- Email: [email protected]
Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium-Intracellulare Complex in a Patient without AIDS
Case Report
Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium-Intracellulare Complex in a Patient without AIDS Ming-Sheng Lim1, Niamh Bermingham2, Cathal O’Broin3, Ayman Khalil1, Catherine Keohane2, Chris Lim1
Key words Cerebellum - Intracranial - Mycobacterium avium complex - T-lymphocytopenia idiopathic CD4-positive -
Abbreviations and Acronyms CD4: Cluster of differentiation 4 HIV: Human immunodeficiency virus MAC: Mycobacterium avium-intracellulare complex From the Departments of 1Neurosurgery, 2Neuropathology, and 3Infectious Diseases, Cork University Hospital, Cork, Ireland To whom correspondence should be addressed: Ming-Sheng Lim, M.B., B.Ch., B.A.O., B.Med.Sci. (Hons) [E-mail: [email protected]] Citation: World Neurosurg. (2016). http://dx.doi.org/10.1016/j.wneu.2016.02.082
- BACKGROUND:
Spindle cell pseudotumors are formed by histiocytes in response to infection by Mycobacterium avium-intracellulare complex (MAC) and are rare in patients without AIDS.
- CASE
DESCRIPTION: A 66-year-old man presented with neck pain, ataxia, and a history of sarcoidosis. A cerebellar lesion was identified on magnetic resonance imaging and surgically excised. Histopathology revealed this to be a spindle cell pseudotumor and MAC was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed cluster of differentiation 4 lymphocytopenia but human immunodeficiency virus serology was negative. The patient was commenced on antimicrobial treatment that included a macrolide and remained well at 1 year follow-up.
- CONCLUSIONS:
This rare presentation of isolated intracranial MAC was treated with surgical excision and antimicrobials with a good outcome.
Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
INTRODUCTION First described in 1985, mycobacterial spindle cell pseudotumors are caused by an inflammatory reaction to infection by Mycobacterium in which histiocytes display a spindle cell morphology. Mycobacterium avium-intracellulare complex (MAC) is the most common cause and is thought to be acquired primarily through inhalation or ingestion. The lymph nodes are most commonly affected but lung, skin, and brain involvement have been reported.1 Most cases in the literature were in patients who were immunocompromised with human immunodeficiency virus (HIV)/AIDS, and even then, such cases are rare. We present a case of isolated intracranial MAC in the absence of AIDS and review the literature on this rare pathologic condition. CASE DESCRIPTION A 66-year-old man presented to our neurosurgical service with neck pain and ataxia over the previous few weeks on a background of sarcoidosis diagnosed 28
years previously. He was otherwise asymptomatic, taking only warfarin, rosuvastatin, and bisoprolol because of a history of pulmonary embolism and pulmonary hypertension. He had never received immunosuppressive therapy. He had coarse crackles on chest auscultation bilaterally, consistent with his previous diagnosis of sarcoidosis, and also mild ataxia on physical examination. A chest radiograph showed fibrotic changes bilaterally that were not new, and magnetic resonance imaging of his head revealed a lesion in his right cerebellar hemisphere that was isointense on both T1- and T2-weighted sequences. The lesion enhanced homogenously with contrast (Figure 1A). The patient was brought to the operating theatre where a wellcircumscribed, firm, and featureless lesion, with a dural attachment on the tentorium, was completely excised via the standard approach. Although the lesion was relatively avascular intraoperatively, these findings pointed toward an initial diagnosis of meningioma. Histology showed a predominantly spindled cell lesion with oval nuclei surrounded by foci of epithelioid macrophages in meningeal tissue that extended into the cerebellar cortex. Numerous
WORLD NEUROSURGERY -: ---, MONTH 2016
slender acid-fast bacilli were seen on Ziehl-Neelsen staining. This lacked the typical features of necrotizing granulomatous inflammation with multinucleated cells characteristic of Mycobacterium tuberculosis and was instead consistent with atypical mycobacteria (Figure 1BeD). A lumbar puncture was performed and Mycobacterium avium was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed white cell counts in the normal range but the differential showed lymphocytes to be depleted at 0.65 109/L (normal range, 0.9e3.2). HIV serology was negative but the patient had a reduced absolute count of cluster of differentiation 4þ (CD4þ) Th lymphocytes (CD4) at 81 cells/mL (normal range, 400e1590). The cause of his lymphocytopenia has not been clarified despite extensive immunologic investigations. His immunoglobulin levels were normal, as was his interleukin 12:interferon g receptor axis. Specialized phenotyping of his T lymphocytes revealed most of them to be naive rather than mature. A normal neutrophil oxidative burst test suggested that despite his history, he was not affected by chronic granulomatous disease. Further investigations also failed to identify any
www.WORLDNEUROSURGERY.org
1.E1
CASE REPORT MING-SHENG LIM ET AL.
CASE REPORT: ISOLATED CEREBELLAR MAC
Figure 1. (A) Axial magnetic resonance imaging of the head, T1 with gadolinium, showing a homogenously enhancing lesion in the right cerebellar hemisphere. (B, C) Hematoxylin-eosin stain showing spindled and epithelioid histiocytes containing numerous slender acid-fast bacilli (D, Ziehl-Neelsen stain).
other location of infection. In particular, we were concerned that his MAC could have an intrapulmonary source, even in the absence of symptoms such as dyspnea or coughing. However, pulmonary function tests were completely normal, and a computed tomography scan of the thorax was performed but did not reveal anything new. We stopped short of bronchoalveolar lavage because this invasive test would not change his management. He was commenced on rifampicin, ethambutol, cotrimoxazole, and clarithromycin, and has remained well after 1 year. DISCUSSION MAC inhibits vacuole fusion with lysosomes, preventing their acidification and destruction and enabling them to survive and replicate within macrophages.2 However, natural killer cells and CD4 cells are effective against MAC, thus making MAC unusual in immunocompetent hosts. To our knowledge, only 2 cases of intracranial MAC in the absence of CD4 lymphocytopenia have been reported.3,4 Other cases in the literature report concurrent CD4 lymphocytopenia, usually
1.E2
www.SCIENCEDIRECT.com
secondary to HIV.3 In patients with HIV, a CD4 count of less than 50 cells/mm3 is an indication for MAC prophylaxis. Patients with autoimmune disease with a history of systemic steroid or immunosuppressive therapy are also understandably at greater risk.5,6 In disseminated MAC, the interleukin 12:interferon g axis has been implicated,7 but this was not the case for our patient. In our case, the patient had a history of sarcoidosis but otherwise had no reason to be immunocompromised. His sarcoidosis presented unusually with a swelling of the phalanges of his right hand and was confirmed on bone biopsy. Further investigations then revealed bilateral lung fibrosis with hilar lymphadenopathy on chest radiography and mild mitral valve prolapse on echocardiography. However, because the finger swelling resolved spontaneously, and he was asymptomatic otherwise, he was never commenced on steroids. Sarcoidosis has in rare cases been linked with idiopathic CD4 lymphocytopaenia.8 Sarcoidosis has also been reported in previous cases of isolated intracranial spindle cell pseudotumors,5,6 suggesting a potential link between these diseases.
Disseminated MAC usually presents with nonspecific symptoms such as fever, weight loss, and abdominal pain. The effects of isolated spindle cell pseudotumors are more localized. In intracranial MAC, the presentation varies depending on location and mass effect. In our case, the patient’s complaint of ataxia is consistent with the cerebellar location of the pseudotumor. Other cases reported patients presenting with suspected seizure, disturbed consciousness, headaches, meningism, and hemiparesis.5,9-11 Most of these cases were MAC abscesses rather than spindle cell pseudotumors. Treatment of MAC involves the use of systemic antimicrobials including macrolides and the initiation of antiretroviral therapy if it is the first presentation of HIV/AIDS. Sternfeld et al.12 described the use of interferon g and interleukin 2 to stimulate CD4 growth in a case of recurrent disseminated MAC. Dickerman et al.5 performed surgical excision in their case of isolated intracranial MAC that was refractory to medical management and reported favorable results. Unlike previous reported cases, MAC was successfully isolated from culture of
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2016.02.082
CASE REPORT MING-SHENG LIM ET AL.
cerebrospinal fluid obtained from lumbar puncture in our case, suggesting this as a possible means of diagnosis without the need for tissue biopsy. However, because our patient presented only with neck pain, ataxia, and imaging consistent with a meningioma, the correct diagnosis was made only after histopathologic analysis. We treated our case with complete surgical excision followed by the standard antimicrobial therapy, with a good result at follow-up after a year. This case illustrates an unusual presentation of a rare disease. We highlight the importance of multidisciplinary input in the diagnosis and management of intracranial lesions. REFERENCES 1. Miranda R, Khoury J, Medeiros LJ. Mycobacterial spindle cell pseudotumor. In: Atlas of Lymph Node Pathology SE-8. Atlas of Anatomic Pathology. New York, NY: Springer; 2013:33-34. 2. Early J, Fischer K, Bermudez LE. Mycobacterium avium uses apoptotic macrophages as tools for spreading. Microb Pathog. 2011;50:132-139. 3. Chowdhary M, Narsinghani U, Kumar RA. Intracranial abscess due to Mycobacterium avium
CASE REPORT: ISOLATED CEREBELLAR MAC
complex in an immunocompetent host: a case report. BMC Infect Dis. 2015;15:281.
HIV-infected patient: case report and review. J Microbiol Immunol Infect. 2013;46:68-72.
4. Dubbioso R, Cerillo I, D’Arco F, D’Amico A, Pettinato G, Boldorini R, et al. Isolated intracranial Mycobacterium avium complex granulomas in an immune-competent man. J Neurol Sci. 2015;349: 264-265.
10. Karne SS, Sangle SA, Kiyawat DS, Dharmashale SN, Kadam DB, Bhardwaj RS. Mycobacterium avium-intracellulare brain abscess in HIV-positive patient. Ann Indian Acad Neurol. 2012; 15:54-55.
5. Dickerman RD, Stevens QE, Rak R, Dorman SE, Holland SM, Nguyen TT. Isolated intracranial infection with Mycobacterium avium complex. J Neurosurg Sci. 2003;47:101-105.
11. Kishida S, Ajisawa A. Probable cerebral Mycobacterium avium complex-related immune reconstitution inflammatory syndrome in an HIV-infected patient. Intern Med. 2008;47:1349-1354.
6. Morrison A, Gyure KA, Stone J, Wong K, McEvoy P, Koeller K, et al. Mycobacterial spindle cell pseudotumor of the brain: a case report and review of the literature. Am J Surg Pathol. 1999;23: 1294-1299.
12. Sternfeld T, Nigg A, Belohradsky BH, Bogner JR. Treatment of relapsing Mycobacterium avium infection with interferon-gamma and interleukin-2 in an HIV-negative patient with low CD4 syndrome. Int J Infect Dis. 2010;14:198-201.
7. O’Connell E, Rosen LB, LaRue RW, Fabre V, Melia MT, Auwaerter PG, et al. The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-g autoantibodies. J Clin Immunol. 2014;34:928-932. 8. Freymond N, Malcus C, Pacheco Y, Devouassoux G. Lymphocytopenia-associated sarcoidosis: CD4þ T-cell hypo-responsiveness to IL-2 and lectin. Respir Med CME. 2010;3:113-115.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 22 January 2016; accepted 18 February 2016 Citation: World Neurosurg. (2016). http://dx.doi.org/10.1016/j.wneu.2016.02.082 Journal homepage: www.WORLDNEUROSURGERY.org
9. Lee Y-C, Lu C-L, Lai C-C, Tseng Y-T, Sun H-Y, Hung C-C. Mycobacterium avium complex infectionrelated immune reconstitution inflammatory syndrome of the central nervous system in an
WORLD NEUROSURGERY -: ---, MONTH 2016
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
1.E3
Isolated Cerebellar Spindle Cell Pseudotumor Caused by Mycobacterium Avium-Intracellulare Complex in a Patient without AIDS Ming-Sheng Lim1, Niamh Bermingham2, Cathal O’Broin3, Ayman Khalil1, Catherine Keohane2, Chris Lim1
Key words Cerebellum - Intracranial - Mycobacterium avium complex - T-lymphocytopenia idiopathic CD4-positive -
Abbreviations and Acronyms CD4: Cluster of differentiation 4 HIV: Human immunodeficiency virus MAC: Mycobacterium avium-intracellulare complex From the Departments of 1Neurosurgery, 2Neuropathology, and 3Infectious Diseases, Cork University Hospital, Cork, Ireland To whom correspondence should be addressed: Ming-Sheng Lim, M.B., B.Ch., B.A.O., B.Med.Sci. (Hons) [E-mail: [email protected]] Citation: World Neurosurg. (2016). http://dx.doi.org/10.1016/j.wneu.2016.02.082
- BACKGROUND:
Spindle cell pseudotumors are formed by histiocytes in response to infection by Mycobacterium avium-intracellulare complex (MAC) and are rare in patients without AIDS.
- CASE
DESCRIPTION: A 66-year-old man presented with neck pain, ataxia, and a history of sarcoidosis. A cerebellar lesion was identified on magnetic resonance imaging and surgically excised. Histopathology revealed this to be a spindle cell pseudotumor and MAC was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed cluster of differentiation 4 lymphocytopenia but human immunodeficiency virus serology was negative. The patient was commenced on antimicrobial treatment that included a macrolide and remained well at 1 year follow-up.
- CONCLUSIONS:
This rare presentation of isolated intracranial MAC was treated with surgical excision and antimicrobials with a good outcome.
Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
INTRODUCTION First described in 1985, mycobacterial spindle cell pseudotumors are caused by an inflammatory reaction to infection by Mycobacterium in which histiocytes display a spindle cell morphology. Mycobacterium avium-intracellulare complex (MAC) is the most common cause and is thought to be acquired primarily through inhalation or ingestion. The lymph nodes are most commonly affected but lung, skin, and brain involvement have been reported.1 Most cases in the literature were in patients who were immunocompromised with human immunodeficiency virus (HIV)/AIDS, and even then, such cases are rare. We present a case of isolated intracranial MAC in the absence of AIDS and review the literature on this rare pathologic condition. CASE DESCRIPTION A 66-year-old man presented to our neurosurgical service with neck pain and ataxia over the previous few weeks on a background of sarcoidosis diagnosed 28
years previously. He was otherwise asymptomatic, taking only warfarin, rosuvastatin, and bisoprolol because of a history of pulmonary embolism and pulmonary hypertension. He had never received immunosuppressive therapy. He had coarse crackles on chest auscultation bilaterally, consistent with his previous diagnosis of sarcoidosis, and also mild ataxia on physical examination. A chest radiograph showed fibrotic changes bilaterally that were not new, and magnetic resonance imaging of his head revealed a lesion in his right cerebellar hemisphere that was isointense on both T1- and T2-weighted sequences. The lesion enhanced homogenously with contrast (Figure 1A). The patient was brought to the operating theatre where a wellcircumscribed, firm, and featureless lesion, with a dural attachment on the tentorium, was completely excised via the standard approach. Although the lesion was relatively avascular intraoperatively, these findings pointed toward an initial diagnosis of meningioma. Histology showed a predominantly spindled cell lesion with oval nuclei surrounded by foci of epithelioid macrophages in meningeal tissue that extended into the cerebellar cortex. Numerous
WORLD NEUROSURGERY -: ---, MONTH 2016
slender acid-fast bacilli were seen on Ziehl-Neelsen staining. This lacked the typical features of necrotizing granulomatous inflammation with multinucleated cells characteristic of Mycobacterium tuberculosis and was instead consistent with atypical mycobacteria (Figure 1BeD). A lumbar puncture was performed and Mycobacterium avium was isolated by bacterial culture of cerebrospinal fluid. Hematology revealed white cell counts in the normal range but the differential showed lymphocytes to be depleted at 0.65 109/L (normal range, 0.9e3.2). HIV serology was negative but the patient had a reduced absolute count of cluster of differentiation 4þ (CD4þ) Th lymphocytes (CD4) at 81 cells/mL (normal range, 400e1590). The cause of his lymphocytopenia has not been clarified despite extensive immunologic investigations. His immunoglobulin levels were normal, as was his interleukin 12:interferon g receptor axis. Specialized phenotyping of his T lymphocytes revealed most of them to be naive rather than mature. A normal neutrophil oxidative burst test suggested that despite his history, he was not affected by chronic granulomatous disease. Further investigations also failed to identify any
www.WORLDNEUROSURGERY.org
1.E1
CASE REPORT MING-SHENG LIM ET AL.
CASE REPORT: ISOLATED CEREBELLAR MAC
Figure 1. (A) Axial magnetic resonance imaging of the head, T1 with gadolinium, showing a homogenously enhancing lesion in the right cerebellar hemisphere. (B, C) Hematoxylin-eosin stain showing spindled and epithelioid histiocytes containing numerous slender acid-fast bacilli (D, Ziehl-Neelsen stain).
other location of infection. In particular, we were concerned that his MAC could have an intrapulmonary source, even in the absence of symptoms such as dyspnea or coughing. However, pulmonary function tests were completely normal, and a computed tomography scan of the thorax was performed but did not reveal anything new. We stopped short of bronchoalveolar lavage because this invasive test would not change his management. He was commenced on rifampicin, ethambutol, cotrimoxazole, and clarithromycin, and has remained well after 1 year. DISCUSSION MAC inhibits vacuole fusion with lysosomes, preventing their acidification and destruction and enabling them to survive and replicate within macrophages.2 However, natural killer cells and CD4 cells are effective against MAC, thus making MAC unusual in immunocompetent hosts. To our knowledge, only 2 cases of intracranial MAC in the absence of CD4 lymphocytopenia have been reported.3,4 Other cases in the literature report concurrent CD4 lymphocytopenia, usually
1.E2
www.SCIENCEDIRECT.com
secondary to HIV.3 In patients with HIV, a CD4 count of less than 50 cells/mm3 is an indication for MAC prophylaxis. Patients with autoimmune disease with a history of systemic steroid or immunosuppressive therapy are also understandably at greater risk.5,6 In disseminated MAC, the interleukin 12:interferon g axis has been implicated,7 but this was not the case for our patient. In our case, the patient had a history of sarcoidosis but otherwise had no reason to be immunocompromised. His sarcoidosis presented unusually with a swelling of the phalanges of his right hand and was confirmed on bone biopsy. Further investigations then revealed bilateral lung fibrosis with hilar lymphadenopathy on chest radiography and mild mitral valve prolapse on echocardiography. However, because the finger swelling resolved spontaneously, and he was asymptomatic otherwise, he was never commenced on steroids. Sarcoidosis has in rare cases been linked with idiopathic CD4 lymphocytopaenia.8 Sarcoidosis has also been reported in previous cases of isolated intracranial spindle cell pseudotumors,5,6 suggesting a potential link between these diseases.
Disseminated MAC usually presents with nonspecific symptoms such as fever, weight loss, and abdominal pain. The effects of isolated spindle cell pseudotumors are more localized. In intracranial MAC, the presentation varies depending on location and mass effect. In our case, the patient’s complaint of ataxia is consistent with the cerebellar location of the pseudotumor. Other cases reported patients presenting with suspected seizure, disturbed consciousness, headaches, meningism, and hemiparesis.5,9-11 Most of these cases were MAC abscesses rather than spindle cell pseudotumors. Treatment of MAC involves the use of systemic antimicrobials including macrolides and the initiation of antiretroviral therapy if it is the first presentation of HIV/AIDS. Sternfeld et al.12 described the use of interferon g and interleukin 2 to stimulate CD4 growth in a case of recurrent disseminated MAC. Dickerman et al.5 performed surgical excision in their case of isolated intracranial MAC that was refractory to medical management and reported favorable results. Unlike previous reported cases, MAC was successfully isolated from culture of
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2016.02.082
CASE REPORT MING-SHENG LIM ET AL.
cerebrospinal fluid obtained from lumbar puncture in our case, suggesting this as a possible means of diagnosis without the need for tissue biopsy. However, because our patient presented only with neck pain, ataxia, and imaging consistent with a meningioma, the correct diagnosis was made only after histopathologic analysis. We treated our case with complete surgical excision followed by the standard antimicrobial therapy, with a good result at follow-up after a year. This case illustrates an unusual presentation of a rare disease. We highlight the importance of multidisciplinary input in the diagnosis and management of intracranial lesions. REFERENCES 1. Miranda R, Khoury J, Medeiros LJ. Mycobacterial spindle cell pseudotumor. In: Atlas of Lymph Node Pathology SE-8. Atlas of Anatomic Pathology. New York, NY: Springer; 2013:33-34. 2. Early J, Fischer K, Bermudez LE. Mycobacterium avium uses apoptotic macrophages as tools for spreading. Microb Pathog. 2011;50:132-139. 3. Chowdhary M, Narsinghani U, Kumar RA. Intracranial abscess due to Mycobacterium avium
CASE REPORT: ISOLATED CEREBELLAR MAC
complex in an immunocompetent host: a case report. BMC Infect Dis. 2015;15:281.
HIV-infected patient: case report and review. J Microbiol Immunol Infect. 2013;46:68-72.
4. Dubbioso R, Cerillo I, D’Arco F, D’Amico A, Pettinato G, Boldorini R, et al. Isolated intracranial Mycobacterium avium complex granulomas in an immune-competent man. J Neurol Sci. 2015;349: 264-265.
10. Karne SS, Sangle SA, Kiyawat DS, Dharmashale SN, Kadam DB, Bhardwaj RS. Mycobacterium avium-intracellulare brain abscess in HIV-positive patient. Ann Indian Acad Neurol. 2012; 15:54-55.
5. Dickerman RD, Stevens QE, Rak R, Dorman SE, Holland SM, Nguyen TT. Isolated intracranial infection with Mycobacterium avium complex. J Neurosurg Sci. 2003;47:101-105.
11. Kishida S, Ajisawa A. Probable cerebral Mycobacterium avium complex-related immune reconstitution inflammatory syndrome in an HIV-infected patient. Intern Med. 2008;47:1349-1354.
6. Morrison A, Gyure KA, Stone J, Wong K, McEvoy P, Koeller K, et al. Mycobacterial spindle cell pseudotumor of the brain: a case report and review of the literature. Am J Surg Pathol. 1999;23: 1294-1299.
12. Sternfeld T, Nigg A, Belohradsky BH, Bogner JR. Treatment of relapsing Mycobacterium avium infection with interferon-gamma and interleukin-2 in an HIV-negative patient with low CD4 syndrome. Int J Infect Dis. 2010;14:198-201.
7. O’Connell E, Rosen LB, LaRue RW, Fabre V, Melia MT, Auwaerter PG, et al. The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-g autoantibodies. J Clin Immunol. 2014;34:928-932. 8. Freymond N, Malcus C, Pacheco Y, Devouassoux G. Lymphocytopenia-associated sarcoidosis: CD4þ T-cell hypo-responsiveness to IL-2 and lectin. Respir Med CME. 2010;3:113-115.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 22 January 2016; accepted 18 February 2016 Citation: World Neurosurg. (2016). http://dx.doi.org/10.1016/j.wneu.2016.02.082 Journal homepage: www.WORLDNEUROSURGERY.org
9. Lee Y-C, Lu C-L, Lai C-C, Tseng Y-T, Sun H-Y, Hung C-C. Mycobacterium avium complex infectionrelated immune reconstitution inflammatory syndrome of the central nervous system in an
WORLD NEUROSURGERY -: ---, MONTH 2016
Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2016 Elsevier Inc. All rights reserved.
www.WORLDNEUROSURGERY.org
1.E3