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Neuropathology 2015; 35, 343–347
doi:10.1111/neup.12193
C a se Repor t
Neurogenic pulmonary edema following Cryptococcal meningoencephalitis associated with HIV infection Reiichiro Kondo,1,2,3 Yasuo Sugita,1 Kenji Arakawa,4 Shinji Nakashima,1 Yumi Umeno,1 Keita Todoroki,1 Tomoko Yoshida,3 Yorihiko Takase,3 Masayoshi Kage,2,3 Koichi Oshima1 and Hirohisa Yano1 1
Department of Pathology, Kurume University School of Medicine, 2Cancer Center, 3Department of Diagnostic Pathology, Kurume University Hospital and 4Department of Neurology, Saiseikai Futsukaichi Hospital, Fukuoka, Japan
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40-year-old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Noncontrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H2O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm3. The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow-Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow-Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus.
Correspondence: Reiichiro Kondo, MD, PhD, Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Email: [email protected] Received 30 October 2014; revised 15 December 2014 and accepted 16 December 2014; published online 7 May 2015.
© 2015 Japanese Society of Neuropathology
Key words: autopsy, cryptococcus, HIV, meningitis, pulmonary edema.
INTRODUCTION Neurogenic pulmonary edema (NPE) is defined as acute pulmonary edema developing after a significant CNS insult.1,2 Any acute CNS insult can lead to pulmonary edema. It has been reported in patients with subarachnoid hemorrhage, traumatic brain injury, intracerebral hemorrhage, status epilepticus, meningitis, spinal cord injury, intracranial tumors, ischemic stroke and multiple sclerosis.3–9 Some cases of NPE after meningitis have been reported in the English literature.10–15 Only a few cases of NPE following Cryptococcal meningitis have been reported.15 Herein we report a case of NPE following Cryptococcal meningoencephalitis.
CLINICAL SUMMARY A 40-year-old man with no medical history presented to the emergency department for disturbance of consciousness. He was not a homosexual and had no drug use history. On initial presentation, the patient had a blood pressure of 180/90 mmHg, heart rate of 120 beats per minute, respiratory rate of 18 breaths per minute and temperature of 37.2°C. Physical examination revealed normal breath and heart sounds. Oxygen saturation was 98% on room air. Initial evaluation showed consciousness disturbance and a Glasgow Coma Scale level of 12 (E3V4M5). Initial laboratory findings are shown in Table 1. The results included a white blood cell (WBC) count of 13 700/μL, serum C-reactive protein of 0.55 mg/dL, and blood glucose level
344
R Kondo et al.
Table 1 Initial laboratory findings Hematological analysis
Blood chemistry
WBC Neutrophil Lymphocyte Monocyte Eosinophil Basophil RBC Hb Ht Plt
AST ALT LDH ALP T-Bil T.P Alb Na K Cl BUN Creatinine Blood sugar CRP
13 700/μL 11 343/μL 1 589/μL 740/μL 14/μL 14/μL 667 × 104/μL 19.7 g/dL 54.8% 15.2 × 104/mm3
21 IU/L 25 IU/L 844 IU/L 182 IU/L 1.7 mg/dL 7.9 g/dL 3.9 g/dL 141 mEq/L 3.4 mEq/L 92 mEq/L 18.5 mg/dL 0.70 mg/dL 124 mg/dL 0.55 mg/dL Fig. 2 Macroscopic findings of the brain. In the brain, small hemorrhage of right basal ganglia was seen.
PATHOLOGICAL FINDINGS
Fig. 1 Imaging findings. (a) Non-contrast chest CT scan disclosed marked peripheral interlobular septal thickening and diffuse ground glass opacities mixed with consolidation in both lungs. (b) Non-contrast head CT scan showed sulcal effacement in the frontal lobe.
of 124 mg/dL. Chest radiograph and non-contrast head CT scan showed no significant abnormality. Lumbar puncture revealed a pressure of over 300 mm H2O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm3. The CSF glucose level was 0 mg/dL. The CSF protein level was 87 mg/dL. He was empirically started on treatment for presumptive bacterial and herpes viral meningitis. On day 4, oxygen saturation of the patient suddenly reduced and respiratory distress with copious amounts of pink frothy sputum occurred. Chest radiograph revealed generalized increased pulmonary infiltration, consistent with acute pulmonary edema. Chest CT scan disclosed marked peripheral interlobular septal thickening and diffuse ground glass opacities mixed with consolidation in both lungs (Fig. 1a). Head CT scan showed sulcal effacement in the frontal lobe, consistent with brain edema (Fig. 1b). Brain herniation was not present. Electrocardiogram and blood test including cardiac enzymes were normal limits. The patient died and an autopsy was performed
At autopsy, the patient was found to have brain edema, small hemorrhage of right basal ganglia, severe pulmonary edema and mild cardiomegaly (Fig. 2). The brain weighed 1696 g. Coronary artery and cerebral arterial circles were intact. In the spleen, atrophy of white pulp was observed. There was no lymphadenopathy. Histologically, there was inflammatory reaction with Cryptococci in the arachnoid membrane and the meninges (Fig. 3a). Ependymitis was not seen. In the bilateral frontal lobe, temporal lobe, parietal lobe, hippocampus, thalamus, basal ganglia, cerebellum, midbrain, pons, dilated VirchowRobin spaces, were crowded with Cryptococci and no inflammatory responses were observed (Fig. 3b). There was only slight inflammatory response in the dilated Virchow-Robin spaces and adjacent brain caused by the dissemination of the meningeal infection along the perivascular spaces. In the right basal ganglia, VirchowRobin spaces were destroyed with hemorrhaging and Cryptococci had spread to parenchyma of the brain (Fig. 3c). Inflammatory cell infiltration was mainly with T lymphocytes (Fig. 3d). There were no Cryptococci spreading to parenchyma in the pituitary gland. In the pituitary gland and thalamus, parenchymal necrosis was not seen. Human immunodeficiency virus (HIV) encephalopathy, progressive multifocal leukoencephalopathy and cytomegalovirus infection were not present. In the lung, pulmonary edema was seen (Fig. 4a). There were Cryptococci with no inflammatory reaction in the lung (Fig. 4b). Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for HIV serum antibody. © 2015 Japanese Society of Neuropathology
NPE following Cryptococcal meningitis
345
Fig. 3 Microscopic findings of the brain. (a) There is inflammatory reaction with Cryptococci in the arachnoid membrane. (b) In the cerebrum, dilated Virchow-Robin spaces, crowded with Cryptococci are observed. There is only slight inflammatory response in the dilated Virchow-Robin spaces. (c) In right basal ganglia, Virchow-Robin spaces are destroyed and Cryptococci spread to parenchyma of the brain. (d) Serial section shown in (c) stained for antibody against CD3. Lymphocytic infiltrates mainly consist of T cells. Scale bars = 100 μm.
Fig. 4 Microscopic findings of the lung. (a) Broad pulmonary edema is seen. Scale is 500 μm. (b) There are Cryptococci with no granulomatous inflammation. Periodic acid-Schiff stain. Scale bars = 500 μm (a), 50 μm (b).
DISCUSSION NPE is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. Although NPE has been recognized for a long time, it is still underdiagnosed in clinical practice.1,2 Any acute CNS insult can lead to pulmonary edema.3–9 The severity and acuity of the insult may play an important role.1 The exact mechanism of NPE remains unclear. Neurologic © 2015 Japanese Society of Neuropathology
insults that cause sudden and severe intracranial pressure (ICP) elevation pose the greatest risk. Elevated ICP leads to neuronal compression or ischemia, activation of the sympathetic nervous system, and the release of catecholamines that can lead to cardiopulmonary dysfunction.1,2 Certain brain regions have been implicated in the genesis of sympathetic hyperactivity, including the insular cortex, hypothalamus and medulla.1 In our case, elevated ICP was caused by brain edema associated with
346
R Kondo et al.
Table 2 Reported cases of acute respiratory failure following Cryptococcal meningoencephalitis Author/year
Visnegarwala15 1998
Current case 2014
Age
Gender
CSF opening pressure (mm H20)
Brain herniation
HIV infection
Survival (days)
35 years 31 years 47 years 37 years 35 years 40 years
Male Female Male Male Female Male
450 30 250 45 14 >300
Present None Present None None None
Positive Positive Positive Positive Positive Positive
20 1 19 19 2 1
Survival, survival time after the onset of acute respiratory failure.
Cryptococcal meningoencephalitis. A summary of acute respiratory failure following Cryptococcal meningoencephalitis in previous and current cases is shown in Table 2. Among the six cases previously reported in the literature (including the current case), three cases (50%) died within 2 days after the onset of acute respiratory failure; none of the three cases had brain herniation. The average age of patients was 37.5 years (range, 31–47 years). There were four men and two women. All patients were positive for HIV infection. The pathogenic mechanism is believed to occur at the level of pulmonary vascular endothelium. Several theories have been proposed, such as direct myocardial injury caused by: a surge in catecholamines (neuro-cardiac NPE); direct pulmonary vascular bed injury caused by massive sympathetic discharge (pulmonary venule adrenergic hypertensitivity); indirect left ventricular failure caused by increased systemic and pulmonary pressures after catecholamine surge (neuro-hemodynamic NPE); and high hydrostatic pressure and pulmonary endothelial injury caused by catecholamine surge (blast theory).1 NPE usually occurs within minutes to hours after a CNS insult. Diagnosis of NPE is difficult because of its relatively unpredictable nature and lack of specific signs and diagnostic tests. Differential diagnoses include pneumonia, congestive heart failure and acute respiratory distress syndrome.1,2 Our patient presented with the usual clinical features of NPE and signs without evidence of congestive heart failure, pneumonia, or other systemic causes for the pulmonary edema. After autopsy, we found that our patient was positive for HIV serum antibody. However, we could not confirm whether our patient had acquired Immune Deficiency Syndrome (AIDS). Cryptococcal infections are most commonly seen in immunocompromised patients.15,16 Disease disseminates typically, having defects in T cell function, through malignancy, immunosuppressive medication, autoimmune disease, sarcoidosis or HIV infection, indicating the role of T cell-mediated immunity in host defences.16 Recently, neuropathologic legions of
Cryptococcal meningoencephalitis in patients with HIV infection have been reported.17–19 Pathological findings revealed significant differences in the inflammatory response to Cryptococcal meningoencephalitis in patients with and without HIV infection.17–19 Typically, AIDS patients have no granulomatous inflammation, whereas most non-HIV-associated cases had granulomas, supporting a role for cell-mediated immunity in Cryptococcal meningoencephalitis. Lymphocytic infiltrate in both groups consisted of T cells.19 In addition, in patients with HIV infection, the presence of multiple gelatinous pseudocysts with abundant Cryptococci in the VirchowRobin spaces and adjacent brain were frequently observed, caused by the dissemination of the meningeal infection along the perivascular spaces.17–19 In this case, these neuropathologic legions were present. Dilated Virchow-Robin spaces, crowded with Cryptococci and no granulomatous inflammation were observed. It was suggested that Cryptococcal meningoencephalitis in this case was associated with HIV infection. In conclusion, NPE is a rapidly developing and sometimes life-threatening complication of CNS insult. Physicians should remember this clinical entity when caring for patients with acute respiratory distress following neurologic events.
DISCLOSURE We know of no financial conflicts of interest concerning this work.
REFERENCES 1. Davison DL, Terek M, Chawla LS. Neurogenic pulmonary edema. Crit Care 2012; 16: 212–218. 2. Baumann A, Audibert G, McDonnell J, Mertes PM. Neurogenic pulmonary edema. Acta Anaesthesiol Scand 2007; 51: 447–455. 3. Fontes RB, Aguiar PH, Zanetti MV, Andrade F, Mandel M, Teixeira MJ. Acute neurogenic pulmonary edema: case reports and literature review. J Neurosurg Anesthesiol 2003; 15: 144–150. © 2015 Japanese Society of Neuropathology
NPE following Cryptococcal meningitis 4. Bahloul M, Chaari AN, Kallel H et al. Neurogenic pulmonary edema due to traumatic brain injury: evidence of cardiac dysfunction.Am J Crit Care 2006;15:462–470. 5. Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB. Neurogenic pulmonary edema in fatal and nonfatal head injuries. J Trauma 1995; 39: 860–866. 6. Padley JR, Feneley MP, Hayward CS, Markus R. Neurocardiogenic pulmonary oedema: initial presentation of multiple sclerosis. Heart Lung Circ 2012; 21: 853–855. 7. Muroi C, Keller M, Pangalu A et al. Neurogenic pulmonary edema in patients with subarachnoid hemorrhage. J Neurosurg Anesthesiol 2008; 20: 188–192. 8. Makaryus JN, Kapphahn S, Makaryus AN. Unilateral neurogenic pulmonary oedema and severe left ventricular dysfunction secondary to acute multiple sclerosis exacerbation. Heart Lung Circ 2009; 18: 155–158. 9. Pai-Ching T, Helen LP. Neurogenic pulmonary edema following acute ischemic stroke: a case report and literature review. Neurol Asia 2014; 19: 195–198. 10. Krous HF, Chadwick AE, Miller DC, Crandall L, Kinney HC. Sudden death in toddlers with viral meningitis, massive cerebral edema, and neurogenic pulmonary edema and hemorrhage: report of two cases. Pediatr Dev Pathol 2007; 10: 463–469. 11. Peter P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis
© 2015 Japanese Society of Neuropathology
347
12.
13.
14.
15.
16. 17.
18.
19.
is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med 2003; 4: 377–381. D’Souza R, Kerr F. Neurogenic pulmonary oedema induced by bacterial meningitis: a case report. Scott Med J 2001; 46: 115–116. Frankel RJ, Bennett ED, Borland CD. Pulmonary oedema in meningococcal meningitis. Postgrad Med J 1976; 52: 529–531. Chotmongkol V, Thiensiri C, Boonma P. Neurogenic pulmonary edema associated with meningitis. J Med Assoc Thai 1990; 9: 530–532. Visnegarwala F, Graviss EA, Lacke CE et al. Acute respiratory failure associated with Cryptococcosis in patients with AIDS: analysis of predictive factors. Clin Infect Dis 1998; 27: 1231–1237. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS 2007; 21: 2119–2129. Bos HM, Hofman PAM, Schreij G, Bot FJ, van Oostenbruggen RJ. Overwhelming CNS cryptococcus in AIDS. Neurology 2001; 57: 1560. Klock C, Cerski M, Goldani LZ. Histopathological aspects of neurocryptococcosis in HIV-infected patients: autopsy report of 45 patients. Int J Surg Pathol 2009; 17: 444–448. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27: 839–847.
Neuropathology 2015; 35, 343–347
doi:10.1111/neup.12193
C a se Repor t
Neurogenic pulmonary edema following Cryptococcal meningoencephalitis associated with HIV infection Reiichiro Kondo,1,2,3 Yasuo Sugita,1 Kenji Arakawa,4 Shinji Nakashima,1 Yumi Umeno,1 Keita Todoroki,1 Tomoko Yoshida,3 Yorihiko Takase,3 Masayoshi Kage,2,3 Koichi Oshima1 and Hirohisa Yano1 1
Department of Pathology, Kurume University School of Medicine, 2Cancer Center, 3Department of Diagnostic Pathology, Kurume University Hospital and 4Department of Neurology, Saiseikai Futsukaichi Hospital, Fukuoka, Japan
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant central nervous system insult. Only a few cases of NPE after Cryptococcal meningitis have been reported. We report a case of NPE following Cryptococcal meningoencephalitis. A 40-year-old man with no medical history was hospitalized for disturbance of consciousness. Blood glucose level was 124 mg/dL. Noncontrast head computed tomography showed no abnormalities. Lumbar puncture revealed a pressure of over 300 mm H2O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm3. The CSF glucose level was 0 mg/dL. The patient was empirically started on treatment for presumptive bacterial and viral meningitis. Four days after, the patient died in a sudden severe pulmonary edema. Autopsy was performed. We found at autopsy a brain edema with small hemorrhage of the right basal ganglia, severe pulmonary edema and mild cardiomegaly. Histologically, dilated Virchow-Robin spaces, crowded with Cryptococci were observed. In the right basal ganglia, Virchow-Robin spaces were destroyed with hemorrhage and Cryptococci spread to parenchyma of the brain. No inflammatory reaction of the lung was seen. Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for serum antibodies to human immunodeficiency virus.
Correspondence: Reiichiro Kondo, MD, PhD, Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. Email: [email protected] Received 30 October 2014; revised 15 December 2014 and accepted 16 December 2014; published online 7 May 2015.
© 2015 Japanese Society of Neuropathology
Key words: autopsy, cryptococcus, HIV, meningitis, pulmonary edema.
INTRODUCTION Neurogenic pulmonary edema (NPE) is defined as acute pulmonary edema developing after a significant CNS insult.1,2 Any acute CNS insult can lead to pulmonary edema. It has been reported in patients with subarachnoid hemorrhage, traumatic brain injury, intracerebral hemorrhage, status epilepticus, meningitis, spinal cord injury, intracranial tumors, ischemic stroke and multiple sclerosis.3–9 Some cases of NPE after meningitis have been reported in the English literature.10–15 Only a few cases of NPE following Cryptococcal meningitis have been reported.15 Herein we report a case of NPE following Cryptococcal meningoencephalitis.
CLINICAL SUMMARY A 40-year-old man with no medical history presented to the emergency department for disturbance of consciousness. He was not a homosexual and had no drug use history. On initial presentation, the patient had a blood pressure of 180/90 mmHg, heart rate of 120 beats per minute, respiratory rate of 18 breaths per minute and temperature of 37.2°C. Physical examination revealed normal breath and heart sounds. Oxygen saturation was 98% on room air. Initial evaluation showed consciousness disturbance and a Glasgow Coma Scale level of 12 (E3V4M5). Initial laboratory findings are shown in Table 1. The results included a white blood cell (WBC) count of 13 700/μL, serum C-reactive protein of 0.55 mg/dL, and blood glucose level
344
R Kondo et al.
Table 1 Initial laboratory findings Hematological analysis
Blood chemistry
WBC Neutrophil Lymphocyte Monocyte Eosinophil Basophil RBC Hb Ht Plt
AST ALT LDH ALP T-Bil T.P Alb Na K Cl BUN Creatinine Blood sugar CRP
13 700/μL 11 343/μL 1 589/μL 740/μL 14/μL 14/μL 667 × 104/μL 19.7 g/dL 54.8% 15.2 × 104/mm3
21 IU/L 25 IU/L 844 IU/L 182 IU/L 1.7 mg/dL 7.9 g/dL 3.9 g/dL 141 mEq/L 3.4 mEq/L 92 mEq/L 18.5 mg/dL 0.70 mg/dL 124 mg/dL 0.55 mg/dL Fig. 2 Macroscopic findings of the brain. In the brain, small hemorrhage of right basal ganglia was seen.
PATHOLOGICAL FINDINGS
Fig. 1 Imaging findings. (a) Non-contrast chest CT scan disclosed marked peripheral interlobular septal thickening and diffuse ground glass opacities mixed with consolidation in both lungs. (b) Non-contrast head CT scan showed sulcal effacement in the frontal lobe.
of 124 mg/dL. Chest radiograph and non-contrast head CT scan showed no significant abnormality. Lumbar puncture revealed a pressure of over 300 mm H2O and cerebrospinal fluid (CSF) confirmed a white blood cell count of 65/mm3. The CSF glucose level was 0 mg/dL. The CSF protein level was 87 mg/dL. He was empirically started on treatment for presumptive bacterial and herpes viral meningitis. On day 4, oxygen saturation of the patient suddenly reduced and respiratory distress with copious amounts of pink frothy sputum occurred. Chest radiograph revealed generalized increased pulmonary infiltration, consistent with acute pulmonary edema. Chest CT scan disclosed marked peripheral interlobular septal thickening and diffuse ground glass opacities mixed with consolidation in both lungs (Fig. 1a). Head CT scan showed sulcal effacement in the frontal lobe, consistent with brain edema (Fig. 1b). Brain herniation was not present. Electrocardiogram and blood test including cardiac enzymes were normal limits. The patient died and an autopsy was performed
At autopsy, the patient was found to have brain edema, small hemorrhage of right basal ganglia, severe pulmonary edema and mild cardiomegaly (Fig. 2). The brain weighed 1696 g. Coronary artery and cerebral arterial circles were intact. In the spleen, atrophy of white pulp was observed. There was no lymphadenopathy. Histologically, there was inflammatory reaction with Cryptococci in the arachnoid membrane and the meninges (Fig. 3a). Ependymitis was not seen. In the bilateral frontal lobe, temporal lobe, parietal lobe, hippocampus, thalamus, basal ganglia, cerebellum, midbrain, pons, dilated VirchowRobin spaces, were crowded with Cryptococci and no inflammatory responses were observed (Fig. 3b). There was only slight inflammatory response in the dilated Virchow-Robin spaces and adjacent brain caused by the dissemination of the meningeal infection along the perivascular spaces. In the right basal ganglia, VirchowRobin spaces were destroyed with hemorrhaging and Cryptococci had spread to parenchyma of the brain (Fig. 3c). Inflammatory cell infiltration was mainly with T lymphocytes (Fig. 3d). There were no Cryptococci spreading to parenchyma in the pituitary gland. In the pituitary gland and thalamus, parenchymal necrosis was not seen. Human immunodeficiency virus (HIV) encephalopathy, progressive multifocal leukoencephalopathy and cytomegalovirus infection were not present. In the lung, pulmonary edema was seen (Fig. 4a). There were Cryptococci with no inflammatory reaction in the lung (Fig. 4b). Finally, acute pulmonary edema in this case was diagnosed as NPE following Cryptococcal meningoencephalitis. After autopsy, we found that he was positive for HIV serum antibody. © 2015 Japanese Society of Neuropathology
NPE following Cryptococcal meningitis
345
Fig. 3 Microscopic findings of the brain. (a) There is inflammatory reaction with Cryptococci in the arachnoid membrane. (b) In the cerebrum, dilated Virchow-Robin spaces, crowded with Cryptococci are observed. There is only slight inflammatory response in the dilated Virchow-Robin spaces. (c) In right basal ganglia, Virchow-Robin spaces are destroyed and Cryptococci spread to parenchyma of the brain. (d) Serial section shown in (c) stained for antibody against CD3. Lymphocytic infiltrates mainly consist of T cells. Scale bars = 100 μm.
Fig. 4 Microscopic findings of the lung. (a) Broad pulmonary edema is seen. Scale is 500 μm. (b) There are Cryptococci with no granulomatous inflammation. Periodic acid-Schiff stain. Scale bars = 500 μm (a), 50 μm (b).
DISCUSSION NPE is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. Although NPE has been recognized for a long time, it is still underdiagnosed in clinical practice.1,2 Any acute CNS insult can lead to pulmonary edema.3–9 The severity and acuity of the insult may play an important role.1 The exact mechanism of NPE remains unclear. Neurologic © 2015 Japanese Society of Neuropathology
insults that cause sudden and severe intracranial pressure (ICP) elevation pose the greatest risk. Elevated ICP leads to neuronal compression or ischemia, activation of the sympathetic nervous system, and the release of catecholamines that can lead to cardiopulmonary dysfunction.1,2 Certain brain regions have been implicated in the genesis of sympathetic hyperactivity, including the insular cortex, hypothalamus and medulla.1 In our case, elevated ICP was caused by brain edema associated with
346
R Kondo et al.
Table 2 Reported cases of acute respiratory failure following Cryptococcal meningoencephalitis Author/year
Visnegarwala15 1998
Current case 2014
Age
Gender
CSF opening pressure (mm H20)
Brain herniation
HIV infection
Survival (days)
35 years 31 years 47 years 37 years 35 years 40 years
Male Female Male Male Female Male
450 30 250 45 14 >300
Present None Present None None None
Positive Positive Positive Positive Positive Positive
20 1 19 19 2 1
Survival, survival time after the onset of acute respiratory failure.
Cryptococcal meningoencephalitis. A summary of acute respiratory failure following Cryptococcal meningoencephalitis in previous and current cases is shown in Table 2. Among the six cases previously reported in the literature (including the current case), three cases (50%) died within 2 days after the onset of acute respiratory failure; none of the three cases had brain herniation. The average age of patients was 37.5 years (range, 31–47 years). There were four men and two women. All patients were positive for HIV infection. The pathogenic mechanism is believed to occur at the level of pulmonary vascular endothelium. Several theories have been proposed, such as direct myocardial injury caused by: a surge in catecholamines (neuro-cardiac NPE); direct pulmonary vascular bed injury caused by massive sympathetic discharge (pulmonary venule adrenergic hypertensitivity); indirect left ventricular failure caused by increased systemic and pulmonary pressures after catecholamine surge (neuro-hemodynamic NPE); and high hydrostatic pressure and pulmonary endothelial injury caused by catecholamine surge (blast theory).1 NPE usually occurs within minutes to hours after a CNS insult. Diagnosis of NPE is difficult because of its relatively unpredictable nature and lack of specific signs and diagnostic tests. Differential diagnoses include pneumonia, congestive heart failure and acute respiratory distress syndrome.1,2 Our patient presented with the usual clinical features of NPE and signs without evidence of congestive heart failure, pneumonia, or other systemic causes for the pulmonary edema. After autopsy, we found that our patient was positive for HIV serum antibody. However, we could not confirm whether our patient had acquired Immune Deficiency Syndrome (AIDS). Cryptococcal infections are most commonly seen in immunocompromised patients.15,16 Disease disseminates typically, having defects in T cell function, through malignancy, immunosuppressive medication, autoimmune disease, sarcoidosis or HIV infection, indicating the role of T cell-mediated immunity in host defences.16 Recently, neuropathologic legions of
Cryptococcal meningoencephalitis in patients with HIV infection have been reported.17–19 Pathological findings revealed significant differences in the inflammatory response to Cryptococcal meningoencephalitis in patients with and without HIV infection.17–19 Typically, AIDS patients have no granulomatous inflammation, whereas most non-HIV-associated cases had granulomas, supporting a role for cell-mediated immunity in Cryptococcal meningoencephalitis. Lymphocytic infiltrate in both groups consisted of T cells.19 In addition, in patients with HIV infection, the presence of multiple gelatinous pseudocysts with abundant Cryptococci in the VirchowRobin spaces and adjacent brain were frequently observed, caused by the dissemination of the meningeal infection along the perivascular spaces.17–19 In this case, these neuropathologic legions were present. Dilated Virchow-Robin spaces, crowded with Cryptococci and no granulomatous inflammation were observed. It was suggested that Cryptococcal meningoencephalitis in this case was associated with HIV infection. In conclusion, NPE is a rapidly developing and sometimes life-threatening complication of CNS insult. Physicians should remember this clinical entity when caring for patients with acute respiratory distress following neurologic events.
DISCLOSURE We know of no financial conflicts of interest concerning this work.
REFERENCES 1. Davison DL, Terek M, Chawla LS. Neurogenic pulmonary edema. Crit Care 2012; 16: 212–218. 2. Baumann A, Audibert G, McDonnell J, Mertes PM. Neurogenic pulmonary edema. Acta Anaesthesiol Scand 2007; 51: 447–455. 3. Fontes RB, Aguiar PH, Zanetti MV, Andrade F, Mandel M, Teixeira MJ. Acute neurogenic pulmonary edema: case reports and literature review. J Neurosurg Anesthesiol 2003; 15: 144–150. © 2015 Japanese Society of Neuropathology
NPE following Cryptococcal meningitis 4. Bahloul M, Chaari AN, Kallel H et al. Neurogenic pulmonary edema due to traumatic brain injury: evidence of cardiac dysfunction.Am J Crit Care 2006;15:462–470. 5. Rogers FB, Shackford SR, Trevisani GT, Davis JW, Mackersie RC, Hoyt DB. Neurogenic pulmonary edema in fatal and nonfatal head injuries. J Trauma 1995; 39: 860–866. 6. Padley JR, Feneley MP, Hayward CS, Markus R. Neurocardiogenic pulmonary oedema: initial presentation of multiple sclerosis. Heart Lung Circ 2012; 21: 853–855. 7. Muroi C, Keller M, Pangalu A et al. Neurogenic pulmonary edema in patients with subarachnoid hemorrhage. J Neurosurg Anesthesiol 2008; 20: 188–192. 8. Makaryus JN, Kapphahn S, Makaryus AN. Unilateral neurogenic pulmonary oedema and severe left ventricular dysfunction secondary to acute multiple sclerosis exacerbation. Heart Lung Circ 2009; 18: 155–158. 9. Pai-Ching T, Helen LP. Neurogenic pulmonary edema following acute ischemic stroke: a case report and literature review. Neurol Asia 2014; 19: 195–198. 10. Krous HF, Chadwick AE, Miller DC, Crandall L, Kinney HC. Sudden death in toddlers with viral meningitis, massive cerebral edema, and neurogenic pulmonary edema and hemorrhage: report of two cases. Pediatr Dev Pathol 2007; 10: 463–469. 11. Peter P, Nolan M, Andrews IP, Williams GD. Neurogenic pulmonary edema in enterovirus 71 encephalitis
© 2015 Japanese Society of Neuropathology
347
12.
13.
14.
15.
16. 17.
18.
19.
is not uniformly fatal but causes severe morbidity in survivors. Pediatr Crit Care Med 2003; 4: 377–381. D’Souza R, Kerr F. Neurogenic pulmonary oedema induced by bacterial meningitis: a case report. Scott Med J 2001; 46: 115–116. Frankel RJ, Bennett ED, Borland CD. Pulmonary oedema in meningococcal meningitis. Postgrad Med J 1976; 52: 529–531. Chotmongkol V, Thiensiri C, Boonma P. Neurogenic pulmonary edema associated with meningitis. J Med Assoc Thai 1990; 9: 530–532. Visnegarwala F, Graviss EA, Lacke CE et al. Acute respiratory failure associated with Cryptococcosis in patients with AIDS: analysis of predictive factors. Clin Infect Dis 1998; 27: 1231–1237. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS 2007; 21: 2119–2129. Bos HM, Hofman PAM, Schreij G, Bot FJ, van Oostenbruggen RJ. Overwhelming CNS cryptococcus in AIDS. Neurology 2001; 57: 1560. Klock C, Cerski M, Goldani LZ. Histopathological aspects of neurocryptococcosis in HIV-infected patients: autopsy report of 45 patients. Int J Surg Pathol 2009; 17: 444–448. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27: 839–847.
