Cerebral vasculitis associated with an Echovirus 6 meningoencephalitis—Case report and review of the literature

Key Clinical Message When a previously healthy child presents to the hospital with a stroke, generally a Varicella zoster virus vasculopathy seems most likely. However, other causes of a local cerebral vasculitis are possible and need to be explored.


| CASE PRESENTATION
An 8-month-old female presented to the emergency department of our hospital with a right-sided hemiparesis and a mild right-sided facial paresis, which had been progressive since one day. Further clinical examination was normal and there were no apparent skin lesions. The week before, she had experienced high fever for two days followed by irritability, anorexia, and low-grade fever. She was born full term via uncomplicated vaginal delivery after a normal pregnancy and was the third child of healthy non-consanguineous parents from African European descent. Besides an uncomplicated Varicella infection at the age of 6 months, anamnesis and family history did not reveal any relevant information.
Laboratory investigation, including complete blood count, C-reactive protein, liver function tests, kidney function, and electrolytes, was within the normal range.

CAUWENBERGHS Et Al.
Computed tomography of the brain did not show any abnormalities, whereas the magnetic resonance imaging (MRI) with angiography of the brain revealed a (sub) acute ischemic lesion of the left capsule-thalamic region with irregularities of the left arteria cerebri media, suggestive of vasculitis ( Figure 1). The vasculitis lesion can be classified as benign (single, concentric, graduated, and smooth aspect of the lesion) and proximal (location on the M1 segment of the left middle cerebral artery). Electroencephalography was normal. Lumbar puncture was done showing normal liquor opening pressure. Examination of liquor indicated an elevated white blood cell count (186 cells/mm 3 ) with normal glucose (55 mg/dL) and protein levels (20 mg/ dL). While in-house PCR for Varicella zoster virus and Herpes simplex virus were negative, PCR for enterovirus (GeneXpert, Cepheid) was positive. Bacterial culture remained negative. The sample was sent to the national reference center, and the strain was typed as Echovirus 6 by sequencing. Echocardiography and Doppler ultrasound of the lower limbs and abdomen were normal. Hereditary and acquired hypercoagulability workup (activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimers, antithrombin III, protein C activity, activated protein C resistance, protein S activity, prothrombin G20210A mutation) was normal. Lupus anticoagulant was negative. Since the focal origin of the vasculitis, and the suspected cause of this, a brain biopsy was not considered.
Intravenous methylprednisolone (1 mg/kg/d, 5 days) and acyclovir (30 mg/kg/d, 14 days) were administered as initial therapy. Even though PCR for Varicella zoster and Herpes simplex were found to be negative, the treatment with corticosteroids and acyclovir was completed because of the clear neurologic deficit and the history of the Varicella zoster infection. Because of the severity of the neurologic deficit and in anticipation of the results of the coagulopathy screening, subcutaneous enoxaparin (2 mg/d) was started. Neurologic abnormalities recovered slowly during the following weeks.
Enoxaparin was discontinued after eight weeks, and oral aspirin (30 mg/d, for two years) was initiated.

| DISCUSSION
Enterovirus infection usually presents as a mild febrile illness, but is also known to cause meningitis in children. Rarely, it presents with acute focal neurological symptoms such as seizures, hemiplegia, and focal weakness. In previous literature, this clinical image has been referred to as focal encephalitis. Cerebral vasculitis has been proposed as an underlying cause for cerebral infarction in this particular disease. [2][3][4] In 2016, Benschop et al, 5 report an increase in Echovirus 6 infections associated with general neurological symptoms such as aseptic meningitis, encephalitis, and convulsion.
A PubMed search was conducted in the English-language literature using the keywords "focal neurological signs" and "enterovirus infection" in the age group 0-16 years between 1975 and 2016. Table 1 gives a summary of the collected cases, including our own case. [2][3][4][6][7][8][9][10] In all but one case, the symptoms improved spontaneously.
In our patient, brain MRI with angiography showed an ischemic lesion on the left side with associated vasculitis of the left arteria cerebri media. This was also reported by Tsai et al, 3 describing a 2-month-old boy with focal seizure and right hemiparesis. MRI and angiography showed vasculitis in the left anterior cerebral artery with cerebral infarction. To our knowledge, the presence of cerebral vasculitis in enterovirus infection has not been reported in previous cases.
Two other case reports, however, have also proposed local cerebral vasculitis as a cause of vascular occlusion. Wakamoto et al report a 4-year-old male with focal Coxsackie A3 encephalitis who presented with seizures and acquired aphasia. Brain single-photon emission computed  tomography (SPECT) disclosed hypoperfusion in the right frontal lobe, which completely resolved on follow-up imaging. 4 They propose that these mild ischemic changes are most probably caused by local cerebral vasculitis. Roden et al describe a case of a 16-month-old girl with an acute hemiplegia associated with Coxsackie A9 encephalitis. Technetium-99 brain scans revealed a lesion within the region of the right middle cerebral artery. 2 They also propose that the most likely underlying mechanism is a vascular occlusion caused by focal vasculitis. Both case reports were not able to identify the presence of vasculitis on imaging. Until now, the underlying pathogenesis of focal enterovirus encephalitis remains under speculation. Older cases described, suggest direct cytotoxicity of the virus causing focal necrotizing encephalitis. 7,9 In general, focal neurological symptoms and focal cortical hyperintensity on brain MRI are associated with a poor neurological outcome. 11 Although the extent of the ischemic lesion seen on MRI in our patient was substantial, the general course of the disease remained benign. Only one of the patients described with focal neurological symptoms in enterovirus meningoencephalitis had persistent neurological defects. 7 As in our patient, all other patients made a complete or near complete recovery. It is important to differentiate this self-limiting disease from intracerebral Varicella zoster virus vasculopathy, in which intravenous methylprednisolone and acyclovir are often added to the therapy.

| CONCLUSION
When a previously healthy child presents to the hospital with a stroke, generally a Varicella zoster virus vasculopathy seems most likely. However, other causes of a local cerebral vasculitis are possible and need to be explored. We present an infant with a hemiparesis and an ischemic lesion on MRI due to a local Echovirus 6 vasculitis. The clinical evolution was favorable.