Journal of the Neurological Sciences 349 (2015) 20–32

Contents lists available at ScienceDirect

Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns

Review article

Neurologic manifestations of the neglected tropical diseases Aaron L. Berkowitz a,b, Pooja Raibagkar a,b,c, Bobbi S. Pritt d, Farrah J. Mateen b,c,⁎ a

Brigham and Women's Hospital, Department of Neurology, Boston, MA, United States Harvard Medical School, Boston, MA, United States c Massachusetts General Hospital, Department of Neurology, Boston, MA, United States d Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN, United States b

a r t i c l e

i n f o

Article history: Received 9 October 2014 Received in revised form 24 December 2014 Accepted 2 January 2015 Available online 9 January 2015 Keywords: Central nervous system helminthiasis Central nervous system parasitic infections Central nervous system protozoal infections Neglected diseases Tropical medicine

a b s t r a c t 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. © 2015 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reported neurologic manifestations of the NTDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Protozoa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Chagas disease (Trypanosoma cruzi) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Human African trypanosomiasis (Trypanosoma brucei) . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Leishmaniasis (Leishmania species) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Helminths . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Cysticercosis (Taenia solium) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Dracunculiasis (Dracunculus medinensis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Echinococcosis (Echinococcus species) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.4. Foodborne trematodiases (primarily species in genera: Clonorchis, Opisthorchis, Paragonimus, and Fasciola)

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⁎ 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. E-mail address: [email protected] (F.J. Mateen).

http://dx.doi.org/10.1016/j.jns.2015.01.001 0022-510X/© 2015 Elsevier B.V. All rights reserved.

A.L. Berkowitz et al. / Journal of the Neurological Sciences 349 (2015) 20–32

4.2.5. 4.2.6. 4.2.7. 4.2.8.

Filariasis (Wuchereria bancrofti, Brugia malayi, Brugia timori, Loa loa, Mansonella perstans) . . . . . . . . . . . . . . . . Onchocerciasis (Onchocerca volvulus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Schistosomiasis (Schistosoma species) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Soil transmitted helminthiases Ascaris lumbricoides, whipworm (Trichuris trichiura) and hookworms (Necator americanus and Ancylostoma duodenale) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Dengue (Dengue virus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Rabies (Rabies virus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Buruli ulcer (Mycobacterium ulcerans) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Leprosy (Mycobacterium leprae) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.3. Trachoma (Chlamydia trachomatis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.4. Yaws (Treponema pallidum pertenue) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Authors' contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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.” [1] The World Health Organization (WHO) has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations (Table 1) [1]. The NTDs cause significant disfigurement, morbidity, and mortality, accounting for 1% of the global burden of disability adjusted-life years (DALYs) lost in 2010 [2], though this is likely to be an underestimate [3]. Notably, the NTDs can be controlled – and, in some cases, eliminated or eradicated – through low-cost, strategic interventions [1]. 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 [1]. 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 [4]. 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

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Center for Evidence-based Medicine guidelines [5]. 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. Figs. 1 and 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,

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Table 1 Background characteristics of the neglected tropical diseases. Estimated global prevalence

Endemic regions

Causative organism

Vector/intermediate Mode of host transmission

Non-neurologic manifestations

Treatment

Control, elimination, eradication, and prevention strategies

Chagas disease

7–8 million

Latin America

Trypanosoma cruzi

Triatomine bug

Insect bite

Benznidazole and nifurtimox

Vector control, house improvement, bed nets, food hygiene

Human African trypanosomiasis

30,000

Africa

Trypanosoma brucei and brucei gambiense

Tsetse fly

Insect bite

Leishmaniasis

1.3 million

Africa, Middle East, Central and South Asia, South Europe, South America

Leishmania species

Sandfly

Insect bite

Africa, Asia, Latin America

Taenia solium

Pigs, humans

Dracunculiasis

148

Chad, Ethiopia, Mali and South Sudan

Dracunculus medinensis (guinea worm)

Cyclops water flea

Undercooked pork, contaminated soil/water/food, fecal-oral Contaminated drinking water

Pentamidine, suramin, melarsoprol and eflornithine Pentavalent antimonials, liposomal amphotericin B, miltefosine, paromomycin Praziquantel, steroids, anti-epileptics

Eradication efforts target tsetse fly via traps, insecticide spraying Elimination through vector management

Taeniasis/Cysticercosis 50 million

Acute phase: Skin lesions, lymphadenopathy, fevers Chronic phase: Organomegaly, cardiomyopathy Fever, weakness, arthralgias, psychiatric symptoms Skin ulcer, fever, weight loss, enlargement of the spleen and liver, anemia, leukopenia, thrombocytopenia. No significant non-neurologic manifestations

Removal of worm by winding

Eradication through water treatment

Echinococcosis

1 million

EG: Regions of China, Russian Echinococcus granulosus (EG), Echinococcus multilocularis (EM) Federation, continental Europe, North America EM: Central Europe, Russia, Turkey, Japan, China, Eastern France, North America

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 animals

Painful blister/ulcer, edema, fever, nausea/vomiting Abdominal pain, nausea/vomiting, chronic cough, chest pain, and/or dyspnea

Surgical or percutaneous intervention and albendazole

Prevention and control through deworming of dogs, improved slaughterhouse hygiene, vaccination of livestock

Foodborne trematodiasis: Clonorchiasis

15,313,219 [57]

China, Korea, Russia, Vietnam

Clonorchis sinensis

Raw, undercooked freshwater fish

Cholangitis, cholecystitis, hepatitis, pancreatitis, cholangiocarcinoma

Praziquantel

Control and prevention through MDA

Opisthorchiasis

8,398,230 [57]

Eastern Europe, Central and southeast Asia

Opisthorchis viverrini and felineus

Raw, undercooked freshwater fish

Cholangitis, cholecystitis, hepatitis, pancreatitis, cholangiocarcinoma

Praziquantel

Control and prevention through MDA

Fascioliasis

2,646,515 [57]

South America, China, North Africa, Middle East, Western Europe, Oceania

Fasciola hepatica and gigantica

Freshwater snails, freshwater fish, fish-eating carnivores Freshwater snails, freshwater fish, fish-eating carnivores Freshwater snails, herbivores

Aquatic plants (e.g., watercress)

Cholangitis, pancreatitis, gall stones

Triclabendazole

Control and prevention through MDA

Control through improved pig husbandry

A.L. Berkowitz et al. / Journal of the Neurological Sciences 349 (2015) 20–32

NTD

Freshwater snails, crustacean-eating mammals

Raw, undercooked freshwater crustaceans

Cough, dyspnea, fever, bloody sputum

Triclabendazole or Praziquantel

Control and prevention through MDA

Mosquitos (Culex, Anopheles, Aedes, Mansoni)

Mosquito bite

Lymphedema (elephantiasis), hydrocele, genital edema

Elimination by MDA

Onchocerca volvulus

Blackfly (Similium)

Insect bite

Skin lesions, blindness

Diethylcarbamazine citrate (DEC) or albendazole and ivermectin Ivermectin

Sub Saharan Africa, Latin America and Asia

Schistosoma japonicum, mansoni, and haematobium

Fresh water snail

Hematuria, urogenital disease, abdominal pain, diarrhea, ascites

Praziquantel

1.5 billion

Central/South America, Africa, South/Southeast Asia

(humans)

Diarrhea, malnutrition, intestinal obstruction, rectal prolapse

Albendazole mebendazole or levamisole

Control through MDA

Dengue

50–100 million

Aedes aegypti

Mosquito bite

Fever, myalgias, arthralgias, and rash

Supportive care

Vector control

Rabies

60,000

Africa, Americas, Eastern Mediterranean, South-east Asia, Western Pacific All continents (except Antarctica)

Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), Necator americanus and Ancylostoma duodenale (hookworms) Dengue virus (Flavivirus)

Contaminated fresh water with larval forms (cercaria) Contaminated vegetable, water, soil; skin penetration

Rabies virus (Lyssavirus)

Wild carnivores

Animal bites or scratches

5000

Mycobacterium ulcerans

Leprosy

189,018

Mycobacterium leprae

Aquatic insects, adult mosquitoes, arthropods Armadillo

Exact mode of transmission unknown Human–human

No effective therapy; post-exposure prophylaxis Rifampicin and streptomycin/amikacin

Elimination by vaccination of dogs

Buruli ulcer

No significant non-neurologic manifestations Painless necrotizing skin ulceration Single or multiple skin lesions

Elimination by treatment of affected individuals

Trachoma

2.2 million

Chlamydia trachomatis

N/A

Treponema pallidum, subspecies Pertenue

N/A

Human–human contact; eye-seeking flies Human-human contact

Rifampicine, clofazimine and dapsone Tetracycline eye ointment

Paragonimiasis

23,155,105 [57]

East and Southeast Asia, West and Central Africa, Central and South America

Lymphatic filariasis

120 million

South-east Asia and Africa

Onchocerciasis

26 million

Africa, Yemen, Central/South America

Schistosomiasis

240 million

Soil transmitted helminthiasis

Africa, Asia, Central and South America, Australia, Middle East 460,000 in 1995; Africa, Asia, Western Pacific, more recent data Latin America not available

Blindness, genital infection Skin lesions

Azithromycin or benzathine penicillin

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).

Elimination by vector control via insecticides and MDA Prevention and control through MDA

Elimination by treatment of affected patients

Elimination via surgery, antibiotics, improved facial cleanliness. Elimination by treatment of affected patients

A.L. Berkowitz et al. / Journal of the Neurological Sciences 349 (2015) 20–32

Yaws

Sub-Saharan Africa, Americas, Asia, Western Pacific Africa, South Asia, Southeast Asia, Brazil, China

Pagaronia westermani, heterotremus, philippinensi, Africanus, Uterobilateral, caliensis, kellicotti, and mexicanus Wuchereria bancrofti, Brugia malayi and Brugia timori.

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Table 2 Neurologic manifestations of the neglected tropical diseases. NTD

Chagas disease Human African trypanosomiasis Leishmania Taeniasis/Cysticercosis Dracunculiasis Echinococcus Foodborne trematodiasis: Clonorchiasis Opisthorchiasis Fascioliasis Paragonimiasis Lymphatic filariasis Onchocerciasis Schistosomiasis Soil transmitted helminthiasis Dengue Rabies Buruli ulcer Leprosy Trachoma

Level(s) of neuraxis affected

Reported neurologic manifestations

Reported mortality secondary to neurologic manifestations

CNS

PNS

ANS

Stroke

Space-occupying lesion

Meningo-encephalitis

Myelopathy

x x x x x x

x x x

x

x

x

x x x

x

x x x

x x x

Neuropathy x

x x

x x x x

x x x

x x x x x x x x x x x

x x

x x

x

x x x x

x x

x

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.

x x x

x x x x x x

x x x

x x

x

disease [17]. The development of cognitive impairment following Chagas disease has been described in case–control and large, population-based cohort studies [18], but a causal relationship has not been confirmed [8,19].

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 [6]. 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 [7–9]. Children and immunocompromised individuals may be more susceptible to severe neurologic involvement in acute Chagas disease [7,8]. Congenital Chagas disease due to maternal infection is characterized by newborn meningoencephalitis, microcephaly, and brain calcifications [10]. 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 [8,11,12]. Although Chagas-related strokes are uncommon (1–3% of cases of Chagas disease) [8,13–15], they account for 10% of Chagas disease-related mortality, and may be the presenting manifestation of the infection in up to 40% of patients [8,13–15]. The middle cerebral arterial territory is most commonly affected (87% of cases of Chagas-associated stroke) [16]. Intravenous tissue plasminogen activator (IV-tPA) appears to be safe for treatment of acute stroke in Chagas

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 [20]. Between 2000 and 2012, elimination efforts reduced the incidence of the disease by 73% [20]. 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%) [21]. 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 [22]. 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 [22,23]. T. brucei rhodesiense often causes an acute, fulminant form of the disease compared to the more chronic course of T. brucei gambiense [24]. 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 [25], 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 [23], and meningeal thickening may be seen on magnetic resonance imaging (MRI) in rare cases caused by T. rhodesiense [26]. 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 [25–28].

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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 [29]. Leishmaniasis causes three primary distinct syndromes: cutaneous, mucocutaneous, and visceral, all of which have reported involvement of the central and peripheral nervous systems [30–32]. Meningitis is caused by either direct extension from sinusitis in mucocutaneous forms of leishmaniasis [31] 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 [33]. Cranial nerve dysfunction including optic neuropathy has been described by case report [34]. Sensorimotor peripheral neuropathy occurred in 46% of patients with leishmaniasis in one series [35]. Nerve biopsy in patients with Leishmania-associated neuropathy did not reveal inflammation or direct parasitic nerve involvement [35,36], although perineural Leishmania amastigotes and inflammation have rarely been identified in infected patients without signs or symptoms of neuropathy [37,38]. A predisposition to Leishmania-associated neuropathy in patients with concurrent vitamin deficiency has been debated [35]. Development of Guillain–Barré syndrome and Wilson disease have rarely been reported to be temporally associated with visceral leishmaniasis, but causality was not established [39,40]. 4.2. Helminths 4.2.1. Cysticercosis (Taenia solium) Neurocysticercosis (NCC) may be associated with up to 7.6 million cases of epilepsy worldwide [41], occurring in 29% of people with epilepsy in endemic regions [42]. 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 [43]. 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 [43]. Cysticercotic encephalitis, caused by a large burden of cerebral cysts, occurs more commonly in children and young women [44,45]. Spinal cord involvement has been reported in case reports and case series [46,47]; it appears to be more common in patients with basal subarachnoid NCC [48]. Ocular NCC most commonly causes periocular swelling, proptosis, and/or ptosis [49]. NCC is one of only a few NTDs with randomized controlled trial data and evidence-based guidelines for CNS manifestations of the disease [50]. In spite of this, controversies remain with respect to optimal treatment depending on the burden and stage of intracranial cysts [51]. Eradication efforts focus on hygiene, sanitation, improved pig husbandry, and treatment of affected humans and pigs [52]. 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 [53]. 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 [53, 54]. 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 [55]. 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

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during surgical laminectomy [55–57]. A single case of median nerve involvement by forearm parasitic abscess has been reported [58]. There are rare descriptions of encephalopathy due to intracerebral granulomas and elevated intracranial pressure due to granulomatous obstruction of the ventricular system [55]. 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 [59–61]. It has been hypothesized that predilection for the middle cerebral arterial territory reflects embolization of the parasite as a mechanism for brain involvement [62]. 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 [62]. Myelopathy and radiculopathy from vertebral lesions and intradural extramedullary echinococcal cysts have been described [63,64]. Cystic compression of individual peripheral nerves has also been reported [65,66]. 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 [67,68], the central nervous system (CNS) is involved in 30–60% of extra-pulmonary paragonimiasis [69]. CNS involvement is the most lethal manifestation of the disease [67]. The first case series described meningitic, subacute encephalitic, tumorous, dementing, epileptic, and hemiplegic forms of cerebral paragonimiasis [68,70]. 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 [71–73]. Approximately 70% of cases of Paragonimus infection with neurologic involvement have prior pulmonary manifestations [74]. Intracerebral [75,76] and spinal epidural [77] 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 [75]. In a 30-year-old woman with subacute paraplegia, the parasite was visible to the naked eye in the epidural space during surgery [77]. 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 [78]. 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 [79]. 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 [80,81]. It is unclear whether the

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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) [82,83], from the brain at autopsy [80], and in cyst fluid surrounding intracranial neoplasms [84]. 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) [85]. Filaria have been reported to cause post-infectious inflammatory neurologic syndromes such as acute disseminated encephalomyelitis [86] and Guillain–Barré syndrome [87]. Post-treatment encephalopathy in patients with L. loa treated with anti-parasitic medication is thought to be due to an immune-mediated mechanism [88]. 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 [89,90]. 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 [91,92]. Microfilariae have occasionally been identified in the CSF [93], though it is uncertain whether the presence of microfilariae in patients' skin snip biopsies is sufficient to attribute neurologic disease to O. volvulus [94]. 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 [94]. Although studies reporting a potentially increased prevalence of epilepsy in regions where onchocerciasis is endemic date back to the 1930s [95], 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) [96]. 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 [97]. 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 [98]. 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 [99], or acute transverse myelitis or subacute myeloradiculopathy due to spinal involvement in Schistosoma mansoni and Schistosoma haematobium infection [100]. Although cases of schistosomiasis-associated CNS vasculitis and pelvic floor myopathy have been described, a causal relationship was not definitively confirmed [101–104]. Although randomized trials have demonstrated the benefits of praziquantel for nonneurologic manifestations of schistosomiasis such as intestinal or urinary tract involvement [105–109], the management of neuroschistosomiasis is described only in case series [110–112]. 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

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hypersensitivity reaction with features including headache, hemiparesis, seizure, encephalopathy and cerebellar signs [99]. Surgical excision followed by praziquantel therapy is recommended for schistosomal cerebral mass lesions [99]. 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 [113]. The WHO has committed to ongoing treatment of 75% of affected children in endemic areas by 2020 [114]. 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 [115–117], and are attributed to parasitic toxins and/or immune-mediated hypersensitivity reactions to them [118]. Cognitive changes may occur in the setting of malnutrition due to gastrointestinal involvement [113]. 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 [119]. 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 [120]. 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) [121]. 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 [122]. 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 [122,123]. 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 [124,125].

Fig. 1. Protozoal 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×).

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4.3.2. Rabies (Rabies virus) Rabies is a uniformly fatal yet entirely preventable disease [126]. 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) [127,128]. 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 [127, 128]. 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) [129], 26 subsequent patients treated under this protocol died [130]. 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 [131]. 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 [132]. 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 [133]. 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 [134,135]. This intraneural invasion may be responsible for the painlessness of Buruli ulcer, which may lead to the delays in care-seeking by infected individuals [134,135].

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uniform multidrug therapy (U-MDT, rifampicin, clofazimine, dapsone for 6 months) for all types of leprosy [140–142]. Although prednisolone is commonly used for the treatment of neuropathy, the long-term benefit is uncertain [143]. 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 [144]. 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 [145]. 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 [145]. 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 [146, 147]. Case reports from the 1930s to 1940s described meningoencephalitis in patients with lymphogranuloma venereum [148–150], however an association between the two could not be proven based on the diagnostic tests available at the time [151]. Even as recently as the 1980s, a report of C. trachomatis as the causative agent in a case of meningoencephalitis [152] was challenged based on inadequate serological proof of association [153]. 4.4.4. Yaws (Treponema pallidum pertenue) Several authors report no nervous system manifestations of yaws [154,155]. 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

4.4.2. Leprosy (Mycobacterium leprae) Leprosy is one of the most common, treatable causes of peripheral neuropathy worldwide [136]. 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) [137]. 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 [137,138]. Nerve abscess and T2 hyperintensities in the spinal cord on MRI have been rarely reported [136,139]. 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

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

Fig. 2. Helminth, 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×).

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Neurologic manifestations of the neglected tropical diseases.

The World Health Organization has identified 17 neglected tropical diseases (NTDs) that disproportionately affect the world's poorest populations. The...
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