VZV infections, especially CNS infections, showed a bimodal age distribution with a first peak in the 20s and a second peak in the 70s. Patients with VZV CNS infection, especially encephalitis, may present with headache, fever, altered mental status and seizures, as reported in this case.
VSV vasculopathy, another rare CNS manifestation of VZV infection, is well described in primary infection (varicella) and reactivation (zoster). Historically, VZV vasculopathy was described in 1896 as herpes zoster ophthalmicus with contralateral hemiparesis(3). Later studies showed evidence of focal stenosis on angiographic imaging of the brain ipsilateral to the herpes zoster ophthalmicus. It is postulated that the virus enters the central nervous system via the dorsal roots innervating the intracranial portion of the internal carotid arteries. This originates from the ophthalmic part of the trigeminal nerve and leads to various complications affecting the central nervous system, such as vasculopathy and stroke (1). In contrast, autoantibodies associated with VZV infection may also play a role in cerebral artery occlusion. Studies showed the presence of VZV antibodies in the CSF, VZV DNA and VZV-specific antigen in the cerebral arteries of a patient with vasculitis(3).
The diagnosis of VZV CNS infection is based on clinical presentation, neurological symptoms, CSF analysis and imaging. The typical zoster exanthem does not always occur in patients with VZV CNS disease. It is reported that 44–68% of VZV CNS infections have no accompanying rash(4). In the presence of a rash, the average time to onset of neurological manifestations is 4.1 months, but may occur on the same day and up to 2.5 years. The pattern of skin involvement can be explained by the pattern of viral invasion. If the virus has centripetal invasion as described above, CNS disease may develop without accompanying skin rashes. However, if the virus also spreads centrifugally, the patient will develop varicella or zoster. As in this case, the patient did not report the development of rashes until he was admitted to the casualty department.
VZV vasculopathy can manifest in a range of neurological symptoms including stroke, aneurysm and venous sinus thrombosis. There is an increased risk of stroke of 2–9% in the first year after VZV infection, and the risk is higher in people under 40 years of age, regardless of their immune status. Previous studies have shown that 50% of cases of VZV-related strokes have mixed involvement of the large and small arteries. Multifocal vasculopathy can often manifest in immunocompromised patients.
The investigation of choice in patients with VZV infection involving the central nervous system is lumbar puncture. In more than half of the patients with VZV vasculopathy, CSF analysis showed mononuclear pleocytosis, typically less than 100 cells/ 〖mm〗^3. On the contrary, it has been reported that up to 30% of patients had a normal white blood cell count in the CSF. In addition, the glucose level in the CSF is usually normal, while the protein concentration in the CSF is slightly elevated.
The CSF is then analysed for the presence of anti-VZV antibodies and VZV DNA. It is reported that the diagnostic value of detecting anti-VZV IgG antibodies in CSF was greater than that of VZV DNA. 28 out of 30 patients with VZV vasculopathy had anti-VZV IgG antibodies in CSF compared to 9 patients who had VZV DNA in CSF(5). Therefore, a positive VZV DNA PCR is a helpful tool in the diagnosis of VZV vasculopathy, but its absence does not exclude the diagnosis.
Imaging in viral encephalitis helps in early diagnosis and follow-up despite many reports of non-specific findings such as cerebral oedema, enhancement, altered focal or diffuse cerebral signal intensity and haemorrhages. HSV-1 encephalitis, a common cause of viral encephalitis, describes a typical MRI brain with high signal intensity in the orbitofrontal and temporal lobes with involvement of the insular cortex on T2-weighted images. Unlike HSV-1 encephalitis, the MRI findings in VZV encephalitis are not limited to the area surrounding the temporal lobe(4). Rather, it is widespread in several areas, such as multifocal nodular enhancement on T1-enhanced images and frequently reported haemorrhagic or ischaemic complications due to vasculopathy. In our case, the first contrasted CT brain on imaging showed bilateral insular and anterior temporal lobe lesions as seen in HSV-1 infection, but the presence of hypodense lesions in the thalamus and midbrain, suggestive of ischaemia, could indicate concomitant vasculopathy seen in VZV infection. Contrast MRI of the brain one month later showed hyperintense signals involving the left insular cortex and right anterior temporal lobe, suggesting residual viral encephalitis masquerading as HSV-1 infection. However, the presence of subcortical haemorrhage, as seen in the previous contrasted CT brain scan, showed possible evidence of vasculopathy.
In VZV vasculopathy, angiography performed in 23 patients revealed that both small and large arteries were affected in 70%, small arteries in 37% and large arteries in the remaining 13%(3). The anterior and middle cerebral arteries and the external and internal carotid arteries are the most commonly affected large arteries. Normal angiography does not rule out VZV vasculopathy. An MRA of the brain and an CT angiography of the brain can only provide evidence of stenosis or aneurysm, but unable to differentiate between vasculitis and atherosclerosis. To distinguish between vasculitis and atherosclerosis, MRA imaging of the black blood can be performed to identify the pathological conditions.