.
      Chagas disease predicts 10-year stroke mortality in community-dwelling elderly: the Bambui cohort study of aging.
      ], they account for 10% of Chagas disease-related mortality, and may be the presenting manifestation of the infection in up to 40% of patients [
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ,
      • Nunes M.C1.
      • Barbosa M.M.
      • Ribeiro A.L.
      • Barbosa F.B.
      • Rocha M.O.
      Ischemic cerebrovascular events in patients with Chagas cardiomyopathy: a prospective follow-up study.
      ,
      • Sousa A.S1.
      • Xavier S.S.
      • Freitas G.R.
      • Hasslocher-Moreno A.
      Prevention strategies of cardioembolic ischemic stroke in Chagas' disease.
      ,
      • Lima-Costa M.F1.
      • Matos D.L.
      • Ribeiro A.L.
      Chagas disease predicts 10-year stroke mortality in community-dwelling elderly: the Bambui cohort study of aging.
      ]. The middle cerebral arterial territory is most commonly affected (87% of cases of Chagas-associated stroke) [
      • Carod-Artal F.J.
      Trypanosomiasis, cardiomyopathy and the risk of ischemic stroke.
      ]. Intravenous tissue plasminogen activator (IV-tPA) appears to be safe for treatment of acute stroke in Chagas disease [
      • Cougo-Pinto P.T.
      • Dos Santos B.L.
      • Dias F.A.
      • Camillo M.R.
      • Alessio-Alvez F.F.
      • Barreira C.M.
      • et al.
      Safety of IV thrombolysis in acute ischemic stroke related to Chagas disease.
      ]. The development of cognitive impairment following Chagas disease has been described in case–control and large, population-based cohort studies [
      • Oliveira-Filho J.
      • Vieira-de-Melo R.M.
      • Reis P.S.
      • Lacerda A.M.
      • Neville I.S.
      • Cincura C.
      • et al.
      Chagas disease is independently associated with brain atrophy.
      ], but a causal relationship has not been confirmed [
      • Py M.O.
      Neurologic manifestations of Chagas disease.
      ,
      • Maud A1.
      • Qureshi A.I.
      Parasympathetic nervous system dysfunction and neurological consequences of chagas disease. Mediator or bystander?.
      ].

      4.1.2 Human African trypanosomiasis (Trypanosoma brucei)

      African sleeping sickness, caused by T. brucei (T. brucei gambiense and T. brucei rhodesiense) and transmitted by the tsetse fly, is endemic in 36 sub-Saharan African countries [
      • World Health Organisation
      Trypanosomiasis, Human African (sleeping sickness).
      ]. Between 2000 and 2012, elimination efforts reduced the incidence of the disease by 73% [
      • World Health Organisation
      Trypanosomiasis, Human African (sleeping sickness).
      ]. Approximately 75% of infected patients develop “sleeping sickness,” characterized by headache (79% of patients), weakness (35%), psychiatric disturbances (25%), gait disturbance (22%), tremors (21%), other abnormal movements such as chorea (11%), and speech disturbance (14%) [
      • Blum J.
      • Schmid C.
      • Burri C.
      Clinical aspects of 2541 patients with second stage human African trypanosomiasis.
      ]. Rarer manifestations, reported by case reports and series, include myelitis, neuropathy, painful limb hyperesthesias, seizures, and visual disturbances, the latter due to optic nerve involvement [
      • Kennedy P.G.
      Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness).
      ]. The prominent neuropsychiatric manifestations are thought to be due to direct involvement of the nervous system, while the myelitis, optic neuropathy, and peripheral neuropathy are likely due to inflammation rather than direct neurologic involvement [
      • Kennedy P.G.
      Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness).
      ,
      • Kennedy P.G.
      The continuing problem of human African trypanosomiasis (sleeping sickness).
      ]. T. brucei rhodesiense often causes an acute, fulminant form of the disease compared to the more chronic course of T. brucei gambiense [
      • Haller L.
      • Adams H.
      • Merouze F.
      • Dago A.
      Clinical and pathological aspects of human African trypanosomiasis (T. b. gambiense) with particular reference to reactive arsenical encephalopathy.
      ]. A post-treatment encephalopathy accompanied by seizures has been reported in up to 10% of patients treated with arsenic-derivative melarsoprol, with up to 50% mortality [
      • Sabbah P.
      • Brosset C.
      • Imbert P.
      • Bonardel G.
      • Jeandel P.
      • Briant J.F.
      Human African trypanosomiasis: MRI.
      ], however, this complication has not been reported with modern-day therapy (nifurtimox and eflornithine).
      As early as 10 days after initial infection, cerebrospinal fluid (CSF) abnormalities such as lymphocytic pleocytosis, moderate increase in protein, and presence of CSF trypanosomal IgM antibodies may be present [
      • Kennedy P.G.
      The continuing problem of human African trypanosomiasis (sleeping sickness).
      ], and meningeal thickening may be seen on magnetic resonance imaging (MRI) in rare cases caused by T. rhodesiense [
      • Rodgers J.
      Trypanosomiasis and the brain.
      ]. Neuroimaging findings evolve from the meningitic phase to the development of multiple white matter T2 hyperintense lesions, ventriculomegaly, and eventually parenchymal atrophy that often persists, even in patients who recover clinically [
      • Sabbah P.
      • Brosset C.
      • Imbert P.
      • Bonardel G.
      • Jeandel P.
      • Briant J.F.
      Human African trypanosomiasis: MRI.
      ,
      • Rodgers J.
      Trypanosomiasis and the brain.
      ,
      • Kager P.A.
      • Schipper H.G.
      • Stam J.
      • Majoie C.B.
      Magnetic resonance imaging findings in human African trypanosomiasis: a four-year follow-up study in a patient and review of the literature.
      ,
      • Gill D.S.
      • Chatha D.S.
      • del Carpio-O'Donovan R.
      MR imaging findings in African trypansomiasis.
      ].

      4.1.3 Leishmaniasis (Leishmania species)

      Leishmaniasis is transmitted by the female sandfly, and has an estimated annual mortality of 20,000 to 40,000 across the 98 countries and 3 territories where it is endemic [
      • World Health Organization
      Sustaining the drive to overcome the global impact of neglected tropical diseases.
      ]. Leishmaniasis causes three primary distinct syndromes: cutaneous, mucocutaneous, and visceral, all of which have reported involvement of the central and peripheral nervous systems [
      • Petersen C.A.
      • Greenlee M.H.
      Neurologic Manifestations of Leishmania spp. Infection.
      ,
      • Walker M.
      • Kublin J.G.
      • Zunt J.R.
      Parasitic central nervous system infections in immunocompromised hosts: malaria, microsporidiosis, leishmaniasis, and African trypanosomiasis.
      ,
      • Pahwa R.
      • Gupta S.K.
      • Singh T.
      • Nigam S.
      Acute fulminant visceral leishmaniasis in children–a report of two cases.
      ].
      Meningitis is caused by either direct extension from sinusitis in mucocutaneous forms of leishmaniasis [
      • Walker M.
      • Kublin J.G.
      • Zunt J.R.
      Parasitic central nervous system infections in immunocompromised hosts: malaria, microsporidiosis, leishmaniasis, and African trypanosomiasis.
      ] or reticulo-endothelial spread of the disease when the liver and spleen are predominantly involved, however the parasite has only rarely been isolated from the CSF [
      • Prasad L.S.
      • Sen S.
      Migration of Leishmania donovani amastigotes in the cerebrospinal fluid.
      ].
      Cranial nerve dysfunction including optic neuropathy has been described by case report [
      • Huna-Baron R.
      • Warren F.A.
      • Miller W.
      • Jacobs J.
      • Green J.
      • Kupersmith M.J.
      Mucosal leishmaniasis presenting as sinusitis and optic neuropathy.
      ]. Sensorimotor peripheral neuropathy occurred in 46% of patients with leishmaniasis in one series [
      • Hashim F.A.
      • Ahmed A.E.
      • el Hassan M.
      • el Mubarak M.H.
      • Yagi H.
      • Ibrahim E.N.
      • et al.
      Neurologic changes in visceral leishmaniasis.
      ]. Nerve biopsy in patients with Leishmania-associated neuropathy did not reveal inflammation or direct parasitic nerve involvement [
      • Hashim F.A.
      • Ahmed A.E.
      • el Hassan M.
      • el Mubarak M.H.
      • Yagi H.
      • Ibrahim E.N.
      • et al.
      Neurologic changes in visceral leishmaniasis.
      ,
      • Diniz L.M.
      • Duani H.
      • Freitas C.R.
      • Figueiredo R.M.
      • Xavier C.C.
      Neurological involvement in visceral leishmaniasis: case report.
      ], although perineural Leishmania amastigotes and inflammation have rarely been identified in infected patients without signs or symptoms of neuropathy [
      • Kubba R.
      • el-Hassan A.M.
      • Al-Gindan Y.
      • Omer A.H.
      • Bushra M.
      • Kutty M.K.
      Peripheral nerve involvement in cutaneous leishmaniasis (Old World).
      ,
      • Elhassan A.M.
      • Ali M.S.
      • Zijlstra E.
      • Eltoum I.A.
      • Ghalib H.W.
      • Ahmed H.M.
      Post-kala-azar dermal leishmaniasis in the Sudan: peripheral neural involvement.
      ]. A predisposition to Leishmania-associated neuropathy in patients with concurrent vitamin deficiency has been debated [
      • Hashim F.A.
      • Ahmed A.E.
      • el Hassan M.
      • el Mubarak M.H.
      • Yagi H.
      • Ibrahim E.N.
      • et al.
      Neurologic changes in visceral leishmaniasis.
      ]. Development of Guillain–Barré syndrome and Wilson disease have rarely been reported to be temporally associated with visceral leishmaniasis, but causality was not established [
      • Pandey K.
      • Sinha P.K.
      • Das V.N.
      • Kumar N.
      • Verma N.
      • Bimal S.
      • et al.
      Wilson disease with visceral leishmaniasis: an extremely uncommon presentation.
      ,
      • Attarian S.
      • Serratrice J.
      • Mazodier C.
      • Disdier P.
      • Azulay J.P.
      • Pouget J.
      Guillain-Barré syndrome revealing visceral leishmaniasis in an immunocompetent woman.
      ].

      4.2 Helminths

      4.2.1 Cysticercosis (Taenia solium)

      Neurocysticercosis (NCC) may be associated with up to 7.6 million cases of epilepsy worldwide [
      • Coyle C.M.
      • Mahanty S.
      • Zunt J.R.
      • Wallin M.T.
      • Cantey P.T.
      • White A.C.
      • et al.
      Neurocysticercosis: Neglected but Not Forgotten.
      ], occurring in 29% of people with epilepsy in endemic regions [
      • Ndimubanzi P.C.
      • Carabin H.
      • Budke C.M.
      • Nguyen H.
      • Qian Y.-J.
      • Rainwater E.
      • et al.
      A Systematic Review of the Frequency of Neurocyticercosis with a Focus on People with Epilepsy.
      ]. Whereas human intestinal infection occurs through ingestion of T. solium larvae in raw or undercooked pork, neurocysticercosis is caused by ingestion of T. solium eggs through human-to-human fecal–oral transmission and therefore can occur without pork consumption [
      • Garcia H.H.
      • Del Brutto O.H.
      Neurocysticercosis: updated conepts about an old disease.
      ]. The brain and subarachnoid space are the most frequent neurologic sites of infection, leading to seizures and/or hydrocephalus as the most common clinical manifestations [
      • Garcia H.H.
      • Del Brutto O.H.
      Neurocysticercosis: updated conepts about an old disease.
      ]. Cysticercotic encephalitis, caused by a large burden of cerebral cysts, occurs more commonly in children and young women [
      • Rangel R.
      • Torres B.
      • Del Brutto O.
      • Sotelo J.
      Cysticercotic encephalitis: a severe form in young females.
      ,
      • Del Brutto O.H.
      • Campos X.
      Massive Neurocysticercosis: Encephalitic versus Non-encephalitic.
      ]. Spinal cord involvement has been reported in case reports and case series [
      • Colli B.O.
      • Assirati Júnior J.A.
      • Machado H.R.
      • dos Santos F.
      • Takayanagui O.M.
      Cysticercosis of the central nervous system. II. Spinal cysticercosis.
      ,
      • Colli B.O.
      • Valença M.M.
      • Carlotti Jr., C.G.
      • Machado H.R.
      • Assirati J.A.
      Spinal cord cysticercosis: neurosurgical aspects.
      ]; it appears to be more common in patients with basal subarachnoid NCC [
      • Callacondo D.
      • Garcia H.H.
      • Gonzales I.
      • Escalante D.
      • Nash T.E.
      Cysticercosis Working Group in Peru. High frequency of spinal involvement in patients with basal subarachnoid neurocysticercosis.
      ]. Ocular NCC most commonly causes periocular swelling, proptosis, and/or ptosis [
      • Rath S.
      • Honavar S.G.
      • Naik M.
      • Anand R.
      • Agarwal B.
      • Krishnaiah S.
      • et al.
      Orbital cysticercosis: clinical manifestations, diagnosis, management, and outcome.
      ]. NCC is one of only a few NTDs with randomized controlled trial data and evidence-based guidelines for CNS manifestations of the disease [
      • Baird R.A.
      • Wiebe S.
      • Zunt J.R.
      • Halperin J.J.
      • Gronseth G.
      • Roos K.L.
      Evidence-based guideline: Treatment of parenchymal neurocysticercosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology.
      ]. In spite of this, controversies remain with respect to optimal treatment depending on the burden and stage of intracranial cysts [
      • Burnio J.G.
      • Escalaya A.L.
      • Carpio A.
      • Fleury A.
      • Vega-Gama G.
      • Garcia Pedroz F.
      • et al.
      Responses to Evidence-based guideline: Treatment of parenchymal neurocysticercosis: Report of the Guideline Development Subcommittee of the American Academy of Neurology.
      ]. Eradication efforts focus on hygiene, sanitation, improved pig husbandry, and treatment of affected humans and pigs [
      • World Health Organization
      Taeniasis: Surveillance, Prevention and Control.
      ].

      4.2.2 Dracunculiasis (Dracunculus medinensis)

      Dracunculiasis, also known as guinea-worm disease, is acquired through ingestion of water containing infected copepods (microscopic crustaceans). An aggressive eradication campaign has reduced the number of cases of dracunculiasis from 3.5 million in 1988 to just 148 in four countries within 25 years [
      • World Health Organization
      ]. This was accomplished through case containment, improved access to safe drinking water and filters for water treatment, vector control (such as treating water sources with the larvicidal temephos), and community health education [
      • World Health Organization
      ,
      • Biswas G.
      • Sankara D.P.
      • Agua-Agum J.
      • Maiga A.
      Dracunculiasis (guinea worm disease): eradication without a drug or a vaccine.
      ]. Dracunculiasis most commonly manifests as an ulcerated blister from which the worm emerges. Neurologic involvement has been described rarely in case reports. The most frequently reported neurologic manifestation is paraplegia due to spinal epidural involvement [
      • Legmann P.
      • Chiras J.
      • Launay M.
      • Philippon J.
      • Bories J.
      Epidural Drucunculiasis: a rare cause of spinal cord compression.
      ]. Although the diagnosis can be suggested by spinal calcifications on plain radiograph or an epidural lesion seen via myelography, definitive diagnosis can be made by gross or microscopic pathologic examination during surgical laminectomy [
      • Legmann P.
      • Chiras J.
      • Launay M.
      • Philippon J.
      • Bories J.
      Epidural Drucunculiasis: a rare cause of spinal cord compression.
      ,
      • Khwaja M.S.
      • Dosseton J.F.B.
      • Lawrie J.H.
      Extradural guinea worm abscess: report of two cases.
      ,
      • Reddy C.R.R.M.
      • Valli V.V.
      Extradural guinea worm abscess: report of two cases.
      ]. A single case of median nerve involvement by forearm parasitic abscess has been reported [
      • Balasubramanian V.
      • Ramamurthi B.
      An unusual location of guineaworm infestation: report of a case.
      ]. There are rare descriptions of encephalopathy due to intracerebral granulomas and elevated intracranial pressure due to granulomatous obstruction of the ventricular system [
      • Legmann P.
      • Chiras J.
      • Launay M.
      • Philippon J.
      • Bories J.
      Epidural Drucunculiasis: a rare cause of spinal cord compression.
      ].

      4.2.3 Echinococcosis (Echinococcus species)

      Echinococcosis is acquired through ingestion of eggs in contaminated food or water, and humans are the host for the larval tapeworm. Echinococcal (hydatid) cysts most commonly affect the liver, but can affect any organ including any level of the nervous system, as documented in case reports and case series. Intracerebral cysts may lead to focal neurologic deficits, seizures, and/or elevated intracranial pressure [
      • Aleksic-Shihabi A.
      • Vidolin E.P.
      Cystic echinococcosis of the heart and brain: a case report.
      ,
      • Aydinli B.
      • Aydin U.
      • Yazici P.
      • Oztürk G.
      • Onbaş O.
      • Polat K.Y.
      Alveolar echinococcosis of liver presenting with neurological symptoms due to brain metastases with simultaneous lung metastasis: a case report.
      ,
      • Limaiem F.
      • Bellil S.
      • Bellil K.
      • Chelly I.
      • Mekni A.
      • Kallel J.
      • et al.
      Hydatid cyst of the cranial vault.
      ]. It has been hypothesized that predilection for the middle cerebral arterial territory reflects embolization of the parasite as a mechanism for brain involvement [
      • Bükte Y.
      • Kemaloglu S.
      • Nazaroglu H.
      • Ozkan U.
      • Ceviz A.
      • Simsek M.
      Cerebral hydatid disease: CT and MR imaging findings.
      ]. Neuroimaging features of cysts may help to differentiate Echinococcus granulosus from Echinococcus multilocularis, as the former causes well-circumscribed, non-enhancing, thin-walled cysts, while the latter often demonstrates complex cysts with calcification and contrast enhancement [
      • Bükte Y.
      • Kemaloglu S.
      • Nazaroglu H.
      • Ozkan U.
      • Ceviz A.
      • Simsek M.
      Cerebral hydatid disease: CT and MR imaging findings.
      ]. Myelopathy and radiculopathy from vertebral lesions and intradural extramedullary echinococcal cysts have been described [
      • Güneçs M1.
      • Akdemir H.
      • Tuğcu B.
      • Günaldi O.
      • Gümüçs E.
      • Akpinar A.
      Multiple intradural spinal hydatid disease: a case report and review of literature.
      ,
      • Kaen A1.
      • Lagares A.
      • Perez-Nuñez A.
      • Rivas J.J.
      • Ramos A.
      • Lobato R.D.
      Intradural extramedullary spinal hydatidosis: case report.
      ]. Cystic compression of individual peripheral nerves has also been reported [
      • Kalaci A1.
      • Sevinç T.T.
      • Yanat A.N.
      Sciatica of nondisc origin: hydatid cyst of the sciatic nerve. Case report.
      ,
      • Bilanović D1.
      • Zdravković D.
      • Randjelović T.
      • Tosković B.
      • Gacić J.
      Lesion of the femoral nerve caused by a hydatid cyst of the right psoas muscle.
      ].

      4.2.4 Foodborne trematodiases (primarily species in genera: Clonorchis, Opisthorchis, Paragonimus, and Fasciola)

      These parasites infect humans when ingested in raw or undercooked freshwater fish (Clonorchis, Opisthorchis), crustaceans such as crayfish and crabs (Paragonimus), and aquatic plants such as watercress (Fasciola). Of these four parasites, Paragonimus is the most likely to affect the nervous system. Although the nervous system is affected in just under 1% of cases of paragonimiasis [
      • Fürst T.
      • Keiser J.
      • Utzinger J.
      Global burden of human food-borne trematodiasis: a systematic review and meta-analysis.
      ,
      • Oh S.J.
      Cerebral Paragonimiasis.
      ], the central nervous system (CNS) is involved in 30–60% of extra-pulmonary paragonimiasis [
      • Oh S.J.
      Cerebral and Spinal Paragonimiasis: A Histopathological Study.
      ]. CNS involvement is the most lethal manifestation of the disease [
      • Fürst T.
      • Keiser J.
      • Utzinger J.
      Global burden of human food-borne trematodiasis: a systematic review and meta-analysis.
      ]. The first case series described meningitic, subacute encephalitic, tumorous, dementing, epileptic, and hemiplegic forms of cerebral paragonimiasis [
      • Oh S.J.
      Cerebral Paragonimiasis.
      ,
      • Oh S.J.
      Paragonimus Meningitis.
      ]. An acute focal presentation can be caused by intracerebral hemorrhage, whereas a dementing or subacute focal form occurs with long-standing calcified brain lesions. Paraplegia from spinal involvement has been reported less commonly [
      • Kim M.K.
      • Cho B.M.
      • Yoon D.Y.
      • Nam E.S.
      Imaging features of intradural spinal paragonimiasis: a case report.
      ,
      • Moon T.J.
      • Yoon B.Y.
      • Hahn Y.S.
      Spinal paragonimiasis.
      ,
      • Oh S.J.
      Spinal Paragonimiasis.
      ]. Approximately 70% of cases of Paragonimus infection with neurologic involvement have prior pulmonary manifestations [
      • Chen J.
      • Chen Z.
      • Li F.
      • Lin J.
      • Meng H.
      • Feng H.
      Cerebral paragonimiasis that manifested as intracranial hemorrhage.
      ].
      Intracerebral [
      • Zhou L.
      • Luo L.
      • You C.
      • Wang B.
      • Xu J.
      • Liao L.
      • et al.
      Multiple brain hemorrhages and hematomas associated with ectopic fascioliasis in brain and eye.
      ,
      • Ruggieri F.
      • Correa A.J.E.
      • Martinez E.
      Cerebral Distomiasis.
      ] and spinal epidural [
      • Vatsal D.K.
      • Kapoor S.
      • Venkatesh V.
      • Vatsal P.
      • Husain N.
      Ectopic fascioliasis in the dorsal spine: case report.
      ] fascioliasis have been reported rarely. The most recently reported cases are dramatic. In a 10-year-old boy presenting with intracerebral hemorrhage, the parasite emerged from the patient's eye [
      • Zhou L.
      • Luo L.
      • You C.
      • Wang B.
      • Xu J.
      • Liao L.
      • et al.
      Multiple brain hemorrhages and hematomas associated with ectopic fascioliasis in brain and eye.
      ]. In a 30-year-old woman with subacute paraplegia, the parasite was visible to the naked eye in the epidural space during surgery [
      • Vatsal D.K.
      • Kapoor S.
      • Venkatesh V.
      • Vatsal P.
      • Husain N.
      Ectopic fascioliasis in the dorsal spine: case report.
      ].
      There are no definitive reports of Clonorchis or Opisthorchis infections affecting the nervous system. Although there is a single report of multiple embolic infarctions in the setting of active Clonorchis sinensis infection-induced eosinophilia, other potential etiologies of stroke (e.g., atrial fibrillation) do not appear to have been excluded [
      • Hwang K.J.
      • Heo S.H.
      • Chang D.I.
      Multiple microembolic brain infarctions in Clonorchis sinensis infestation.
      ].

      4.2.5 Filariasis (Wuchereria bancrofti, Brugia malayi, Brugia timori, Loa loa, Mansonella perstans)

      Filariasis causes elephantiasis, a debilitating and disfiguring illness affecting approximately 120 million individuals worldwide []. Neurologic manifestations of filariasis have been reported rarely, many of which appear to be due to an inflammatory reaction to filarial infection rather than direct involvement of the nervous system. All of the neurological manifestations described below have occurred in patients infected with W. bancrofti, unless otherwise noted. An acute encephalopathy marked by seizures and coma has been reported in patients with filaria in the serum but normal CSF studies [
      • Shah M.D.
      • Shrimanker D.K.
      • Saifee H.
      Filarial encephalopathy. Congenital intracranial filariasis: a case report.
      ,
      • Deodhar L.P.
      • Deshpande C.K.
      • Anand R.K.
      • Ahuja K.K.
      Acute microfilarial encephalopathy: a case report.
      ]. It is unclear whether the CNS symptoms in these cases were a result of high fever and systemic complications of parasitemia or true CNS involvement. Filaria have rarely been isolated from the CSF in cases of meningoencephalitis (Mansonella species) [
      • Dukes D.C.
      • Gelfand M.
      • Gadd K.G.
      • Clarke V.
      • Goldsmid J.M.
      Cerebral Filariasis Caused by Acanthocheilonema Perstans.
      ,
      • Fonticiella M.
      • L6pez-Negrete L.
      • Prieto A.
      • Garcia-Hernfindez J.B.
      • Orense M.
      • Fernfindez-Diego J.
      • et al.
      ], from the brain at autopsy [
      • Shah M.D.
      • Shrimanker D.K.
      • Saifee H.
      Filarial encephalopathy. Congenital intracranial filariasis: a case report.
      ], and in cyst fluid surrounding intracranial neoplasms [
      • Aron M.
      • Kapila K.
      • Sarkar C.
      • Verma K.
      Microfilariae of Wuchereria bancrofti in Cyst Fluid of Tumors of the Brain A Report of Three Cases.
      ]. A single case of paraplegia from a Pott's-like syndrome caused by pathologically confirmed microfilariasis of vertebral and paravertebral tissue was reported to have resolved completely with diethylcarbamazine citrate (DEC) [
      • Garg R.K.
      • Jain S.
      • Kar A.M.
      Pott's paraplegia like presentation: a neurological complication of lymphatic filariasis.
      ].
      Filaria have been reported to cause post-infectious inflammatory neurologic syndromes such as acute disseminated encephalomyelitis [
      • Paliwal V.K.
      • Goel G.
      • Vema R.
      • Pradhan S.
      • Gupta R.K.
      Acute disseminated encephalomyelitis following filarial infection.
      ] and Guillain–Barré syndrome [
      • Bhatia B.
      • Misra S.
      Recurrent Guillain-Barre Syndrome following acute filariasis.
      ]. Post-treatment encephalopathy in patients with L. loa treated with anti-parasitic medication is thought to be due to an immune-mediated mechanism [
      • Carme B.
      • Boulesteix J.
      • Boutes H.
      • Puruehnce M.f.
      Five Cases Of Encephalitis During Treatment Of Loiasiswith Diethylcarbamazine.
      ]. Several cases of pathologically confirmed myositis occurred in patients infected with W. bancrofti and resolved completely with DEC, but no biopsy evidence of direct muscle involvement by filaria was seen [
      • Poddar S.K.
      • Misra S.
      • Singh N.K.
      Acute polymyositis associated with W. bancrofti.
      ,
      • Narasimhan C.
      • George T.J.
      • George K.T.
      • Mathai D.
      • CHandi S.M.
      • Pulimood B.M.
      W bancrofti as a causal agent of polylmyositis.
      ].

      4.2.6 Onchocerciasis (Onchocerca volvulus)

      River blindness is caused by infection with O. volvulus, transmitted through the bite of the blackfly (Simulium species). Onchocerciasis has been implicated in epilepsy, cognitive impairment, and growth delay [
      • Ovuga E.
      • Kipp W.
      • Mungherera M.
      • Kasoro S.
      Epilepsy and retarded growth in a hyperendemic focus of onchocerciasis in rural western Uganda.
      ,
      • Newell E.D.
      • Vyungimana F.
      • Bradley J.E.
      Epilepsy, retarded growth and onchocerciasis, in two areas of different endemicity of onchocerciasis in Burundi.
      ]. Microfilariae have occasionally been identified in the CSF [

      Duke ROL, Vincelette J, Moore PJ. Microfilariae in the cerebrospinal fluid, and neurological complications, during treatment of onchocerciasis with diethylcarbamazine. Trop Med Parasitol 27, 123-32.

      ], though it is uncertain whether the presence of microfilariae in patients' skin snip biopsies is sufficient to attribute neurologic disease to O. volvulus [
      • Burnham G.
      Onchoceriasis.
      ]. Microfilariae may live up to two years, and the interval between the bite of an infected fly and the presence of skin lesions may be as long as 20 months [
      • Burnham G.
      Onchoceriasis.
      ].
      Although studies reporting a potentially increased prevalence of epilepsy in regions where onchocerciasis is endemic date back to the 1930s [
      • Casis-Sacre G.
      El dindrome epileptico y su relacion con onchocercosis.
      ], the causal relationship remains uncertain. A meta-analysis of nine observational African studies found a relative risk of 1.21 for epilepsy in onchocerciasis-endemic compared to non-endemic zones (95% CI 0.99–1.47, p = 0.06) [
      • Druet-Cabanac M.
      • Boussinesq M.
      • Dongmo L.
      • Farnarier G.
      • Bouteille B.
      • Preux P.M.
      Review of epidemiological studies searching for a relationship between onchocerciasis and epilepsy.
      ]. O. volvulus is further implicated in the “nodding syndrome,” a presumed epileptic disorder, characterized in Eastern Africa and associated with fatality, particularly in younger adults [
      • Kaiser C.
      • Pion S.
      • Boussinesq M.
      Letter to the editor: Do helminths cause epilepsy? The case of Onchcerca volvulus.
      ].

      4.2.7 Schistosomiasis (Schistosoma species)

      Schistosomes infect an estimated 3% of the global population, acquired through direct skin exposure to water containing the organism [
      • Elliott D.E.
      Schistosomiasis. Pathophysiology, diagnosis, and treatment.
      ]. CNS involvement is seen in 3–5% of infected patients, causing seizures, focal neurologic deficits and/or acute encephalopathy due to brain involvement in the case of Schistosoma japonicum [
      • Ferrari T.C.
      • Moreira P.R.
      Neuroschistosomiasis: clinical symptoms and pathogenesis.
      ], or acute transverse myelitis or subacute myeloradiculopathy due to spinal involvement in Schistosoma mansoni and Schistosoma haematobium infection [
      • Carod-Artal F.J.
      Neurological complications of Schistosoma infection.
      ]. Although cases of schistosomiasis-associated CNS vasculitis and pelvic floor myopathy have been described, a causal relationship was not definitively confirmed [
      • Camuset G.
      • Wolff V.
      • Marescaux C.
      • Abou-Bacar A.
      • Candlfi E.
      • Lefebvre N.
      • et al.
      Cerebral vasculitis associated with Schistosoma mansoni infection.
      ,
      • Jauréguiberry S.
      • Ansart S.
      • Perez L.
      • Danis M.
      • Bricaire F.
      • Caumes E.
      Acute neuroschistosomiasis: two cases associated with cerebral vasculitis.
      ,
      • Liblau R.
      • Chiras J.
      • Orssaud C.
      • Dormont D.
      • Duclos H.
      • Gentilini M.
      Spinal infarction in the anterior spinal territory with possible relation with bilharziasis.
      ,
      • Hussein A.M.
      • Helal S.F.
      Schistosomal pelvic floor myopathy contributes to the pathogenesis of rectal prolapse in young males.
      ]. Although randomized trials have demonstrated the benefits of praziquantel for non-neurologic manifestations of schistosomiasis such as intestinal or urinary tract involvement [
      • Sousa-Figueiredo J.C.
      • Betson M.
      • Atuhaire A.
      • Arinaitwe M.
      • Navratnam A.M.
      • Kabatereine N.B.
      • et al.
      Performance and safety of praziquantel for treatment of intestinal schistosomiasis in infants and preschool children.
      ,
      • Inyang-Etoh P.C.
      • Ejezie G.C.
      • Useh M.F.
      • Inyang-Etoh E.C.
      Efficacy of a combination of praziquantel and artesunate in the treatment of urinary schistosomiasis in Nigeria.
      ,
      • Queiroz L.C.
      • Drummond S.C.
      • Matos M.L.
      • Paiva M.B.
      • Batista T.S.
      • Kansaon A.Z.
      • et al.
      Comparative randomised trial of high and conventional doses of praziquantel in the treatment of schistosomiasis mansoni.
      ,
      • Mutapi F.
      • Rujeni N.
      • Bourke C.
      • Mitchell K.
      • Appleby L.
      • Nausch N.
      • et al.
      Schistosoma haematobium treatment in 1-5 year old children: safety and efficacy of the antihelminthic drug praziquantel.
      ,
      • Keiser J.
      • N'Guessan N.A.
      • Adoubryn K.D.
      • Silué K.D.
      • Vounatsou P.
      • Hatz C.
      • et al.
      Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial.
      ], the management of neuro-schistosomiasis is described only in case series [
      • Ferrari T.C.
      • Moreira P.R.
      • Cunha A.S.
      Clinical characterization of neuroschistosomiasis due to Schistosoma mansoni and its treatment.
      ,
      • Ferrari T.C.
      • Moreira P.R.
      • Cunha A.S.
      Spinal cord schistosomiasis: a prospective study of 63 cases emphasizing clinical and therapeutic aspects.
      ,
      • Lei T.
      • Shu K.
      • Chen X.
      • Li L.
      Surgical treatment of epilepsy with chronic cerebral granuloma caused by Schistosoma japonicum.
      ]. For the treatment of CNS involvement, experts recommend praziquantel with concurrent corticosteroids, both to treat neuro-inflammatory sequalae of schistosomiasis, and since anti-parasitic treatment can induce a hypersensitivity reaction with features including headache, hemiparesis, seizure, encephalopathy and cerebellar signs [
      • Ferrari T.C.
      • Moreira P.R.
      Neuroschistosomiasis: clinical symptoms and pathogenesis.
      ]. Surgical excision followed by praziquantel therapy is recommended for schistosomal cerebral mass lesions [
      • Ferrari T.C.
      • Moreira P.R.
      Neuroschistosomiasis: clinical symptoms and pathogenesis.
      ].

      4.2.8 Soil transmitted helminthiases Ascaris lumbricoides, whipworm (Trichuris trichiura) and hookworms (Necator americanus and Ancylostoma duodenale)

      Soil-transmitted helminth infections cause gastrointestinal disturbances, which can lead to malnutrition, diarrhea, gastrointestinal bleeding, rectal prolapse and/or bowel obstruction [
      • World Health Organization
      ]. The WHO has committed to ongoing treatment of 75% of affected children in endemic areas by 2020 [
      • World Health Organisation
      ]. Nervous system manifestations of the disease appear to be rare: most case reports and small case series of encephalitis, meningitis, epilepsy, myelopathy and myeloradiculopathy occurred in outbreaks in endemic regions [
      • Inatomi Y.
      • Murakami T.
      • Tokunaga M.
      • Ishiwata K.
      • Nawa Y.
      • Uchino M.
      Encephalopathy caused by visceral larva migrans due to Ascaris suum.
      ,
      • Umehara F.
      • Ookatsu H.
      • Hayashi D.
      MRI studies of spinal visceral larva migrans syndrome.
      ,
      • Selimoğlu M.A.
      • Oztürk C.F.
      • Ertekin V.
      A rare manifestation of ascariasis: encephalopathy.
      ], and are attributed to parasitic toxins and/or immune-mediated hypersensitivity reactions to them [
      • Bapat S.S.
      • Pulikot A.M.
      Hepato-cerebral complications in ascariasis.
      ]. Cognitive changes may occur in the setting of malnutrition due to gastrointestinal involvement [
      • World Health Organization
      ].

      4.3 Viruses

      4.3.1 Dengue (Dengue virus)

      Dengue fever is a mosquito-borne illness that affects up to 50–100 million people each year, representing a 30-fold increase in incidence since it was first recognized in the 1950s []. Four viral types exist, and the presence of dengue virus is emerging in new geographic locations. Campaigns to control dengue have not been uniformly successful, and both effective vaccines and targeted treatment remain elusive. Dengue infection may lead to CNS involvement in the form of encephalitis, meningitis, meningoencephalitis, or myelitis. In a study of 150 patients in Brazil with death due to suspected infectious disease, 84 patients had dengue virus identified in the serum and 41 had the virus isolated from the CSF [
      • Araújo F.M.C.
      • Araújo M.S.
      • Nogueira R.M.
      • Brilhante R.S.
      • Oliveira D.N.
      • Rocha M.F.
      • et al.
      Central nervous system involvement in dengue.
      ]. Headache, fever, irritability, vomiting, fatigue, dizziness, seizure, neck stiffness, coma, abdominal pain, and breathlessness were reported manifestations. A study of multiple etiologies of viral encephalitis in India found that 24% of patients with dengue encephalitis experience seizures (10/42 cases), mostly generalized tonic-clonic events; by comparison, seizures occurred in 54% of people with Japanese encephalitis (32/59) and 75% of those with herpes simplex virus encephalitis (6/8) [
      • Misra U.K.
      • Kalita J.
      Seizures in encephalitis: predictors and outcomes.
      ]. Fatal hemorrhagic encephalitis may occur in the setting of dengue-associated thrombocytopenia.
      Dengue virus may cause additional neurologic manifestations aside from encephalitis. In an epidemic of cases of dengue fever seen in a hospital in India in 2010, 21 of 799 (2.6%) were noted to have neurologic complications of the disease [
      • Koshy J.M.
      • Josph D.M.
      • John M.
      • Mani A.
      • Malhotra N.
      • Abraham G.M.
      • et al.
      Spectrum of neurological manifestations in dengue virus infection in Northwest India.
      ]. The most common was hypokalemic quadriparesis, followed by myositis and encephalitis. Other less commonly reported conditions include ischemic stroke, lumbosacral plexopathy, and mononeuropathy, as well as post-infectious Guillain–Barré syndrome, acute disseminated encephalomyelitis, and parkinsonism [
      • Koshy J.M.
      • Josph D.M.
      • John M.
      • Mani A.
      • Malhotra N.
      • Abraham G.M.
      • et al.
      Spectrum of neurological manifestations in dengue virus infection in Northwest India.
      ,
      • Fong C.Y.
      • Hlaing C.S.
      • Tay C.G.
      • Ong L.C.
      Post-dengue encephalopathy and parkinsonism.
      ]. Although diagnostic criteria for dengue encephalitis have been proposed, they are controversial since detection of dengue viral RNA and specific IgM antibodies in the CSF may be disease-course dependent and diagnostic tests are inconsistently available in endemic regions [
      • Carod-Artal F.J.
      • Wichmann O.
      • Farrar J.
      • Gascón J.
      Neurological complications of dengue virus infection.
      ,
      • Soares C.
      • Puccioni-Sohler M.
      Diagnosis criteria of dengue encephalitis.
      ].

      4.3.2 Rabies (Rabies virus)

      Rabies is a uniformly fatal yet entirely preventable disease []. Centripetal (retrograde) propagation from infected muscles to dorsal root ganglia to the CNS leads to both the classic encephalitic form (fever, encephalopathy, hydrophobia or aerophobia, inspiratory spasms, autonomic signs) and the paralytic form (neuropathic pain, progressive ascending weakness, areflexia), as well as more rarely reported neurologic manifestations (focal brainstem signs, cranial neuropathies, myoclonus, hemichorea, tetanus like syndrome, and Horner's syndrome) [
      • Hemachudha T.
      • Ugolini G.
      • Wacharapluesadee S.
      • Sungkarat W.
      • Shuangshoti S.
      • Laothamatas J.
      Human rabies: neuropathogenesis, diagnosis, and management.
      ,
      • Hemachudha T.
      • Laothamatas J.
      • Rupprecht C.E.
      Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges.
      ]. Later, centrifugal (anterograde) propagation of the virus to extraneural tissues including the skin, heart, blood vessels, and salivary glands leads to multi-organ system dysfunction [
      • Hemachudha T.
      • Ugolini G.
      • Wacharapluesadee S.
      • Sungkarat W.
      • Shuangshoti S.
      • Laothamatas J.
      Human rabies: neuropathogenesis, diagnosis, and management.
      ,
      • Hemachudha T.
      • Laothamatas J.
      • Rupprecht C.E.
      Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges.
      ]. Once the virus spreads to the nervous system, mortality is inevitable. Despite one patient with advanced encephalitic rabies surviving on the “Milwaukee protocol” (induction of therapeutic coma using γ-aminobutyric acid (GABA)-receptor agonism with benzodiazepines and barbiturates, along with N-methyl-d-aspartate (NMDA) receptor antagonism with ketamine and amantadine to reduce excitotoxicity, brain metabolism, and autonomic reactivity) [
      • Willoughby Jr., R.E.
      • Tieves K.S.
      • Hoffman G.M.
      • Ghanayem N.S.
      • Amlie-Lefond C.M.
      • Schwabe M.J.
      • et al.
      Survival after treatment of rabies with induction of coma.
      ], 26 subsequent patients treated under this protocol died [
      • Jackson A.C.
      Current and future approaches to the therapy of human rabies.
      ]. Therefore, early identification, post-exposure prophylaxis and prevention are critical. Randomized trials of the effectiveness of pre- and post-exposure prophylaxis have not been performed in humans due to the presumed high mortality without such treatments [
      • Manning S.E.
      • Rupprecht C.E.
      • Fishbein D.
      • Hanlon C.A.
      • Lumlertdacha B.
      • Guerra M.
      • et al.
      Human rabies prevention–United States, 2008: recommendations of the Advisory Committee on Immunization Practices.
      ]. Since dogs remain the primary reservoir in areas of highest incidence, breaking the cycle of transmission in dogs and from dogs to humans by vaccinating at least 70% of dogs is one of the key elements in the WHO rabies elimination campaigns in endemic regions [
      • World Health Organisation
      Neglected Tropical Diseases. WHO Expert Consultation on Rabies re-evaluates the burden and methods of treatment.
      ].

      4.4 Bacteria

      4.4.1 Buruli ulcer (Mycobacterium ulcerans)

      Buruli is a painless necrotizing skin ulceration due to infection by the slowly growing bacterium M. ulcerans. When severe, Buruli ulcer may lead to deformity of the joints and resultant motor disability. In a study of 312 cases in Côte d'Ivoire, 26% of individuals with healed ulcers had chronic functional disability as a result of contraction deformities [
      • Marston B.J.
      • Diallo M.O.
      • Horsburgh C.R.
      • Diomande I.
      • Saki M.Z.
      • Kanga J.M.
      • et al.
      Emergence of Buruli Ulcer disease in the Daloa region of Côte d’Ivoire.
      ]. Limb amputation has been used as treatment for severe disease given disappointing results with medications, particularly at later stages of Buruli ulcer. The only potential neurologic aspect of the disease is intraneural invasion of the bacilli and the production of a toxic lipid (mycolactone) that causes vacuolar degeneration in Schwann cells [
      • Goto M.
      • Nakanaga K.
      • Aung T.
      • Hamada T.
      • Yamada N.
      • Nomoto M.
      • et al.
      Nerve damage in Mycobacterium ulcerans-infected mice: probable cause of painlessness in Buruli Ulcer.
      ,
      • En J.
      • Goto M.
      • Nakanaga K.
      • Higashi M.
      • Ishii N.
      • Saito H.
      • et al.
      Mycolactone is responsible for the painless of Mycobacterium ulcerans infection (Buruli Ulcer) in a murine study.
      ]. This intraneural invasion may be responsible for the painlessness of Buruli ulcer, which may lead to the delays in care-seeking by infected individuals [
      • Goto M.
      • Nakanaga K.
      • Aung T.
      • Hamada T.
      • Yamada N.
      • Nomoto M.
      • et al.
      Nerve damage in Mycobacterium ulcerans-infected mice: probable cause of painlessness in Buruli Ulcer.
      ,
      • En J.
      • Goto M.
      • Nakanaga K.
      • Higashi M.
      • Ishii N.
      • Saito H.
      • et al.
      Mycolactone is responsible for the painless of Mycobacterium ulcerans infection (Buruli Ulcer) in a murine study.
      ].

      4.4.2 Leprosy (Mycobacterium leprae)

      Leprosy is one of the most common, treatable causes of peripheral neuropathy worldwide [
      • Nascimento O.J.
      Leprosy neuropathy: clinical presentations.
      ]. The global elimination campaign has led to a 90% reduction in the global prevalence since 1991, largely by providing free multidrug treatment (rifampicin, clofazimine and dapsone) [
      • World Health Organisation
      ]. The most common neurologic manifestations of leprosy are peripheral mononeuritis, mononeuritis multiplex, and polyneuropathy, although cranial neuropathy (most commonly nerves V and VII), and autonomic neuropathy also occur frequently [
      • World Health Organisation
      ,
      • Daniel E.
      • Ffytche T.J.
      • Kempen J.H.
      • Rao P.S.
      • Diener-West M.
      • Courtright P.
      Incidence of ocular complications in patients with multibacillary leprosy after completion of a 2 year course of multidrug therapy.
      ]. Nerve abscess and T2 hyperintensities in the spinal cord on MRI have been rarely reported [
      • Nascimento O.J.
      Leprosy neuropathy: clinical presentations.
      ,
      • Khadilkar S.V.
      • Kasegaonkar P.S.
      • Ursekar M.
      Spinal cord involvement and ganglionitis in leprosy.
      ]. Leprosy is one of the few NTDs for which multiple clinical trials have been conducted, demonstrating success of RCD (rifampicin, clofazimine, dapsone) for multibacillary leprosy, ROM (rifampicin, ofloxacin, minocycline) for paucibacillary leprosy, and uniform multidrug therapy (U-MDT, rifampicin, clofazimine, dapsone for 6 months) for all types of leprosy [
      • Kroger A.
      • Pannikar V.
      • Htoon M.T.
      • et al.
      International open trial of uniform multi-drug therapy regimen for 6 months for all types of leprosy patients: rationale, design and preliminary results.
      ,
      • Manickam P.
      • Nagaraju B.
      • Selvaraj V.
      • Balasubramanyam S.
      • Mahalingam V.N.
      • Mehendale S.M.
      • et al.
      Efficacy of single-dose chemotherapy (rifampicin, ofloxacin and minocycline-ROM) in PB leprosy patients with 2 to 5 skin lesions, India: randomised double-blind trial.
      ,
      • Penna M.L.
      • Buhrer-Sékula S.
      • Pontes M.A.
      • Cruz R.
      • Goncalves Hde S.
      • Penna G.O.
      • et al.
      Primary results of clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): reactions frequency in multibacillary patients.
      ]. Although prednisolone is commonly used for the treatment of neuropathy, the long-term benefit is uncertain [
      • van Veen N.H.
      • Nicholls P.G.
      • Smith W.C.
      • Richardus J.H.
      Corticosteroids for treating nerve damage in leprosy. A Cochrane review.
      ]. The TENLEP (Treatment of Early Neuropathy in LEProsy) study is an ongoing clinical trial to assess the efficacy of prednisolone for the prevention and recovery of patients with leprosy neuropathy [
      • Wagenaar I.
      • Brandsma W.
      • Post E.
      • van Brakel W.
      • Lockwood D.
      • Nicholls P.
      • et al.
      Two randomized controlled clinical trials to study the effectiveness of prednisolone treatment in preventing and restoring clinical nerve function loss in leprosy: the TENLEP study protocols.
      ].

      4.4.3 Trachoma (Chlamydia trachomatis)

      Trachoma is the leading cause of blindness due to infection, responsible for visual impairment in over 2 million individuals worldwide []. Through the SAFE strategy (surgery for inturned eyelashes, antibiotics, facial cleanliness, and environmental improvement), the Alliance for Global Elimination of Trachoma seeks to eliminate the disease by 2020 []. The blindness caused by C. trachomatis is due to direct ocular involvement rather than due to a neurologic cause. However, there are rare reports of C. trachomatis causing meningoencephalitis, with a few case reports documenting C. trachomatis in the CSF [
      • Bertsche A.
      • Wagner M.H.
      • Bollmann R.
      • Obladen M.
      • Felderhoff-Mueser U.
      An Unusual Manifestation of a Neonatal Chlamydia Infection.
      ,
      • Myre E.B.
      • Mardh P.
      Chlamydia trachomatis infection in a patient with meningoencephalitis.
      ]. Case reports from the 1930s to 1940s described meningoencephalitis in patients with lymphogranuloma venereum [
      • Rajam R.V.
      Report of a fatal case of lymphogranuloma inguinale from meningo-encephalitis.
      ,
      • Sabin A.B.
      • Aring C.D.
      Meningoencephalitis in man caused by the virus of lymphogranuloma venereum.
      ,
      • Zarafonetis C.J.D.
      Meningoencephalitis in lymphogranuloma venereum: A Report of Two Cases.
      ], however an association between the two could not be proven based on the diagnostic tests available at the time [
      • Korman T.M.
      • Turnidge J.D.
      • Grayzon M.L.
      Neurological Complications of Chlamydial Infections: Case Report and Review.
      ]. Even as recently as the 1980s, a report of C. trachomatis as the causative agent in a case of meningoencephalitis [
      • Goldman J.M.
      • McIntosh C.S.
      • Calver G.P.
      • Perinpanayagam R.M.
      Meningoencephalitis associated with Chlamydia trachomatis infection.
      ] was challenged based on inadequate serological proof of association [
      • Hawkins D.A.
      • Thomas B.J.
      • Munday P.E.
      Meningoencephalitis associated with Chlamydia trachomatis infection.
      ].

      4.4.4 Yaws (Treponema pallidum pertenue)

      Several authors report no nervous system manifestations of yaws [
      • Smith J.L.
      Neuro-ophthalmological study of late yaws. I. An introduction to yaws.
      ,
      • Hewer T.F.
      Some observations on yaws and syphilis in the Southern Sudan.
      ]. However, given the inability of laboratory testing to distinguish the spirochete causing yaws from other treponemal species, it is not currently possible to know if T. pallidum pertenue is specifically associated with neurologic disease.

      5. Conclusions

      The NTDs cause a substantial burden of disease and disability for the world's poorest populations. Neurologic manifestations of these diseases contribute significantly to their morbidity and mortality. With increased numbers of neurologists working in endemic regions, and with increasing globalization and international travel, the neurologic manifestations of the NTDs must be better recognized and understood. Neurologists should therefore not neglect these diseases, but rather devote attention and resources to their study, their treatment, and ultimately, their elimination and eradication.

      6. Authors' contributions

      FJM conceived of the idea for the paper; FJM, ALB, and PR participated in the literature review, drafted the initial manuscript, and revised the manuscript; BP contributed images and accompanying legends and edited key aspects of the manuscript.

      7. Funding

      None.

      8. Competing interests

      ALB reports no competing interests relevant to the manuscript, but receives royalties from Clinical Pathophysiology Made Ridiculously Simple (Medmaster, Inc.) and The Improvising Mind (Oxford University Press). FJM, PR, and BP report no competing interests.

      Acknowledgments

      The authors thank Dr. E. Tessa Hedley-White, Professor, Department of Pathology and Laboratory Medicine, Massachusetts General Hospital and Harvard Medical School, for identifying slides and images presented Fig. 1, Fig. 2.

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