Expanding spectrum of TORCH infections: A possible case of congenital Zika syndrome

INTRODUCTION

Intrauterine infections are the common cause of microcephaly with intracranial calcifications. Among these, congenital cytomegalovirus (cCMV) is the most common etiology. Non-infectious causes such as Aicardi–Goutières syndrome (AGS), and genetic heterogeneous group of pseudo-toxoplasmosis, others (syphilis, HIV, parvovirus, and varicella), rubella, cytomegalovirus (CMV), and herpes simplex (TORCH) syndrome band-like calcification with simplified gyration and polymicrogyria (BLCPMG), are mimickers of TORCH infections. Reports of congenital Zika syndrome (CZS) in Brazil after the Zika epidemic in 2015 added one new etiology in the TORCH group of infections. The Zika outbreak in Rajasthan and Madhya Pradesh, and sporadic cases in other states of India, raised concerns for CZS in India.^[1,2] CZS is diagnosed by characteristic clinical findings, neuroimaging, and laboratory tests (Nucleic acid amplification test [NAAT] and immunoglobulin M [IgM] antibodies testing in infant serum, and NAAT on infant urine).^[3] Here, we are presenting a probable case of CZS.

CASE REPORT

A 3-day-old baby presented with neonatal hyperbilirubinemia. The baby had severe microcephaly (occipitofrontal circumference [OFC] 2 9 cm, <−3 standard deviation (SD) on the World Health Organization growth chart), collapsed skull, low sloping forehead, disproportionately large face, overlapping of sutures, and small anterior fontanelle [Figure 1a]. There was no dysmorphism, organomegaly, cataract, contractures, midline, and other malformation. Parents belong to central India. There was no history of febrile illness, rash, drug, or alcohol intake during the antenatal period. There was no bad obstetrics history and no family history of neurological disorders. The antenatal HIV test was negative. This was a full-term, normal vaginal delivery with a birth weight of 2400 g.

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Figure 1:

(a) Cranial-facial disproportion with small head size. (b) Chorioretinal atrophic patch (arrow), retinal pigmentary mottling (star), and tortuous vessels (arrowhead). (c) T1 sagittal sequence showing pontocerebellar hypoplasia (star) and scalloped skull sign (arrow). (d) T2 sequence thick smooth cortex suggestive of lissencephaly (arrow) and widened cerebrospinal fluid spaces (star), (e) T2 sequence showing cerebellar hypoplasia (arrow), (f) Computed tomography head showing calcifications in the basal ganglia and thalamus (arrows).

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Based on severe congenital disproportionate microcephaly, low birth weight, and neonatal hyperbilirubinemia, intrauterine infections (TORCH) were considered. Other differentials were genetic causes of non-syndromic microcephaly (autosomal recessive, autosomal dominant, and X-linked), AGS, and BLCPMG mutation.

Routine investigations, echocardiogram, ultrasonography of the abdomen, and brainstem evoked response audiometry (BERA) were normal. Total serum bilirubin was 16 mg/dL (indirect 15.6mg/dL). Ophthalmic examination reported retinal scars and retinal pigmentation [Figure 1b]. Magnetic resonance imaging (MRI) brain on the 7^th postnatal day (PND) showed lissencephaly, ponto cerebellar hypoplasia, and scalloped skull sign [Figure 1c-e]. Computed tomography head on 9^th PND showed basal ganglia and thalamic calcification [Figure 1f]. Urinary CMV polymerase chain reaction (PCR) and TORCH serology were negative. TORCH serology of the mother was also negative. Zika virus PCR was negative in the serum and cerebrospinal fluid (CSF) of the baby and the serum of the mother. Whole exome sequencing (WES) was normal. Zika serology could not be done.

CZS was considered due to the endemicity of the Zika virus, classical collapsed skull sign, compatible MRI and retinal findings, as well as exclusion of other causes. Parents were counselled about high risk for cerebral palsy, developmental delay, and epilepsy. Early interventions were started in the neonatal period itself. At 1 month of age, the baby had spasticity in all four limbs, and by 3 months of age, spasticity progressed despite physiotherapy and Baclofen, and there was an absence of neck holding and social smile.

DISCUSSION

Microcephaly is defined as OFC <−2 SD and severe microcephaly as OFC <−3 SD. Microcephaly may be congenital (identified at birth) or postnatal (developed later on). It may be proportionate when the growth of the whole body is equally affected, such as Seckel syndrome, or disproportionate, where the brain growth is primarily affected. If the baby has severe congenital microcephaly without other major brain or somatic malformations, it is termed primary microcephaly.^[4] Our case had severe congenital disproportionate microcephaly. Based on clinical and neuroimaging findings, our differential restricted to CZS, cCMV, AGS, and BLCPMG. AGS and BLCPMG were ruled out by genetic testing.

Intrauterine Zika virus infections cause direct neurological injury and severe loss of brain volume leads to FBDS. The FBDS phenotype is characterized by severe microcephaly, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and facial disproportion. It is postulated to arise from partial brain destruction leading to a fall in intracranial pressure and subsequent skull collapse. The most common cause is intrauterine infections. It is common in CZS, although not specific.^[5,6]

Neuroimaging findings include brain anomalies, cerebral cortex thinning, cerebral volume loss, increased fluid spaces, abnormal gyral patterns such as lissencephaly and polymicrogyria, calcifications in subcortical, basal ganglia, and thalamic regions, corpus callosum anomalies, reduced white matter, and cerebellar hypoplasia.^[7]

Ophthalmic finding includes macular scarring, focal pigmentary retinal mottling, chorioretinal atrophy, or optic nerve hypoplasia/atrophy; structural anomalies (microphthalmia, coloboma, cataracts, and posterior anomalies). Congenital contractures involving one or multiple joints such as club foot or arthrogryposis has been reported in CZS. These babies usually have pronounced early hypertonia/spasticity with extrapyramidal symptoms, motor disabilities, cognitive disabilities, irritability/excessive crying, tremors, swallowing dysfunction, hearing impairment, and epilepsy.^[5,7]

Zika virus infection is usually asymptomatic (about 80%), but manifests as acute flu-like illness with rash, conjunctivitis, and fever. Centers for Disease Control and Prevention recommends that for suspected CZS, NAAT and IgM testing should be performed on infant serum and CSF, and NAAT on infant urine.^[8] NAAT is usually positive transiently in acute infection (within 2 weeks), so a negative test does not rule out Zika infection.^[9] IgM antibodies will also be negative if done after a few weeks, as antibodies wane with time. IgM antibody tests for dengue virus, West Nile fever, and Zika virus share considerable epitope cross-reactivity, leading to false positivity. If the IgM is positive, it should be confirmed by the plaque reduction neutralization test.

Neuroimaging in CZS closely resembles that of cCMV. The most prominent difference is the distribution of intracranial calcifications, which are typically subcortical, basal ganglia, thalamic, and brainstem in CZS, while periventricular and cortical in cCMV.^[10] Differences in cCMV and CZS are summarized in Supplementary Table 1.

Although in our case, it was difficult to differentiate between cCMV and CZS based on neuroimaging findings alone, FBDS, isolated CNS involvement, posterior fossa malformations, negative urine CMV PCR, negative TORCH serology in baby and mother, normal BERA, retinal scar, early development of spasticity, and epidemiological correlation helped us conclude CZS as the probable diagnosis.

CONCLUSION

The spectrum of infectious and genetic causes of intracranial infections is expanding, and all the possibilities should be kept in mind. The Zika virus is an important differential for babies with microcephaly and intracranial calcifications. FBDS, posterior fossa malformation, calcifications in the subcortical, basal ganglia, and brainstem, retinal scar, and retinal pigmentary mottling can differentiate CZS from cCMV. Availability of serological test for Zika virus infection will help in early identification and prevention of Zika spread in the community.

Strength our case report is that we excluded all possible causes of congenital microcephaly and intracranial calcification, and epidemiological correlation was used as supportive evidence.

A limitation of our study is that we could not prove our diagnosis by a serological test.