Cerebral aneurysmal arteriopathy in childhood AIDS

Over 80% of children with AIDS have CNS involvement including acquired microcephaly, diffuse cerebral atrophy, calcifications of the basal ganglia, and HIV-associated encephalitis.^1-3 Cognitive decline and signs of pyramidal tract involvement are comparable to HIV-associated dementia in adults; however, opportunistic CNS infections and primary lymphomas are very uncommon in childhood.^3-5 The incidence of symptomatic cerebrovascular disease in pediatric AIDS is only 1.3%, but at autopsy, lesions are present in 25%.^1,3 The mechanisms include hypoperfusion and septic or thrombotic emboli with cardiomyopathy or endocarditis, thrombocytopenia, and infectious vasculitis of intracranial vessels caused by cytomegalovirus (CMV), varicella zoster virus (VZV), and mycobacterial or fungal infections.^1,3,4,6-10 Aneurysmal arteriopathy is characterized by diffuse dilatation of the major arteries of the circle of Willis. We present five patients with aneurysm and compare the clinical and pathologic findings with those of eight patients described in the literature.

Case reports. Patient 1. A 13-year-old boy, born at 30 weeks' gestation, required 1½ months of neonatal intensive care that may have involved blood or blood product transfusions. Information about his natural parents is unavailable; therefore, the source of HIV transmission is uncertain. Medical history reveals failure to thrive, allergic rhinitis, congenital left hemiparesis, and a febrile seizure. Physical examination at 10 years of age showed mild mental retardation and left hemiparesis.

At 11½ years of age, he developed recurrent oral thrush and a persistent varicella rash. He had a positive HIV enzyme-linked immunosorbent assay (ELISA) test and azidothymidine (AZT) was initiated. Two months later, he developed supraclavicular lymphadenopathy. A diagnosis of mycobacterium avium intracellular (MAI) infection was confirmed by lymph node biopsy, and antimycobacterial therapy was started. Brain computerized tomography (CT) with contrast showed minimal vascular ectasia of the circle of Willis(figure 1A).

Eleven months later he developed an acute right hemiparesis. Imaging studies (CT and MRI) revealed an infarction in the left caudate nucleus and diffuse fusiform dilatation of the arteries of the circle of Willis(figure 1B). No CNS infection was detected. Antibody titers to VZV and toxoplasmosis were low. There was no evidence of clinically apparent herpes simplex virus (HSV) infection. Results of ophthalmologic evaluation were normal. Erythrocyte sedimentation rate (ESR) was 28 and serum antinuclear antibodies (ANA) screen was negative. Results of rapid plasma reagin (RPR) and fluorescent treponemal antibody absorption (FTA-ABS) tests were negative. Antithrombin III, protein C, protein S, and antiphospholipid antibodies were normal. Echocardiography was normal, and an electroencephalogram (EEG) showed mild diffuse slowing consistent with encephalopathy.

Three months later, he developed transient muscle cramps followed by bilateral choreoatetosis and painful dystonic posturing. A CT revealed bilateral hypodensities involving basal ganglia and internal capsule. Three days later, he had cardiorespiratory arrest and died. Autopsy permission was denied.

Patient 2. An 11-year-old girl with perinatally acquired HIV was diagnosed with AIDS at 10 years of age when she developed cervical adenitis due to an MAI infection. She started taking AZT and antimycobacterial therapy. Despite frequent opportunistic infections, she completed fourth grade without scholastic difficulty.

At age 11, she required hospitalization for pneumonia, staphylococcal otitis, mastoiditis, and sinusitis. A few days after admission, she developed an acute change in mental status manifested by a flat affect, bradykinesia, motor apraxia, abulia, and urinary incontinence. Neuropsychologic testing confirmed a diffuse cognitive dysfunction, and neurologic examination revealed a mild spastic paraparesis. She had normal results on ophthalmologic examination. T2-weighted MR images of the brain showed diffuse atrophy and hyperintensity in the left internal capsule and lenticular nucleus. A three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiogram(MRA) showed fusiform dilatation of the arteries in the circle of Willis(figure 2). Analysis of the CSF, blood, urine, and bone marrow failed to reveal a bacterial, mycobacterial, viral, or fungal infection. Serum titer results were HSV immunoglobulin G (IgG), 3.0 (normal, 0 to 0.78); VZV IgG, 4.33 (0 to 0.75); CMV IgG, initially 7.13, decreased to 6.52 (0 to 0.78); and toxoplasma IgG, 0. Additional laboratory results included ANA 160, positive neutrophil cytoplasmic antibodies (c-ANCA) 1:80, negative double-stranded DNA antibodies, and normal complement levels. She was treated with broad spectrum antibiotics, acyclovir, and antitoxoplasma medications, but did not improve.

She died at the age of 11½ years following recurrent infections, nephropathy, cardiomyopathy, and chronic lung disease. Permission for an autopsy was denied.

Patient 3. A previously healthy 2-year-old girl developed herpes zoster lesions on her right face and eye. She and her mother were found to be HIV positive, and AZT therapy was initiated. Subsequent illnesses included osteomyelitis of the left femur, severe gastroenteritis, multiple lung infections, bilateral parotitis, atopic dermatitis, and autoimmune thrombocytopenia.

At age 6½ she had a generalized tonic-clonic seizure. A 3D TOF MRA revealed a fusiform dilatation of the right supraclinoid internal carotid artery (ICA) and proximal right middle cerebral artery (MCA)(figure 3). Gadolinium-enhanced MRI showed a mass in the left posterior cingulate gyrus. Neurologic examination failed to reveal any focal abnormality, and there was no laboratory evidence of CNS infection. CNS lymphoma was diagnosed by stereotactic biopsy of the mass, and radiation therapy was initiated. Over the next 3 months, she required multiple hospitalizations for sepsis. She had several episodes of expressive aphasia without a focal motor deficit. From age 6 to 7½ years, a right hemiparesis and bilateral pyramidal signs became apparent. There were no clinical or radiologic signs of stroke and no progression of the arteriopathy by MRI. The patient's status slowly deteriorated. She died at age 6 years and 8 months following a persistent VZV keratitis and HIV enteropathy. Autopsy permission was denied.

Patient 4. A 12-year-old boy with HIV infection acquired by a neonatal blood transfusion had developmental delay in infancy and was diagnosed with autism at 3 years of age. He had a generalized tonic-clonic seizure at 10 years of age. Results of EEG and brain CT were normal, but a diagnosis of AIDS was established, and 2′,3′-dideoxyinisine (DDI) therapy was initiated.

At age 12, he developed an acute left-sided weakness preceded by a 2-day history of headaches and irritability. Examination revealed a left hemiparesis including the face and bilateral pyramidal tract dysfunction. MRI showed atrophy and a right MCA infarct. MRI and MRA showed dilatation of the left ICA and MCA. Cerebral angiography revealed a fusiform aneurysm of the left ICA at the bifurcation into MCA and the anterior cerebral artery (ACA). There was occlusion of the right MCA at the M1-M2 junction with a moya-moya appearance. CSF, blood, and urine tests were normal, including negative bacterial, viral, mycobacterial, and fungal cultures. Normal coagulopathy investigations included prothrombin time (PT), partial thromboplastin time(PTT), protein C, and protein S. Echocardiogram results were also normal.

The patient's health steadily declined because of recurrent sinusitis, thrush, multiple lung infections, and dental caries. At 13 years of age, sputum cultures grew MAI, and antimycobacterial therapy was instituted. A CT showed multiple foci of encephalomalacia consistent with old infarctions without clear evidence of new strokes. He gradually developed wasting, altered mentation, and generalized spasticity. He died at age 14½ years. Autopsy permission was denied.

Patient 5. A 10-year-old boy was diagnosed with AIDS at 7 years of age when he presented with oral thrush and an esophageal ulcer. He was treated with AZT followed by DDI. During 6 months on DDI monotherapy, his CD4 count steadily declined. Periodic neurologic examinations including psychological assessments failed to reveal any abnormalities. Serum titers were CMV IgG, 7.33 (normal, 0 to 0.78); HSV IgG, 3.32 (0 to 0.79); and VZV IgG, 2.92 (0 to 0.75). Three sputum studies for MAI and acid-fast bacilli were negative. At age 10, he collapsed while in school, and could not be resuscitated.

Postmortem examination of the brain revealed an extensive subarachnoid hemorrhage primarily located at the base of the brain with secondary extension into the posterior fourth ventricle. The circle of Willis was complete. The proximal portions of the right internal carotid artery; right anterior, middle, and posterior cerebral arteries; and left anterior cerebral artery were dilated and ectatic with focal thickenings(figure 4). The arterial diameters measured were distal internal carotid artery: right, 0.7 cm; left, 0.4 cm; proximal middle cerebral artery: right, 0.8 cm; left, 0.3 cm; proximal posterior cerebral artery: right, 0.6 cm; left, 0.4 cm. The junction of the right internal carotid and middle cerebral arteries was markedly dilated and measured approximately 2× 2.4 cm. A specific rupture site was not identified and no saccular aneurysms were found.

The brain was slightly edematous with mild bilateral uncal and tonsillar herniation. Two shrunken, slightly discolored cystic infarcts of the anterior left frontal lobe measured approximately 0.2 × 0.4 cm. The lateral ventricles were mildly dilated and the aqueduct and fourth ventricle were compressed. Fresh blood was present in the occipital horns of the lateral ventricles, the aqueduct, and the fourth ventricle.

Microscopic examination of the ectatic arteries showed mural fibrosis and thickening. The muscularis layer was largely absent, and the elastic lamina was either absent or markedly disrupted and fragmented. Small arteries and arterioles in the leptomeninges and brain were normal. Intranuclear and cytoplasmic viral inclusions were not seen. Multiple microglial nodules containing the multinucleated cells characteristic of HIV encephalitis were scattered throughout the brain. Immunostains for CMV, VZV, and HSV in brain and arteries were negative. HIV immunoreactivity in the brain and arteries was equivocal.

DNA extracted from deparaffinized sections of the brain and from the right proximal MCA was amplified by polymerase chain reaction (PCR) using primers Henv-1 and Henv-2 for the first round PCR and internal primers Henv 3 and Henv 4 for subsequent nested PCR. The reaction detected HIV sequences in both, although it was stronger in the brain than the artery.

Results. Table 1 summarizes the clinical information obtained from our five patients (Patients 1 to 5) and the eight patients described in the literature.^1,3,4,7,8 Seven acquired infection prenatally, five contracted HIV through blood transfusions, and one had both risk factors. Of interest, the transfusion was received during the neonatal period in three. The diagnosis of AIDS was delayed an average of 6½ years. Four patients(Patients 1, 2, 4, and 13) were asymptomatic for 10 to 11 years without antiretroviral therapy. Only two (Patients 3 and 10) had a relatively short latent period of 2 and 3 years.

Nine children were treated with AZT or DDI. However, their immune systems steadily declined, and at the time of arteriopathy diagnosis, the mean CD4 count was 23 (range, 0 to 107). Aneurysmal arteriopathy was discovered an average of 2½ years after the diagnosis of AIDS. Normal imaging results were noted 4 months to 2 years earlier in five patients. Four children had an aneurysmal dilatation of the circle of Willis without cerebrovascular symptoms. Patient 1 was symptom-free for 11 months, and Patient 11, for 20 months.

Ten patients had cerebrovascular symptoms and signs: eight had thromboembolism and two developed fatal intracranial hemorrhages. Patients 7 and 8 were described while asymptomatic, and Patient 3 had transient neurologic deficits. Five presented with unilateral strokes involving the basal ganglia or thalamus, and three had bihemispheric involvement. Only Patient 10 had secondary bleeding into an infarct. A second cerebrovascular event occurred in three of the eight stroke patients (1, 6, and 9). The mean survival time after CT or MRI diagnosis of arteriopathy was 8 months. The time shortened to 5.5 months after cerebrovascular accident.

The vascular pathology was similar in the four patients in whom postmortem examinations were performed (Patients 5, 6, 11, and 12). The vascular ectasia and aneurysmal dilatation were confined to the large arteries of the circle of Willis and the leptomeningeal and intraparenchymal arteries and arterioles were spared. Medial fibrosis with loss of muscularis, destruction of the internal elastic lamina, and intimal hyperplasia were common.

Table 2 summarizes studies done to detect infectious agents in these four cases. Intramural cells immunoreactive for HIV protein and focal accumulations of MAI bacilli were identified in Patient 6, and amplified HIV DNA was detected in a deparaffinized section of artery in Patient 5. Immunostains for HSV were negative in three of three patients for HSV, two of two patients for VZV, and one for CMV; intranuclear or cytoplasmic viral inclusions were absent. Encephalitis due to HIV occurred in the two patients in whom HIV was identified in the ectatic arteries and either absent or not described in the remaining two patients.

Discussion. In the second decade of the AIDS epidemic, we continue to accumulate data about HIV and neurologic conditions associated with HIV infection. Our series of cerebral aneurysmal childhood arteriopathy(CACA) includes 13 patients, five of whom are from our institution and are described in detail. All of the patients had aneurysmal dilatation of the major arteries of the circle of Willis. No patients had evidence of coagulopathy, collagen vascular disease, or an embolic source. Five patients(Patients 4, 7, 8, 9, and 11) had normal neuroimaging studies before the arteriopathy diagnosis, suggesting it is an acquired condition. Radiographic progression of the vasculopathy was evident in Patients 1 and 8. Clinical signs were delayed for up to 20 months, but eventually the patients presented acutely with cognitive changes and motor deficits associated with infarction or fatal hemorrhage. In the survivors, progressive deterioration led to death in less than 6 months.

All patients had a severely depressed immune system with a history of multiple opportunistic infections preceding a diagnosis of aneurysmal arteriopathy. Two (Patients 1 and 2) had MAI infections and one (Patient 9) had CMV before the arteriopathy diagnosis. Four patients (Patients 1, 3, 6, and 8) had a history of clinically apparent VZV infection, and two (Patients 2 and 5) had elevated spot-checked VZV antibody titers. None had a laboratory-confirmed CNS infection at the time of the diagnosis. However, three of the VZV infected or exposed patients (Patients 3, 5, and 8) had unilateral involvement of cerebral arteries. Furthermore, ipsilateral involvement of dermatomes and the cerebral vessels documented in Patient 3 implicates VZV as a possible causative factor.

The pathogenesis of CACA is unclear. Although vascular inflammation was sparse or absent in the four autopsy cases, the pathology is consistent with a prior vasculitis and the clinical histories clearly indicate an acquired lesion of subacute onset. VZV vasculitis is likely for several reasons. It is a well-recognized complication of VZV infection. The pathology is similar to that described in the four reported cases, including our current one. In addition, the striking unilateral arterial involvement in our Patient 5 is highly consistent with VZV infection. Vasculitis due to HIV is another possible cause of CACA and evidence of this infection was suggested by detection of HIV protein or genomic material in two of the four autopsy cases. Lastly, an autoimmune vasculitis cannot be excluded, although this group of vasculitides rarely involves brain vessels.

The source of HIV acquisition had no effect on the clinical course or outcome. The same holds true for the AZT and DDI treatment modalities. One-third of the patients in our series had 10 to 11 years of latent HIV infection without retroviral therapy. The reason for this extraordinary longevity is unknown, but it may be related to the special qualities of the virus or the unique features of the patient's immune system. The deterioration of mental status with or without clinically apparent cerebrovascular events is best explained by a progression of the HIV encephalitis, but cerebral aneurysmal arteriopathy in childhood AIDS signifies a grave prognosis.