A case of postvaricella cerebral angiopathy with a good outcome in a child.

Cerebral vasculopathy is a serious but uncommon complication of varicella-zoster-virus (VZV) infection. Diagnosis is based on a recent history of VZV infection, signs and symptoms of transient ischemic attack or stroke, and vascular anomalies on neuroimaging. We report a case of postvaricella cerebral angiopathy in a 5-year-old child, who was admitted after three episodes of transient right hemiplegia, each one lasting a few minutes. He had contracted chicken pox, the month prior to admission. Brain magnetic resonance imaging showed hyperintense signals in the left lenticular and caudate nuclei, which can be considered to be a result of vasculopathy.

Introduction

Cerebral vasculopathy is an uncommon complication of varicella-zoster-virus (VZV) infection. In fact, while primary VZV infection is frequent, neurological complications are rare, with a 0.1–0.75% incidence,[1] and include: Cerebellar ataxia, meningoencephalitis, aseptic meningitis, polyradiculoneuropathy, optic neuritis, transverse myelitis, and Reye's syndrome.[23] Another complication is postvaricella stroke with an incidence of 1/15,000.[4] The basal ganglia are the most involved part of the brain in VZV vasculopathy,[5] where the angiopathy causes transient ischemic attack (TIA) and/or stroke with transient or permanent hemiplegia. The differential diagnosis for VZV vasculopathy includes other diseases that cause hemiplegia, such as trauma, congenital heart disease, vascular malformations, hypercoagulable states, malignancy, congenital errors of metabolism, and infections.[6] A study by Fullerton et al.[7] demonstrated the pathogens most commonly implicated to be herpes viruses, such as VZV, Epstein–Barr virus, and herpes simplex virus.

With regards to the pathogenesis of VZV vasculopathy, the literature is unclear but describes different possible mechanisms. A genetic predisposition is suspected, but not yet demonstrated, in addition to other pathogenic factors.

The clinical diagnosis is based on a recent history of VZV infection, and is further supported by neurologic signs and symptoms due to TIA or stroke, presence of anti-VZV IgM antibody, and vascular anomalies on neuroimaging.

Case Report

We report a case of postvaricella cerebral angiopathy in a 5-year-old child, admitted to the Clinical Pediatric Division of the Department of Pediatrics, Hospital “Policlinico-Vittorio Emanuele,” in Catania, Italy. The patient presented with three episodes of transient right hemiplegia without consciousness modification, occurring over an hour, each lasting for a few minutes.

The child was vaginally delivered at term; he was the first-born of nonconsanguineous parents and had normal psychomotor development. He had chicken pox the month prior to admission, approximately 30 days before hospitalization. He had the following clinical presentation: First, he had an episode of right hypotonia (upper and lower right limbs) with normal consciousness but speech impairment, lasting 2–3 min. After a few minutes, he had another longer (20–30 min) episode of motor incoordination, with the loss of fine motor skills in the right limb and speech impairment. After approximately 30 min, he had a third episode, similar to the previous ones. Each episode ended spontaneously.

He was admitted to the Ragusa Hospital Emergency Room, where he underwent laboratory testing and a brain computed tomography, which were all normal. The child was admitted to the Pediatric Department. On admission, his weight was recorded as 18.3 kg (25th percentile), his height was 117 cm (<90th percentile), and his head circumference was 52 cm (50th to 75th percentile). On physical examination, he displayed no fever, an alert sensorium, no meningism, a normal cranial nerve examination, a normal gait, and no hemiplegia. The following tests were performed: Complete blood count, inflammatory markers, hepatorenal function, coagulation, plasma amino acids, homocysteine, and transferin, electrocardiogram, echocardiogram, and electroencephalography: All were normal. Instead, there was an increase in anti-VZV IgM and IgG antibody levels (1/120 and 1/160, respectively). To eliminate the possibility of vascular abnormalities, a duplex ultrasound of the supra-aortic vessels was performed and was also normal. Therefore, we suspected a cerebral angiopathy. A brain magnetic resonance imaging (MRI) demonstrated hyperintense signals in the left lenticular and caudate nuclei, which can be considered to be a sign of postviral vasculitis [Figures 1 and 2].

Figure 1

Brain magnetic resonance imaging (MRI) – Axial T2-weighted MRI acquisitions demonstrate hyperintense signals in the left lenticular nucleus

Figure 2

Brain magnetic resonance imaging (MRI) – Coronal T2-weighted MRI acquisitions demonstrate hyperintense signals in the left lenticular and caudate nuclei

According to these clinical, laboratory, and instrumental results, the following diagnosis was made: “Transient hemiplegia due to cerebral vasculitis caused by VZV infection.” The patient was treated with acyclovir (360 mg 4 times a day for 14 days). There were no new episodes noted or other related disorders. The patient was discharged home in good condition. Ten days later, he was followed up; his physical and neurological examination were normal.

Discussion

Reactivation of VZV is one of the causes of cerebral vasculopathy, and in childhood should be taken into account in the differential diagnosis of TIA and/or stroke. In our case, the patient presented with a transient hemiplegia or a short-lived cerebrovascular event. For this reason, several laboratory and diagnostic tests were performed to exclude other causes of TIA and/or stroke, such as: Congenital or acquired cardiomyopathies, arrhythmias, congenital heart defects, endocarditis, rheumatic heart disease, cardiac tumors, hemoglobinopathies, coagulation disorders, arterial steno-occlusive disease, vascular dissections of the cervical district, Moyamoya disease, primitive or systemic or drug-caused vasculitis, as well as arteriovenous malformations and metabolic diseases such as Fabry disease, homocystinuria, MELAS, urea cycle defects, organic-acidurias syndrome, and congenital deficiency of glycoprotein.[89101112]

Considering the wide range and difficulty of differential diagnoses, it is clear that the impact of this disease is understated. The literature confirms this diagnostic difficulty and further discusses the lead time between VZV infection and the cerebrovascular event, even without a significant anti-VZV antibody titer. In a third of cases, the results of cerebrospinal fluid analysis are not diagnostic because of the absence of pleocytosis, and low PCR sensitivity to VZV-DNA. Unlike adults, anti-VZV IgG antibody titers in the cerebrospinal fluid are not as sensitive in the pediatric population.

With regards to pathogenesis, the most important mechanism is VZV intraneuronal migration from the trigeminal ganglion to the medial cerebral arteries through the ophthalmic branch of the trigeminal nerve. Then, multinucleated cell-mediated granulomatous angiitis of large vessels causes functional endothelial damage and thrombosis. To enforce this hypothesis, histologic studies demonstrated the presence of viral particles in the tunica media and a lymphocytic infiltrate in the vessel wall with segmental destruction of the internal elastic lamina. Other pathogenetic hypotheses include the following: Hematologic spread of VZV; a postinfection vascular immune-mediated reaction; sympathetic activation due to local irritation caused by infection in the superior cervical ganglion; VZV-linked thrombotic vascular occlusion for direct endothelial damage; an acquired transient deficiency of proteins S/C.[4]

From a clinical point of view, the literature especially describes cases of hemiparesis and movement disorders; in our case, the patient presented with transient hemiplegia. This vascular lesion is recognized by neuroimaging, which is the gold standard for definitive diagnosis of both stroke and TIA (as in our case). The most damaged tissue is perfused by arteries in the lenticulostriate regions (basal ganglia and internal capsule). With regards to outcome, the literature reports cases with complete resolution of arterial abnormalities; complete regression but no improvement; and neurological improvement but the absence of a definitive vascular regression.[4]

The therapeutic treatment is still not standardized as a consequence of pathogenetic heterogeneity. Stroke therapy is based on antiplatelet and anticoagulant drugs: First aspirin is administered, followed by low molecular weight heparin. In our case, considering the good outcome and the definitive diagnosis of TIA, we did not follow this protocol; in fact, the patient was treated with acyclovir due to previous VZV infection and the presence of anti-VZV IgG and IgM.

Finally, the literature shows that the prognosis is good, even if we need to distinguish between stroke and TIA. In one report, both full resolution and variable severity of neurological damage were described; in another, as in our case, motor impairment resolved quickly without immediate or permanent sequelae, during hospitalization or in follow-up.

Conclusion

Thanks to this clinical experience, we affirm that the diagnosis of postvaricella vasculopathy remains difficult, supporting the hypothesis that the true incidence of the disease is higher than estimated so that some cases remain undiagnosed.[13] In addition, VZV reactivation is one of the potential causes of cerebral vasculopathy; for this reason, it must be considered in the differential diagnosis of pediatric TIA and/or stroke, even when the rash is temporally remote from the acute event. Therefore, when a patient presents with TIA and/or stroke, all tests must be performed to obtain the correct diagnosis, starting with a good history, physical, and neurological examination and finishing with laboratory tests and diagnostic exams, especially the brain MRI and magnetic resonance angiogram. Moreover, the pathogenetic heterogeneity of the clinical findings has resulted in a lack of standardized treatment protocols. Finally, the outcome of TIA, in contrast to stroke, is better and without neurological sequelae, as in our patient.