An 11-year-old girl with known HIV developed sudden onset right-sided weakness and dysphasia 1 month after starting highly active antiretroviral therapy (HAART). She was born by spontaneous vaginal delivery in Botswana following an uneventful pregnancy. She was formula-fed from birth and was vaccinated as per the World Health Organization “Expanded Programme” immunization schedule, which included Bacillus Calmette–Guérin and hepatitis B. She developed chickenpox at 4 years of age, the course of which was uncomplicated. After migration to the United Kingdom, she received a measles, mumps and rubella vaccine booster dose. She was otherwise well until she began experiencing epigastric pain at the age of 10 years, which was associated with weight loss of 6 kg during a 4-month period. Six months later she developed right lower lobe pneumonia and subsequently oral candidiasis, which prompted a number of investigations that led to the diagnosis of HIV infection (World Health Organization stage III disease). Vertical transmission was most likely, as her mother also tested positive for HIV. Her absolute CD4 count was 6 × 106 cells/L and the HIV viral load 250,000 copies/mL. HLA B5701 was negative, and HIV resistance testing revealed no mutations. She was commenced on cotrimoxazole prophylaxis and HAART (lamivudine, abacavir and efavirenz).
The patient presented 4 weeks after starting HAART with a right-sided hemiplegia, right-sided facial nerve palsy and dysphasia (expressive and receptive). Therapy was empirically started with intravenous cefotaxime, acyclovir and antimycobacterial treatment (isoniazid, rifampicin, ethambutol and clarithromycin). Her HIV viral load showed a marked reduction from 250,000 copies/mL at commencement of HAART to 404 copies/mL at the time of admission and her absolute CD4 count was 30 × 106 cells/L.
Magnetic resonance imaging and angiography showed an occlusion of the left internal carotid artery (ICA) from just above its origin up to its termination (Fig. A, Supplemental Digital Content 1, https://links.lww.com/INF/B567). There was poor flow in the left middle cerebral artery (MCA) with acute infarction within the left MCA and anterior perforator territories (Fig. B, Supplemental Digital Content 1, https://links.lww.com/INF/B567). There was moderately reduced flow in the mid basilar artery but no brainstem infarction. She was started on low molecular weight heparin therapy. Echocardiography showed a structurally normal heart without evidence of vegetations.
Analysis of cerebrospinal fluid (CSF) showed the following: white blood cells 1/mm3, protein 432 mg/dL and glucose 4.2 mmol/L. CSF cultures revealed no growth, and CSF polymerase chain reaction (PCR) testing was negative for herpes simplex virus, enterovirus, parechovirus, cytomegalovirus, human herpes virus 6, epstein-barr virus, toxoplasmosis, mumps, measles, rubella, HIV, bartonella and mycoplasma. However, varicella zoster virus (VZV) was detected in the CSF by TaqMan PCR1 (Public Health England Microbiology Services, University Hospital Southampton).
She was treated with a 3-week course of intravenous acyclovir followed by a 6-month course of oral valaciclovir. She made steady clinical progress and was discharged after 4 weeks with a mild right-sided hemiplegia.
A carotid artery Doppler scan repeated after 3 months showed persisting occlusion of the left ICA. Antinuclear antigen, antineutrophil cytoplasmic antibody and anticardiolipin antibodies were negative, and no Factor V Leiden or prothrombin gene mutations were detected. Magnetic resonance angiography performed after 12 months showed persistence of the left ICA stenosis (Fig. C, Supplemental Digital Content 1, https://links.lww.com/INF/B567). There was significant progression of arteriopathy at the level of the skull base and of the intracranial arteries with new severe stenoses of the right ICA and proximal segments of the right middle, right posterior and both anterior cerebral arteries. The stenosis of the basilar trunk had progressed, whereas both middle meningeal arteries had hypertrophied to provide dural collateral supply to distal MCA territories. Despite these findings, the patient’s neurology continues to improve. Her most recent scan, performed at 15 months after the stroke, showed some improvement of the vascular abnormalities.
Immune reconstitution inflammatory syndrome (IRIS) is a complication of antiretroviral therapy occurring due to partial recovery of the immune system or exuberant host immune response to antigenic stimuli, most commonly directed against opportunistic pathogens. It is thought to occur in approximately 15–35% of HIV-infected children.2 The precise pathogenesis of IRIS remains largely unknown.3,4 Risk factors include severe immunosuppression (CD4 < 350 cells × 106/L) at the initiation of HAART, a low CD4+ nadir, a rapid decline in HIV viral load on starting HAART and the presence of subclinical or clinically apparent opportunistic infections.2
Central nervous system (CNS) IRIS, which is T-cell–mediated encephalitis, is a recently recognized, potentially devastating form of IRIS.3 Diagnosis and management are challenging due to the nonspecific clinical features, the absence of a universally accepted case definition, the poorly understood immunopathogenesis and absence of an optimal treatment strategy. Features suggestive of CNS IRIS include (1) worsening of neurological status after initiation of HAART, (2) deterioration of or new radiological findings suggestive of inflammation, (3) symptoms not explained by newly acquired disease or by the usual course of previously acquired disease and (4) histopathology demonstrating T-cell infiltration.2
VZV has been recently implicated in CNS vasculopathy.5–7 After primary infection with VZV, there is persistence of the virus in a noninfectious latent form in ganglionic neurons along the entire neuraxis, with intermittent periods of reactivation. After reactivation, it is thought that the virus spreads to both intracranial and extracranial blood vessels via a hematogenous route as well as through the sensory nerves. Within the cerebral arteries, VZV replication results in inflammation, leading to vasculopathy.8 This is evidenced by neuropathologic brain biopsy findings of multinucleated giant cells, Cowdry A inclusion bodies, herpes virus particles, VZV antigen and VZV DNA in cerebral vessels.9
A clinical history of recent chickenpox followed by neurologic symptoms and signs and abnormal brain imaging are indicative of VZV vasculopathy. Diagnosis often relies on CNS virologic confirmation. Anti-VZV IgG antibodies in CSF are a more sensitive indicator of VZV vasculopathy than VZV PCR.2,10 Brain imaging may show cerebral ischemia, infarction, hemorrhage or evidence of narrowing or beading of the cerebral arteries. Typically, large arteries of the anterior and posterior circulation are affected. However, multifocal vasculopathy, usually affecting branches of the large cerebral arteries or small cerebral arteries, occurs in immunocompromised patients. The diagnosis of VZV-related vasculopathy can be challenging as there is often a time lag between neurological features and the primary chickenpox infection, which may have been subclinical in the first instance.
Our patient’s presentation with cerebral infarction within the left MCA distribution shortly after starting HAART, associated with a significant decline in HIV viral load and detection of VZV in the CSF following a history of chickenpox a number of years previously, strongly suggests a diagnosis of VZV-related CNS IRIS.
To our knowledge, this is the first report of VZV-related CNS IRIS in a pediatric patient. The only previous report of this entity is in a 42-year-old HIV-positive woman, who presented with facial herpes zoster, weakness and ataxia 2 weeks after starting HAART.11 She made an initial recovery after intravenous acyclovir treatment for 2 weeks but subsequently relapsed, requiring a prolonged course of steroid treatment. Similar to our patient, her brain magnetic resonance imaging showed changes in keeping with ischemia which in the presence of positive VZV PCR is the most consistent criterion to support the diagnosis of VZV vasculopathy.2,8,10
The authors thank the patient and her family for their permission to discuss this case.
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