JPC SYSTEMIC PATHOLOGY
NERVOUS SYSTEM
February 2023
N-P08 (NP)
Signalment (JPC #1085340): A cow
HISTORY: This cow from southern Africa was experiencing signs of a CNS disturbance.
HISTOPATHOLOGIC DESCRIPTION: Cerebrum, level of the hippocampus: Diffusely filling leptomeningeal and to a lesser extent cerebral blood vessels, occasionally infiltrating blood vessel walls, and occasionally expanding the perivascular space are numerous lymphoblastic cells that are up to 15 µm in diameter and often contain intracytoplasmic, round to oval, 2-3 µm diameter, basophilic, protozoal macroschizonts that are surrounded by a clear halo (Koch's blue bodies). There are scattered mitotic figures among the lymphoblastic cells in the vascular lumina. Rarely, vessel lumina within the leptomeninges are occluded by abundant eosinophilic fibrillar material (organizing thrombi) with enmeshed lymphocytes. Blood vessels are often lined by hypertrophied endothelium. There is multifocal necrotizing vasculitis characterized by disruption of vascular endothelium and portions of the vessel wall with replacement by variable amounts of necrotic debris and lymphoblast infiltration. There is a focus of liquefactive necrosis within the white matter characterized by loss of architecture with replacement by scattered eosinophilic cellular and karyorrhectic debris, spongiosis, and mild gliosis. At the periphery of the area of necrosis, there are few swollen, eosinophilic axons (spheroids).
MORPHOLOGIC DIAGNOSIS: Cerebrum and leptomeninges, blood vessels: Lymphocytosis, lymphoblastic, intravascular, diffuse, severe, with lymphoblastic and necrotizing vasculitis, multifocal necrotizing encephalitis, and intralymphoblastic intracytoplasmic protozoal macroschizonts, breed unspecified, bovine.
ETIOLOGIC DIAGNOSIS: Cerebral theileriosis
CAUSE: Theileria taurotragi
CONDITION: Turning sickness
GENERAL DISCUSSION:
· Theileria spp. are obligate intracellular protozoa of the order Piroplasmida, family Theileriidae, and are the only genus that transforms its mammalian host cells
· OIE listed reportable disease in cattle, endemic in Africa
· Theileria spp. are tick transmitted, live within circulating blood cells, with leukocytic phase (macro- and then micro-schizonts) & erythrocytic phase (merozoites), infected lymphocytes transformed to lymphoblasts; cause vascular infarcts within the CNS
· Theileria spp. reproduce by schizogony in lymphocytes (leukocytic or tissue phase) and are subsequently found in red cells (erythrocytic phase)
· In ruminants, disease caused by Theileria spp. is characterized by fever, lymphoproliferative disorders, and varying degrees of leukopenia and/or anemia
· The outcome of exposure is largely determined by the susceptibility of the cattle; indigenous animals may have a morbidity rate of 100% but mortality of less than 5%, whereas introduced animals can have 100% morbidity with 90% mortality
· African buffalo and waterbuck are reservoirs of infection
· Bovine cerebral theileriosis is an aberrant form of theilerial infection (T. taurotragi or T. parva) characterized by the accumulation of parasitized lymphoblasts in the cerebral blood vessels which leads to thrombosis and infarction
PATHOGENESIS:
· Parasitic schizont induced transformation, proliferation, and dissemination of schizont-infected lymphoblasts to multiple organs and bloodstream resulting in intravascular lymphoproliferative foci that mix with fibrin thrombi and result in thrombosis (of meningocerebral and spinal cord vessels among others), infarction, hemorrhage, necrosis, edema, and CNS signs
· Acquired immunity to T. parva primarily involves CD8+ T cell lysis of schizont infected cells
· Considered the result of a massive reinfection of a partially immune animal
· Infected lymphocytes are transformed in vitro into lymphoblastic cells: uncontrolled proliferation is induced via activated signaling pathways as well as degradation of the inhibitor of NF-kB; NF-kB becomes persistently activated, protecting the cell from apoptosis; NF-kB upregulates IL-2 and IL-2R, which is mitogenic for T cells.
LIFE CYCLE:
· Tick (usually Rhipicephalus spp.) bites host, transmits sporozoite > sporozoite invades T cells (primarily CD4+), B cells, and monocytes/macrophages through receptor-mediated parasite-directed phagocytosis > infected lymphocytes are transformed into lymphoblastic cells > macroschizonts (Koch’s blue body) develop in the cytoplasm of the transformed cells then divide synchronously with host lymphocytes, infecting the daughter cells > after a few days, macroschizonts enter the microschizont stage, host cells are destroyed, and merozoites are released > merozoites parasitize erythrocytes > infected erythrocytes ingested by tick nymph > with maturation to adult tick, sporozoites proliferate in salivary glands
· Incubation period of 8-21 days
TYPICAL CLINICAL FINDINGS:
· Acute: Cerebral theileriosis is usually afebrile, with sudden onset of circling, staggering, head pressing, blindness, opisthotonus, nystagmus, recumbency, and death in 2 to 21 days
· Chronic: Muscular incoordination, blindness, and death within 6 months
· Anemia, thrombocytopenia, lymphopenia, icterus
TYPICAL GROSS FINDINGS:
· Acute: Multifocal infarcts; meningocerebral congestion, hemorrhage, and thrombosis; yellowish discoloration of brain; intraventricular hemorrhage
· Chronic: Resorption of necrotic tissue results in intracerebral cystic spaces
TYPICAL LIGHT MICROSCOPIC FINDINGS:
· Schizonts within lymphocytes, piroplasms within erythrocytes
· Parasitized lymphocytes containing macroschizonts (Koch’s bodies) localize by embolism or sequestration in cerebrospinal vessels and produce hemorrhagic infarcts; up to 60% of lymphocytes may contain macroschizonts
· Piroplasms within erythrocytes: pleomorphic; cocci, rings, rods, pears, Maltese crosses 1.5-2 µm x 0.5-1 µm
ULTRASTRUCTURAL FINDINGS:
· Apicomplexan: Acristate mitochondria, conid, micronemes, rhoptres, subplasmalemmal membrane
ADDITIONAL DIAGNOSTIC TESTS:
· Giemsa: Stains intraerythrocytic piroplasms (blood smears, lymph node biopsies, impression smears of many tissues)
· Speciation requires DNA-based molecular (PCR) or serologic assays (e.g. IFA, ELISA)
DIFFERENTIAL DIAGNOSIS:
Microscopic lesions:
· Cerebral babesiosis (N-P07): intraerythrocytic protozoan with a monomorphic population of piroplasms, causes acute hemolytic anemia, hemoglobinuria, and chronic weight loss
· Lymphoblastic leukemia: no macroschizonts
· Malignant catarrhal fever (D-V15, S-V01): perivascular lymphocytic proliferation
Clinical differentials:
· Heartwater (Ehrlichia ruminatum (formerly Cowdria ruminatum)),
· Rabies (N-V06)
· Listeriosis (N-B04)
· Anaplasma marginale (bovine infectious anemia)
· Thrombotic meningoencephalitis (Histophilus somni, N-B03)
· Sporadic bovine encephalomyelitis (Chlamydia pecorum, N-B05)
· Cerebral cortical polioencephalomalacia (N-T02)
· Lead poisoning (N-T05)
COMPARATIVE PATHOLOGY:
· Theileria spp., Babesia spp., and Cytauxzoon spp. are related piroplasms that infect erythrocytes
o Theileria also forms schizonts in lymphocytes
o Cytauxzoon also forms schizonts in subendothelial and intravascular macrophages
· Theileria spp are classified as pathogenic (schizont transforming), and benign to mildly pathogenic (non-transforming)
· Oriental theileriosis caused by T. orientalis, transmitted by Haemophysalis ticks, is increasingly being associated with disease outbreaks in Asia and Australia, with similar signs to East Coast fever and Tropical/Mediterranean fever
· T. buffeli causes mild anemia and lymphoid hyperplasia, and is the only species found in the US (one case report of affected beef cattle in Missouri)
· Other Theileria spp: T. mutans, T. velifera, T. taurotragi, T. buffeli, T sergenti: usually asymptomatic; can increase severity of East Coast fever and tropical theileriosis
· Giraffe: one report of Theileria spp.
· Bovids: African buffalo, blue wildebeest, tsessebe, waterbuck, Grant’s gazelle, klipspringer, blesbok, reedbuck, bushbuck, nyala, common eland, sable, roan, kudu, gray duiker, and American bison; multiple Theileria spp. causing lymphadenopathy, splenomegaly, pulmonary edema, and petechial and ecchymotic hemorrhage, lymphoid proliferation. In addition to lymphoid tissue, infiltration of schizont-containing cells may occur in any tissue including kidney, gastrointestinal tract, liver, lung, heart, and brain
· Indian water buffalo and non-indigenous cattle: The worst theilerial diseases with high mortality in non-indigenous cattle and Indian water buffalo:
o East Coast fever (ECF, H-P05) (east and central Africa) caused by T. parva, also transmitted by Rhipicephalus spp. ticks, myocarditis
o Tropical/Mediterranean theileriosis (North Africa and central Asia) caused by T. annulata, transmitted by Hyalomma spp. ticks
Both replicate in macrophages; acute disease due to massive lympholysis and progressive anemia, progresses to massive leukopenia and terminally, hypoplastic bone marrow; grossly resembles malignant catarrhal fever.
· African wild artiodactyls (e.g. roan antelope) Theileria spp. associated mortality
· Equids, camels, South American tapir: T. equi (formerly Babesia equi), Babesia caballi, either can cause autoimmune inflammatory myopathy with chronic infection
· Small ruminants
o Malignant Ovine Theileriosis, caused by T. lestoquardi, is the most virulent species; occurs in Asia, the Middle East, and parts of Africa and Europe
o T. separate and T. ovis can also infect sheep and goats
Cervids: Amblyomma americanum vector of T. cervi
o Mule deer: T. cervi rarely mild anemia; vector is Amblyomma Americanum
o Reindeer: T. tarandirangiferis
o Others: T. uilenbergi, T. luwenshuni, T. capreoli, and T. ovis, and Theileria OT3
· Dogs: T. annae in Spain; caused anemia and protein-losing nephropathy
· Red fox: T. anna in Croatia
· Domestic and wild cats: Cytauxzoon felis (H-P04, T. felis) occurs in South and Midwest US and causes anemia, pallor, icterus, acute death; many large schizonts (megaloschizonts) are found within macrophages, and signet ring shape/bipolar organisms are within erythrocytes
References:
1. Agnew D. Camelidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:169.
2. Burgess HJ, Lockerbie BP, Ayalew LE, Dibernardo A, Hrazdilová K, Modry D, Bollinger TK. Species-specific PCR assay for the detection of Babesia odocoilei. J Vet Diagn Invest. 2021;33(6):1188-1192.
3. Clift SJ, Collins NE, Oosthuizen MC, et al. The pathology of pathogenic theileriosis in African wild artiodactyls. Vet Pathol. 2020; 57(1):24-48.
4. Clift SJ, Martí-Garcia B, Lawrence JA, Mitchell EP, Fehrsen J, Martínez J, Williams JH, Steyl JCA. Theileriosis in naturally infected roan antelope (Hippotragus equinus). Vet Pathol. 2022;59(6):1031-1046.
5. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:450-451.
6. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:832-833.
7. Gal A, Castillo-Alcala F. Cardiovascular System, Pericardial Cavity, and Lymphatic Vessels. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 655, 687.
8. Jones MEB, Gasper DJ, Mitchell E. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:140.
9. Oakes VJ, Todd SM, Carbonello AA, Michalak P, Lahmers KK. Coinfection of cattle in Virginia with Theileria orientalis Ikeda genotype and Anaplasma marginale. J Vet Diagn Invest. 2022 Jan;34(1):36-41.
10. Pasolini MP, Pagano TB, Costagliola A, et al. Inflammatory Myopathy in Horses With Chronic Piroplasmosis [published correction appears in Vet Pathol. 2018 May;55(3):478]. Vet Pathol. 2018;55(1): 133-143.
11. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 81, 139, 171-172, 177, 185, 234, 242.
12. Summers BA, Cummings JF, de Lahunta A. In: Summers BA, Cummings JF, de Lahunta A, eds. Veterinary Neuropathology. St. Louis, MO: Mosby-Year Book Inc; 1995:171.
13. Valli VEO, Kiupel M, Bienzle D, Wood RD. Hematopoietic system. In: Maxie, MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals, Vol 3. 6th ed. Philadelphia, PA: Elsevier Ltd; 2016:176-178.
