Cerebral thrombosis

To our knowledge we report the first case of meningitis from Coccidioides immitis associated with massive dural and cerebral venous thrombosis and with mycelial forms of the organism in brain tissue. The patient was a 43-yearold man with late-stage acquired immunodeficiency syndrome (AIDS) whose premortem and postmortem cultures confirmed C immitis as the only central nervous system pathogenic organism. Death was attributable to multiple hemorrhagic venous infarctions with cerebral edema and herniation. Although phlebitis has been noted parenthetically to occur in C immitis meningitis in the past, it has been overshadowed by the arteritic complications of the disease. This patient's severe C immitis ventriculitis with adjacent venulitis appeared to be the cause of the widespread venous thrombosis. AIDS-related coagulation defects may have contributed to his thrombotic tendency.

(Arch Pathol Lab Med. 2000;124:310-314)

In the southwestern United States where Coccidioides immitis is endemic, it is one of the -most frequent opportunistic infections in persons with the acquired immunodeficiency syndrome (AIDS), with a significant percentage of disease due to recent infection, rather than reactivation.1-3 Extrapulmonary manifestations of C immitis, including meningitis, appear to be more frequent in individuals infected with the human immunodeficiency virus (HIV).2 Despite the increasing recognition of fungal meningitis due to C immitis among HIV-infected patients, to our knowledge no case has been reported in association with massive dural and cerebral venous thrombosis in either AIDS or non-AIDS patients. While several reports over the past 20 years have emphasized the arteritis and arterial infarctions that can complicate coccidioidomycosis meningitis,4-1 venulitis or venous infarctions have rarely been noted,4,6,9 despite excellent detailed pathologic studies.9

We report what we believe to be the first case of dural and cerebral venous thrombosis associated with C immitis meningitis and review the literature on cerebral venous thrombosis in AIDS patients. An additional unique microbiologic aspect to the case was the finding of the mycelial form of the organism within necrotic granulomas in the meninges.

REPORT OF A CASE

The patient was a 43-year-old man with history of injection drug use who was first noted to be HIV positive in 1987, and subsequently he was diagnosed as having oral candidiasis, seborrheic dermatitis, and hepatitis C. He had lived intermittently in Southern California between 1967 and 1974 and in Arizona in 1995. In December 1996 he presented with fever, cough, headache, and abnormal mental status. A chest x-ray film revealed bilateral nodular infiltrates; his CD4 cell count was 0.026 X 10^sup 9^/1, and plasma HIV RNA was 258000 copies/mL. Initial computed tomographic (CT) scan of the head was normal, but a later scan subsequently showed frontal lesions consistent with meningeal inflammation with normal ventricles. Lumbar puncture demonstrated 390 white blood cells with 89% polymorphonuclear leukocytes, 10% lymphocytes, and 1% monocytes, cerebrospinal fluid (CSF) protein level was 123 mg/dL, and CSF glucose was 24 mg/dL. Cultures of CSF and bronchoalveolar lavage fluid grew C immitis, and a blood culture grew Mycobacterium avium complex. Complement fixing antibody titer to C immitis was 1:2. The patient was treated with intravenous amphotericin B and fluconazole with gradual improvement, and he was discharged on a regimen of high-dose oral fluconazole, clarithromycin, and ethambutol.

Antiretroviral therapy resulted in a CD4 cell count as high as 0.108 X 10^sup 9^/1, and decreases in viral load, but adherence with medications was inconsistent. He had no symptoms or signs of recurrent meningitis for 18 months. In July 1998 he complained of headache, subacute onset of right arm weakness, and confusion of several weeks duration. He was admitted to the hospital, treated with intravenous fluconazole, and a CT scan of the head showed dilated ventricles. Cerebrospinal fluid grew C immitis; the minimum inhibitory concentration was 32 (mu)g / mL (borderline resistant). A ventriculotomy was performed for obstructive hydrocephalus, with resultant dramatic improvement of his mental status, and a ventriculoperitoneal shunt was placed. He was discharged to a nursing home. His last CD4 cell count was 0.044 X 10^sup 9^/L, with a viral load of 240000 copies/mL.

Two weeks later, the patient returned to the hospital after a fall at the nursing home. History obtained from the staff suggested that he experienced some mental status changes in the days prior to the fall. In the hospital, he had a witnessed generalized seizure and was given anticonvulsant therapy, but he became unresponsive and unable to follow commands and showed flexion only to pain. A CT scan of the head revealed sagittal sinus thrombosis with the "empty delta" sign near the confluence of the sinuses (torcula), classic for dural venous thrombosis (Figure 1). Remote anterior cerebral infarctions were also noted. The patient remained obtunded, and due to the advanced stage of his AIDS, his family chose to give supportive care only. He was discharged to a hospice, where he remained unresponsive until his death 4 days later. Permission for autopsy was granted.

PATHOLOGIC FINDINGS

General postmortem examination showed a severely cachectic man with decubitus ulcers and necrotizing bacterial pneumonia with gram-positive cocci identified on Gram stain. Pulmonary abscesses were devoid of histiocytes or multinucleated giant cells, and no fungi were seen on Gomori methenamine silver stains. Multiple venous small thrombi were noted immediately adjacent to the pulmonary abscesses but nowhere else in lung or other organs. Lymphocytic depletion of lymph nodes and spleen was found, but no other AIDS-defining illnesses were identified.

Neuropathologic examination demonstrated massive distention of the entire dural venous sinus system by dark blue-purple thrombi. The entire length of the superior sagittal sinus, including the torcula, was thrombosed in continuity, as were adjacent segments of major cerebral veins feeding into the superior sagittal sinus (Figure 2). Both right and left transverse sinuses were completely filled with thrombi, with the right side distended up to 1.2 cm in diameter. The straight sinus was also thrombosed. Neither acute nor chronic subdural hematomas, neomembranes, or empyema were identified.

Grossly the 1560-g brain showed massive cerebral edema with extensive venous thromboses ramifying over the surface of the brain to even the most distal leptomeningeal branches. Discolored, wedged-shaped venous infarctions could be seen from the surface (Figure 3). Bilateral uncal and tonsillar herniations were present, and a thick graywhite exudate entrapped the vasculature of the circle of Willis, optic chiasm, infundibular stalk, and cranial nerves. Mild opacification of the meninges was noted bilaterally over the convexities. A ventriculoperitoneal shunt was in place in the left occipital lobe (Figure 3).

The multiple superficial and deep venous hemorrhagic infarctions were best demonstrated on coronal sections, as was mild right-to-left shift. Large right frontal (4.3 X 2.8 X 2.2 cm), left posterior frontal (3.0 X 2.7 X 2.4 cm), bilateral thalamic, and bilateral occipital venous hemorrhagic infarctions were noted (Figure 4). Hemorrhage extended into both gray and white matter and was associated with thrombosis of intraparenchymal veins. Yellow-white purulent material rimmed the lateral and third ventricles and exudate and encased the shunt (Figure 4). Subependymal and large internal cerebral veins were thrombosed adjacent to these areas.

In addition to the extensive acute venous infarctions and thromboses, large, bilateral, remote, cavitated anterior cerebral artery infarctions of medial frontal lobes and the genu of the corpus callosum were found.

Microscopically, leptomeningeal and parenchymal veins were extensively thrombosed and often immediately juxtaposed to granulomas and meningeal or ventricular inflammation (Figure 5). Inflammation involved the wall of the nearby thrombosed veins (Figure 6). The meningitis was characterized by necrotizing granulomas surrounded by epithelioid histocytes and multinucleated giant cells, many of which engulfed thick-walled spherules containing endospores consistent with C immitis (Figure 6, inset). Surrounding the granulomas were meningeal fibrosis and intense lymphoplasmacytic infiltrates. Granulomatous ependymitis with fungal organisms involved the lateral and third ventricles, with adjacent venulitis and thrombosis of the lateral striate veins near the head of the caudate. No ependymal viral inclusions were noted and immunostains for herpes simplex virus I and 2 (Signet Corp, Dedham, Mass) and cytomegalovirus (Fisher Corp, Houston, Tex) were negative.

Within the necrotizing granulomas near the basis pontis, neutrophilic debris and numerous hyphal forms were found. By Gomori methenamine silver and periodic acidSchiff stains for fungi, endospores could clearly be seen to be emerging from fractured spherules and undergoing germination, with formation of mycelia and arthroconidia (Figure 7). Stains for bacteria (Gram), acid-fast bacilli (Ziehl-Neelsen), and Gomori methenamine silver stain for other fungi were negative. Postmortem cultures from meninges, CSF, and brain parenchyma grew only C immitis.

Microscopically areas of remote, cavitated arterial infarctions within bilateral anterior cerebral territories were associated with intimal proliferation and narrowing of the pericallosal artery, ferrugination of neurons within the infarcts, and dystrophic calcification of the meninges. Deep white matter sections showed no multinucleated giant cells suggestive of HIV-associated encephalopathy, although sheets of macrophages were noted near infarctions.

COMMENT

This dramatic and unique case underscores again the unusual features of opportunistic infections in AIDS patients. Although C immitis meningitis has been increasingly recognized in endemic areas in HfV-positive patients,1-3 massive dural and cerebral venous thromboses have not been previously reported, to our knowledge. While phlebitis was mentioned briefly in several detailed pathologic studies in the past on non-HIV-positive patients,4,6,9 massive cerebral and venous thrombosis was also not a feature of C immitis meningitis in the pre-AIDS era.

Histologically, parenchymal venous thrombi and venulitis in our case were immediately juxtaposed to necrotizing granulomas in meninges or to ventriculitis due to C immitis. The proximity of the processes indicated that venous thrombosis was probably the result of the infection, but the thrombotic tendency may have been accentuated by the fact that the patient was HIV positive. HIV-infected patients have known coagulation defects, with the presence of antiphospholipid antibodies and free protein 5 deficiency the best documented abnormalities.10 Premortem he had no clinical indications of coagulopathy, hence no extensive work-up for coagulation defects was undertaken prior to his death, and premortem serum was unavailable for retrospective testing. Hematologic complications of HIV infection include both cytopenias and coagulopathies,11 but in the past the emphasis has been on cellular defects or vascular accidents that involve the arterial side of circulation. Recently, systemic venous thrombosis in HIV infection has been recognized,12 but there have been few reports on dural or cerebral venous thrombosis in HIV-positive patients.13-19 With the exception of a single case report, 17 all these patients have been reported in the non-English-language literature,15,18 briefly as letters to the editor,14,19 or in abstract forM16 (Table). Nevertheless, despite the limited details in most of these reports, it is clear that the cerebral venous thrombosis usually occurred in HIV-positive patients with concomitant infectious or neoplastic processes (Table). This suggests that in our patient and in other HIV-positive patients infection with HIV alone is usually not sufficient to cause dural and cerebral thromboses, despite the known coagulation defects.

In contrast to the unique, extensive venous thromboses and hemorrhagic venous infarcts in this patient, the remote anterior cerebral arterial infarcts are a well-recognized complication of C immitis meningitis. Although detailed pathologic studies have noted endarteritis obliterans in at least half of patients with C immitis meningitis,9 until recently this complication had been underappreciated clinically. Our case demonstrated the remote arteritic change in the pericallosal branches of the anterior cerebral artery that supplied the infarcted territories. While bilateral medial frontal lobe arterial infarcts may have contributed to chronic cognitive dysfunction, the patient's acute mental status changes correlated most dramatically with the obstructive hydrocephalus. The patient showed significant improvement in his mental status upon placement of the ventriculostomy and the ventriculoperitoneal shunt. Terminally, with the development of the massive cerebral venous thromboses and acute venous infarcts, the patient experienced a generalized seizure and an obtundation from which he never recovered.

The final interesting aspect of this case was the finding of hyphal forms in necrotizing granulomas within the meninges. While diverse morphologic forms of the fungus have been well documented to occur in lung,20 we were unable to locate another example of arthroconidia in brain tissue. A literature search generated only 2 reports in the literature documenting arthroconidia in cerebrospinal fluid.21,22 One of these 2 patients died, and autopsy revealed mycelial forms in the tip of the catheter entering the Rickham reservoir in the patient, but "other granulomas contained only spherules and endospores," not the mycelial forms.21

Our case report expands the clinical and pathologic spectrum of coccidioidomycosis meningitis and once again illustrates the myriad variations that can occur when infections develop or recur in severely immunosuppressed patients such as those with AIDS. Such cases give us further insight into host-organism interactions in central nervous system infectious disease.

The authors thank Virginia Woodward for manuscript preparation, Bob McCullough for photographic expertise, Roberto Gianani, MD, for assistance with the Spanish translation of reference 18, and Loes Nardi-Korver, MD, for the Dutch translation of reference 15.

References

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13. Rhodes RH. Histopathology of the CNS in the acquired immunodeficiency syndrome. Hum PathoL 1987;18:636-643.

14. Meyohas MC, Roullet E, Rouzioux C, et al. Cerebral venous thrombosis and dual primary infection with human immunodeficiency virus and cytomegalovirus. J Neurol Neurosurg Psychiatry. 1989;52:1010-1011.

15. Beishuizen A, Derksen-Lubsen G. Los F, et al. An infant with AIDS [in Dutch]. Ned Tijdschr Geneeskd. 1989;133:123-126.

16. Fernandez-Martin J, Raguin G, Perronne V, et al. Cerebral venous thrombosis in three AIDS patients [abstract]. Int Conf AIDS. 1991;7:183.

17. Dobersen M), Kleinschmidt-De Masters BK. Superior sagittal sinus thrombosis in a patient with acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1994; 118:844-846.

18. Pedraza S, Rovira A, Saballs M, et al. Thrombosis of the superior longitudinal sinus in patients with AIDS: a review of the literature [in Spanish]. Rev Neurol. 1997;25:247-249.

19. Iranzo A, Domingo P, Cadafalch L et al. Intracranial venous and dural sinus thrombosis due to protein S deficiency in a patient with AIDS. I Neurol Neurosurg Psychiatry. 1998;64:688.

20. Kaufman L, Valero G. Padhye AA. Misleading manifestations of Coccidioides immitis in vivo. I Clin Microbiol. 1998;36:3721-3723.

21. Meyer PR, Hui AN, Biddle M. Coccidioides immitis meningitis with arthroconicia in cerebrospinal fluid: report of the first case and review of the arthroconiclia literature. Hum Pathol. 1982;13:1136-1138.

22. Wages DS, Helfend L. Finkle H. Coccidioides immitis presenting as a hyphal form in a ventriculoperitoneal shunt. Arch Pathol Lab Med. 1995;119:91-93.

Accepted for publication May 27, 1999.

From the Departments of Pathology (Drs Kleinschmidt-DeMasters, Bonds, and Wilson), Neurology (Drs Kleinschmidt-DeMasters and Mazowiecki), and Medicine (Dr Cohn), University of Colorado Health Sciences Center, and Departments of Pathology and Public Health, Denver Health Medical Center (Drs Cohn and Wilson), Denver, Colo.

Reprints: B. K. Kleinschmidt-DeMasters, MD, Department of Pathology, Box B216, University of Colorado Health Sciences Center, 4200 Ninth Ave, Denver, CO 80262.

Copyright College of American Pathologists Feb 2000
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