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Septation and focal dilatation of ventricles associated with cryptococcal meningoencephalitis
Surg Neurol 1986;25:253-60
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Septation and Focal Dilatation of Ventricles Associated with Cryptococcal Meningoencephalitis S. Kwame Ofori-Kwakye, M.D., Ay-Ming Wang, M.D., James H. Morris, M.D., Gerald V. O'Reilly, M.D., Edwin G. Fischer, M.D., and Calvin L. Rumbaugh, M.D. Departments of Surgery (Division of Neurosurgery), Radiology, and Pathology (Section of Neuropathology), Brigham and Women's Hospital, Department of Radiology, Beth Israel Hospital, and Harvard Medical School, Boston, Massachusetts
Ofori-Kwakye SK, Wang A-M, Morris JH, O'Reilly GV, Fischer EG, Rumbaugh CL. Septation and focal dilatation of ventricles associated with cryptococcal meningoencephalitis. Surg Neurol 1985;25;253-60. A 35-year-old woman developed temporal lobe seizures. Isolated dilatation of the right temporal horn was demonstrated by computed tomography. She was asymptomatic for the next 10 months while on anticonvulsants before severe headaches, vomiting, and mental confusion prompted hospitalization. Both temporal horns were now dilated, there was marked periventricular edema, and cryptococci were cultured from the ventricular fluid. She succumbed after prolonged systemic and intrathecal antifungal therapy, having developed isolation and dilatation of both frontal horns and third and fourth ventricles. Cryptococcal or other fungal meningoencephalitis should be considered in the differential diagnosis of isolated dilatations of the ventricular chambers as noted in the present case. KEY WORDS: Cranial (brain) computed tomography; Cryptococcal meningoencephalitis; Hydrocephalus; Ventriculostomy
Cryptococcal infection is the most c o m m o n fungal infection o f the central nervous system (CNS) [1,2], although it is rarely encountered in clinical practice. When encountered, the diagnosis is often difficult to make by clinical or radiologic characteristics [3]. We recently managed a case of cryptococcal meningoencephalitis that highlights the varied clinical and radiologic presentation of C N S cryptococcosis.
Case Report
History This 35-year-old w o m a n was admitted to the Brigham and W o m e n ' s Hospital in S e p t e m b e r 1983 for evalua-
Address reprint requests to: S. Kwame Ofori-Kwakye, M.D., Neurosurgery Office, 300 LongwoodAvenue, Boston, Massachusetts02115. © 1986 by ElsevierSciencePublishingCo., Inc.
tion of headache and acute change in mental status. The patient had a history of diet-controlled diabetes mellitus and was otherwise healthy until N o v e m b e r 1982, when she had an illness characterized by chills, headache, and photophobia. She was admitted to a local hospital where she was noted to have fuguelike states with occasional myoclonic jerks of the left side. An electroencephalogram (EEG) showed intermittent right temporal slow waves with occasional epileptiform spikes. A cranial computed tomography (CT) scan, obtained in February 1983 (Figure 1), showed dilatation of the right temporal horn and right choroidal fissure, with e d e m a of the surrounding brain. Dense contrast enhancement along the body of the right lateral ventricle was noted. Lumbar puncture was not performed at this time. X-ray examination of the chest showed probable left lower lobe atelectasis, and the patient had a mild cough. T h e clinical impression at this time was temporal lobe epilepsy associated with a porencephalic cyst. She was treated with Tegretol to control the seizures. The medication was discontinued at the end of August 1983 after a 10-month seizure-free interval. Soon thereafter she became acutely ill with pounding occipital headaches, nausea, and vomiting and was noted to be confused at times. She was brought to the Brigham and W o m e n ' s Hospital Emergency R o o m obtunded and was admitted for further evaluation and care.
Physical Examination Examination on admission in September 1983 showed she was lethargic and disoriented to time, place, and person. H e r pupils were equal (5 mm) and sluggishly reactive to light and she manifested bilateral papilledema. The rest of the examination of her cranial nerves gave unremarkable results. Motor strength appeared diffusely diminished. H e r deep tendon reflexes were brisk, and plantar reflexes were extensor bilaterally. N o focal sensory loss with pinprick or light touch could be detected. Vibration sensation in the lower extremities appeared diminished. 0090-3019/86/$3.50
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Figure 1. Initial cranial CT scans were done at an outside hospital in February 1983, first without (a-c) and then with (d-f) intravenous contrast material. They demonstrate marked dilatation of the temporal horn of the right lateral ventricle and a choroidal fissure on the right with surrounding edema of the brain. There is a very densely enhanced area involving the body and atrium of the lateral ventricles, more obvious on the right.
Hospital Course
The cranial CT scan obtained during admission to the Brigham and Women's Hospital (Figure 2) showed marked dilatation of the temporal horns of both lateral ventricles, with surrounding brain edema. The ventricular system appeared smaller now than it appeared on the CT scan of February 1983, suggesting a further diffuse edema of the brain. The possibility of an infiltrating brain tumor in the splenium of the corpus callosum was entertained. Treatment with mannitol, steroids, and fluid restriction brought prompt improvement. The patient also received a 2-week course of radiation therapy to the area of the presumed tumor. Over the next 2 weeks her condition deteriorated progressively. Bilateral temporal horn ventriculostomies with external drainage of cerebrospinal fluid (CSF) were performed after the patient developed signs of cerebellar and brainstem
Ofori-Kwakye et al
compression. Cerebrospinal fluid obtained during the ventriculostomy showed yeastlike forms consistent with Cryptococcus neoformans. Cerebrospinal fluid cryptococcal antigen titer of 1:512 was noted and the CSF cultures grew Cryptococcus neoformans. Therapy with intrathecal amphotericin B and intravenous amphotericin B and 5fluorocytosine (5-FC) was initiated. A repeat CT scan about 2 weeks later showed marked reduction of the size of the temporal horns, but significant dilatations of the frontal horns of the lateral ventricles and the third and fourth ventricles, with evidence of periventricular edema (Figure 3). Septation could be seen along the body of the lateral ventricles. A left frontal ventriculostomy was then performed and a repeat CT scan 10 days later showed adequate decompression of the frontal horns (Figure 4). Three weeks later, a CT scan was performed after injection of 4 mL of metrizamide into the right lateral ventricle (Figure 5). The foramen of Monro was seen to be obstructed, and multiple revisions of the ventriculostomies were performed over the next 2 weeks because of the patient's deteriorating condition. Additional scans obtained 3 weeks later showed a significant decrease in the size of the lateral ventricles (Figure 6). Bilateral dilatation of the temporal horns of the lateral ventricle was now noted
Cryptococcal Meningoencephalitis
in association with surrounding edema of the brain. Highdensity areas were seen along the choroidal fissure and the body of the lateral ventricles bilaterally. By D e c e m b e r 1983, the patient's CSF cryptococcus antigen titer had fallen from 1:512 to 1:32, and the cultures were negative. H e r subsequent hospital course was marked by numerous complications, including urinary tract infections, and Staphylococcus epidermidis CSF superinfection. After a brief period of overall improvement in the patient's mental status, her condition began to deteriorate again. A C T scan obtained in January 1984 (Figure 7) showed isolated dilatation of the third and fourth ventricles as well as diffuse periventricular edema. There were areas of increased enhancement in the body of both lateral ventricles. The patient expired shortly thereafter and an autopsy was performed.
Pathology At autopsy, the fresh brain weighed 1260 g. The gyral pattern of the brain was normal and there was no significant gyral flattening. The leptomeninges over the cerebral convexities were dotted with small (approxi-
Surg Neurol 1986;25:253-60
255
Figure 2. Cranial C T scans taken at the time of hospital admission without (a-c) and with (d-f) intravenous administration of contrast demonstrate markedly dilated temporal horns of both lateral ventricles, as well as severe brain edema. The third and fourth ventricles are smaller than they were on the initial C T scans. The contrast-enhanced areas involving the body and atrium of both lateral ventricles were less impressive here than on the initial C T scans.
mately 1.5 x 1.5 mm) white firm nodules, which were most frequently seen adjacent to the superficial cortical blood vessels. At the base of the brain, around the pituitary stalk, in the prepontine and medullary subarachnoid space and in the subarachnoid space over the cerebellar tonsils there was gross thickening and opacification of the meninges. Sections through the brain (Figure 8) showed that the ventricles were not dilated but were partially filled with a gray shaggy material that occupied a large fraction (varying between 10% and 60%) of the lumen of the ventricle. There was some diffuse softening of the cerebral parenchyma immediately adjacent to the ventricles for a distance of up to 1.0 cm. In addition, a small area (0.5 x 0.5 cm) of focal softening could be seen in the
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Figure 3 (opposite, top). Cranial C T scans obtained 3 weeks after the patient's hospital admission without intravenous administration of contrast (a-f) demonstrate marked reduction of the temporal horns. One drainage catheter is seen in each temporal horn. There is significant dilatation of the lateral, third, and fourth ventricles, with a periventricular low-attenuation zone. The left frontal horn is more prominent than the right. Horizontal septations are seen along the body of the lateral ventricles. Figure 4 (opposite, bottom). Plain cranial C T scan obtained 10 days later demonstrates new placement of left frontal horn drainage catheter and significant intem~al change with reduction in size of the left frontal horn and increase in size of the right frontal horn and the third ventricle.
right globus pallidus, and focal areas of vascular congestion could be seen throughout the brain parenchyma. The spinal cord showed some cloudiness of the men* inges, without focal nodularities, and some incidental focal arachnoid calcification. The parenchyma appeared to be grossly unremarkable. N o focal or general lesions were seen on multiple slices through the spinal cord. Microscopic examination showed a severe chronic meningitis and ventriculitis characterized by a lymphoplasmacytic infiltrate, epithelioid histiocytes, giant cells, and fibroblasts. Large numbers ofcryptococci were pres-
Figure 5. Cranial C T scans (a-d) were obtained 3 weeks after the one shown in Figure 4. Metrizamide ~4 mL), 170 mg/mL, was used to place a new drainage catheter in the right frontal horn. No metrizamide was noted in the third and fourth ventricles, suggesting obstruction of the foramen of Monro on the right. The temporal horns again appeared further dilated. a
b
Figure 6. Plain cranial C T scans obtained 3 weeks later ~a-d) demonstrate a significant decrease in the size of the lateral ventricles as well as replacement of the drainage catheters in the frontal horn. Dilatation of the temporal horns of the lateral ventricles with surrounding brain edema is more prominent. High-density areas representing granulations are seen in the bilateral choroidal fissures and body of the lateral ventricles.
ent both as individual organisms scattered in the infiltrate and as clumps (Figure 9). The focal nodularities seen on the surface of the cerebral cortex proved to be focal granulomas histologically similar to the more widespread inflammation seen in the posterior fossa and in the ventricles. In addition to the inflammatory infiltrate, there was a severe endarteritis in many of the subarachnoid blood vessels that were embedded in the infiltrate. In most cases there appeared to be only narrowing of the lumen of the vessels (Figure 9), but some vessels appeared actually to be occluded by the endarteritis. The infection was mostly confined to the ventricular lumens and subarachnoid space, but in a few places, most notably an area of the cerebellar vermis adjacent to the fourth ventricle, there was some extension of the inflammation and infection down the Virchow-Robin spaces with the formation of perivascular focal granulomatous inflammation within the parenchyma of the brain. In those regions of the brain that were softened on gross examination (i.e., the periventricular tissue, the globus pallidus, and regions adjacent to the severe men-
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Ofori-Kwakye et al
a
b
d
. . . .
Figure 7. The plain cranial CT scans obtained 2 days before the patient's death (a-d) demonstrate marked reduction in size of the temporal horns.
High-density areas in the body of the lateral ventricles and choroidalfissures are again seen. There is slight dilatation of the third ventricle.
ingitis), there was tissue vacuolation consistent with edema, gliosis, and a variable degreee of neuronal loss. Because these changes were seen mostly adjacent to areas of inflammatory infiltrate and obliterative endarteritis, one may conclude that they are ischemic changes resulting from vascular narrowing caused by endarteritis. In the remainder of the cerebral parenchyma there were scattered small perivascular lymphocytic infiltrates, and many of the astrocytic nuclei were enlarged and irregular with a watery chromatin content. These astrocytic changes are seen in patients with a variety of metabolic disturbances and are not etiologically specific. The corpus callosum showed moderate vacuolation and gliosis in the areas that were adjacent to the inflammatory reaction but was otherwise normal. Sections from the spinal cord showed thickening of the arachnoid but only rare scattered individual lymphocytes in the subarachnoid space. There were no parenchymal lesions in the sections examined. In the general autopsy, the principal abnormal findings were noncaseating, well-formed granulomata in the periphery of the lung, the paratracheal nodes, and the spleen; an acute and a resolving bronchocentric pneumonia; and micronodular cirrhosis with mild fatty infiltration. N o cryptococci were seen in, or cultured from, the lung.
Figure 8. The gross appearance of a brain slice showing the shaggy gelatinous material filling most of the lateral and third ventricles. There is softening and edema of the periventricular brain tissue, most clearly indicated b~ the partial disintegration of the head of the right caudate nucleus.
Discussion Cryptococcosis (formerly called torulosis) has been reported as the most common fungal infection of the central nervous system [1,2], although the large and increasing number of therapeutically or otherwise immunosuppressed patients means that it has been overtaken at least at autopsy, by organisms such as Candida [10] and Aspergillus spp. However, it is still almost certainly the commonest infection in patients who are not immunosuppressed. It is caused by the yeastlike soil fungus Cryptococcus neoformans, which is widely distributed in nature but has a prediliction for growth in the feces of pigeons, although the birds themselves are not infected. It is not established that human infection follows exposure to the pigeon feces, as there is some evidence that the serotypes of human infections often differ from those in bird droppings to which they are alleged to have been exposed. The most frequently established portal of infection is pulmonary, with about 50% of patients in most series of cryptococcosis of the nervous system having either radiological or autopsy evidence of pulmonary infection [5]. Pulmonary infection has a tendency to spontaneous resolution and is frequently asymptomatic with presumed silent hematogenous dissemination to the brain.
Cryptococcal Meningoencephalitis
In our patient there is suggestive, but not conclusive, evidence of pulmonary cryptococcosis. The history of an upper respiratory infection and left lower lobe atelectasis would certainly be consistent with a cryptococcal infection of the lung, and the findings at autopsy of sterile but well-formed granulomas in the lung and adjacent lymph nodes are also suggestive, but not definitive evidence, of cryptococcal pulmonary disease. Most clinical reports show that more than half of the cases of cryptococcal CNS infection are superimposed on an immunosuppressive or other general debilitating condition. Lymphoreticular malignancy and corticosteroid treatment are particular risks [3,7,11]. Most series also contain a few diabetics, some of whom are diabetic as a consequence of prior steroid treatment [8]. This patient, however, had only mild diet-controlled diabetes, and given the number of similar patients in the general population, it is hard to see diabetes as a serious risk factor in this case. The micronodular cirrhosis found at autopsy has no~ been recorded as a risk factor in cryptococcosis. As already mentioned, corticosteroids are frequently implicated as a risk factor, but in this case steroids were not given before the presumed onset of the central nervous system infection. Most likely the
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Figure 9. A microscopic illustration of the character of the meningitis in the prepontine subarachnoid space. Present in this picture are giant cells in a dense fibrous reaction with a lymphoplasmacytic infiltrate. Loculations of cryptococci are seen within the reaction and the blood ~essels seen in this z'iew show a pronounced endarteritis with gross narrowing of their lumens ¢hematoxylin and eosin stain. × 200),
initial treatment with Decadron exacerbated her existing infection. The pathological picture of cryptococcal infection of the nervous sytem most frequently encountered at autopsy is that of a meningoencephalitis in which the meningitic component has a predominantly lymphohistiocytic reaction with only occasional giant cells and not much true granuloma formation or fibrous reaction [9]. In the cerebral parenchyma there are varying numbers of "cysts," often called "soap bubbles," containing organisms that are associated with very little, if any, cellular or inflammatory reaction in the surrounding brain. These so-called "cysts" are in fact the distended Virchow-Robin spaces of penetrating blood vessels into which the cryptococci are thought to gain entry from the subarachnoid space. This patient is unusual both in the distribution of the
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infection and, to a lesser extent, in the histologic character of the pathological reaction. The distribution was unusual in that there was a severe choroid plexitis, ventriculitis, and meningitis in the almost complete absence of any penetration of the infection into the cerebral parenchyma, and no detectable "cysts" at all. Histologically, the character of the reaction, even within the ventricles, was strikingly granulomatous with a very pronounced fibroblastic and endarteritic component. Infection of the choroid plexus is well described in cryptococcal meningoencephalitis, but it is not clear how frequently it occurs. Ventriculitis seems to be exceedingly uncommon, and the severity of the ventricular granulomatous reaction seen in this patient even more so. Part of the explanation for this unusual pathological appearance may lie in the steroid treatment that this patient received before the diagnosis of cryptococcal infection was made. It can be hypothesized that the immunosuppression that the steroid treatment would produce would result in the augmented production and dissemination of cryptococci in the CSF. Subsequent withdrawal of steroids, and restoration of normal immune reactions, could result in the production of a m o r e floridly granulomatous reaction in the subarachnoid space and ventricles than is usually encountered. Further, the presence in the subarachnoid space of an unusually dense fibroblastic reaction might also impede the entry of cryptococci into the V i r c h o w - R o b i n spaces, thereby reducing the likelihood of formation of cryptococcal filled "cysts," and perhaps might explain the unexpected paucity of parenchymal involvement in this patient. If this explanation is correct, then this case would be representative of a type of patient with well-preserved immune reactions who, as Myerowitz [9] suggests, rarely comes to autopsy. The findings in this case would support his contention that the usual pathological picture of cryptococcal meningoencephalitis at autopsy with a poorly developed granulomatous reaction is as much a reflection of the type of patient who succumbs to infection as of the fundamental type of pathological reaction elicited by the cryptococcus. C o m p u t e d tomographic findings are nonspecific in cryptococcosis [4]. Hydrocephalus is the most frequent abnormality. Less commonly seen computed tomographic findings include cerebral enhancing masses
Ofori-Kwakye et al
(granulomata) [6,12] and diffuse meningeal enhancement. In the series of Cornell and Jacoby [4], 6 out of 12 patients showed no abnormalities on CT. In the present case, the initial CT scan led to the diagnosis of a porencephaly. In retrospect, the abnormal enhancement along the body of the lateral ventricles could represent granulomata, and the focal dilatation of the right temporal horn and choroid fissure with periventricular edema o f the brain could represent ventriculitis, with trapping of the local CSF pathway. Although asymmetric ventricular dilatation is not widely appreciated as a radiologic feature o f C N S infection, one of the patients in the series o f D e W y t t et al [5] is described as having the computed tomographic finding of an "enlarged right ventricular horn only." The present case is a reminder that the differential diagnosis of unexplained focal dilatations and septation of the ventricular system should include cryptococcal meningoencephalitis.
References 1. Baker LH, Baker AB. Nonviral forms of encephalitis. In: Baker AB, Baker LH, eds. Clinical neurology, vol 2. New York: Harper and Row, 1980:1-57. 2. Bennett JE. The deep mycoses. In: Petersdorf RG, Adams RD, Braunwald E. Isselbacher KJ, Martin JB, Wilson JD, eds. Harrison's principles of internal medicine. New York: McGraw-Hill, 1983:1056-60. 3. Berger MP, Paz J. Diagnosis of cryptococcat meningitis. JAMA 1976;236:2517-8. 4. Cornell SH, Jacoby CG. The varied computed tomographic appearance ofintracranial cryptococcosis.Radiology 1982;143:703-7. 5. DeWytt C, Dickson PL, Holt GW. Cryptococcal meningitis: a review of 32 years' experience. J Neurol Sci 1982;53:283-92. 6. Fijita NK, Reynard M, Sapico FL, Guze LB, EdwardsJE Jr. Cryptococcalintracerebralmasslesions. Ann Intern Med 1981;94:382-8. 7. Kaplan MH, Rosen PP, Armstrong D. Cryptococcosisin a cancer hospital: clinical and pathological correlates in 46 patients. Cancer 1977;39:2265-74. 8. Lewis JL, Rabinwich S. The wide spectrum of cryptococcal infections. AmJ Med 1972;53:315-22. 9. Myerowitz RL. In: The pathology of opportunistic infections. New York: Raven, 1983:145-60. 10. Parker JC, McCloskeyJJ, Lee RS. The emergence of candidosis: the dominant post-mortem cerebral mycosis. Am J Clin Pathol 1978;70:31-6. 11. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine (Baltimore) 1983;62:98-109. 12. Tress B, Davis S. Computed tomography of intracerebral toruloma. Neuroradiology 1979;17:223-6.
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Septation and Focal Dilatation of Ventricles Associated with Cryptococcal Meningoencephalitis S. Kwame Ofori-Kwakye, M.D., Ay-Ming Wang, M.D., James H. Morris, M.D., Gerald V. O'Reilly, M.D., Edwin G. Fischer, M.D., and Calvin L. Rumbaugh, M.D. Departments of Surgery (Division of Neurosurgery), Radiology, and Pathology (Section of Neuropathology), Brigham and Women's Hospital, Department of Radiology, Beth Israel Hospital, and Harvard Medical School, Boston, Massachusetts
Ofori-Kwakye SK, Wang A-M, Morris JH, O'Reilly GV, Fischer EG, Rumbaugh CL. Septation and focal dilatation of ventricles associated with cryptococcal meningoencephalitis. Surg Neurol 1985;25;253-60. A 35-year-old woman developed temporal lobe seizures. Isolated dilatation of the right temporal horn was demonstrated by computed tomography. She was asymptomatic for the next 10 months while on anticonvulsants before severe headaches, vomiting, and mental confusion prompted hospitalization. Both temporal horns were now dilated, there was marked periventricular edema, and cryptococci were cultured from the ventricular fluid. She succumbed after prolonged systemic and intrathecal antifungal therapy, having developed isolation and dilatation of both frontal horns and third and fourth ventricles. Cryptococcal or other fungal meningoencephalitis should be considered in the differential diagnosis of isolated dilatations of the ventricular chambers as noted in the present case. KEY WORDS: Cranial (brain) computed tomography; Cryptococcal meningoencephalitis; Hydrocephalus; Ventriculostomy
Cryptococcal infection is the most c o m m o n fungal infection o f the central nervous system (CNS) [1,2], although it is rarely encountered in clinical practice. When encountered, the diagnosis is often difficult to make by clinical or radiologic characteristics [3]. We recently managed a case of cryptococcal meningoencephalitis that highlights the varied clinical and radiologic presentation of C N S cryptococcosis.
Case Report
History This 35-year-old w o m a n was admitted to the Brigham and W o m e n ' s Hospital in S e p t e m b e r 1983 for evalua-
Address reprint requests to: S. Kwame Ofori-Kwakye, M.D., Neurosurgery Office, 300 LongwoodAvenue, Boston, Massachusetts02115. © 1986 by ElsevierSciencePublishingCo., Inc.
tion of headache and acute change in mental status. The patient had a history of diet-controlled diabetes mellitus and was otherwise healthy until N o v e m b e r 1982, when she had an illness characterized by chills, headache, and photophobia. She was admitted to a local hospital where she was noted to have fuguelike states with occasional myoclonic jerks of the left side. An electroencephalogram (EEG) showed intermittent right temporal slow waves with occasional epileptiform spikes. A cranial computed tomography (CT) scan, obtained in February 1983 (Figure 1), showed dilatation of the right temporal horn and right choroidal fissure, with e d e m a of the surrounding brain. Dense contrast enhancement along the body of the right lateral ventricle was noted. Lumbar puncture was not performed at this time. X-ray examination of the chest showed probable left lower lobe atelectasis, and the patient had a mild cough. T h e clinical impression at this time was temporal lobe epilepsy associated with a porencephalic cyst. She was treated with Tegretol to control the seizures. The medication was discontinued at the end of August 1983 after a 10-month seizure-free interval. Soon thereafter she became acutely ill with pounding occipital headaches, nausea, and vomiting and was noted to be confused at times. She was brought to the Brigham and W o m e n ' s Hospital Emergency R o o m obtunded and was admitted for further evaluation and care.
Physical Examination Examination on admission in September 1983 showed she was lethargic and disoriented to time, place, and person. H e r pupils were equal (5 mm) and sluggishly reactive to light and she manifested bilateral papilledema. The rest of the examination of her cranial nerves gave unremarkable results. Motor strength appeared diffusely diminished. H e r deep tendon reflexes were brisk, and plantar reflexes were extensor bilaterally. N o focal sensory loss with pinprick or light touch could be detected. Vibration sensation in the lower extremities appeared diminished. 0090-3019/86/$3.50
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Figure 1. Initial cranial CT scans were done at an outside hospital in February 1983, first without (a-c) and then with (d-f) intravenous contrast material. They demonstrate marked dilatation of the temporal horn of the right lateral ventricle and a choroidal fissure on the right with surrounding edema of the brain. There is a very densely enhanced area involving the body and atrium of the lateral ventricles, more obvious on the right.
Hospital Course
The cranial CT scan obtained during admission to the Brigham and Women's Hospital (Figure 2) showed marked dilatation of the temporal horns of both lateral ventricles, with surrounding brain edema. The ventricular system appeared smaller now than it appeared on the CT scan of February 1983, suggesting a further diffuse edema of the brain. The possibility of an infiltrating brain tumor in the splenium of the corpus callosum was entertained. Treatment with mannitol, steroids, and fluid restriction brought prompt improvement. The patient also received a 2-week course of radiation therapy to the area of the presumed tumor. Over the next 2 weeks her condition deteriorated progressively. Bilateral temporal horn ventriculostomies with external drainage of cerebrospinal fluid (CSF) were performed after the patient developed signs of cerebellar and brainstem
Ofori-Kwakye et al
compression. Cerebrospinal fluid obtained during the ventriculostomy showed yeastlike forms consistent with Cryptococcus neoformans. Cerebrospinal fluid cryptococcal antigen titer of 1:512 was noted and the CSF cultures grew Cryptococcus neoformans. Therapy with intrathecal amphotericin B and intravenous amphotericin B and 5fluorocytosine (5-FC) was initiated. A repeat CT scan about 2 weeks later showed marked reduction of the size of the temporal horns, but significant dilatations of the frontal horns of the lateral ventricles and the third and fourth ventricles, with evidence of periventricular edema (Figure 3). Septation could be seen along the body of the lateral ventricles. A left frontal ventriculostomy was then performed and a repeat CT scan 10 days later showed adequate decompression of the frontal horns (Figure 4). Three weeks later, a CT scan was performed after injection of 4 mL of metrizamide into the right lateral ventricle (Figure 5). The foramen of Monro was seen to be obstructed, and multiple revisions of the ventriculostomies were performed over the next 2 weeks because of the patient's deteriorating condition. Additional scans obtained 3 weeks later showed a significant decrease in the size of the lateral ventricles (Figure 6). Bilateral dilatation of the temporal horns of the lateral ventricle was now noted
Cryptococcal Meningoencephalitis
in association with surrounding edema of the brain. Highdensity areas were seen along the choroidal fissure and the body of the lateral ventricles bilaterally. By D e c e m b e r 1983, the patient's CSF cryptococcus antigen titer had fallen from 1:512 to 1:32, and the cultures were negative. H e r subsequent hospital course was marked by numerous complications, including urinary tract infections, and Staphylococcus epidermidis CSF superinfection. After a brief period of overall improvement in the patient's mental status, her condition began to deteriorate again. A C T scan obtained in January 1984 (Figure 7) showed isolated dilatation of the third and fourth ventricles as well as diffuse periventricular edema. There were areas of increased enhancement in the body of both lateral ventricles. The patient expired shortly thereafter and an autopsy was performed.
Pathology At autopsy, the fresh brain weighed 1260 g. The gyral pattern of the brain was normal and there was no significant gyral flattening. The leptomeninges over the cerebral convexities were dotted with small (approxi-
Surg Neurol 1986;25:253-60
255
Figure 2. Cranial C T scans taken at the time of hospital admission without (a-c) and with (d-f) intravenous administration of contrast demonstrate markedly dilated temporal horns of both lateral ventricles, as well as severe brain edema. The third and fourth ventricles are smaller than they were on the initial C T scans. The contrast-enhanced areas involving the body and atrium of both lateral ventricles were less impressive here than on the initial C T scans.
mately 1.5 x 1.5 mm) white firm nodules, which were most frequently seen adjacent to the superficial cortical blood vessels. At the base of the brain, around the pituitary stalk, in the prepontine and medullary subarachnoid space and in the subarachnoid space over the cerebellar tonsils there was gross thickening and opacification of the meninges. Sections through the brain (Figure 8) showed that the ventricles were not dilated but were partially filled with a gray shaggy material that occupied a large fraction (varying between 10% and 60%) of the lumen of the ventricle. There was some diffuse softening of the cerebral parenchyma immediately adjacent to the ventricles for a distance of up to 1.0 cm. In addition, a small area (0.5 x 0.5 cm) of focal softening could be seen in the
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Figure 3 (opposite, top). Cranial C T scans obtained 3 weeks after the patient's hospital admission without intravenous administration of contrast (a-f) demonstrate marked reduction of the temporal horns. One drainage catheter is seen in each temporal horn. There is significant dilatation of the lateral, third, and fourth ventricles, with a periventricular low-attenuation zone. The left frontal horn is more prominent than the right. Horizontal septations are seen along the body of the lateral ventricles. Figure 4 (opposite, bottom). Plain cranial C T scan obtained 10 days later demonstrates new placement of left frontal horn drainage catheter and significant intem~al change with reduction in size of the left frontal horn and increase in size of the right frontal horn and the third ventricle.
right globus pallidus, and focal areas of vascular congestion could be seen throughout the brain parenchyma. The spinal cord showed some cloudiness of the men* inges, without focal nodularities, and some incidental focal arachnoid calcification. The parenchyma appeared to be grossly unremarkable. N o focal or general lesions were seen on multiple slices through the spinal cord. Microscopic examination showed a severe chronic meningitis and ventriculitis characterized by a lymphoplasmacytic infiltrate, epithelioid histiocytes, giant cells, and fibroblasts. Large numbers ofcryptococci were pres-
Figure 5. Cranial C T scans (a-d) were obtained 3 weeks after the one shown in Figure 4. Metrizamide ~4 mL), 170 mg/mL, was used to place a new drainage catheter in the right frontal horn. No metrizamide was noted in the third and fourth ventricles, suggesting obstruction of the foramen of Monro on the right. The temporal horns again appeared further dilated. a
b
Figure 6. Plain cranial C T scans obtained 3 weeks later ~a-d) demonstrate a significant decrease in the size of the lateral ventricles as well as replacement of the drainage catheters in the frontal horn. Dilatation of the temporal horns of the lateral ventricles with surrounding brain edema is more prominent. High-density areas representing granulations are seen in the bilateral choroidal fissures and body of the lateral ventricles.
ent both as individual organisms scattered in the infiltrate and as clumps (Figure 9). The focal nodularities seen on the surface of the cerebral cortex proved to be focal granulomas histologically similar to the more widespread inflammation seen in the posterior fossa and in the ventricles. In addition to the inflammatory infiltrate, there was a severe endarteritis in many of the subarachnoid blood vessels that were embedded in the infiltrate. In most cases there appeared to be only narrowing of the lumen of the vessels (Figure 9), but some vessels appeared actually to be occluded by the endarteritis. The infection was mostly confined to the ventricular lumens and subarachnoid space, but in a few places, most notably an area of the cerebellar vermis adjacent to the fourth ventricle, there was some extension of the inflammation and infection down the Virchow-Robin spaces with the formation of perivascular focal granulomatous inflammation within the parenchyma of the brain. In those regions of the brain that were softened on gross examination (i.e., the periventricular tissue, the globus pallidus, and regions adjacent to the severe men-
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a
b
d
. . . .
Figure 7. The plain cranial CT scans obtained 2 days before the patient's death (a-d) demonstrate marked reduction in size of the temporal horns.
High-density areas in the body of the lateral ventricles and choroidalfissures are again seen. There is slight dilatation of the third ventricle.
ingitis), there was tissue vacuolation consistent with edema, gliosis, and a variable degreee of neuronal loss. Because these changes were seen mostly adjacent to areas of inflammatory infiltrate and obliterative endarteritis, one may conclude that they are ischemic changes resulting from vascular narrowing caused by endarteritis. In the remainder of the cerebral parenchyma there were scattered small perivascular lymphocytic infiltrates, and many of the astrocytic nuclei were enlarged and irregular with a watery chromatin content. These astrocytic changes are seen in patients with a variety of metabolic disturbances and are not etiologically specific. The corpus callosum showed moderate vacuolation and gliosis in the areas that were adjacent to the inflammatory reaction but was otherwise normal. Sections from the spinal cord showed thickening of the arachnoid but only rare scattered individual lymphocytes in the subarachnoid space. There were no parenchymal lesions in the sections examined. In the general autopsy, the principal abnormal findings were noncaseating, well-formed granulomata in the periphery of the lung, the paratracheal nodes, and the spleen; an acute and a resolving bronchocentric pneumonia; and micronodular cirrhosis with mild fatty infiltration. N o cryptococci were seen in, or cultured from, the lung.
Figure 8. The gross appearance of a brain slice showing the shaggy gelatinous material filling most of the lateral and third ventricles. There is softening and edema of the periventricular brain tissue, most clearly indicated b~ the partial disintegration of the head of the right caudate nucleus.
Discussion Cryptococcosis (formerly called torulosis) has been reported as the most common fungal infection of the central nervous system [1,2], although the large and increasing number of therapeutically or otherwise immunosuppressed patients means that it has been overtaken at least at autopsy, by organisms such as Candida [10] and Aspergillus spp. However, it is still almost certainly the commonest infection in patients who are not immunosuppressed. It is caused by the yeastlike soil fungus Cryptococcus neoformans, which is widely distributed in nature but has a prediliction for growth in the feces of pigeons, although the birds themselves are not infected. It is not established that human infection follows exposure to the pigeon feces, as there is some evidence that the serotypes of human infections often differ from those in bird droppings to which they are alleged to have been exposed. The most frequently established portal of infection is pulmonary, with about 50% of patients in most series of cryptococcosis of the nervous system having either radiological or autopsy evidence of pulmonary infection [5]. Pulmonary infection has a tendency to spontaneous resolution and is frequently asymptomatic with presumed silent hematogenous dissemination to the brain.
Cryptococcal Meningoencephalitis
In our patient there is suggestive, but not conclusive, evidence of pulmonary cryptococcosis. The history of an upper respiratory infection and left lower lobe atelectasis would certainly be consistent with a cryptococcal infection of the lung, and the findings at autopsy of sterile but well-formed granulomas in the lung and adjacent lymph nodes are also suggestive, but not definitive evidence, of cryptococcal pulmonary disease. Most clinical reports show that more than half of the cases of cryptococcal CNS infection are superimposed on an immunosuppressive or other general debilitating condition. Lymphoreticular malignancy and corticosteroid treatment are particular risks [3,7,11]. Most series also contain a few diabetics, some of whom are diabetic as a consequence of prior steroid treatment [8]. This patient, however, had only mild diet-controlled diabetes, and given the number of similar patients in the general population, it is hard to see diabetes as a serious risk factor in this case. The micronodular cirrhosis found at autopsy has no~ been recorded as a risk factor in cryptococcosis. As already mentioned, corticosteroids are frequently implicated as a risk factor, but in this case steroids were not given before the presumed onset of the central nervous system infection. Most likely the
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Figure 9. A microscopic illustration of the character of the meningitis in the prepontine subarachnoid space. Present in this picture are giant cells in a dense fibrous reaction with a lymphoplasmacytic infiltrate. Loculations of cryptococci are seen within the reaction and the blood ~essels seen in this z'iew show a pronounced endarteritis with gross narrowing of their lumens ¢hematoxylin and eosin stain. × 200),
initial treatment with Decadron exacerbated her existing infection. The pathological picture of cryptococcal infection of the nervous sytem most frequently encountered at autopsy is that of a meningoencephalitis in which the meningitic component has a predominantly lymphohistiocytic reaction with only occasional giant cells and not much true granuloma formation or fibrous reaction [9]. In the cerebral parenchyma there are varying numbers of "cysts," often called "soap bubbles," containing organisms that are associated with very little, if any, cellular or inflammatory reaction in the surrounding brain. These so-called "cysts" are in fact the distended Virchow-Robin spaces of penetrating blood vessels into which the cryptococci are thought to gain entry from the subarachnoid space. This patient is unusual both in the distribution of the
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infection and, to a lesser extent, in the histologic character of the pathological reaction. The distribution was unusual in that there was a severe choroid plexitis, ventriculitis, and meningitis in the almost complete absence of any penetration of the infection into the cerebral parenchyma, and no detectable "cysts" at all. Histologically, the character of the reaction, even within the ventricles, was strikingly granulomatous with a very pronounced fibroblastic and endarteritic component. Infection of the choroid plexus is well described in cryptococcal meningoencephalitis, but it is not clear how frequently it occurs. Ventriculitis seems to be exceedingly uncommon, and the severity of the ventricular granulomatous reaction seen in this patient even more so. Part of the explanation for this unusual pathological appearance may lie in the steroid treatment that this patient received before the diagnosis of cryptococcal infection was made. It can be hypothesized that the immunosuppression that the steroid treatment would produce would result in the augmented production and dissemination of cryptococci in the CSF. Subsequent withdrawal of steroids, and restoration of normal immune reactions, could result in the production of a m o r e floridly granulomatous reaction in the subarachnoid space and ventricles than is usually encountered. Further, the presence in the subarachnoid space of an unusually dense fibroblastic reaction might also impede the entry of cryptococci into the V i r c h o w - R o b i n spaces, thereby reducing the likelihood of formation of cryptococcal filled "cysts," and perhaps might explain the unexpected paucity of parenchymal involvement in this patient. If this explanation is correct, then this case would be representative of a type of patient with well-preserved immune reactions who, as Myerowitz [9] suggests, rarely comes to autopsy. The findings in this case would support his contention that the usual pathological picture of cryptococcal meningoencephalitis at autopsy with a poorly developed granulomatous reaction is as much a reflection of the type of patient who succumbs to infection as of the fundamental type of pathological reaction elicited by the cryptococcus. C o m p u t e d tomographic findings are nonspecific in cryptococcosis [4]. Hydrocephalus is the most frequent abnormality. Less commonly seen computed tomographic findings include cerebral enhancing masses
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(granulomata) [6,12] and diffuse meningeal enhancement. In the series of Cornell and Jacoby [4], 6 out of 12 patients showed no abnormalities on CT. In the present case, the initial CT scan led to the diagnosis of a porencephaly. In retrospect, the abnormal enhancement along the body of the lateral ventricles could represent granulomata, and the focal dilatation of the right temporal horn and choroid fissure with periventricular edema o f the brain could represent ventriculitis, with trapping of the local CSF pathway. Although asymmetric ventricular dilatation is not widely appreciated as a radiologic feature o f C N S infection, one of the patients in the series o f D e W y t t et al [5] is described as having the computed tomographic finding of an "enlarged right ventricular horn only." The present case is a reminder that the differential diagnosis of unexplained focal dilatations and septation of the ventricular system should include cryptococcal meningoencephalitis.
References 1. Baker LH, Baker AB. Nonviral forms of encephalitis. In: Baker AB, Baker LH, eds. Clinical neurology, vol 2. New York: Harper and Row, 1980:1-57. 2. Bennett JE. The deep mycoses. In: Petersdorf RG, Adams RD, Braunwald E. Isselbacher KJ, Martin JB, Wilson JD, eds. Harrison's principles of internal medicine. New York: McGraw-Hill, 1983:1056-60. 3. Berger MP, Paz J. Diagnosis of cryptococcat meningitis. JAMA 1976;236:2517-8. 4. Cornell SH, Jacoby CG. The varied computed tomographic appearance ofintracranial cryptococcosis.Radiology 1982;143:703-7. 5. DeWytt C, Dickson PL, Holt GW. Cryptococcal meningitis: a review of 32 years' experience. J Neurol Sci 1982;53:283-92. 6. Fijita NK, Reynard M, Sapico FL, Guze LB, EdwardsJE Jr. Cryptococcalintracerebralmasslesions. Ann Intern Med 1981;94:382-8. 7. Kaplan MH, Rosen PP, Armstrong D. Cryptococcosisin a cancer hospital: clinical and pathological correlates in 46 patients. Cancer 1977;39:2265-74. 8. Lewis JL, Rabinwich S. The wide spectrum of cryptococcal infections. AmJ Med 1972;53:315-22. 9. Myerowitz RL. In: The pathology of opportunistic infections. New York: Raven, 1983:145-60. 10. Parker JC, McCloskeyJJ, Lee RS. The emergence of candidosis: the dominant post-mortem cerebral mycosis. Am J Clin Pathol 1978;70:31-6. 11. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine (Baltimore) 1983;62:98-109. 12. Tress B, Davis S. Computed tomography of intracerebral toruloma. Neuroradiology 1979;17:223-6.