Severe Headaches and Cerebrovascular Disease in a Young Man With Perinatally Acquired HIV Infection

Cerebrovascular disease (CVD) in HIV may be associated with multiple concurrent etiologies and with varying presentations, from chronic asymptomatic microvascular calcifications or vascular anomalies to intracerebral hemorrhage to thrombotic stroke. A pattern of fusiform aneurysmal dilatations of intracerebral arteries, particularly in the circle of Willis, has been identified as a characteristic of HIV-associated vasculopathy¹ in congenitally HIV-infected children.

There may be a similar pathological pattern in adult-acquired HIV infection, although this is not as well described, and young adults certainly present with evidence of cerebrovascular disease atypical for their age group. Here we present a case of a young man, congenitally infected with HIV, who has headache and evidence of cerebrovascular disease.

CASE SUMMARY
A 22-year-old Hispanic man with perinatally acquired HIV infection was hospitalized for evaluation of severe, frequent, and disabling headaches. These headaches had worsened recently and were associated with a few months' history of epigastric pain that radiated from the left parasternal side of his chest. The patient's most recent CD4⁺ cell count was 6/µL; an HIV reverse transcription polymerase chain reaction (PCR) assay showed more than 2 million HIV RNA copies/mL while the patient was receiving antiretroviral treatment.

The patient described his headaches as "ice cream" headaches––ie, short-lived but severe and always located in the right temporal region. They occurred multiple times a day and were associated with movement and changes in temperature. The headaches were exacerbated by cold and were associated with conjunctival injection and bilateral tearing.

The patient first presented to our clinic when he was 8 years old, after he had been hospitalized for HIV-associated thrombocytopenia, which had been treated successfully with plasmapheresis. His initial CD4⁺ cell count was 122/µL. He was also found to have chronic hepatitis B virus (HBV) infection. At age 9 years, he had presented with transient right-sided weakness and slurred speech in association with a low platelet count. Findings on the initial noncontrast CT scan of the head were normal. However, a follow-up noncontrast CT scan of the head obtained 5 days later showed new bilateral foci of high density within the ambient cisterns, suggestive of hemorrhage. MRI and magnetic resonance angiography (MRA) that were performed the next day failed to show any collections in the ventricles or defect in visualized vessels.

Although the transient neurological deficits did not recur, headaches began when the patient was about 11 years old. These headaches were thought to be secondary to acute and chronic sinusitis seen on sinus CT scans or to a new diagnosis of migraine. Follow-up CT brain imaging was done at age 13 years, when the patient’s headaches worsened. The scans showed new evidence of mild cerebral atrophy but no other changes, and persistent but slightly improved chronic pansinusitis.

The patient was treated intermittently for sinusitis and symptomatically for migraine headaches. Recurrent candidal esophagitis had been treated most recently with posaconazole for documented Candida krusei infection. The patient had also been treated for recurrent varicella-zoster virus (VZV) infection involving his left axilla.

At age 15 years, the patient had wasting associated with severe GI intolerance of his antiretroviral drugs. He responded to percutaneous endoscopic gastrostomy tube (PEG-tube) placement and pancrelipase. He has had persistent hyperlipidemia––primarily elevated triglyceride levels––and pancreatic abnormalities consistent with chronic pancreatitis on imaging studies.

HOSPITALIZATION FOR SEVERE DEPRESSION
At age 20 years, the patient was hospitalized in the psychiatric unit for severe depression. An MRI scan obtained at that time as part of his neuropsychiatric evaluation showed evidence of chronic hemorrhagic lacunar infarcts in the right basal ganglia in addition to the previously described mild cerebral atrophy. No further workup was obtained as a result of the MRI changes at that time, because they appeared to be chronic. Two months later, the patient sustained head trauma. MRI scans showed no change from previous images.

Medication History
Multidrug-resistant HIV has been documented by genotyping and phenotyping. The patient's antiretroviral history (paired with CD4 count and HIV RNA level using PCR assay) and toxicities are detailed in Table 1. The multidrug resistance reflects the availability of antiretroviral agents approved or in clinical trials for treatment of pediatric HIV infection at the time. His adherence to medication regimens had been poor because of adverse effects. On admission, however, he was on the best-tolerated and most effective regimen, given the few treatment options available to him.

Other medications the patient was taking on admission included monthly intravenous immunoglobulin injections, trimethoprim/sulfamethoxazole (TMP/SMX) 3 times weekly, gemfibrozil 2 times daily, pancrelipase with meals, ranitidine daily, calcium carbonate and vitamin D daily, azithromycin weekly, and posaconazole daily.

Medical and Surgical History
Low bone mineral density was diagnosed in March 2005.

The surgical history included PEG-tube placement (from August to December 2000) for severe wasting associated with nausea and vomiting from a new antiretroviral regimen. On September 11, 2006, the patient had a right hemotympanum and right temporoparietal scalp hematoma secondary to head trauma after he fell off a bike. A scalp laceration resulting from the fall required 12 staples. In November 2006, the patient was assaulted and robbed.

A review of systems revealed no cough, dyspnea, shortness of breath, or fever. The patient was mildly nauseated but did not have vomiting or diarrhea.

Social History
The patient lived with his maternal grandmother. On occasion, he stayed with his aunt since the death of both parents when he was 10 years old. His older brother, who is HIV-negative, is supportive. Because of adverse effects from his medication, the patient left high school before graduation. He was unemployed because of disability. The patient smoked 5 cigarettes daily and admitted to occasional limited use of marijuana and alcohol. He did not use other illicit drugs.

Physical Examination
The patient was a thin young man of short stature but normally developed. He was lying flat in no acute distress except for intermittent episodes of severe headache pain that lasted approximately 2 minutes. Oxygen saturation on room air was 98%; pulse rate, 90 beats per minute; blood pressure, 100/60 mm Hg; and respiration rate, 12 breaths per minute. The chest was clear to auscultation. Cardiac examination results were normal. The abdomen was scaphoid with a visible, slightly enlarged liver and mild epigastric tenderness to palpation. There was a 1-cm deep puncture scar at the insertion site of the earlier gastric feeding tube.

The genitalia and extremities were normal. The neurological evaluation was nonfocal, with normal mentation, judgment, and insight.

Results of laboratory tests included white blood cell count, 1400/µL (normal, 3400 to 11,200); hemoglobin level, 11.9 g/dL (normal, 11.7 to 16.0); platelet count, 146,000/µL (normal, 150,000 to 450,000); lactate dehydrogenase level, 261 U/L (normal, 96 to 200); and albumin level, 2.8 g/dL (normal, 3.0 to 5.0). Levels of serum transaminases, lipase, amylase, and electrolytes were all within normal limits.

Figure 1. A CT scan of the chest following administration of intravenous contrast showing new innumerable bilateral pulmonary nodules measuring up to 1.6 × 1.5 cm in the left upper lobe. Some nodules are cavitary.

CT imaging of the chest following oral and intravenous contrast administration is shown in Figure 1. There were innumerable new bilateral pulmonary nodules, some with cavitation. The largest nodule in the left upper lobe measured 1.6 × 1.5 cm.

Hospital Course
Findings on the chest CT scan raised concerns about tuberculosis and fungal infection. Sputum smears were obtained to screen for acid-fast bacilli; test results were negative. The patient underwent a bronchoscopic evaluation with bronchoalveolar lavage and biopsy; results were positive for a few Pneumocystis jiroveci organisms in clumps.

The patient was treated for Pneumocystis pneumonia with a 3-week course of intravenous TMP/SMX. By the end of the 3 weeks, there was some exacerbation of chronic neutropenia, but the left-sided chest pain had resolved. CT images showed some small improvement in the larger nodules.

Because of the epigastric pain, the patient underwent upper endoscopy and biopsy. Results showed no evidence of fungal disease but did reveal evidence of a chemical gastropathy, which failed to respond clinically to antacid therapy with a proton pump inhibitor.

Neurology consultants thought the patient's headache presentation was most consistent with SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing).² They were also concerned that vasculitis could mimic SUNCT, and therefore recommended an evaluation for vasculitis––including repeated MRI and MRA of the cerebral circulation, measurement of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and serological tests.

Figure 2.MRI scans of the brain following administration of gadolinium contrast showing stable parenchymal volume loss greater than expected for age and a stable chronic right basal ganglia/caudate lacunar infarct.

Although SUNCT is refractory to most treatments, a treatment trial with lamotrigine is generally recommended.² MRI scans again showed chronic right basal ganglia infarcts with evidence of prior hemorrhage (Figure 2). Findings on MRA scans were normal; there was no evidence of atheromatous change, aneurysmal dilatation, or vasculitis. However, the neuroradiologists stated that small-vessel vasculitis might not be visualized on MRA. The ESR was slightly elevated at 31 mm/h; the CRP level was normal. Serological test results were unchanged (ie, positive for VZV IgG, Toxoplasma IgG, hepatitis B surface antigen, and hepatitis B e antigen). However, the HBV DNA level (using PCR assay) was less than 40 IU/mL––down from more than 50 million IU/mL before lamivudine and tenofovir therapy.

The patient's ongoing symptoms and the radiologically significant but apparently clinically silent right basal ganglia infarct that had appeared sometime when the patient was between 13 and 20 years old raised questions about whether the headaches and hemorrhagic infarcts were related. There was also concern about the patient's ongoing risk of additional complications of HIV-associated cerebrovascular disease, especially in view of high-level viral replication, a failing antiretroviral regimen, and significant hypertriglyceridemia.

DISCUSSION
CVD has been reported in patients of all ages with HIV infection. Overall, however, HIV-infected patients with CVD are substantially younger than patients with CVD who are HIV-negative.^1,3,4 The annual incidence of stroke in persons with AIDS from a population-based study in Baltimore was reported in 2004 as 0.2% per year with an odds ratio for ischemic stroke of 13.7 and for intracerebral hemorrhage of 25.5.³ Observations from the Edinburgh HIV autopsy cohort reported that in 10 of 183 autopsies of adults with AIDS, there were manifestations of CVD independent of opportunistic infections, lymphoma, intracerebral hemorrhage, or embolic strokes.⁵ Age at death in this subset was 22 to 47 years, and half had antibody to hepatitis C virus.

A very early clinical case series published in 1989 attempted to estimate the frequency of CVD in persons with AIDS.⁶ The authors found CVD in 12 of 1600 cases reviewed, which was substantially higher than an age-matched population sample. Some methodological questions have been raised about comparison groups in that article.⁷

The pathology of CVD in HIV-infected patients includes vasculitis associated with a few opportunistic pathogens, vasculopathy apparently as a direct consequence of HIV, atheromatous disease, hypercoagulability with thrombosis, and hemorrhage. A review of patients with HIV-associated acute strokes who presented to a Miami hospital between 1996 and 2004 identified 82 adults with CVD: 77 had ischemic stroke and 5 had intracerebral hemorrhage.⁸ The mean age was 42 years (range, 3 to 72 years). Causes of ischemic stroke in these patients included large-artery atherosclerosis (12%), cardiac embolism (18%), small-vessel occlusion (18%), vasculitis (13%), and hypercoagulability (9%). Twenty-nine percent were of indeterminate cause (multiple causes or incomplete evaluation). Protein S deficiency was identified in 10 of 22 patients tested and anticardiolipin antibodies were seen in 9 of 31 patients tested. There was a divergence in age but not in CD4 count or history of receipt of antiretroviral therapy in patients with thrombotic strokes versus all other causes. Those with nonatheromatous strokes were significantly younger and more likely to have had cocaine exposure. Outcomes were fatal or severely disabling in 35%. No correlation was found between use of combination antiretroviral therapy and stroke mechanism (ie, to evaluate for accelerated atherosclerotic change in patients with metabolic syndrome secondary to antiretroviral treatment). However, the authors note that they were not able to evaluate the duration of antiretroviral therapy.

An earlier review of 11 autopsy series and 6 clinical series of CVD in persons with HIV infection published between 1976 and 1994 summarized 1885 cases.⁷ Again, ischemic infarcts were more frequent (68%) than intracerebral hemorrhage (32%). Of patients with intracerebral hemorrhage, premorbid thrombocytopenia, primary CNS lymphoma, and metastatic Kaposi sarcoma were most common. Ischemic infarctions were associated with opportunistic infections or nonbacterial thrombotic endocarditis. Vasculitis was also identified in some cases of thrombotic stroke in association with VZV infection or syphilis.

Postmortem evidence of vasculitis was common in the 11 autopsy series reviewed from the pre-HAART era. Vasculitis in association with HIV infection may be attributable to infectious agents. Cytomegalovirus, VZV, HBV, Toxoplasma, Pneumocystis, Salmonella, and Mycobacterium tuberculosis have all been described, although it is thought that the actual incidence of solely HIV-related vasculitis is only about 1%.⁹ The pathology and patterns of HIV-associated vasculitides have been reviewed extensively by Chetty¹⁰ and are summarized in Table 2.

Most case series have addressed CVD in adults. Another case series has focused on the pediatric population.¹¹ The authors looked at CVD in 567 HIV-infected pediatric patients who were undergoing evaluation for participation in clinical research trials at the NIH. Patients aged 1 month to 29 years (median age, 5.5 years) who had acquired HIV in childhood (69% via vertical transmission) were evaluated from 1986 through 2001. Neuroimaging studies were performed in 75% of patients for either study entry evaluations or clinical indications, and they were subject to blinded reviews by 2 neuroradiologists. Cerebrovascular lesions were found on imaging studies in 11 patients (2.6%) aged 8 months to 15 years (median age, 9.3 years) at the time of initial radiological abnormality. Among these patients, 7 were asymptomatic, 2 had headache, and 1 had an acute stroke syndrome. The youngest patient presented with nonfocal developmental delay. Imaging studies documented cerebral artery aneurysm in the majority, most commonly involving the proximal segments of the middle and anterior cerebral arteries. These were predominantly fusiform aneurysms (92%), and frequently multiple aneurysms were noted. Ischemic infarcts were seen in 8 of the 11 patients, most involving the basal ganglia.

The most common infection observed was VZV infection, which was usually recurrent; it was noted in 6 of the 11 patients.¹¹ In addition, protein C and protein S deficiencies were documented in 1 patient; another was found to have only protein S deficiency. The median CD4⁺ cell count was 6/µL at the time of diagnosis of CVD.

Dubrovsky and colleagues¹² studied HIV-infected children with documented cerebral aneurysms. All patients had either a history of VZV infection or elevated VZV antibody titers. Park and coworkers¹ reported a similar fusiform aneurysmal vasculopathy associated with AIDS in a series of 68 pediatric patients, 4 of whom had had a stroke.

A variation on this theme is the possible role of immune reconstitution inflammatory syndrome (IRIS) resulting in CVD from vascular inflammation. In the present case, the patient had a brief but substantial virological response to a clinical trial with ritonavir-boosted lopinavir when he was 15 years old. During this period, he also had a severe episode of VZV infection that required hospitalization. This correlation of events raises the possibility of an IRIS-associated cerebral vasculitis and resultant CVD subsequently visualized on MRI images. A recent case report of IRIS presenting as encephalitis and cerebral VZV vasculitis with infarct following treatment of thoracic VZV infection is instructive in that the patient recovered completely with high-dose acyclovir therapy.¹³

In most of the cases reported above, CVD was found in association with other pathology, but the entity of HIV vasculopathy assumes a direct effect of HIV on the cerebral vasculature in the absence of other causes. A study of stroke and HIV infection in Cape Town, South Africa, found that 67 of 1087 stroke patients were HIV-infected and that 13 (20%) of those patients had evidence of HIV-associated vasculopathy.¹⁴ In this cohort, patients with intracranial vasculopathy had lower CD4 counts than those with extracranial (carotid disease); postmortem histological analysis showed aneurysmal vasculopathy with intimal hyperplasia; fibrosis; and thickened, beaded, and fragmented internal elastic lamina. These authors suggested that the focus of the insult in the intracranial vasculopathy may be the intima, as opposed to large-vessel extracranial vasculopathy. The latter, also observed in this study, was characterized by insults to the vasa vasorum.

Mechanisms of HIV-associated CVD have also been the subject of additional laboratory investigations as the interaction of vascular endothelium and chemokines are better understood. A recent article presented data on the effect of HIV itself on the blood vessel wall in the pathogenesis of atherosclerosis.¹⁵ The investigators were able to document HIV infection of vascular smooth muscle cells in vivo from vascular sections. Results of in vitro experiments by the same investigators suggest that HIV entry into human smooth muscle cells is CD4- and CCR5- or CXCR4-dependent. Further, these authors suggest that endocytosis triggers infection and viral replication in the smooth muscle cell itself.

Despite the age of the patient described in this case, accelerated atheromatous disease should be considered in the differential diagnosis, given the above information and given the role of antiretroviral-associated metabolic syndrome and dyslipidemias with endothelial cell dysfunction.

Our patient had a partial clinical response to escalating doses of lamotrigine for SUNCT. The headaches did not completely resolve, but their frequency and severity improved somewhat after the dosage was maximized. Because the patient had a clinical response and after discussion of the risks of cerebral angiography, a more definitive search for alternative diagnoses to explain his headache and lacunar infarcts was deferred. Therapy was initiated with valacyclovir for possible VZV-associated vasculitis. The patient has recently begun a new regimen of combination novel class therapy and is awaiting evaluation of his response.

Acknowledgment: The images and their interpretation courtesy of New York Presbyterian Hospital––Weill Medical College of Cornell University.

References:

References1. Park YD, Belman AL, Kim TS, et al. Stroke in pediatric acquired immunodeficiency syndrome. Ann Neurol. 1990;28:303-311.
2. Williams MH, Broadley SA. SUNCT and SUNA: clinical features and medical treatment. J Clin Neurosci. 2008;15:526-534.
3. Connor M. Stroke in patients with human immunodeficiency virus infection.J Neurol Neurosurg Psychiatry. 2007;78:1291.
4. Cole JW, Pinto AN, Hebel JR, et al. Acquired immunodeficiency syndrome and the risk of stroke. Stroke. 2004;35:51-56.
5. Connor MD, Lammie GA, Bell JE, et al. Cerebral infarction in adult AIDS patients: observations from the Edinburgh HIV Autopsy Cohort. Stroke. 2000;31:2117-2126.
6. Engstrom JW, Lowenstein DH, Bredesen DE. Cerebral infarctions and transient neurologic deficits associated with acquired immunodeficiency syndrome. Am J Med. 1989;86:528-532.
7. Pinto AN. AIDS and cerebrovascular disease. Stroke. 1996;27:538-543.
8. Ortiz G, Koch S, Romano JG, et al. Mechanisms of ischemic stroke in HIV infected patients. Neurology. 2007;68:1257-1261.
9. Kaye BR. Rheumatologic manifestations of HIV infections. Clin Rev Allergy Immunol. 1996-1997;14:385-416.
10. Chetty R. Vasculitides associated with HIV infection. J Clin Pathol. 2001;54:275-278.
11. Patsalides AD, Wood LV, Atac GK, et al. Cerebrovascular disease in HIV infected pediatric patients: neuroimaging findings. AJR. 2002;179:999-1003.
12. Dubrovsky T, Curless R, Scott G, et al. Cerebral aneurysmal arteriopathy in childhood AIDS. Neurology. 1998;51:560-565.
13. Patel AK, Patel KK, Shah SD, Desai J. Immune reconstitution syndrome presenting with cerebral varicella zoster vasculitis in HIV-1-infected patient: a case report. J Int Assoc Physicians AIDS Care (Chic Ill). 2006;5:157-160.
14. Tipping B, de Villiers L, Wainwright H, et al. Stroke in patients with human immunodeficiency virus infection. J Neurol Neurosurg Psychiatry. 2007;78:1320-1324.
15. Eugenin EA, Morgello S, Klotman ME, et al. Human immunodeficiency virus (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. Am J Pathol. 2008;172:1100-1111.