The returned traveler with neurologic manifestations: could my patient have a parasite?

PURPOSE OF REVIEW: The present review focuses on parasitic infections of the central nervous system (CNS) that can affect the international traveler. RECENT FINDINGS: The epidemiology of imported parasitic infections is changing and clinicians are treating increasing numbers of returned travelers with parasitic infections in the CNS with which they are not familiar. SUMMARY: The epidemiology, life cycle, clinical manifestations, diagnosis, and treatment of parasites that affect the CNS will be discussed.

Toxocara Brain Infection in Pigs is Not Associated with Visible Lesions on Brain Magnetic Resonance Imaging.

Human exposure to Toxocara spp. is very frequent, and its larvae can cross the blood-brain barrier and invade the central nervous system (CNS), causing neurotoxocariasis. We aimed to establish a neurotoxocariasis animal model in pigs confirmed by necropsy. Also, the presence of larvae in the CNS was assessed using magnetic resonance imagings (MRIs), to establish brain lesions caused by the larvae migration. Ten pigs were infected intraperitoneally with 3,000 Toxocara larvae. Cerebral toxocariasis was evaluated using MRIs at days 7, 14, 21, and 49, and pigs were euthanized after the examination. Brain tissues were examined by microscopy, and five pigs presented Toxocara, most frequently at day 21 after infection. None of the 10 pigs showed alterations on MRIs. Our study confirms that intraperitoneal Toxocara infection produces neurotoxocariasis in pigs. Toxocara larvae passage through the brain does not seem to produce lesions detectable at MRIs.

Neurotoxocariasis.

Human toxocariasis, caused by larvae of the Toxocara spp., is one of the most prevalent zoonosis with a worldwide distribution. Toxocara larvae can cross the blood-brain barrier, invading the central nervous system (CNS), leading to neurotoxocariasis. The clinical presentation consists of a wide spectrum of neurological manifestations such as meningitis, encephalitis, myelitis and cerebral vasculitis, but asymptomatic CNS infection is common. Despite the high seroprevalence, neurotoxocariasis is thought to be rare, even if in many animal models larvae usually migrate to the brain. Indeed, diagnosis of neurotoxocariasis is rarely considered, and the exact prevalence of CNS involvement is still unknown. Diagnosis of neurotoxocariasis is generally based on the detection of specific antibodies to Toxocara excretory-secretory antigens by ELISA in CSF or serum, and clinical and radiological improvement after anthelmintic therapy, but definitive diagnosis is given by histological confirmation, which is rarely available. Treatment is based on anti-helminthic drugs, commonly albendazole, generally administered with concomitant corticosteroids coverage. At the population level, serological studies suggest an association between Toxocara infections and epilepsy, as well as with other neurodegenerative and psychiatric disorders. Nonetheless the possible role of Toxocara spp. in the pathogenesis of these disorders is still matter of debate.

Pathogenesis of cerebral toxocariasis and neurodegenerative diseases.

Toxocara canis belongs to one of zoonotic parasites that commonly infects canines worldwide, and its eggs in host faeces may contaminate the food, water, soil and their fur as well as the larvae entrapped in the granuloma can infect paratenic hosts including mice and humans. Survivability of T. canis embryonated eggs under moist, cool conditions may be as long as 2-4 years or more. In paratenic hosts such as mice and humans, T. canis L3 larvae neither moult, grow, nor replicate and will wander through a number of internal organs in humans so as to cause Th2-dominant pathology in various internal organs as leading to neurotoxocariasis (NT), ocular toxocariasis (OT), or visceral larva migrans (VLM). Although the systemic immune response to T. canis has been widely reported, the immune response in the brain has received little attention. Differential cytokine expression and other brain injury-associated biomarkers or neurodegeneration-associated factors have been observed in infected versus uninfected outbred and inbred mice. Preliminary data have also suggested a possible link between significant memory impairment and cytokine production associated with T. canis infection in the hippocampus which has been long recognised as being responsible for learning and memory functions. Notably, it remains an enigma concerning cerebral invasion by T. canis larvae rarely induces a recognisable neurological syndrome or its involvement in neuropathological disorders in humans. Exploration of the relationship between host and parasite in the brain may elucidate the cryptic symptoms of human cerebral toxocariasis, with patients presenting with mental retardation, epilepsy, neurodegeneration and other central nervous system (CNS) disorders.

Simultaneous occurrence of two new myxosporean species infecting the central nervous system of Hypopygus lepturus from Brazil.

This paper describes 2 new myxosporean species, Henneguya lepturus sp. nov. and Thelohanellus lepturus sp. nov., simultaneously infecting the brain and spinal cord of Hypopygus lepturus Hoedeman, 1962 (Teleostei, Hypopomidae) from the Brazilian Amazon (Roraima State). Several spherical cysts of varying dimensions (up to 135 µm) were microscopically observed. The myxospores of H. lepturus sp. nov. measured 25.8 µm in total length, having an ellipsoidal body (12.4 × 6.4 × 2.2 µm) and 2 equal tapering tails (13.4 µm in length). Each of the 2 pyriform polar capsules measured 4.4 × 1.6 µm and possessed a polar filament coiled in 8-9 turns. The myxospores of T. lepturus sp. nov. were pyriform, formed by 2 equal valves (17.7 × 9.1 × 4.3 µm) surrounding a single polar capsule (10.9 × 3.5 µm) that had a coiled polar filament with 13-16 turns and a binucleated sporoplasm that contained several circular sporoplasmosomes. Molecular analysis of the small subunit (SSU) rRNA gene sequences of these 2 species were in agreement with the taxonomic classification derived from the ultrastructure of the myxospores. Histopathology of the host tissue showed degradation of the myelinated axons surrounding the cysts of both species, with the hosts displaying behavioural changes and erratic movements when observed in an aquarium.

Neuroinvasions caused by parasites

Parasitic diseases of the central nervous system are associated with high mortality and morbidity. Many human parasites, such as Toxoplasma gondii, Entamoeba histolytica, Trypanosoma cruzi, Taenia solium, Echinococcus spp., Toxocara canis, T. cati, Angiostrongylus cantonensis, Trichinella spp., during invasion might involve the CNS. Some parasitic infections of the brain are lethal if left untreated (e.g., cerebral malaria ­ Plasmodium falciparum, primary amoebic meningoencephalitis (PAM) ­ Naegleria fowleri, baylisascariosis ­ Baylisascaris procyonis, African sleeping sickness ­ African trypanosomes). These diseases have diverse vectors or intermediate hosts, modes of transmission and endemic regions or geographic distributions. The neurological, cognitive, and mental health problems caused by above parasites are noted mostly in low-income countries; however, sporadic cases also occur in non-endemic areas because of an increase in international travel and immunosuppression caused by therapy or HIV infection. The presence of parasites in the CNS may cause a variety of nerve symptoms, depending on the location and extent of the injury; the most common subjective symptoms include headache, dizziness, and root pain while objective symptoms are epileptic seizures, increased intracranial pressure, sensory disturbances, meningeal syndrome, cerebellar ataxia, and core syndromes. Many early symptoms of CNS invasion are often nonspecific therefore a diagnosis can be difficult. This article presents the epidemiology, pathophysiology and clinical manifestations of selected parasitic neuroinfections.

EGYPTIAN EOSINOPHILIC AND INFECTIOUS MENINGOENCEPHA- LITIS AND THEIR IMPACT ON PSYCHOLOGICAL ASPECTS.

Meningoencephalitis is an acute inflammation of the brain and spinal cord & their covering protective membranes. Meningitis can be life-threatening because of the inflammation's proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency. The commonest symptoms of meningitis are headache and neck stiffness associated with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or loud noises (phonophobia). Children often exhibit only nonspecific symptoms, such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash. A broad variety of allergic, infectious, neoplastic, and idiopathic diseases are associated with increased blood and/or tissue eosinophilia and range in severity from self-limited conditions to life-threatening disorders. Although accepted upper limits of normal blood eosinophil numbers vary somewhat, a value above 600 eosinophils /microL of blood is abnormal in the vast majority of cases. Generally speaking, there are several possible causes of eosinophils in the CSF; undoubtedly parasitic infection is one of the main causes.

Aberrant Ancylostoma sp. in the brain of a dog.

A 14-month-old, male American Bulldog presented to Texas A&M University Veterinary Medical Teaching Hospital in August of 2012 for anorexia, hydrophobia and gradually worsening neurologic signs. Grossly hemorrhage on the left side of the caudal cerebrum and cerebellum was observed and histologically corresponded with necrohemorrhagic and lymphoplasmacytic encephalitis associated with adult nematodes. Based on morphology and molecular analysis, these were identified as Ancylostoma sp.

A rare case of cerebral hydatidosis caused by a G1 genotype of Echinococcus granulosus in a cow from Iran.

Hydatidosis is a medically and veterinary important parasitic disease that is endemic in many parts of the world. Unilocular hydatid cysts may develop in almost any part of the body. Up to 70% of hydatid cysts are located in the liver, followed by 25% in the lungs. Cerebral hydatidosis is an uncommon manifestation of the disease, occurring in less than 1/1000 infected hosts, yet diagnosis does pose a problem. We have reported an exceptionally rare case of cerebral hydatidosis in cattle. This is the first report to describe the characteristic pathological features of the cerebral hydatidosis in cattle caused by the G1 genotype of Echinococcus granulosus. Genotypic analysis was performed on a hydatid cyst from a cow originating from southern Iran, based on the sequence analysis of the cox1 mitochondrial gene.

Rickettsiae, protozoa, and opisthokonta/metazoa.

Rhizobiales (formerly named Rickettsiales) cause in rare instances meningitis and meningovasculitis, respectively. In case of history of exposure, infection by Rhizobiales needs to be considered since both diagnosis and therapy may be extremely difficult and pathogen-specific. The same applies to protozoa; in this chapter, Babesia species, free-living amoebae and Entamoeba histolytica infection, including severe meningitis and brain abscess, infection by Trypanosoma species (South American and African trypanosomiasis) are discussed with respect to history, epidemiology, clinical signs, and symptoms as well as differential diagnosis and therapy. Parasitic flatworms and roundworms, potentially able to invade the central nervous system, trematodes (flukes), cestodes (in particular, Cysticercus cellulosae), but also nematodes (in particular, Strongyloides spp. in the immunocompromised) are of worldwide importance. In contrast, filarial worms, Toxocara spp., Trichinella spp., Gnathostoma and Angiostrongylus spp. are seen only in certain geographically confined areas. Even more regionally confined are infestations of the central nervous system by metazoa, in particular, tongue worms (=arthropods) or larvae of flies (=maggots). The aim of this chapter is (1) to alert the neurologist to these infections, and (2) to enable the attending emergency neurologist to take a knowledgeable history, with an emphasis on epidemiology, clinical signs, and symptoms as well as therapeutic management possibilities.

Mechanisms of CNS invasion and damage by parasites.

Invasion of the central nervous system (CNS) is a most devastating complication of a parasitic infection. Several physical and immunological barriers provide obstacles to such an invasion. In this broad overview focus is given to the physical barriers to neuroinvasion of parasites provided at the portal of entry of the parasites, i.e., the skin and epithelial cells of the gastrointestinal tract, and between the blood and the brain parenchyma, i.e., the blood-brain barrier (BBB). A description is given on how human pathogenic parasites can reach the CNS via the bloodstream either as free-living or extracellular parasites, by embolization of eggs, or within red or white blood cells when adapted to intracellular life. Molecular mechanisms are discussed by which parasites can interact with or pass across the BBB. The possible targeting of the circumventricular organs by parasites, as well as the parasites' direct entry to the brain from the nasal cavity through the olfactory nerve pathway, is also highlighted. Finally, examples are given which illustrate different mechanisms by which parasites can cause dysfunction or damage in the CNS related to toxic effects of parasite-derived molecules or to immune responses to the infection.

Baylisascaris larva migrans.

Baylisascaris procyonis is a roundworm of the raccoon found primarily in North America but also known to occur in other parts of the world including South America, Europe, and Japan. Migration of the larvae of this parasite is recognized as a cause of clinical neural larva migrans (NLM) in humans, primarily children. It is manifested as meningoencephalitis associated with marked eosinophilia of the cerebrospinal fluid and peripheral blood. Diagnosis is made by recovering and identifying larvae in or from the tissues, epidemiological history, serology, and imaging of the central nervous system. Treatment is with albendazole and steroids, although the prognosis is generally poor. This parasite can also cause ocular larva migrans (OLM) which usually presents as diffuse unilateral subacute neuroretinitis (DUSN). The ocular diagnosis can be made by visualizing the larva in the eye and by serology. Intraocular larvae can be destroyed by photocoagulation although albendazole and steroids may also be used. However, once visual disturbance is established the prognosis for improved vision is poor. Related Baylisascaris species occur in skunks, badgers, and certain other carnivores, although most cases of NLM are caused by B. procyonis. Baylisascaris procyonis has also been found in kinkajous in the USA and South America and may also occur in related procyonids (coatis, olingos, etc.).

Paragonimiasis.

Human paragonimiasis is caused by nine species of Paragonimus, namely, P. westermani, P. africanus, P. heterotremus, P. kellicotti, P. mexicanus, P. siamensis, P. skrjabini, P. skrjabini miyazakii, and P. uterobilateralis. Cerebral or spinal involvements are most common in P. westermani, and can also occur in P. skrjabini, P. skrjabini miyazakii, and P. mexicanus. In P. westermani, cerebral paragonimiasis comprises about 45% of all extrapulmonary paragonimiasis cases, and accounts for about 1% of all paragonimiasis patients. In cerebral paragonimiasis, seizure, headache, visual disturbance, and motor and sensory disturbances are the five major clinical symptoms. The most commonly performed diagnostic procedures for cerebral infections are serological tests to detect circulating antibodies or antigens using ELISA or immunoblotting, and radiological examinations, including plain skull x-rays, brain CT, and MR scans. The drug of choice is praziquantel at the dose of 25mg/kg three times daily for 2-3 days. In severe infections, a second set of treatment may be needed. Triclabendazole can be used in P. uterobilateralis, P. mexicanus, and P. skrjabini infections with the dose of 10mg/kg twice a day; however, its efficacy in P. westermani infection, in particular cerebral infections, remains to be elucidated.

Direct and indirect affection of the central nervous system by Fasciola infection.

Fascioliasis is a worldwide, zoonotic disease caused by the liver trematodes Fasciola hepatica and Fasciola gigantica. Neurological fascioliasis has been widely reported in all continents, affecting both sexes and all ages. Two types of records related to two physiopathogenic mechanisms may be distinguished: cases in which the neurological symptoms are due to direct effects of a migrating juvenile present in the brain or neighboring organ and with cerebral lesions suggesting migration through the brain; and cases with neurological symptoms due to indirect immuno-allergic and toxic effects at distance from flukes in the liver. Neurological manifestations include minor symptoms, mainly cephalalgias, and major symptoms which are nonspecific, extremely diverse, varying from one patient to another and even within the same patient, and comprising meningeal manifestations and impressive neurological manifestations. The puzzling neurological polymorphism leads to confusion with cerebral tumors, multiple sclerosis, lesions of the brainstem, or cerebro-meningeal hemorrhages. Only blood eosinophilia and information on infection source guide toward correct diagnosis by appropriate coprological and/or serological techniques. Although neurological patients usually recover after fasciolicide treatment or surgical worm extraction, sequelae, which are sometimes important, remain in several patients. The need to include possible neurological complications within the general frame of fascioliasis becomes evident.

Babesia lengau associated with cerebral and haemolytic babesiosis in two domestic cats.

BACKGROUND: Although reported sporadically from various countries, feline babesiosis appears to be a significant clinical entity only in South Africa, where Babesia felis is usually incriminated as the causative agent. Babesia lengau, recently described from asymptomatic cheetahs, has now possibly been incriminated as the causative agent in two severe clinical cases in domestic cats. FINDINGS: Both cats were euthanised in extremis. While typical feline babesiosis in South Africa is an afebrile disease with a chronic manifestation, there was acute onset of severe clinical signs in both cats and their body temperatures were above the normal range when they were presented for treatment. Haemolytic anaemia was confirmed in one case. To our knowledge, this is the first report of cerebral babesiosis in cats.On reverse line blot 18S rDNA PCR products obtained from both cats showed positive hybridization profiles with the B. lengau species-specific probe. The two partial parasite 18S rRNA gene sequences obtained, showed high sequence similarity (99.9%) to B. lengau. In a representative tree constructed by the neighbor-joining method using the two-parameter model of Kimura the two obtained partial 18S rDNA sequences and that of B. lengau formed a monophyletic group with B. conradae and sequences previously isolated from humans and wildlife in the western USA. CONCLUSION: All clinical cases of feline babesiosis in South Africa are not necessarily caused by B. felis. Other piroplasms, e.g. B. lengau, may be incriminated in clinical cases, especially those occurring outside the known endemic area.

Parasitoses of the human central nervous system.

Cerebral involvement in parasitoses is an important clinical manifestation of most of the human parasitoses. Parasites that have been described to affect the central nervous system (CNS), either as the dominant or as a collateral feature, include cestodes (Taenia solium (neurocysticerciasis), Echinococcus granulosus (cerebral cystic echinococcosis), E. multilocularis (cerebral alveolar echinococcosis), Spirometra mansoni (neurosparganosis)), nematodes (Toxocara canis and T. cati (neurotoxocariasis), Trichinella spiralis (neurotrichinelliasis), Angiostrongylus cantonensis and A. costaricensis (neuroangiostrongyliasis), Gnathostoma spinigerum (gnathostomiasis)), trematodes (Schistosoma mansoni (cerebral bilharziosis), Paragonimus westermani (neuroparagonimiasis)), or protozoa (Toxoplasma gondii (neurotoxoplasmosis), Acanthamoeba spp. or Balamuthia mandrillaris (granulomatous amoebic encephalitis), Naegleria (primary amoebic meningo-encephalitis), Entamoeba histolytica (brain abscess), Plasmodium falciparum (cerebral malaria), Trypanosoma brucei gambiense/rhodesiense (sleeping sickness) or Trypanosoma cruzi (cerebral Chagas disease)). Adults or larvae of helminths or protozoa enter the CNS and cause meningitis, encephalitis, ventriculitis, myelitis, ischaemic stroke, bleeding, venous thrombosis or cerebral abscess, clinically manifesting as headache, epilepsy, weakness, cognitive decline, impaired consciousness, confusion, coma or focal neurological deficits. Diagnosis of cerebral parasitoses is dependent on the causative agent. Available diagnostic tools include clinical presentation, blood tests (eosinophilia, plasmodia in blood smear, antibodies against the parasite), cerebrospinal fluid (CSF) investigations, imaging findings and occasionally cerebral biopsy. Treatment relies on drugs and sometimes surgery. Outcome of cerebral parasitoses is highly variable, depending on the effect of drugs, whether they are self-limiting (e.g. Angiostrongylus costaricensis) or whether they remain undetected or asymptomatic, like 25% of neurocysticerciasis cases.

A recombinant matrix metalloproteinase protein from Gnathostoma spinigerum for serodiagnosis of neurognathostomiasis.

Neurognathostomiasis is a severe form of human gnathostomiasis which can lead to disease and death. Diagnosis of neurognathostomiasis is made presumptively by using clinical manifestations. Immunoblotting, which recognizes antigenic components of molecular mass 21 kDa and 24 kDa in larval extracts of Gnathostoma spinigerum (Gs 21/24), has high sensitivity and specificity for diagnosis of neurognathostomiasis. However, only very small amounts of the Gs 21/24 antigens can be prepared from parasites harvested from natural or experimental animals. To overcome this problem, we recently produced a recombinant matrix metalloproteinase (rMMP) protein from G. spinigerum. In this study, we evaluated this rMMP alongside the Gs 21/24 antigens for serodiagnosis of human neurognathostomiasis. We studied sera from 40 patients from Srinagarind Hospital, Khon Kaen University, Thailand, with clinical criteria consistent with those of neurognathostomiasis, and sera from 30 healthy control adults from Thailand. All sera were tested for specific IgG antibodies against both G. spinigerum crude larval extract and rMMP protein using immunoblot analysis. The sensitivity and specificity for both antigenic preparations were all 100%. These results show that G. spinigerum rMMP protein can be used as an alternative diagnostic antigen, in place of larval extract, for serodiagnosis of neurognathostomiasis.

[The immunologic factors in cerebrospinal liquor under bacterial, fungous or parasitic neuro-infections: a literature review].

The prognosis of course and outcome of inflectional inflammatory diseases of central nervous system, indicators of inflammatory reaction and immune response in cerebrospinal liquor in patients has been investigated.