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Maternal-Neonatal Reports

West Syndrome in Children With Congenital Zika Virus Infection

Bustamante Amador, Jorge MD*; García-Segovia, Roberto MD; García Boyano, Miguel MD; Miño-León, Greta MD§

Author Information
The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p 1108-1110
doi: 10.1097/INF.0000000000003230
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Abstract

In recent years, congenital Zika virus (ZIKV) infection has been related to devastating consequences for newborns, causing apoptosis and modifying the pattern of myelin formation.1 By January 2018, the Pan-American Health Organization reported more than 3700 cases of congenital Zika syndrome2 (CZS) and it could become endemic in South America and Caribbean countries.

Besides microcephaly, clinical characteristics and neuroimaging patterns of CZS have been described.1 However, the full clinical spectrum remains unclear. Seizures are a major complication in infants with evidence of CZS and the prevalence of epilepsy is up to 54%.3,4

We aim to address this gap of knowledge by describing a case series of CZS patients with West syndrome (WS). WS constitutes a unique, age-specific epilepsy syndrome of early infancy characterized by the triad of clustered symmetric arm spasms, hypsarrhythmia electroencephalogram pattern and delayed brain development or regression. Congenital infections are a potential etiology of symptomatic WS.5,6 However, few studies have described the congenital ZIKV infection as a cause of WS.4 The objective of this study is to show the association between CZS and WS and to describe the clinical characteristics of these patients.

MATERIALS AND METHODS

A retrospective descriptive study was performed. All data were collected from November 2017 to December 2018 in a tertiary pediatric hospital in Guayaquil (Ecuador) alongside the ZIKV epidemic outbreak, with the approval of the Ethical Committee.

All children with confirmed or suspected CZS and with WS were included. Suspected CZS was considered when microbiologic tests for ZIKV were negative but alongside the Zika outbreak, these children presented with other clinical characteristics of CZS, including microcephaly and excluding other infectious causes. The diagnosis of WS was established because of spasms, together with hypsarrhythmia and severe impairment of neuropsychomotor development.

Microbiologic tests for ZIKV included a commercial serologic Kit (IgM ELISA, ZIKV Detect, InBios) and RT-PCR, which were performed in plasma, urine, or cerebrospinal fluid of the infant and his mother. Moreover, in all symptomatic mothers during pregnancy, serologic tests for dengue virus (IgG/IgM) were performed.

The national perinatal screening program includes serologic tests for toxoplasmosis, cytomegalovirus, syphilis (VDRL), rubella, herpes simplex, human immunodeficiency virus and B hepatitis, which were executed in all mothers.

RESULTS

Along the period, 147 infants were followed up, 115 (78.2%) with confirmed CZS and 32 (21.8%) without microbiologic confirmation, considering them as suspected CZS. Among them, 6 children with confirmed and 5 children with suspected CZS presented with WS (11 children, 7.5%).

We present 6 girls and 5 boys with infantile spasms secondary to congenital ZIKV infection. All of them had other clinical and radiologic characteristics of congenital ZIKV infection (Table 1). Only 2 were preterm and term newborns had a median of 38 (IQR: 39–37.5) WGA. Their median head circumference at birth was 29.5 (IQR: 31–27.5) cm. All of them started with flexion spasms at a median age of 5 (IQR: 6–4) months with a median diagnostic delay of 5.5 (IQR: 12–6) months.

TABLE 1. - Clinical and Radiologic Characteristics of Patients
Patient WGA Mother Symptoms HC at Birth (cm) Microbiology Other CZS Signs* EEG CT MRI BAERs VEP
1 39 No 30 All neg Yes Modified hypsarrhythmia Microcephaly. Ventriculomegaly. Cerebral atrophy. Basal ganglia and midbrain calcifications ND Mild left hypoac. Normal
2 39 8 WGA 31 All neg Yes Hypsarrhythmia Ventriculomegaly. Basal ganglia calcifications ND Bilat. Hypoac. ND
3 37 16 WGA 25 IgM Zika blood NB Yes Hypsarrhythmia Cerebral atrophy. Basal ganglia and midbrain calcifications Cerebral atrophy. Ventriculomegaly. ND Bilat. Long latency answer
4 40 No 27.5 All neg Yes Hypsarrhythmia Pachygyria. Subcortical calcifications ND ND ND
5 38 10 WGA 31 IgM Zika blood/CSF NB Yes Hypsarrhythmia Pachygyria. Ventriculomegaly. Atrophy corpus callosum ND Normal ND
6 38 No 32 All neg Yes Modified hypsarrhythmia Agenesis corpus callosum. Colpocephaly. Basal ganglia /subcortical calcifications Agenesis corpus callosum. Ventriculomegaly. ND Bilat. Long latency answer
7 38 28 WGA 28.5 IgM Zika blood/CSF NB Yes Modified hypsarrhythmia Cortical calcifications. Cerebral atrophy. Cerebral atrophy. Ventriculomegaly. Lissencephaly. Atrophy corpus callosum ND Bilat. Long latency answer
8 37 24 WGA 29.5 IgM Zika blood/CSF NB Yes Hypsarrhythmia Ventriculomegaly. Cerebral atrophy. Cortical calcifications. Atrophy corpus callosum Atrophy corpus callosum. Cerebral atrophy. Ventriculomegaly. ND Bilat. Long latency answer
9 38 10 WGA 32 PCR mother pos Yes Modified hypsarrhythmia ND Microgyria. Ventriculomegaly. ND ND
10 34 No 28.5 ND Yes Hypsarrhythmia Ventriculomegaly. Cerebral atrophy. Basal ganglia calcifications ND ND Normal
11 31 6 WGA 27 PCR mother pos/IgM Zika blood NB Yes Hypsarrhythmia Cerebral atrophy. Cortical calcifications. Ventriculomegaly. Agenesis corpus callosum. Normal ND
*Other CZS signs: besides the microcephaly all children presented with hypertonia and joint contractures.
†ND: serologic test for cytomegalovirus, Zika virus and toxoplasmosis were performed in another hospital and tested negative.
‡`Modified hypsarrhythmia: atypical patterns, including increased interhemispheric synchronization, episodes of attenuation, asymmetrical hypsarrhythmia and hypsarrhythmia with a consistent focus.
Abbreviations: BAERs, Brainstem Auditory Evoked Response; Bilat., bilateral; CSF, Cerebrospinal fluid; CT, Computed Tomography; CZS, congenital Zika syndrome; EEG, electroencephalogram; HC, head circumference; Hypoac., hypoacusia; MRI, Magnetic resonance imaging; NB newborn; ND, not done; Neg, negative; PCR, polymerase chain reaction; Pos, positive; VEP, visual evoked potential; WGA, weeks for gestational age.

On the physical examination, microcephaly was observed in all children, together with hypertonia and joint contractures.

Regarding complementary examinations, electroencephalogram (EEG) was done in all the cases and hypsarrhythmia was the neurophysiologic marker. Computed tomography was performed in 10/11 cases: 9/10 had calcifications (5/9 in basal nuclei, 3/9 in the subcortical region and 2/9 in the cortical region), 7/9 had ventriculomegaly, 3/9 with corpus callosum abnormalities and 2 neuronal migration alterations, showing pachygyria. Magnetic resonance imaging was performed on 5/11 and revealed another 2 patients with alterations in neuronal migration (lissencephaly and microgyria) in 1 patient and agenesis or hypoplasia of corpus callosum in another 2. Ultrasonography was performed on 3/11 at birth and detected microcephaly during pregnancy in another 3 patients. With regards to Brainstem Auditory Evoked Response were executed in 5/11, showing hypoacusia in 2/5 and visual evoked potential showed long latency answer in 4/6 patients. Funduscopy was explored in 6/11 and optic atrophy was observed in 3/6.

Due to clinical, radiologic and EEG findings, they were diagnosed with WS associated with congenital ZIKV infection. Questions were raised if patient 8 had spasm or just arm hyperextension as they were not in clusters, even though EEG showed hypsarrhythmia. Microbiologic tests for ZIKV, including serology in blood or cerebrospinal fluid in newborns or polymerase chain reaction in mothers’ blood during pregnancy, were positive in 6/11 patients. All the cases tested negative for cytomegalovirus (CMV) and toxoplasmosis, syphilis, rubella and herpes simplex. Regarding patient 10, she was referred at the age of 4 months from a first-level hospital because of microcephaly with negative serologic tests for cytomegalovirus, toxoplasmosis and ZIKV.

Regarding the symptoms of the mother during the pregnancy, 7 of them were symptomatic of ZIKV infection. Their median time of symptoms was 10 (IQR: 24–28) WGA, being more common in the first trimester of pregnancy. In all symptomatic cases, dengue was discarded.

Seizures did not respond to valproate 10–15 mg/kg/d oral administration (PO), initially increasing by 5–10 mg/kg/d weekly up to 40 mg/kg/d. Levetiracetam at 10 mg/kg PO every 12 hours (q12hr), increasing 10 mg/kg q12hr every 2 weeks to 25 mg/kg q12hr was neither effective. All patients underwent both valproate and levetiracetam regimens without response. Vigabatrin (VGB) at 50 mg/kg/d PO divided q12hr initially and, increasing dose by 25–50 mg/kg/d every 3 days if needed, without exceeding 150 mg/kg/d. Vigabatrin could control them, having fewer spasms, with a better partial sustained response.

DISCUSSION

This study describes the association between CZS and WS, both diagnosed during the first year of life. All patients met clinical and radiologic criteria for CZS. However, laboratory diagnosis remains challenging, and malformations without microbiologic confirmation are very common,7 as described in 5 patients of this series.

In our cohort, mothers’ symptoms were predominantly in the first trimester of pregnancy and all newborns presented microcephaly. Birth defects seem to be more common when ZIKV infection happens earlier during pregnancy.8

Carvalho et al reported that 52.7% presented epilepsy by 9 months of age and 71.4% by the end of the second year,9 being spasms more frequent during the first year of age while focal seizures during the second year.3,9 Silva et al3 documented epileptic seizures in 50% being spasms the most common, although most commonly EEG showed multifocal discharges. In other studies, hypsarrhythmia was reported in up to 30% of spasms.10 We found hypsarrhythmia patterns in all children suffering from spasms and diagnosed with CZS. Other authors found that spasms occur in 10%–20% of children,4,6 similar to our study (7.7%). Age of onset of spasms is comparable with other researchers, before 6 months of age,3,4 typically when WS is developed.9

Low doses of adrenocorticotropic hormone (ACTH), VGB and prednisone at high doses have been purposed as first-choice drug.4,5 Alves et al4 found that VGB only controlled 22.7% of spasms. Carvalho et al9 observed that those with lissencephaly are often refractory to treatment. In Ecuador, VGB and ACTH are not available, but the hospital got VGB for some months. During the VGB period, spasms considerably improved. After that, patients underwent valproate or levetiracetam schemes in monotherapy or combination, but no sustained response was achieved.

The etiology of WS is essential for long-term neurodevelopmental outcomes. To note, congenital CMV or rubella infection have been described as an underlying cause.4 ZIKV has been associated with encephalitis, encephalopathy, myelitis and Guillain-Barré Syndrome, but congenital ZIKV infection is also a potential etiology of WS.

The retrospective nature of this study along with the lack of microbiologic confirmation in some patients is the main limitations of this research study. Serologic IgG tests against ZIKV were not available in Ecuador, and, therefore, we lack serologic confirmation after seroconversion. Moreover, we only included children with microcephaly, the main suspicion sign of CZS, which may potentially lead to selection bias. Recent reviews have shown that CZS can occur without microcephaly, which is not the most prevalent malformation but seems to be linked to severe brain damage.9 Some authors have associated microcephaly, as well as neuronal migration alterations, with the risk of epilepsy.9 Nevertheless, 50% of patients with late-onset microcephaly develop seizures during the first year of life.3 The study design and the small number of patients included did not allow us to evaluate the efficacy of the different drug regimens in this sample.

In conclusion, our data reveal that congenital ZIKV infection may be an underlying cause of WS as at least 6 children with microbiologic confirmation presented with WS. Long-term follow-up of neurologic development in children with congenital Zika syndrome associated with infantile spasms may improve with standardized management guidelines, and randomized clinical trials on antiepileptic treatments for this entity are recommended.

ACKNOWLEDGMENTS

The authors would like to acknowledge all the families affected by the Zika virus epidemic infection, mainly those having a baby with congenital Zika syndrome. We also would like to thank Dr. Luis Prieto-Tato, Dr. Antoni Soriano-Arandes and Dr. Carlo Giaquinto for encouraging us to publish our work. Finally, thanks to all the nurses and social workers who provided care for these patients and gave support to their families.

REFERENCES

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Keywords:

West syndrome; Zika virus infection; ongenital Zika syndrome; hypsarrhythmia

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