Fatal parasitic meningoencephalomyelitis caused by Halicephalobus deletrix: a case report and review of the literature.
* Infection with the saprophagous nematode Halicephalobus species
is uncommon but has been reported in horses worldwide. Only 3 human
cases have been previously described, all of which have been fatal. We
report a fourth fatal case, which occurred in a 39-year-old woman who
presented with meningeal signs, altered mental status, and a prodromal
pruritic rash. Diagnostic evaluation included an open brain biopsy,
which was diagnosed as granulomatous vasculitis. The patient
subsequently died after a course of steroids and cyclophosphamide. At
autopsy, a robust perivascular mixed inflammatory infiltration of the
brain parenchyma, meninges, and ventricular system was present with
larval forms and mature nematodes morphologically consistent with
Halicephalobus deletrix. Although extremely rare, this organism needs to
be considered in the differential diagnosis of human helminthic
infection of the central nervous system.
(Arch Pathol Lab Med. 2010;134:625-629)
|Article Type:||Case study|
(Complications and side effects)
Helminthiasis (Case studies)
Antiparasitic agents (Dosage and administration)
Meningoencephalitis (Risk factors)
Meningoencephalitis (Drug therapy)
Meningoencephalitis (Case studies)
Ondrejka, Sarah L.
Procop, Gary W.
Lai, Keith K.
Prayson, Richard A.
|Publication:||Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165|
|Issue:||Date: April, 2010 Source Volume: 134 Source Issue: 4|
|Geographic:||Geographic Scope: United States Geographic Code: 1USA United States|
Halicephalobiasis is a helminthic infection caused by the genus
Halicephalobus, which is a free-living soil saprophyte belonging to the
nematode order Rhabditida. Halicephalobic infection is intermittently
encountered in horses. Although multiple species of Halicephalobus
exist, the species Halicephalobus deletrix is responsible for equine
infection and the small number of fatal infections in humans. The
organism is commonly referred to by its genus name, because the species
are difficult to distinguish morphologically.
Infections caused by Halicephalobus sp are occasionally encountered in equine veterinary practices. Infections in horses cause extensive tissue destruction and granulomatous lesions that most commonly affect the central nervous system (CNS), skin, and kidneys. The varied manifestations have included nasal tumor involvement, (1) osteomyelitis, (2) granulomatous prepuce infection,3 granulomatous nephritis, (4) meningoencephalitis, (4,5) and occasionally disseminated disease. (6) Several equine cases involving the CNS have presented with ataxia, all of which culminated in euthanasia or death by overwhelming infection. (5,7,8) The postulated route of entry in horses is penetration of skin and mucous membranes by the free-living soil nematode with invasion of other adjacent organs including bone and sinuses followed by hematogenous spread. Evidence of either prenatal transmission or transmission through breast milk was documented in 1 equine case report. (9)_
We report the fourth human with an infection caused by Halicephalobus; the patient, who presented acutely, was a 39-year-old woman with a history of migraine headaches. The clinicopathologic features of the case and the differential diagnosis are discussed.
REPORT OF A CASE
The patient was a 39-year-old woman from Kentucky with a past medical history significant for migraine headaches, depression, and vitiligo. She presented to a local emergency department with the acute onset of headache, altered mental status, and neck pain. Symptoms were preceded 2 weeks earlier by a pruritic rash that involved the upper and lower extremities and subsequently progressed to involve the neck, breast, and abdominal wall. Empiric intravenous antibiotic therapy was initiated. After admission, the patient had a seizure, which prompted an additional workup including lumbar puncture, magnetic resonance imaging, electroencephalogram, and cerebral angiography; the results of these yielded no specific diagnostic abnormalities.
A right temporal lobe biopsy was performed, which was reported to contain chronic active meningoencephalitis with focal chronic granulomatous vasculitis. Possible intracellular, bacteriallike structures were noted at the time of biopsy. No viral inclusions or parasitic organisms were recognized. Differential diagnostic considerations at the time included varicella-zoster viral infection and primary CNS vasculitis.
Cyclophosphamide, prednisone, and antiepileptic therapy was initiated. Her mental status gradually improved from unresponsive to the point that she could follow commands with 1- to 2word responses. She was then discharged to a long-term acute care facility 48 days after initial presentation. She continued to make slow progress for several days but then suffered an abrupt decline in responsiveness with development of fever and leukocytosis. The patient was readmitted to the hospital. Magnetic resonance imaging showed multiple, bilateral contrast-enhancing lesions throughout the brain, which were suggestive of progressive disease (Figure 1). A lumbar puncture showed an elevated white blood cell count with lymphocytic pleocytosis and high protein content consistent with CNS vasculitis. The patient's cerebrospinal fluid was tested for and showed no evidence of infection with cytomegalovirus, herpes simplex viruses, West Nile virus, St Louis virus, coxsackievirus, human immunodeficiency virus, Eastern and Western equine viruses, cryptococcus, and mycobacteria. Lyme and Ehrlichia antibodies were negative and rapid plasminogen reagent testing was nonreactive. The patient developed respiratory failure and died.
[FIGURE 1 OMITTED]
A complete autopsy with evaluation of the brain was performed. Postmortem examination revealed a Hurthle cell adenoma of the thyroid, mild acute bronchopneumonia, and uterine leiomyomata. No nematodes were present in any of organs outside the CNS. Similarly, microscopic examination of all organs and additional sections of peripheral muscular arteries showed no evidence of a systemic vasculitis.
The brain weighed 1230 g. There was mild diffuse cerebral edema with no evidence of subfalcial, uncal, or cerebellar tonsillar herniation present. Microscopic examination of the brain demonstrated an extensive inflammatory process involving the parenchyma, meninges, and ventricular system. The parenchymal lesions were marked by an inflammatory infiltrate composed of macrophages, lymphocytes, plasma cells, and eosinophils, with scattered foreign-body giant cells, Langhans-type giant cells, and occasional neutrophils. Blood vessels showed extensive mural lymphoplasmacytic and histiocytic infiltrates with associated focal hemorrhage and adjacent gliosis. Poorly formed, nonnecrotizing granulomas were present in the parenchyma of the brain (Figure 2, A through C). There were no viral inclusions. Necrotic foci and hemosiderin were present at the site of prior surgical instrumentation, with evidence of regenerative proliferation.
Associated with the inflammatory infiltrates were nematode worms (Figure 2, D). It was not possible to determine the length of the nematodes because an intact complete longitudinal section was not present, but the diameters ranged from 14 to 18 [micro]m (mean, 15.7 [micro]m). The cuticle of the worm was thin and demonstrated fine striations. Characteristic of Halicephalobus deletrix, a rhabditiform esophagus containing a corpus, isthmus, and bulb was observed (Figure 2, E). Lateral alae were not present. Nuclei were seen throughout the internal aspect of the worm. In 1 section, a structure consistent with a reflected ovary was seen (Figure 2, F). Nematodes were identified in the brainstem, cerebellum, and both cerebral hemispheres. Inflammatory foci were noted in the spinal cord without identifiable parasites. Additional organisms were not identified on Gomori methenamine silver, Gram, Ziehl-Nelson, and trichrome stains.
Halicephalobiasis is a rare infection caused by the free-living saprophagous nematodes of the genus Halicephalobus. In humans, the free-living form of this organism appears to enter its host through a break in the skin or oral cavity and proceeds to invade and replicate parthenogenetically within mammalian tissue with a predilection for the CNS. After migration to the CNS, Halicephalobus provokes a brisk inflammatory response, resulting in progressive mental confusion, lethargy, and death. (10)
To our knowledge, the current report is the fourth reported human infection with Halicephalobus (Table). Previous patients with these infections also had brain involvement and infections were uniformly fatal. (11-13) Clinical symptoms common to these cases include mental status changes, lethargy, and fever. Cerebrospinal fluid studies were reported in 2 of the 3 previous patients and showed an elevated white blood cell count with a lymphocytic predominance; this is comparable to findings in the current patient, who also had elevated protein later in her course of illness. The distribution of the disease has consistently included the meninges and parenchyma, with a myelitis component recognized in half of the patients. In 1 patient, a few juvenile forms of the nematodes were found in pulmonary capillaries in sections of the lungs, but it is believed that the worms were carried to the lungs from the CNS not the reverse.11 Another patient case had sections of worms associated with inflammatory infiltrates in the liver and a single nematode in the heart, which incited no cellular response. (13)
Based on the reported instances of previous infections, characteristic gross pathologic findings have included edema, focal hemorrhage, and variable evidence of necrosis. The typical histopathologic pattern is that of predominantly perivascular acute and chronic inflammation, including multinucleated giant cells. Most reports describe regions of gliosis or glial cellular proliferation. In some instances, a more intense inflammatory infiltrate occasionally accompanied by granulomatous inflammation has been observed in association with the organisms themselves.
The typical morphologic features of Halicephalobus deletrix are the distinctive rhabditiform esophagus with corpus, isthmus, and bulb and the dorsiflexed ovary. Only female worms are found in tissue. Adult female worms are 250 to 460 [micro]m by 15 to 25 [micro] m. The larval stages are smaller and have the same features as the fully developed worms but lack a reproductive system. This nematode characteristically lacks lateral or cuticular alae. The cuticle of the worm is thin and has fine striations. (10)
There has been speculation concerning the potential risk factors for the patients reported in the literature. One patient with halicephalobiasis suffered a traumatic farming accident, which resulted in extensive lacerations and considerable wound contamination with manure.11 The second patient reported was admitted to a hospital with leg pain and mental confusion and died 18 days later; the mechanism of infection is unknown. That patient was a small ranch owner on which a few horses were stabled, but he had little to no contact with them. (12) The third fatal infection occurred in a man who was clinically debilitated and possibly acquired the infection from decubitus ulcers. (13) The patient reported here had no known contact with horses and performed only minimal gardening duties. She maintained a koi pond in her backyard, from which she frequently cleared leaves and debris. At the time of initial rash formation, the patient did have a bandage covering a knee scrape. It is possible that contamination of the wound occurred at the time of either the initial injury or thereafter while cleaning around the pond. The 2 previous reports of halicephalobiasis in humans who had wounds as a probable site of entry commented that neither the healed traumatic wounds sustained in a farming accident nor the decubitus ulcers were sampled for microscopic analysis. (11,13) The knee scrape, described in the current case, was well healed and not evident on postmortem examination.
[FIGURE 2 OMITTED]
The presence of nematodes in the CNS is uncommon, and the differential diagnosis is limited. The most common nematodes to consider include Strongyloides stercoralis as part of a hyperinfection syndrome, Toxocara species or less commonly Baylisascaris species as agents of visceral larva migrans, or other nematode worms that may involve the CNS such as Angiostrongylus and Gnathostoma species. The infective forms of Strongyloides are filariform rather than rhabditiform larva and do not have an esophagus that contains a corpus, isthmus, and bulb. In a Strongyloides hyperinfection syndrome, infective larvae should be seen in other organs, particularly the lungs, and adult females should be found in the upper gastrointestinal tract. (10) Toxocara and Baylisascaris both contain lateral alae and possess divergent characteristics compared with the morphologic features of nematodes described in this case. Toxocara larvae have extensive lateral alae, which would be present in all cross sections except the most posterior and anterior ends. In addition to lateral alae, Baylisascaris are 60 [micro] m in diameter and have large excretory columns on cross section. (10,14) Both Angiostrongylus and Gnathostoma species are much larger than Halicephalobus and have other distinguishing features. Angiostrongylus are filariform not rhabditiform structures, and lateral cords are conspicuous at most cross-sectional levels. All Gnathostoma sp share the same morphologic characteristics, including an anterior head bulb with cephalic hooklets and a body covered in cuticular spines. (10,14)
This is the fourth instance of halicephalobiasis in humans and the first report of Halicephalobus deletrix in a female patient. Presenting symptoms were similar among the 4 patients with documented disease and included fever, neurologic signs, headache, mental confusion, and coma. Cerebrospinal fluid analysis is most often nonspecific, disclosing only a lymphocytic pleocytosis. No serologic test currently exists for detection of the organism. No effective therapy exists for the encephalitic or disseminated forms, according to attempts in horses. (15) Antiparasitic agents have been variably successful in only the most localized equine granulomatous infections. Although only a limited number of humans have contracted halicephalobiasis, it is important to include this infection in the differential diagnosis when nematodes are detected in the CNS of a patient.
(1.) Anderson RV, Bemrick WJ. Micronema deletrix n. sp., saprophagous nematode inhabiting a nasal tumor of a horse. Proc Helminthol Soc Wash. 1965;32: 74-75.
(2.) Kreuder C, Kirker-Head CA, Rose P, Gliatto J. What is your diagnosis?: severe granulomatous osteomyelitis associated with Micronema deletrix infection in a horse. J Am Vet Med Assoc. 1 996;209:1070-1071.
(3.) Muller S, Grzybowski M, Sager H, Bornand V, Brehm W. A nodular granulomatous posthitis caused by Halicephalobus sp. in a horse. Vet Dermatol. 2008;19(1):44-48.
(4.) Masataka A, Tomoyuki S, Toyoshi Y, et al. Granulomatous nephritis and meningoencephalomyelitis caused by Halicephalobus gingivalis in a pony gelding. J Vet Med Sci. 2007;69(11):1 187-1190.
(5.) Powers RD, Benz GW. Micronema deletrix in the central nervous system of a horse. J Am Vet Med Assoc. 1977;170:175-177.
(6.) Ruggles AJ, Beech J, Gillette DM, Midla LT, Reef VB, Freeman DE. Disseminated Halicephalobus deletrix infection in a horse. JAm Vet Assoc. 1993;203: 550-552.
(7.) Bryant UK, Lyons ET, Bain FT, Hong CB. Halicephalobus gingivalis-associated meningoencephalitis in a thoroughbred foal. J Vet Diagn Invest. 2006;18(6): 612-615.
(8.) Brojer JT, Parsons DA, Linder KE, Peregrine AS, Dobson H. Halicephalobus gingivalis encephalomyelitis in a horse. Can Vet J. 2000;41(7):559-561.
(9.) Wilkins PA, Wacholder S, Nolan TJ, et al. Evidence for transmission of Halicephalobus deletrix (H. gingivalis) from dam to foal. J Vet Intern Med. 2001; 15(4):412-417.
(10.) Gardiner CH, Meyers WM, Neafie RC, Marty AM. Halicephalobiasis. Strongyloidiasis. Angiostrongyliasis cantonensis. Toxocariasis. In: Meyers WM, Neafie RC, Marty AM, Wear DJ, eds. Helminthiases. Vol 1. Washington, DC: Armed Forces Institute of Pathology; 2000:493-497, 341-347, 375-376, 412-414.
(11.) Hoogstraten J, Young WG. Meningo-encephalomyelitis due to the saprophagous nematode, Micronema deletrix. Can J Neurol Sci. 1 975;2(2):121-126.
(12.) Shadduck JA, Ubelaker J, Telford VQ. Micronema deletrix meningoencephalitis in an adult man. Am J Clin Pathol. 1979;72(4):640-643.
(13.) Gardiner CH, Koh DS, Koh DS, CardellaTA. Micronema in man: third fatal infection. Am J Trop Med Hyg. 1981;30(3):586-589.
(14.) Johnstone PAS, Hira PR, Neafie RC, Klassen-Fischer MK, Marty AM, Ash LR. Gnathostomiasis. Miscellaneous nematodiases. In: Meyers WM, Neafie RC, Marty AM, Wear DJ, eds. Helminthiases. Vol 1. Washington, DC: Armed Forces Institute of Pathology; 2000:448, 516.
(15.) Trostle SS, Wilson DG, Steinburg H, Dzata G, Dubielzig RR. Antemortum diagnosis and attempted treatment of (Halicephalobus) Micronema deletrix infection in a horse. Can Vet J. 1993;34:117-118.
Sarah L. Ondrejka, DO; Gary W. Procop, MD; Keith K. Lai, MD; Richard A. Prayson, MD
Accepted for publication May 15, 2009.
From the Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio.
The authors have no relevant financial interest in the products or companies described in this article.
Reprints: Sarah L. Ondrejka, DO, Cleveland Clinic, Anatomic and Clinical Pathology, 9500 Euclid Ave, L25, Cleveland, OH 44195 (e-mail: firstname.lastname@example.org).
Clinicopathologic Features of Human Halicephalobiasis Case Age, y/Sex Location Presentation Hoogstraten 5/M Manitoba Fever, lethargy, & Young, focal neuro- 1975 (11) logic signs Shadduck et 47/M Texas Headache, nu- al, 1979 (12) chal rigidity, confusion, lethargy Gardiner et 54/M Washington, Fever, chronic al, 1981 (13) DC illness, leth- argy Current case 39/F Kentucky Headache, neck pain, confu- sion, rash Case Gross Findings Histopathology Hoogstraten Hyperemia of Perivascular mixed inflam- & Young, white matter matory infiltrate, large 1975 (11) macrophages, multinucle- ated giant cells, hemor- rhages, fibrin thrombi Shadduck et Edema, dull me- Perivascular mixed inflam- al, 1979 (12) ninges, focal matory infiltrate, multinu- necrosis cleated giant cells, necro- sis, hemorrhages, gliosis Gardiner et Soft, autolytic Perivascular mixed inflam- al, 1981 (13) changes, focal matory infiltrate, paren- necrosis and chymal microabscesses hemorrhage Current case Minimal edema Perivascular mixed inflam- matory infiltrate, multinu- cleated giant cells, gliosis Case Distribution Hoogstraten Meningoencephalomye- & Young, litis 1975 (11) Immature forms in alve- olar capillary walls Shadduck et Meningoencephalitis al, 1979 (12) Gardiner et Meningoencephalitis al, 1981 (13) Liver with microabscess- es and sections of worms Single nematode with no inflammatory re- sponse in myocardium Current case Meningoencephalomye- litis
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