Congenital Toxoplasmosis with Extensive Coagulative Necrosis of Brain and Spinal Cord LiLi Miles Cincinnati Children's Hospital Medical Center Cincinnati, OH

Clinical History: This 1170 stillborn male fetus was delivered to a 26 year- old G3P2 mother at a gestational age of 27 weeks. The mother had been receiving prenatal care and was referred to Parkland Hospital after documentation of severe fetal hydrops. The fetus was re-imaged, with significant findings including severe fetal hydrops, a markedly enlarged placenta, ascites, a large pericardial effusion, an enlarged heart, and a severe elevation of the middle cerebral artery pressure (maximum peak systolic velocity of 130 cm/sec). The mother was admitted for an intrauterine transfusion and the fetus's hematocrit increased from 5.4 to 10.2 g/dL. Despite intrauterine transfucion, the fetus continued to have severe anemia and decelerations. Therefore, it was decided to induce labor. The infant was delivered by vaginal delivery without complications two days after initial presentation. Apgar scores were 0. Fetal examination showed a 1170 gram male infant with the only significant findings being hydrops and focal skin slippage. Introduction: Congenital encephalopathy may be caused by hypoxic/ischemic injuries, metabolic disorders and infections. It was estimated that 4/10,000 infants suffering from neurological disease are caused by TORCH (Toxoplasma gondii, Other microorganisms, Rubella virus, Cytomegalovirus and Herpes virus) infection. This was an autopsy case of a 3 week old infant girl born at 39 weeks gestational age. She had no lower extremity movement at birth and later developed progressive respiratory distress and died. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The brain weighed 225 gm (normal 382 gm). The leptomeninges were thickened and appeared opaque. The subarachnoid space contained yellow-white exudates. The cerebral hemispheres were atrophic, presented with widened sulci and sharp edged gyri. The cerebellum was also small with deceased foliation. Coronal sections of the cerebrum and cerebellum showed significantly dilated ventricles and diffuse yellow discoloration of the ependyma. Cystic cavities as well as gelatinous/yellow areas surrounded by calcifications were seen scattered throughout cerebral and cerebellar gray and white matter. The same changes were also seen in multiple levels of brain stem and lumbar spinal cord. Microscopically, the leptomeninges were thickened and infiltrated by acute and chronic inflammatory cells with multifocal calcifications. Nearly all regions of the brain were involved by coagulative necrosis of variable stages. In those areas, there was extensive vascular necrosis and vasculitis, with predominantly lymphocytic infiltration of the vascular wall. At the margins of the lesion, encysted organisms appeared as spherical structures, filled with bradyzoites were seen. Extensive calcification was seen surrounding the necrotic areas. The remainder of the brain showed many microglial nodules and gliosis. In the uninvolved areas, there was no evidence of brain structural abnormalities, or neuronal loss. Bilateral chorioretinitis was reported by the ophthalmology pathologist. Other autopsy findings included interstitial pneumonitis and carditis, muscular atrophy of the lower extremities, hepatomegaly with central necrosis, splenomegaly with white pulp hyperplasia, and hypercellular bone marrow with markedly increased eosinophilic precursors. Extramedullary hematopoiesis was seen in multiple organs. Qualitative PCR study on spinal fluid was positive for Toxoplasma gondii DNA. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 This coronal section of cerebrum shows multiple areas of necrosis, scattered in the gray and white matter. One white matter cystic necrosis surrounded by calcification is also seen. Figure 2 Closer view of similar changes as those described in the previous figure. Figure 3 The lateral ventricular ependymal lining is destroyed (upper left), the wall of the white matter cystic necrosis is composed of lymphocytes and macrophages (lower left). The surrounding white matter contains many microglial nodules. Figure 4 Coagulative necrosis with calcification involving superficial cortex and leptomeninges. Figure 5 Early cystic changes with the accumulation of proteinaceous material. Figure 6 At the edge of white matter necrosis, there are microglial nodules and gemistocytic astrocytes. Figure 7 Coagulative necrosis of inferior olive with no viable neurons. Figure 8 Only rare viable anterior horn neurons are seen in the lumbar spinal cord. Figure 9 At the margins of the necrotic lesions, spherical structures, filled with bradyzoites are identified. Differential Diagnoses: Hypoxic-ischemic/traumatic injury Metabolic disorders Congenital TORCH infection Final Diagnosis: Congenital Toxoplasmosis with Extensive Coagulative Necrosis of Brain and Spinal Cord. Case Discussion: This is a typical case of antenatal brain injury. The most common causes are cerebral hypoxic-ischemic/traumatic injury, genetic abnormalities/metabolic disorders/malformations, and TORCH infection [1]. In this infant, the presence of diffuse coagulative necrosis with calcification, and marked encephalitits and meningitis is diagnostic for TORCH infection. However, the central nervous system (CNS) manifestation for different infectious agents in TOUCH infection is similar with many overlapping features. Toxoplasma gondii infection will be discussed in the next section. Syphilis which is caused by spirochete Treponema pallidum is a major component in the "Others" category of TORCH. Congenital syphilis occurs nearly exclusively in the second trimester. Severe congenital infection may result in still birth. Clinical manifestations of infants with congenital syphilis are infrequent before the third week of life. Early lesions typically are hepatosplenomegaly, anemia, erythroblastosis, and bullae on the skin. Early symptomatic CNS involvement is uncommon. Meningitis and encephalitis are seen commonly including plasma cells. Later in life, usually after 2 years of age, CNS abnormalities will include sensorineural deafness, hydrocephalus, and developmental delay [2]. Since most women are immunized, congenital rubella infection is uncommon. Most cases of congenital rubella occur following primary maternal infection during pregnancy. The risk of fetus infection is approximately 90% if the maternal primary infection occurred in the first trimester. Typical clinical features include growth retardation, ocular abnormalities, such as cataracts and pigmentary retinopathy, congenital heart disease, hepatosplenomegaly, jaundice, purpuric rash, sensorineural hearing loss, and meningoencephalitis. Congenital CMV infection may occur from maternal primary infection or a reactivation of previous infection. Only 5- 15% infants with congenital CMV are symptomatic at birth. The typical clinical manifestation is a triad of jaundice, petechiae, and hepatomegaly. The hallmark for CNS infection is encephalitis and/or meningitis with periventricular calcifications [4]. Neonatal HSV infection is most commonly acquired intrapartum or postnatally and can result from primary or recurrent maternal infection. Clinical manifestations include skin lesions, chorioretinitis, and CNS lesions, such as encephalitis, calcifications of basal ganglia and thalami, diffuse hemispheric cystic necrosis, microcephaly, hydrocephaly, and lissencephaly [2]. Review of the Literature/Treatment Options: Introduction: Toxoplasma gondii is an obligate intracellular protozoan that belongs to the phylum Apicomplexa, subclass coccidia. It has three forms, the oocysts; the tachyzoite; and the cyst, containing bradyzoites. The infection is acquired by three primary routes: ingestions of tissue cysts in undercooked infected meat; ingestion of food and water contaminated with sporulated oocysts shed in the feces of an infected cat; and congenitally, across the placenta from the mother to the fetus [5]. Congenital toxoplasmosis generally occurs when a woman is newly infected with Toxoplasma gondii during pregnancy. The risk of infection is lowest when maternal primary infection is in the first trimester (10-15%) and is the highest when maternal primary infection is in the third trimester (60-90%) [6]. The overall infection rate is approximately 1/10,000-12,000 birth. Diagnosis: The diagnosis of toxoplasmosis may be established by serologic tests, PCR test, histologic demonstration of the parasite and/or antigen (immunohistochemistry stains), and isolation of the organism. The toxoplasmosis serological profile may establish recent (positive IgM) and previous (positive IgG) infections. PCR amplification for detection of Toxoplasma gondii DNA in body fluid and tissue has revolutionized the diagnosis of congenital toxoplasmosis infection [7, 8]. Pathological examination of brain (autopsy) or body fluid may establish the diagnosis of Toxoplasmosis infection with certainty. Gross examination commonly reveals microcephalus, hydrocephalus, necrosis and calcifications which are scattered throughout the brain parenchyma rather than being predominantly periventricular [2]. Retinochoroiditis is also a common finding. Histologically, typical findings are discrete areas of coagulative necrosis with prominent necrotic blood vessels seen throughout the brain. At the margins of the lesions, calcification and spherical structures, 8-10 µm, filled with bradyzoites can be identified on routine H&E stained slides, although they may be better seen on Giemsa preparation. Demonstration of tachyzoites in tissue sections or fluid cytology as well as isolation of the parasites from the body fluid establishes the diagnosis of the acute infection. Treatment: Current treatment options include spiramycin or a combination of pyrimethamine/sulfadoxine/folic acid. When infection in utero is documented, the mother should be treated with a combination of pyrimethamine and sulfadiazine with folic acid, which is the basic treatment protocol recommended by the WHO and CDC. If the fetus is not infected, treatment with spiramycin throughout pregnancy is recommended to prevent late infection. Treatment with pyrimethamine and sulfadiazine during the first trimester of pregnancy to prevent fetal infection is contraindicated due to concerns regarding teratogenicity. After confirmation of fetal infection, postnatal treatment of pyrimethamine and sulfadiazine for one year is recommended [9]. Conclusion(s): Antenatal brain injury is a major cause of still birth, death of early infancy and cerebral dysfunction later in life. Most common etiologies are ischemic/traumatic injury, metabolic disorders, and congenital TORCH infection. Toxoplasma gondii infection, one of the most important components of TORCH, has characteristic CNS manifestations in infants with congenital brain injury. Understanding and recognizing the features of CNS Toxoplasma gondii infection will help us in making the correct diagnosis. References: Hagberg H, Mallard C. Antenatal brain injury: aetiology and possibilities of prevention. Semin Neonatol. 2000 Feb;5(1):41-51. Bale JF Jr. Congenital infections. Neurol Clin. 2002 Nov;20(4):1039-60. França CM, Mugayar LR. Intrauterine infections: a literature review. Spec Care Dentist. 2004 Sep-Oct;24 (5):250-3. 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