Abstract
We investigated the diagnostic usefulness of brain magnetic resonance imaging (MRI) screening in HIV-1-infected patients without neurological symptoms in detecting intracranial diseases at early stages. In this retrospective analysis, the study patients were HIV-1-infected patients who underwent brain MRI scan in clinical practice between 2001 and 2013. We excluded patients with MRI for (1) follow-up examination for prediagnosed intracranial diseases, (2) cancer staging, (3) screening mycobacterium/bacteria/fungi disease proliferation in the brain, and (4) evaluation for meningitis/encephalitis. The study patients (n=485) were classified into two groups: those who underwent brain MRI scan without any neurological symptoms/signs (asymptomatic patients, n=158) and those who underwent MRI due to such symptoms (symptomatic patients, n=327). Asymptomatic patients had lower CD4 counts than symptomatic patients (median 78 versus 241/μl). Intracranial diseases were detected in three (2%) of the asymptomatic patients [two toxoplasmosis and one progressive multifocal leukoencephalopathy (PML)] compared to 58 (19%) of the symptomatic patients (the χ2 test, p<0.01). The latter included toxoplasmosis (n=10), PML (n=7), cytomegalovirus encephalitis (n=3), primary central nervous system lymphoma (n=3), cryptococcoma/meningitis (n=3), and HIV-associated dementia (n=17). Among symptomatic patients, intracranial diseases were common in those with slurred speech (3/6, 50%), seizure (4/10, 40%), eyesight/vision abnormality (5/16, 31%), altered mental status (8/31, 26%), and hemiplegia/numbness (13/50, 26%). For patients with CD4 count <200/μl, intracranial diseases were detected in only 3 (3%) of 144 asymptomatic patients, compared with 46 (32%) of 113 symptomatic patients (p<0.01). Brain MRI screening for HIV-1-infected patients without neurological symptoms is of little value.
Introduction
Patients with advanced HIV-1 infection are prone to develop intracranial opportunistic diseases, such as toxoplasma encephalitis, primary central nervous system lymphoma (PCNSL), progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) encephalitis.1 Although the introduction of antiretroviral therapy (ART) substantially decreased the incidence of neurological opportunistic infections,2,3 such diseases have high associated mortality even with appropriate treatment, and recurrences and residual neurological deficits can occur.4,5 Because delayed diagnosis of these intracranial diseases has a detrimental effect on patients with HIV-1 infection,5,6 early diagnosis, not to mention prevention, of such diseases is of importance.
Brain magnetic resonance imaging (MRI) is often preferred to computed tomography (CT) in establishing the diagnosis of many of these diseases due to its superior sensitivity to subtle white matter and meningeal disease.7–10 However, there is no information on the utility of brain MRI screening for HIV-1-infected patients without neurological symptoms/signs in detecting intracranial opportunistic diseases at early stages. This observational study was designed to assess the usefulness of brain MRI screening of such patients with HIV-1 infection.
Materials and Methods
Study design, setting, and participants
We conducted an observational single-center study to investigate the usefulness of brain MRI screening in HIV-1-infected patients without neurological symptoms who warrant investigation for intracranial diseases. The study was conducted at the AIDS Clinical Center, National Center for Global Health and Medicine (NCGM), Tokyo, the largest referral center for HIV care in Japan.11 The study patients were those who fulfilled the following inclusion criteria: HIV-1-infected patients who underwent brain MRI scan in clinical practice between June 2001 and August 2013. In addition, the following exclusion criteria were applied: patients who underwent brain MRI for (1) follow-up examination during the study period because of intracranial diseases such as opportunistic infections, stroke, or malignancy, which were diagnosed prior to the referral to our clinic, (2) staging of malignant tumors, (3) screening mycobacterium/bacteria/fungi disease proliferation in the brain in patients who were already diagnosed with mycobacterial diseases or bacteremia or fungemia, and (4) evaluation of meningitis/encephalitis.
The study patients (n=485) were classified into those who underwent brain MRI scan without any neurological symptoms, such as seizure, altered mental status, hemiplegia/numbness, headache, or fever (asymptomatic patients, n=158), and those who underwent MRI due to the abovementioned symptoms, which can suggest a focal brain lesion5 (symptomatic patients, n=327). Asymptomatic patients included those who underwent MRI due to positive antitoxoplasma IgG antibody (n=38) and positive serum cryptococcal antigen (n=1). At our clinic, patients with a low CD4 cell count (typically less than 200/μl) often underwent brain MRI even though they had no neurological symptoms/signs that would warrant a brain imaging examination to rule out intracranial opportunistic infections or malignancy at early stages.
The study was approved by the Human Research Ethics Committee of NCGM. All patients included in this study provided written informed consent for their clinical and laboratory data to be used and published for research purposes. The study was conducted according to the principles expressed in the Declaration of Helsinki.
Measurements
At our hospital, brain MRI was routinely read by one experienced radiologist and the findings were confirmed by another radiologist. Furthermore, the MRI diagnosis was confirmed by reviewing the medical records and follow-up brain imaging when available. The diagnostic criteria for cryptococcal meningitis, cytomegalovirus encephalitis, and toxoplasmic encephalitis were those adopted by the AIDS Clinical Trials Group (ACTG)-A5164.12 HIV-associated dementia in this study was diagnosed based on the MRI findings, which included generalized atrophy and prominent white matter changes plus cognitive impairment based on the chart review, and not necessarily required neurocognitive function tests.8 The reasons for conducting an MRI were also extracted from the medical records. Baseline characteristics and HIV-1-related variables at the time of brain MRI were also extracted from the medical records. They included age, sex, ethnicity, history of AIDS, route of HIV-1 transmission, treatment status for HIV-1 infection (either treatment naive or experienced), CD4 cell count, and HIV viral load. For CD4 count and HIV load, we used data collected closest to and preceding by up to 3 months the day of the brain MRI. In Japan, because the prescription period under the health care system is limited to 3 months, patients need to visit the HIV Clinic at least once every 3 months for prescriptions as well as monitoring CD4 cell count and HIV-1 load.11
Statistical analysis
Baseline characteristics were compared between asymptomatic and symptomatic patients using the Student's t-test and χ2 test (Fisher's exact test) for continuous and categorical variables, respectively. Prevalence of intracranial diseases was calculated among asymptomatic patients and compared to that of symptomatic patients with the χ2 test. The logistic regression model was used to estimate the associations of lack of neurological symptoms/signs over the presence of such symptoms/signs with the MRI findings of intracranial diseases. The model was adjusted for age, sex, CD4 count, HIV treatment status, and history of AIDS. Subgroup analysis included the prevalence of intracranial diseases in patients with a CD4 count <200/μl. Statistical significance was defined as two-sided p values<0.05. We used odds ratios (ORs) with 95% confidence intervals (95% CIs). All statistical analyses were performed with The Statistical Package for Social Sciences ver. 21.0 (SPSS, Chicago, IL).
Results
The study included 485 patients who underwent a brain MRI scan in clinical practice, of whom 158 had no neurological symptoms (asymptomatic) and 327 did have such symptoms (symptomatic). Of the total patients, 475 (98%) were Asians, 446 (92%) were males, and 365 (75%) were infected with HIV-1 through homosexual contact (Table 1). The median age of the study patients was 41 [interquartile range (IQR) 34–51]. Asymptomatic patients had a lower CD4 count [median 78/μl, interquartile range (IQR) 21–237, symptomatic: 241/μl, 60–470 (p<0.01)] and higher HIV-1 viral load [4.84 log10/ml, IQR 2.97–5.62, symptomatic: 2.95 log10/ml, 1.70–5.11 (p<0.01)] than symptomatic patients. Asymptomatic patients were more likely to be treatment naive (68% versus 41%, p<0.01) and have a history of AIDS (62% versus 47%, p<0.01). There was no significant difference in other baseline characteristics between the two groups (Table 1).
Table 1.
Clinical Characteristics of the Study Patients According to Neurological Symptoms
| All patients (n=485) | Patients without neurological symptoms (n=158) | Patients with neurological symptoms (n=327) | p value | |
|---|---|---|---|---|
| Male sex, n (%) | 446 (92) | 146 (92) | 300 (92) | 0.86 |
| Agea | 41 (34–51) | 42 (33–52) | 41 (35–49) | 0.95 |
| Asian, n (%) | 475 (98) | 154 (98) | 321 (98) | 0.74 |
| CD4 cell count (/μl)a | 178 (41–420) | 78 (21–237) | 241 (60–470) | <0.01 |
| HIV-1 load (log10/ml)a | 4.20 (1.70–5.26) | 4.84 (2.97–5.61) | 2.95 (1.70–5.11)b | <0.01 |
| Homosexual contact, n (%) | 364 (75) | 117 (74) | 247 (76) | 0.74 |
| Treatment naive, n (%) | 240 (50) | 107 (68) | 133 (41) | <0.01 |
| History of AIDS, n (%) | 250 (52) | 98 (62) | 152 (47) | <0.01 |
Median (interquartile range).
Data on HIV-1 load are not available for two patients.
Among the 158 asymptomatic patients, brain MRI screening detected toxoplasmosis (n=2) and PML (n=1, with CD4 43/μl), i.e., a prevalence of intracranial diseases of 2%. The two patients with toxoplasmosis underwent brain MRI due to positive antitoxoplasma IgG antibody with a titer of 20,480 (CD4 168/μl) and 1,280 (CD4 16/μl) IU/ml. In asymptomatic patients who underwent brain MRI due to positive antitoxoplasma IgG antibody, intracranial diseases were detected in 3 (8%) out of 38 patients (Table 2). On the other hand, brain MRI for symptomatic patients detected 58 intracranial diseases with a prevalence of 19%. The cases included toxoplasmic encephalitis (n=10), PML (n=7), CMV encephalitis (n=3), PCNSL (n=3), cryptococcosis/meningitis (n=3), herpes simplex virus encephalitis (n=1), HIV-associated dementia (n=17), acute cerebral infarction (n=8), gummatous syphilis (n=1), tuberculoma (n=1), metastatic cancer (n=1), chronic subdural hematoma (n=1), schwannoma (n=1), and progressive supranuclear palsy (n=1) (Table 2). In asymptomatic patients, intracranial diseases were less likely to be detected by brain MRI, compared to symptomatic patients [by univariate and multivariate analysis (OR=0.1; 95% CI, 0.03–0.29; p<0.01) (adjusted OR=0.1; 95% CI, 0.02–0.17; p<0.01)]. Patients with higher CD4 counts were also less likely to have intracranial diseases (per 100/μl increment, adjusted OR=0.7; 95% CI, 0.55–0.83; p<0.01). Among the symptomatic patients, those who presented with slurred speech, seizure, eyesight/vision abnormality, altered mental status, and hemiplegia/numbness were highly likely to have intracranial diseases, with a prevalence of 50%, 40%, 31%, 26%, and 26%, respectively (Table 3).
Table 2.
Prevalence of Intracranial Diseases Detected by Brain Magnetic Resonance Imaging According to Neurological Symptoms
| Intracranial diseases | Patients without neurological symptoms (n=158) | Patients without neurological symptoms with CD4 <200/μl (n=144) | Patients with neurological symptoms (n=327) | Patients with neurological symptoms with CD4 <200/μl (n=113) | Positive toxoplasma Ab and without neurological symptoms (n=38) |
|---|---|---|---|---|---|
| Toxoplasmosis | 2 (1) | 2 (2) | 10 (3) | 10 (7) | 2 (1) |
| PML | 1 (1) | 1 (1) | 7 (2) | 7 (5) | 1 (1) |
| HIV-associated dementia | 17 (6) | 13 (9) | |||
| Malignant lymphoma | 4 (1) | 3 (2) | |||
| CMV encephalopathy | 3 (1) | 3 (2) | |||
| Cryptococcoma/meningitis | 3 (1) | 3 (1) | |||
| HSV encephalopathy | 1 | 1 | |||
| Gummatous syphilis | 1 | 1 | |||
| Tuberculoma | 1 | 1 | |||
| Metastatic cancer | 1 | ||||
| Cerebral infarction | 8 (3) | 2 (1) | |||
| Others | 3 (1) | 2 (1) | |||
| Total | 3 (2) | 3 (3) | 59 (19) | 46 (32) | 3 (8) |
Data are numbers (percentages) of patients.
Ab, antibody; PML, progressive multifocal leukoencephalopathy; CMV, cytomegalovirus; HSV, herpes simplex virus.
Table 3.
Prevalence of Intracranial Diseases Detected by Brain Magnetic Resonance Imaging According to Neurological Symptom Categories
| Intracranial diseases | Prevalence of intracranial diseases | |
|---|---|---|
| Slurred speech (n=6) | Cerebral infarction n=2 | 50% |
| PML n=1 | ||
| Seizure (n=10) | Toxoplasmosis n=2 | 40% |
| PML n=1 | ||
| HSV encephalitis n=1 | ||
| Eyesight/vision abnormality (n=16) | Malignant lymphoma n=2 | 31% |
| HIV-associated dementia n=2 | ||
| Metastatic cancer n=1 | ||
| Altered mental status (n=31) | Toxoplasmosis n=2 | 26% |
| HIV-associated dementia n=2 | ||
| Cryptococcoma/meningitis n=2 | ||
| PML n=1 | ||
| Tuberculoma n=1 | ||
| Hemiplegia/numbness (n=50) | Cerebral infarction n=5 | 26% |
| Toxoplasmosis n=3 | ||
| PML n=3 | ||
| HIV-associated dementia n=1 | ||
| Other n=1 | ||
| Neurocognitive impairment (n=62) | HIV-associated dementia n=9 | 19% |
| Cerebral infarction n=1 | ||
| CMV encephalitis n=2 | ||
| Fever work-up (n=12) | Malignant lymphoma n=1 | 17% |
| HIV-associated dementia n=1 | ||
| Dizziness/vertigo/tinnitus (n=45) | Toxoplasmosis n=1 | 11% |
| PML n=1 | ||
| Malignant lymphoma n=1 | ||
| HIV-associated dementia n=1 | ||
| CMV encephalitis n=1 | ||
| Abnormal ophthalmologic examination (n=11) | HIV-associated dementia n=1 | 9% |
| Headache (n=49) | Toxoplasmosis n=2 | 4% |
| Syncope (n=16) | 0% |
PML, progressive multifocal leukoencephalopathy; HSV, herpes simplex virus; CMV, cytomegalovirus.
Subgroup analysis limited to data of patients with CD4 count of <200/μl showed that the abovementioned three intracranial diseases were detected in 144 asymptomatic patients with a prevalence of 3%, compared to 46 (32%) of 113 symptomatic patients (asymptomatic over symptomatic, OR=0.1; 95% CI, 0.02–0.19; p<0.01) (Table 2). Only a few intracranial opportunistic diseases were diagnosed in patients with a CD4 count of ≥200/μl; PCNSL (n=1), HIV-associated dementia (n=4), acute cerebral infarction (n=6), metastatic cancer (n=1), and progressive supranuclear palsy (n=1).
Discussion
In this observational study of patients who underwent brain MRI screening in clinical practice, only 2% of patients without neurological symptoms/signs that warranted investigation of intracranial diseases were found to have intracranial diseases, whereas a significantly higher prevalence (19%) of intracranial diseases was detected in patients who underwent brain MRI due to such symptoms. Among patients with a CD4 count of <200/μl, who are reported to be at high risk for intracranial diseases,5,10 the result was similar; 3% and 32% of asymptomatic and symptomatic patients, respectively, were found to have intracranial diseases. On the other hand, high detection rates of intracranial diseases by brain MRI were observed in patients who presented with slurred speech (50%), seizure (40%), eyesight/vision abnormality (31%), altered mental status (26%), and hemiplegia/numbness (26%). The present study indicates that brain MRI screening for HIV-1-infected patients without neurological symptoms/signs, even those with a low CD4 count (<200/μl), is of little value. In contrast, MRI screening is useful for patients with particular neurological symptoms/signs. These findings can help reduce unnecessary brain MRI examinations and can be helpful in clinical decision making.
Interestingly, in both of the two asymptomatic toxoplasmic encephalitis patients who underwent brain MRI screening because of positive antitoxoplasma IgG antibody, the antibody titer was very high (20,480 IU/ml and 1,280). Together with the fact that the prevalence of intracranial diseases in asymptomatic patients with positive antitoxoplasma IgG antibody was higher (8%) than the 2% in the entire group of asymptomatic patients, brain MRI screening for patients without neurological symptoms/signs who presented with high antitoxoplasma antibody may be of value and clinically justifiable.
Our study has certain limitations. First, because brain MRI was performed at the discretion of the treating physician, patient selection bias, especially among those without neurological symptoms/signs, cannot be ruled out. However, we had a large number of study patients, and considering the availability and cost of an MRI scan, the results of the present study are of value and are useful in clinical decision making. Second, because endemic opportunistic infections vary depending on the region13,14 and the majority of our patients were Asian, the results of the present study might not be applicable to patients in other regions. Third, in this study the diagnosis of HIV-associated dementia was based on the MRI findings plus cognitive impairment based on a chart review, and the patients did not necessarily undergo neurocognitive function tests.8 This is because the present study included patients from 2001, long before the diagnostic Frascati criteria for an HIV-associated neurocognitive disorder that required neurocognitive function tests were established.15
In conclusion, although our results suggest that brain MRI screening is of little value in HIV-1-infected patients without neurological symptoms/signs that warrant investigation on intracranial diseases, it should be performed in HIV-1-infected patients who present with particular neurological symptoms, such as slurred speech and seizure.
Acknowledgments
The authors thank Hirokazu Kumagai, deputy chief radiology technologist, Mikiko Ogata, Michiyo Ishisaka, and Misao Takano for their invaluable contribution to the study. The authors also thank Akiko Nakano, the study coordinator, and all the other staff at the AIDS Clinical Center for their help in the completion of this study.
This work was supported by a Grant-in Aid for AIDS research from the Japanese Ministry of Health, Labour, and Welfare (H23-AIDS-001; H24-AIDS-003).
Author Disclosure Statement
No competing financial interests exist.
References
- 1.Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents: Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf Accessed February27, 2014
- 2.Garvey L, Winston A, Walsh J, et al. : HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011;18:527–534 [DOI] [PubMed] [Google Scholar]
- 3.d'Arminio Monforte A, Cinque P, Mocroft A, et al. : Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 2004;55:320–328 [DOI] [PubMed] [Google Scholar]
- 4.Mocroft AJ, Lundgren JD, d'Armino Monforte A, et al. : Survival of AIDS patients according to type of AIDS-defining event. The AIDS in Europe Study Group. Int J Epidemiol 1997;26:400–407 [DOI] [PubMed] [Google Scholar]
- 5.Tan IL, Smith BR, von Geldern G, et al. : HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012;11:605–617 [DOI] [PubMed] [Google Scholar]
- 6.Antinori A, Larussa D, Cingolani A, et al. : Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy. Clin Infect Dis 2004;39:1681–1691 [DOI] [PubMed] [Google Scholar]
- 7.Cinque P, Koralnik IJ, Gerevini S, et al. : Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis 2009;9:625–636 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Clifford DB. and Ances BM: HIV-associated neurocognitive disorder. Lancet Infect Dis 2013;13:976–986 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Utsuki S, Oka H, Abe K, et al. : Primary central nervous system lymphoma in acquired immune deficiency syndrome mimicking toxoplasmosis. Brain Tumor Pathol 2011;28:83–87 [DOI] [PubMed] [Google Scholar]
- 10.Graham CB, 3rd, Wippold FJ, 2nd, Pilgram TK, et al. : Screening CT of the brain determined by CD4 count in HIV-positive patients presenting with headache. AJNR Am J Neuroradiol 2000;21:451–454 [PMC free article] [PubMed] [Google Scholar]
- 11.Nishijima T, Kawasaki Y, Tanaka N, et al. :. Long-term exposure to tenofovir continuously decrease renal function in HIV-1-infected patients with low body weight. AIDS 2014:1. [DOI] [PubMed] [Google Scholar]
- 12.Zolopa A, Andersen J, Powderly W, et al. : Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: A multicenter randomized strategy trial. PLoS One 2009;4:e5575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.McLeod DS, Mortimer RH, Perry-Keene DA, et al. : Histoplasmosis in Australia: Report of 16 cases and literature review. Medicine (Baltimore) 2011;90:61–68 [DOI] [PubMed] [Google Scholar]
- 14.Ustianowski AP, Sieu TP, and Day JN: Penicillium marneffei infection in HIV. Curr Opin Infect Dis 2008;21:31–36 [DOI] [PubMed] [Google Scholar]
- 15.Antinori A, Arendt G, Becker JT, et al. : Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007;69:1789–1799 [DOI] [PMC free article] [PubMed] [Google Scholar]