Brain biopsy in AIDS patients: diagnostic yield and treatment applications

  • Zion Zibly7,

    Affiliated with

    • Itzchak Levy3,

      Affiliated with

      • Vlady Litchevski3,

        Affiliated with

        • Dvora Nass2,

          Affiliated with

          • Chen Hofmann4,

            Affiliated with

            • Jacob Barham5,

              Affiliated with

              • Christian A Graves6,

                Affiliated with

                • Roberto Spiegelmann1,

                  Affiliated with

                  • Moshe Hadani1 and

                    Affiliated with

                    • Zvi R Cohen1Email author

                      Affiliated with

                      AIDS Research and Therapy201411:4

                      DOI: 10.1186/1742-6405-11-4

                      Received: 30 March 2013

                      Accepted: 2 December 2013

                      Published: 21 January 2014

                      Abstract

                      Objective

                      Central nervous system involvement in AIDS patients can present at any stage of the disease. Brain lesions detected in imaging studies are usually treated empirically. A brain biopsy is indicated in the absence of clinical and radiologic improvement. In the present study, 16 AIDS patients underwent brain biopsy. We evaluated the diagnostic yield of the brain biopsy and the changes in the disease course.

                      Materials and methods

                      Sixteen consecutive AIDS patients (12 men, 4 women; mean age 40.8 years) underwent a brain biopsy at Sheba Medical Center between 1997 and 2009. A retrospective analysis was performed and the clinical outcome was recorded.

                      Results

                      Median CD4 count before biopsy was 62.6. Magnetic resonance images revealed multiple lesions in 12 patients and enhancing lesions in 12 patients. A total of 19 biopsies were performed in 16 patients. In the present series, the initial procedures provided a diagnostic yield of 81.25% (13 diagnostic cases from 16 procedures in 16 patients). Two of these patients underwent repeated biopsies that were eventually diagnostic . If repeated biopsies were taken into consideration, the diagnostic yield was 93.75% (15 diagnostic cases in 16 patients). The rate of hemorrhagic complications was 10.5% (2 hemorrhages in 19 procedures).

                      Pathologic examination revealed parasitic and fungal infections in 6 patients (6/16; 38%), progressive multifocal leukoencephalopathy in 4 patients (4/16; 25%), AIDS encephalopathy in 4 patients (4/16; 25%), and lymphoma in 1 patient (1/16; 6%). One patient had a nonspecific inflammatory process (6%). The treatment modality was modified in 12 patients and led to clinical and radiologic improvement in 8 patients.

                      Conclusions

                      Brain biopsy should be considered when empiric treatment of central nervous system lesions in AIDS patients fails. Biopsy is diagnostic in the majority of patients. The diagnosis allows for treatment modifications, which lead to clinical and radiologic improvement in some patients.

                      Keywords

                      HIV Brain biopsy CNS AIDS Neuroimmunology

                      Introduction

                      Central nervous system (CNS) involvement in AIDS patients is a well-established phenomenon that occurs in approximately 40% to 60% of patients at some stage of the disease. In 10% to 20% of patients, neurologic complications are the first manifestation of HIV infection [1]. The causes of brain involvement include infection, inflammatory changes, and neoplasia [2]. The most common brain lesion in HIV patients worldwide is toxoplasmosis [3], but there is an increased incidence of HIV-associated tuberculosis in focal brain lesions in developing countries [4]. Imaging characteristics of brain lesions in HIV patients have been described [5, 6]. The diagnostic yield of brain biopsy in HIV patients has also been evaluated [79]. In recent years, due to the availability of advanced multidrug therapies such as highly active antiretroviral therapy (HAART), the disease has gained more chronic characteristics and patient prognosis has greatly improved. The increased longevity of the clinical course of AIDS patients requires the establishment of more aggressive therapeutic approaches in patients with CNS involvement. Brain lesions detected on imaging studies are treated empirically according to current clinical guidelines. Brain biopsy is indicated in the absence of clinical and radiologic improvement, based on the recommendations of the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the HIV Medicine Association of the Infectious Diseases Society of America. The objective of this retrospective study was to analyze the data of 16 AIDS patients who underwent a brain biopsy at Sheba Medical Center in Israel to evaluate the diagnostic yield and changes in the disease course.

                      Material and methods

                      Patient selection and study approval

                      The study was conducted according to procedures approved by the Sheba Medical Center Institutional Review Board.

                      Clinical data

                      Sixteen consecutive AIDS patients underwent a brain biopsy at Sheba Medical Center between 1997 and 2009. Patient characteristics; presenting symptoms; neurologic status; CD4 count; radiologic imaging results, including number of lesions, location of the targeted lesion, and presence of post-operative hemorrhage on computed tomography (CT) scans; and pathologic results were retrospectively analyzed. Treatment changes, and clinical and radiologic outcome were recorded.

                      Surgical procedure

                      Stereotactic brain biopsies were performed using a Radionics® CRW™ frame and localizer (except for one patient that underwent an open image-guided navigation system biopsy using pituitary forceps). After performing the CT scan and establishing the target (based on fusion with preoperative MR images and performed by the neurosurgeon), the patient was taken to the operating room and serial stereotactic biopsies were obtained under local anesthesia along the established trajectory using a side-cutting biopsy needle. CT scans were obtained up to 2 hours post-procedure and the patients remained in the neurosurgical department for overnight observation.

                      Tissue analysis

                      Tissue specimens collected in the operation room were placed in individual vials for pathologic analysis; incubated in aerobic, anaerobic, mycobacterium, and fungal cultures; and subjected to PCR analysis for the JC and BK polyomaviruses.

                      Results

                      Twelve patients were men. Mean age at onset of the neurologic manifestations was 40.8 years. The clinical manifestations of the disease were mainly cognitive changes and motor deficits. Mean CD4 count before the brain biopsy was 62.6. A total of 19 brain biopsies were performed in 16 patients. In the present series, the initial procedures provided a diagnostic yield of 81.25% (13 diagnostic cases from 16 procedures in 16 patients). Two of these patients underwent repeated biopsies that were eventually diagnostic. If repeated biopsies were taken into consideration, the diagnostic yield was 93.75% (15 diagnostic cases in 16 patients).

                      Among the three patients with an initially nondiagnostic biopsy, the initial biopsy revealed a nonspecific inflammatory process in two patients, and the procedure was aborted due to hemorrhage in one patient. Two of these patients underwent a repeated biopsy that was eventually diagnostic.

                      One of the patients initially diagnosed with a nonspecific inflammatory process underwent two more biopsies and the third biopsy was eventually diagnostic. The second patient initially diagnosed with a nonspecific inflammatory process improved with HAART and did not require a second biopsy.

                      In the present series, the rate of hemorrhagic complications was 10.5% (2 hemorrhages in 19 procedures). Two of our patients had a hemorrhage; the first had a non-surgical bleeding however we had to abort the procedure and the patient underwent later a second procedure with a diagnostic biopsy. The second patient had a diagnostic biopsy, but due to clinical deterioration underwent evacuation of a hematoma. This patient recovered from the procedure, but did not improve with HAART.

                      Pathologic examination revealed parasitic and fungal infections in 6 patients (6/16) [38%]: toxoplasmosis, N = 4 [67%], aspergillosis N = 1 [17%], and cryptococcosis N = 1 [17%]), progressive multifocal leukoencephalopathy (PML) in 4 (25%) patients, AIDS encephalopathy in 4 patients (25%), and lymphoma in 1 (6%) patient. One patient had a nonspecific inflammatory process (6%), The treatment modality was modified in 12 patients and led to clinical and radiologic improvement in 8 patients (Table 1).
                      Table 1

                      Patients demographic and clinical data

                       

                      Diagnosis

                      Age

                      SBX VS open

                      Sex

                      Solitary vs multiple

                      Target location

                      Side

                      Enhancement

                      Edema

                      Presenting symptoms

                      CD4 pre biopsy

                      Treatment

                      Complications

                      Clinical improvement

                      1

                      PML

                      37

                      sbx

                      Male

                      Multiple

                      BG

                      Right

                      No

                      None

                      Combined

                      69

                      AZT, 3TC

                      No

                      No

                      2

                      Non diagnostic × 1,Toxoplasmosis 2nd

                      36

                      sbx

                      Male

                      Solitary

                      Frontal

                      Right

                      Yes

                      Yes

                      Motor

                      50

                      AZT, 3TC, Antitoxoplasmosis

                      Bleeding

                      No

                      3

                      PML

                      41

                      sbx

                      Male

                      Solitary

                      BG

                      Left

                      No

                      None

                      Cognitive

                      10

                      AZT, 3TC

                      No

                      No

                      4

                      Lymphoma

                      39

                      sbx

                      Male

                      Solitary

                      BG

                      Right

                      Yes

                      yes

                      Motor

                      13

                      Radiation Therapy

                      No

                      Yes

                      5

                      PML

                      32

                      sbx

                      Male

                      Multiple

                      Frontal

                      Right

                      No

                      None

                      Combined

                      57

                      HAART

                      No

                      Yes

                      6

                      Toxoplasmosis

                      24

                      sbx

                      Male

                      Multiple

                      BG

                      Left

                      Yes

                      Yes

                      Combined

                      38

                      HAART, Antitoxoplasmosis

                      No

                      No

                      7

                      Toxoplasmosis

                      29

                      sbx

                      Male

                      Solitary

                      Frontal

                      Right

                      Yes

                      Yes

                      Motor

                      185

                      HAART, Antitoxoplasmosis

                      No

                      Yes

                      8

                      Non Diagnostic × 2 Aspergilosis 3rd

                      78

                      sbx

                      Male

                      Multiple

                      Parietal occipital frontal

                      Right

                      Yes

                      Yes

                      Motor

                      50

                      HAART, Amphotericin

                      No

                      No

                      9

                      HIV encephalopathy

                      33

                      sbx

                      Male

                      Multiple

                      Occipital

                      Right

                      Yes

                      Yes

                      Combined

                      3

                      HAART

                      No

                      Yes

                      10

                      PML

                      48

                      sbx

                      Male

                      Multiple

                      Frontal

                      Right

                      Yes

                      None

                      Combined

                      25

                      HAART

                      No

                      Yes

                      11

                      Non diagnostic inflamatory reactive process

                      41

                      sbx

                      Female

                      Multiple

                      BG

                      Left

                      Yes

                      Yes

                      Motor

                      22

                      HAART

                      No

                      Yes

                      12

                      Viral infection

                      37

                      sbx

                      Male

                      Multiple

                      Frontal

                      Left

                      Yes

                      Yes

                      Combined

                      36

                      HAART

                      No

                      No

                      13

                      Cryptoccocal

                      55

                      sbx

                      male

                      Multiple

                      Temporal

                      Left

                      Yes

                      Yes

                      Motor

                      60

                      HAART, Amphotericin, Intraconazol

                      No

                      No

                      14

                      Viral infection

                      46

                      sbx

                      Female

                      Multiple

                      Occipital

                      Right

                      No

                      None

                      Combined

                      338

                      HAART

                      No

                      Yes

                      15

                      Viral infection

                      46

                      sbx

                      Female

                      Multiple

                      BG

                      Right

                      Yes

                      Yes

                      Combined

                      33

                      HAART

                      Bleeding

                      No

                      16

                      Toxoplasmosis

                      32

                      open

                      Female

                      Multiple

                      Parietal

                      Right

                      Yes

                      Yes

                      Combined

                      14

                      HAART, Antitoxoplasmosis

                      No

                      Yes

                      Discussion

                      Treatment with highly active antiviral drugs (HAART) has resulted in an overall decline in morbidity and mortality among HIV-infected patients with advanced disease [10]. The widespread use of prophylactic regimens has changed the disease pattern and decreased the incidence of opportunistic infections [11]. Vago et al. [12] reported on a large autopsy series that showed a significant reduction in the frequency of HIV-related central nervous system lesions in AIDS patients since the beginning of the HAART era.

                      In patients with HIV, Toxoplasma gondii is the most frequent infectious cause of focal brain lesions [3]. Toxoplasmic encephalitis has a subacute onset with focal neurologic abnormalities frequently accompanied by headache, altered mental status, and fever [13].

                      Diffuse toxoplasmosis encephalitis should be considered in patients with anti-T gondii immunoglobulin G (IgG) antibodies and CD4 T-cell counts of <100/μL who present with unexplained neurologic disease.

                      Since the introduction of HAART, the incidence of toxoplasmic encephalitis has remained stable or decreased, CNS lymphoma has dramatically declined, PML has slightly increased, [11] and the incidence of HIV encephalopathy has increased [14]. Although combination therapies have decreased overall mortality and the prevalence of CNS opportunistic infections, these therapies may be less effective for preventing the direct effects of HIV-1 on the brain. One of our patients presented with histologic features of AIDS encephalopathy. The majority of patients in our cohort were men with a median age of 40, consistent with other studies [15, 16]. These findings are compatible with our data , which is reported to be increasing in prevalence in the HAART era [17].

                      Thallium SPECT and PET scanning in the diagnosis of lymphoma and PCR analysis of the cerebrospinal fluid for the diagnosis of toxoplasmosis and JC virus have led to a shift in the use invasive diagnostic techniques (brain biopsy) to noninvasive diagnostic methods [5]. The patient in our series that was diagnosed with lymphoma had a solitary enhancing lesion. Although CNS lymphoma generally tends to enhance, atypical characteristics may be observed on MR images of immunocompromised patients [18]. Toxoplasma and lymphoma may have similar appearance on MR imaging. Erdag et al. [18] noted that lymphoma usually appears as a solitary lesion, unlike toxoplasmosis, which appears as a multifocal lesion. Only half of our patients with toxoplasmosis, however, had multifocal disease, similar to a previous report [15].

                      The majority of patients in our cohort that were diagnosed with PML had nonenhancing lesions, consistent with previous studies [18, 19]. Other studies, however, report enhancement on MR images of PML patients that may reach 42% [15], and the development of a mass effect and temporary enhancement on MR images in the early phase of treatment might represent positive predictive factors for prolonged survival [19].

                      A literature review revealed several descriptions of stereotactic brain biopsy in AIDS patients. The majority of these were reports on patients treated in the pre-HAART era [79, 16, 2026]. In a recent study, Rosenow et al. [15] divided a large cohort of 246 patients that underwent brain biopsy into two diagnostic groups, before and after the HAART era. The authors concluded that the introduction of HAART led to a steep decrease in the number of biopsies performed annually. Biopsy led to an objective and definitive diagnosis in 96% of patients (48/50), in the patients in the HAART era. Definitive diagnoses were obtained for 91.3% of patients (179/196) in the pre-HAART era. The overall diagnostic yield of biopsy was 92.3% of the total patient cohort. Rosenow et al. [15] suggested that AIDS patients with intra-cerebral lesions should undergo toxoplasmosis titers, and those with negative toxoplasmosis titers should undergo early brain biopsy. In our study, the majority of the patients were treated in the HAART era, which may correlate with the relatively small cohort of patients that underwent stereotactic brain biopsy. The diagnostic yield of the biopsy was high, although lower than previously reported [15].

                      A total of 19 biopsies were performed in 16 patients; one procedure was aborted due to bleeding and three biopsies were nondiagnostic (15%). Significantly, two patients underwent repeated biopsies that were conclusive. Diagnoses were eventually obtained for 93.7% of patients (15/16). Based on the biopsy findings, the treatment modality was modified in 12 patients and led to clinical and radiologic improvement in 8 patients. Modification of the treatment following brain biopsy has also been reported [1, 8].

                      Hemorrhagic complications of biopsy are reported [16, 20, 23, 25]. The incidence of hemorrhage in our small cohort of patients was higher than that reported in a non-HIV group of patients treated in our department [27]. Although the coagulation profile in our patients was within normal limits, there may have been undetectable coagulopathy in this group of patients. Anticoagulopathy regimens have been suggested by others [16] and pre-biopsy correction of thrombopenia less than 100,000/ml is suggested by Rosenow et al. [15]. A larger cohort of patients is required to establish more definitive conclusions.

                      Conclusion

                      We present the results from a single institute HAART era brain biopsy study in a cohort of 16 patients with active AIDS-associated lesions. Our objective diagnostic rates are consistent with those previously reported, allowing for treatment modification and confirming the usefulness of biopsy in these patients.

                      Declarations

                      Authors’ Affiliations

                      (1)
                      Department of Neurosurgery, Sheba Medical Center
                      (2)
                      Institute of Pathology, Sheba Medical Center
                      (3)
                      AIDS Center, Sheba Medical Center
                      (4)
                      Institute of Radiology, Sheba Medical Center
                      (5)
                      The Oncology Center, Sheba Medical Center
                      (6)
                      Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine
                      (7)
                      National Institute of Neurological Disorders and Stroke National Institutes of Health

                      References

                      1. Alesch F, Armbruster C, Budka H: Diagnostic value of stereotactic biopsy of cerebral lesions in patients with AIDS. Acta Neurochir (Wien). 1995, 134 (3–4): 214-9.View Article
                      2. Clifford DB: Focal brain lesions in people with HIV. Curr Treat Options Neurol. 1999, 1 (2): 167-72. 10.1007/s11940-999-0016-6View ArticlePubMed
                      3. Luft BJ, Chua A: Central nervous system toxoplasmosis in HIV pathogenesis, diagnosis, and therapy. Curr Infect Dis Rep. 2000, 2 (4): 358-62. 10.1007/s11908-000-0016-xView ArticlePubMed
                      4. Narain JP, Raviglione MC, Kochi A: HIV-associated tuberculosis in developing countries: epidemiology and strategies for prevention. Tuber Lung Dis. 1992, 73 (6): 311-21. Epub 1992/12/01 10.1016/0962-8479(92)90033-GView ArticlePubMed
                      5. Chang L, Miller BL, McBride D, Cornford M, Oropilla G, Buchthal S: Brain lesions in patients with AIDS: H-1 MR spectroscopy. Radiology. 1995, 197 (2): 525-31.View ArticlePubMed
                      6. Pomper MG, Constantinides CD, Barker PB, Bizzi A, Dobgan AS, Yokoi F: Quantitative MR spectroscopic imaging of brain lesions in patients with AIDS: correlation with [11C-methyl]thymidine PET and thallium-201 SPECT. Acad Radiol. 2002, 9 (4): 398-409. 10.1016/S1076-6332(03)80185-XView ArticlePubMed
                      7. Gervasoni C, Castagna A, Rocca A, Vago L, Cinque P: A comparison of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients. J Neurol. 1997, 244 (1): 35-9.PubMed
                      8. Viswanathan R, Ironside J, Bell JE, Brettle RP, Whittle IR: Stereotaxic brain biopsy in AIDS patients: does it contribute to patient management?. Br J Neurosurg. 1994, 8 (3): 307-11. 10.3109/02688699409029618View ArticlePubMed
                      9. Zimmer C, Marzheuser S, Patt S, Rolfs A, Gottschalk J, Weigel K: Stereotactic brain biopsy in AIDS. J Neurol. 1992, 239 (7): 394-400.PubMed
                      10. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV outpatient study investigators. N Engl J Med. 1998, 338 (13): 853-60. 10.1056/NEJM199803263381301View ArticlePubMed
                      11. Ammassari A, Cingolani A, Pezzotti P, De Luca DA, Murri R, Giancola ML: AIDS-related focal brain lesions in the era of highly active antiretroviral therapy. Neurology. 2000, 55 (8): 1194-200.View ArticlePubMed
                      12. Vago L, Bonetto S, Nebuloni M, Duca P, Carsana L, Zerbi P: Pathological findings in the central nervous system of AIDS patients on assumed antiretroviral therapeutic regimens: retrospective study of 1597 autopsies. Aids. 2002, 16 (14): 1925-8. 10.1097/00002030-200209270-00009View ArticlePubMed
                      13. Renold C, Sugar A, Chave JP, Perrin L, Delavelle J, Pizzolato G: Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome. Med (Baltimore). 1992, 71 (4): 224-39.View Article
                      14. Neuenburg JK, Brodt HR, Herndier BG, Bickel M, Bacchetti P, Price RW: HIV-related neuropathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002, 31 (2): 171-7. 10.1097/00126334-200210010-00007View ArticlePubMed
                      15. Rosenow JM, Hirschfeld A: Utility of brain biopsy in patients with acquired immunodeficiency syndrome before and after introduction of highly active antiretroviral therapy. Neurosurgery. 2007, 61 (1): 130-40. 10.1227/01.neu.0000279733.28768.ff. discussion 40–1View ArticlePubMed
                      16. Gildenberg PL, Gathe JC, Kim JH: Stereotactic biopsy of cerebral lesions in AIDS. Clin Infect Dis. 2000, 30 (3): 491-9. 10.1086/313685View ArticlePubMed
                      17. McArthur JC: HIV dementia: an evolving disease. J of neuroimmunol. 2004, 157 (1–2): 3-10. Epub 2004/12/08View Article
                      18. Erdag N, Bhorade RM, Alberico RA, Yousuf N, Patel MR: Primary lymphoma of the central nervous system: typical and atypical CT and MR imaging appearances. AJR Am J Roentgenol. 2001, 176 (5): 1319-26. 10.2214/ajr.176.5.1761319View ArticlePubMed
                      19. Thurnher MM, Post MJ, Rieger A, Kleibl-Popov C, Loewe C, Schindler E: Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol. 2001, 22 (5): 977-84.PubMed
                      20. Gildenberg PL, Langford L, Kim JH, Trujillo R: Stereotactic biopsy in cerebral lesions of AIDS. Acta Neurochir Suppl (Wien). 1993, 58: 68-70.
                      21. Levy RM, Breit R, Russell E, Dal Canto MC: MRI-guided stereotaxic brain biopsy in neurologically symptomatic AIDS patients. J Acquir Immune Defic Syndr. 1991, 4 (3): 254-60.PubMed
                      22. Levy RM, Russell E, Yungbluth M, Hidvegi DF, Brody BA, Dal Canto MC: The efficacy of image-guided stereotactic brain biopsy in neurologically symptomatic acquired immunodeficiency syndrome patients. Neurosurgery. 1992, 30 (2): 186-9. discussion 9–90 10.1227/00006123-199202000-00006View ArticlePubMed
                      23. Nielsen CJ, Gjerris F, Pedersen H, Jensen FK, Wagn P: Brain biopsy in AIDS. Diagnostic value and consequence. Acta Neurochir (Wien). 1994, 127 (1–2): 99-102.View Article
                      24. O'Doherty MJ, Lewis P, Nunan TO: Brain biopsy for intracranial mass lesions in AIDS. Lancet. 1993, 341 (8839): 242-3. 10.1016/0140-6736(93)90106-Q.View ArticlePubMed
                      25. Pell MF, Thomas DG, Whittle IR: Stereotactic biopsy of cerebral lesions in patients with AIDS. Br J Neurosurg. 1991, 5 (6): 585-9. 10.3109/02688699109002881View ArticlePubMed
                      26. Preuss M, Schumacher HC, Bergs C, Brock M: Brain biopsy for intracranial mass lesions in AIDS. Lancet. 1993, 341 (8839): 242-3. 10.1016/0140-6736(93)90106-Q.View ArticlePubMed
                      27. Grossman R, Sadetzki S, Spiegelmann R, Ram Z: Haemorrhagic complications and the incidence of asymptomatic bleeding associated with stereotactic brain biopsies. Acta Neurochir (Wien). 2005, 147 (6): 627-31. discussion 31 10.1007/s00701-005-0495-5View Article

                      Copyright

                      © Zibly et al.; licensee BioMed Central Ltd. 2014

                      This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                      Advertisement