Seizures, Confusion, and Strokes in a Patient With AIDS

Clinical Presentation

A 38-year-old right-handed man with acquired immunodeficiency syndrome (AIDS) on antiretroviral therapy (ART) was evaluated for 4 months of progressively worsening confusion, right-sided weakness and numbness, and seizures. He initially presented with a generalized convulsion. After a brain magnetic resonance imaging (MRI), he was started on levetiracetam. In the following months he noticed short-term memory loss, occasional periods of disorientation, and emotional lability. Then he noticed weakness and numbness of his right arm and leg as well as intermittent jerking movements and unsteady gait. He had intermittent headaches for 2 years and lost 50 pounds over the past year. He denied fevers, chills, or night sweats. He subsequently underwent MRI of spine and lumbar puncture and was referred to our institution for further evaluation.

Human immunodeficiency virus (HIV) infection was diagnosed 5 years prior to presentation. He was initially started on ART after developing pulmonary mycobacterium avium complex with CD4 count nadir of <20 cells/μL. His medications included tenofovir/emtricitabine, raltegravir, and levetiracetam. He was born in Mexico and immigrated to United States about 20 years ago. He previously worked maintaining fountains and denied recreational drug use.

His vital signs were unremarkable. He was pale and cachectic. Cardiovascular, pulmonary, and abdominal examination were normal, and there was no palpable lymphadenopathy. He was alert and oriented to his name and location but not to time or situation. His speech was fluent, coherent, and he followed commands briskly. There was break down of smooth pursuit. He had symmetric facial movements. He was spastic in all limbs with mild distal weakness in right arm and leg with slowed finger taps. He was diffusely hyperreflexic with bilateral upgoing toes. He had decreased sensation to light touch over right arm and leg, dysmetria on the right side, and a wide-based unsteady gait with a tendency to lean to the left.

Laboratory and Imaging Studies

His complete blood count and comprehensive metabolic panel were unremarkable. The CD4 count was 177 cells/μL. HIV viral load was undetectable. Cerebrospinal fluid (CSF) was notable for 16 white blood cells/μL (90% lymphocytes, 7% neutrophils, and 3% monocytes), 798 red blood cells/μL, 37 mg/dL of glucose (85 mg/dL in serum), and 144 mg/dL of protein. Cerebrospinal fluid gram stain, acid-fast bacilli (AFB) stain, and India ink staining were unremarkable. Cerebrospinal fluid bacterial, mycobaterial, and fungal cultures were negative. Cerebrospinal fluid cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), and herpes simplex virus (HSV) DNA polymerase chain reaction (PCR) were undetectable. Serum QuantiFERON-tuberculosis (TB) test, enzyme-linked immunosorbent assay for tinea solium, toxoplasma immunoglobulin G (IgG), rapid plasma reagin, VDRL, and syphilis enzyme immunoassay were negative.

Magnetic resonance imaging of the brain and spine revealed T2 hyperintensities as well as T1 postcontrast patchy nodular enhancement in the bilateral cortex, deep gray and white mater, brain stem, and spinal cord (Figure 1). There was patchy diffusion restriction in the bilateral centrum semiovale. The gradient echo sequence showed susceptibility in bilateral caudate nuclei.

Figure 1.

Magnetic resonance imaging of brain, cervical, and thoracic spine. A, Axial T2 FLAIR images showing diffuse hyperintensity involving cortex, deep gray and white matter. B, Axial T1 postcontrast images showing diffuse patchy enhancement (white arrows) involving the same territory. C, Axial gradient echo image showing microhemorrhages in the bilateral caudate nuclei (left caudate head zoomed in view, in the right lower corner). D, Axial diffusion-weighted image and (E) apparent diffusion coefficient showing mild patchy diffusion restriction (white arrows) suggestive of ischemia in the centrum semiovale. F, Sagittal T2 of cervical and (G) thoracic spine showing diffuse hyperintensity. H, T1 precontrast and (I) T1 postcontrast showing diffuse patchy enhancement (white arrows) of thoracic spine.

Clinical Comment (Dr Khatibi)

Seizures, cognitive changes, and multiple abnormalities on neurological examination raise the possibility of more than a singular lesion in nervous system. Seizure is suggestive of cortical involvement. Progressive behavioral changes, cognitive decline, and emotional lability in conjunction with the seizures could further indicate involvement of the limbic system. Bilateral spasticity with right-sided pyramidal pattern of weakness is suggestive of diffuse corticospinal tract involvement in the brain, although additional cervical cord involvement cannot be excluded. The MRI of brain and spine supports such a diffuse central nervous system (CNS) process.

HIV directly affects cell-mediated immunity resulting in immunodeficiency and subsequent infections, as well as immune dysregulation, which could subsequently lead to inflammatory and neoplastic diseases. The prevalence of these processes is dependent on the extent of immunosuppression, the chronicity of infection, and exposure to pathogenic organisms. When faced with diffuse CNS pathology in an HIV-infected patient, a thorough evaluation of potential causes based on characteristic MRI findings is warranted.

Magnetic resonance imaging of the brain in this case revealed a nodular subcortical and cortical pattern of enhancement, which is suggestive of hematogenous dissemination of infectious or sterile clot, metastatic neoplasm, vasculitis, or a perivasculitic process.¹ The foci of restricted diffusion are further suggestive of ischemia from an embolic or vasculitic etiology. The territories involved are most consistent with small perforator vessels and distal branches. Therefore, imaging studies in this case are suggestive of vasculitis or a perivasculitic process. The differential for vasculitis of the CNS in HIV infection remains broad. It includes infections, primary systemic vasculitis with involvement of CNS, secondary autoimmune vasculitis with involvement of CNS, angiocentric lymphoproliferative processes, and primary angiitis of the central nervous system.2

Among infectious etiologies, based on the CSF profile, one should consider atypical bacteria, viruses, or fungi. Tuberculosis should be considered at the patient’s CD4 count. Tuberculosis affects the leptomeninges with thick exudate in the basal cisterns or the brain parenchyma, manifesting as tuberculomas and/or tubercular abscesses. It can lead to small- and medium-vessel vasculitis involving the skull base. However, negative serum QuantiFERON-TB test, negative AFB staining, and mycobacterial culture make TB less likely. Secondary and tertiary syphilis may have features of vasculitis and can manifest as meningitis, meningovasculitis, or involve the parenchyma as parenchymatous or gummatous neurosyphilis. Neurosyphilis affects small and medium cortical arteries and veins; however, serum syphilis serology was negative.

Herpes viruses are associated with CNS vasculitis. Varicella zoster virus is strongly associated with medium and large vessel vasculitis as well as demyelinating lesions of the brain and spine,³ but negative CSF PCR makes VZV infection unlikely. In some cases, IgG and immunoglobulin M against VZV can be detected in the CSF despite negative PCR testing. Cytomegalovirus infection is common at CD4 counts below 200/μL and primarily infects the ependyma and choroid plexus, rarely causing vasculitis. Cytomegalovirus PCR is highly sensitive, and negative CSF PCR makes this an unlikely cause. Herpes simplex virus is rarely associated with vasculitic changes, the disease course is slow for HSV infection and the PCR was negative.

Fungal infections can manifest as cerebral vasculitis. Toxoplasma is the most common CNS opportunistic infection (OI) in AIDS. It manifests as ring-enhancing masses with central necrosis in the brain. Cryptococcus is another common OI. It manifests as leptomeningitis and/or cryptococcosis and nonenhancing pseudocysts in the basal ganglia. Both infections are rarely associated with necrotizing vasculitis.³ The radiographic pattern, the slow course, and the negative serology make them unlikely.

Systemic vasculitides, while uncommon, are well described in HIV infection. HIV is associated with a polyarteritis nodosa-like necrotizing vasculitis affecting small and medium vessels. It affects CNS in less than 10% of cases. The other categories of systemic vasculitis commonly seen in HIV are eosinophilic granulomatosis with polyangiitis, immunoglobulin A vasculitis (Henoch-Schönlein purpura), or Behçet disease. These affect small and medium vessels and primarily involve skin and mucosa and rarely the CNS. Lack of skin, mucosal, and renal involvement make systemic vasculitides less likely.²

Primary angiitis of CNS (PACNS) should also be considered in the setting of immunodysregulation.⁴ It primarily affects small and medium arteries and veins. Despite the pathology being limited to CNS, up to 30% of patients have constitutional symptoms. Cerebrospinal fluid is abnormal in majority of cases with mild pleocytosis and elevated protein. Magnetic resonance imaging shows progressive cortical and subcortical T2 hyperintensity with foci of diffusion restriction, microhemorrhages, and enhancement of small vessel wall and perivascular spaces. The course of the disease is slow and on average takes about 170 days to diagnose after symptom onset.^5,6 This is the likely diagnosis in our patient given the indolent process, imaging findings, and nondiagnostic spinal fluid analysis. For diagnosis of PACNS, histology is usually necessary.⁷

As a possible neoplastic etiology in the setting of AIDS, primary CNS lymphoma (PCNSL) should always be considered. Primary CNS lymphoma is a diffuse large B-cell lymphoma and a rare primary brain tumor, although the risk of this disease has been reported to be up to 1.5% in patients with AIDS.⁸ In immunocompromised patients, PCNSL is more angiocentric and angiodestructive compared to this process in the immunocompetent.⁹ Primary CNS lymphoma in AIDS usually presents as enhancing multifocal lesions on MRI with an irregular or peripheral and ring-like pattern of enhancement. Linear enhancement of perivascular spaces can be suggestive of PCNSL; however, it is not limited to perivascular spaces and the parenchyma of the basal ganglia and the corpus callosum is frequently involved.¹⁰ The CSF in PCNSL may show a mild lymphocytic pleocytosis with mildly elevated protein. Epstein-Barr virus infection has been found to be central to pathobiology of PCNSL in AIDS. Epstein-Barr virus DNA can be measured in approximately 80% of CSF samples of AIDS-related PCNSL.¹¹ Epstein-Barr virus DNA is detected in almost all biopsy and necropsy specimens with PCNSL.¹² Negative DNA PCR and the absence of radiographic mass lesions make PCNSL less likely.

Lymphomatoid granulomatosis (LG) is a subset of post-thymic T-cell lymphoproliferative diseases associated with HIV. In LG, transmural infiltration of lymphocytes leads to ischemia with pulmonary involvement in 90% and CNS disease in 25% to 50% of cases. Lymphomatoid granulomatosis can affect both leptomeninges and parenchyma of spinal cord and brain with multiple focal lesions in the white matter, deep gray, and brain stem. On MRI, there are multiple punctate/linear perivascular contrast-enhancing lesions. Cerebrospinal fluid shows lymphocytic pleocytosis with elevated protein. Epstein-Barr virus IgG is almost always positive.¹³ Absence of pulmonary pathology and negative EBV DNA PCR make LG unlikely.

Finally, given the previous history of ART noncompliance and current use, one should consider immune-reconstitution inflammatory syndrome (IRIS), a complication of restoration of immune function after starting retroviral therapy. Systemic IRIS has a milder course; however, CNS involvement can have up to 75% mortality.¹⁴ Since there is no clear temporal relationship with starting ART, IRIS is unlikely to be the cause of this patient’s symptoms.

Pathological Discussion (Dr Vogel)

The patient underwent MR-guided stereotactic biopsy of a right frontal lesion, and 3 specimens were reviewed. They revealed similar features showing scattered cortical blood vessels with granulomatous perivascular inflammatory infiltrates. There were features suggestive of vascular destruction confirmed by elastin van Gieson stain. Immunohistochemical stains for inflammatory cells demonstrate abundant CD163-positive perivascular infiltrates with associated CD3-positive T cells and rare B cells by CD20 immunostaining. Special stains for organisms including AFB, Fite, and Grocott's methenamine silver stain (GMS) showed no evidence for mycobacterial or fungal organisms. Additional immunohistochemical stains for infectious causes were negative for CMV, EBV, HSV, toxoplasma, and John Cunningham (JC) virus. There was no sign of immunoreactivity for vascular β-amyloid by immunohistochemical staining. These combined features were characteristic of primary CNS granulomatous angiitis (Figure 2).

Figure 2.

Histologic slides of brain biopsy (A) photomicrographs of hematoxylin and eosin staining demonstrates non-necrotizing granulomas (outlined by dashed line), often associated with parenchymal blood vessels. Immunohistochemical phenotyping showing: (B) rare B-cells (CD20-positive staining, red arrows), (C) numerous T cells (CD3-positive staining, red arrows), relatively even admixture of (D) CD4-positive helper T-cells (red arrows), and (E) cytotoxic CD8-positive T-cells (red arrows; magnification 200×).

Note: figures are available in color online.

Patient Outcome

After the biopsy, the patient was treated with prednisone 40 mg daily. The dose was decreased and stopped after a month because of irritability and insomnia. After this brief course of steroids, the patient demonstrated a remarkable functional improvement. He was able to walk without any assistive device, perform his basic activities of daily living, and use public transportation for his medical appointments. He remained functionally stable over the following 8 months and was unfortunately lost to follow-up.

Conclusion

Primary angiitis of CNS is a rare disorder affecting small and medium vessels limited to brain and spine.⁵ The presence of memory T cells suggests antigen-specific immune response, although the trigger remains unknown. Primary angiitis of CNS affects both parenchymal and leptomeningeal vessels. The 3 histological patterns are granulomatous, lymphocytic, and necrotizing vasculitis.⁷ The clinical manifestation can be nonspecific with insidious onset of headache and cognitive decline being the most common symptoms and focal symptoms and seizures being less frequent. Constitutional symptoms are less common compared to other vasculitic processes.

Magnetic resonance imaging is abnormal in 90% to 100% of the cases with multiple foci of T2 hyperintensity, mainly in deep and subcortical white matter. These multiple infarcts are usually seen in different vascular territories and tend to be various stages of infarct progression on MR imaging. There are multiple small-enhancing lesions as well as enhancing perivascular spaces of the penetrating. Multiple microhemorrhages are commonly seen.^7,15 Digital subtraction angiography shows multiple segmental narrowing of small and medium cerebral arteries.¹⁶ However, these findings are not specific for PACNS and sensitivity of angiography has been reported to be as low as 40%.⁷ Cerebrospinal fluid profile is abnormal in 80% to 90% of cases with modest elevations in white blood cell count (median of 5 cells/μL, range: 0-535) and total protein level (median of 0.7 g/dL, range: 0.15-1.03). Given the nonspecific profile, appropriate fungal stains, viral PCR titers, and cytological studies should be performed.

To improve diagnostic accuracy, experts have proposed the following diagnostic criteria: (1) acquired neurologic deficit with unexplained etiology after a vigorous diagnostic workup, (2) either classic angiographic or histopathologic evidence of CNS vasculitis, and (3) absence of any disorder to which the angiographic or pathologic findings can be attributed.¹⁷ Powers et al however claim that angiography, CSF examination, and MRI studies do not have sufficient positive predictive value and histopathological evaluation is necessary.⁷

There are no clinical trials to establish optimal medical management of PACNS. Immunomodulatory strategies are extrapolated from cohort studies, anecdotal reports, and strategies used for other vasculitides. Experts from multiple high-volume institutions recommend the initiation of glucocorticoid and cyclophosphamide treatment, which has been extrapolated from the trial in the treatment of ANCA-associated vasculitis.^18,19 The recommended treatment is daily oral or intermittent pulse intravenous cyclophosphamide and daily prednisone (1 mg/kg/d). In the setting of severe PACNS, a pulse of high-dose methylprednisone (1 g intravenous daily for 3 days) is suggested prior to initiation of daily oral regimen. A slow taper of oral steroids after the first month of treatment is usually attempted over the next 12 months. Oral or pulsed intravenous cyclophosphamide should be continued for 3 to 6 months until induction of remission or occurrence of adverse events. Patients are usually transitioned to Azathioprine after remission, which should be continued for 2 to 3 years. Mycophenolate or methotrexate can also be considered as alternate maintenance immunomodulatory agents.^5,20,21

Salvarani et al retrospectively evaluated the effects of different treatment regimens in a cohort of 163 patients with PACNS. They reported 85% favorable response to prednisone alone and 80% response to combination of prednisone and cyclophosphamide. Favorable response was defined by clinical judgment of treating physician. However, they report relapse rate of 39% in the prednisone alone group compared to 18% in the combination group.²²

In conclusion, PACNS is a rare disorder that can present indolently. A thorough workup including neuroimaging, CSF analysis, screening for systemic inflammatory disorders as well as histopathologic evaluation of CNS lesions is needed. Immunosuppression may favorably modify the course of the disease which otherwise has high mortality and morbidity.