Abstract
We report the case of a newly-diagnosed HIV-positive patient with varicella zoster virus aneurysmal vasculopathy confirmed on intrathecal antibody testing, despite a negative Cerebrospinal fluid (CSF) Varicella Zoster Virus (VZV) Polymerase Chain Reaction (PCR). This highlights the importance of prompt treatment with antiviral and steroid therapy in the presence of clinical or radiological suspicion whilst awaiting further confirmatory testing.
History
A 38-year-old Zimbabwean woman attended the sexual health department for HIV testing. Her general practitioner had identified pancytopenia following investigations which were requested due to a month-long history of general malaise and non-specific headaches. She had been a UK resident for the past 15 years, with her last negative HIV test being in 2004. She tested HIV-positive with a nadir CD4 cell count of 24 cells/mm3 (4%) and a HIV viral load of 1,350,259 copies/ml (log 6.13). The following week, whilst attending her initial HIV appointment, she collapsed, having a witnessed 2-min tonic–clonic seizure.
Investigations
A CT brain scan and then a CT angiogram were performed, which showed multifocal aneurysms involving the both middle cerebral arteries. The patient underwent a contrast MRI brain scan and subsequent vessel wall imaging which demonstrated bilateral distal middle cerebral artery disease with localised dilatation and aneurysm formation. The posterior sylvian aneurysm on the right side demonstrated partial thrombosis and localised haemorrhage. Cerebrospinal fluid (CSF) testing demonstrated: protein 0.34 g/L, WBC <5 g/L, RBC 800, CSF glucose 2.7 (serum glucose 5.5), CSF HIV viral load of 140,882 copies/ml (log 5.15). Bacterial, fungal and viral (including varicella zoster virus [VZV]) CSF testing were negative. Intrathecal VZV antibody testing was requested, the results of which were available several weeks later therefore empirical treatment was commenced. This demonstrated markedly increased CSF/serum ratio of anti-VZV IgG, demonstrating specific intrathecal synthesis of VZV antibodies (see Table 1).
Baseline and post-treatment intrathecal VZV antibody results.
VZV: varicella zoster virus, IgG: Immunoglobulin G, EIA: Enzyme Immunoassay, HSV: Herpes Simplex Virus.
Management
The patient was initially empirically commenced on liposomal amphotericin B, vancomycin, meropenem and aciclovir. Antiretroviral therapy (Truvada and dolutegravir 50 mg OD) was commenced on day four. Three days of intravenous methylprednisolone were administered, which was subsequently switched to a tapering prednisolone regimen.
Liposomal amphotericin, vancomycin and meropenem were discontinued following the results of her lumbar puncture. She was commenced on levitiracetam due to seizure activity. She completed two weeks of intravenous acyclovir and was commenced on oral valaciclovir, whilst her steroid dose was tapered. Following treatment completion, the patient made a full recovery with no neurological sequalae and repeat imaging at two months demonstrated marked radiological improvement. Repeat VZV intrathecal antibody testing had significantly improved (see Table 1).
Discussion
VZV vasculopathy is an under-reported complication of VZV infection, with an increased incidence in immunosuppressed individuals. 1 Infection can manifest in several ways: ischaemic brain or spinal cord infarctions, cerebral and subarachnoid haemorrhage, carotid dissection, peripheral arterial disease and aneurysms. The prevalence of VZV vasculopathy in adults is unknown; however, in children 31% of all arterial ischaemic strokes and 44% of transient cerebral arteriopathy are associated with varicella.2,3
Diagnosis of VZV vasculopathy involves a combination of clinical, radiological and CSF testing. Clinical presentation varies depending on the site of infection. Of note, one-third of individuals with virologically-verified VZV vasculopathy will have no history of dermatomal zoster lesions. 4 A case review of 30 case reports of VZV vasculopathy identified CNS lesions to be more common in white than grey matter, with 70% of those undergoing vascular studies demonstrating abnormalities. 5 The detection of anti-VZV IgG antibody in CSF has been identified to be more sensitive at indicating VZV vasculopathy than detection of CSF VZV PCR. 5 As is the case with this patient, there is a potential for missed diagnosis had intrathecal IgG VZV not been requested, thus highlighting the importance of consideration and empirical treatment of this diagnosis, particularly in advanced immune deficiency.
There is a paucity of published cases of HIV-positive individuals diagnosed with VZV aneurysmal vasculopathy in English language. A French case series reported three HIV-positive individuals with cerebral angiopathy with aneurysms. 6 All had positive CSF VZV PCRs which aided in a prompt diagnosis and timely management. A further American case series of nine patients with either HIV vasculopathy or VZV vasculitis identified two patients with VZV vasculitis who also presented with fusiform aneurysms. 7 To our knowledge, this is the first published case report of VZV aneurysmal vasculopathy in an HIV-positive individual where the VZV CSF PCR was negative with a positive intrathecal VZV antibody assay. Despite HIV-associated aneurysmal vasculopathy having a similar radiological presentation of fusiform aneurysmal dilatations of the cerebral vessels, it is a diagnosis of exclusion and it is anticipated that many cases of HIV-associated vasculopathy are undiagnosed cases of VZV vasculopathy.8,9
Optimal antiviral dose, frequency and duration of VZV vasculopathy have not yet been established. However, in a patient with high clinical, radiological and CSF suspicion of VZV vasculopathy, intravenous aciclovir 10–15 mg/kg three times per day for a minimum of 14 days is advised, whilst the results of further intrathecal testing is awaited, and adjunctive treatment with a maximum of one week of steroids should also be considered. 9 In this case, we continued steroids with valaciclovir cover beyond this due to very good evidence of vasculitis of the vessel wall on gadolinium-enhanced 3-tesla MRI vessel wall imaging (Phillips, Salford, UK), an investigation which is not available at every unit.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.