Acute leukoencephalopathy with restricted diffusion following mumps infection in a pediatric patient: A case report

INTRODUCTION

Mumps is endemic in India and usually seen in outbreaks. Recent outbreaks in India have raised concern about this infectious disease.^[1] It usually affects the young children, but it can affect adolescents and adults, more in countries where the mumps vaccine has been included in the routine immunization schedule, due to waning immunity.^[2] Mumps is a self-limiting, vaccine-preventable, acute viral infection, and presents as fever and parotitis, but can lead to complications such as meningitis, encephalitis, and orchitis or oophoritis (in adolescents). Uncommon complications are optic neuritis, pneumonia, nephritis, pancreatitis, mastitis, hearing impairment, meningitis, and hydrocephalus.^[3] Mumps is also reported to cause para-infectious and post-infectious complications.^[4]

CASE REPORT

A 1 year 8 month, old female child was admitted with a history of swelling on the left side of the neck, fever, and seizure. She had swelling on day 1 of illness, fever on day 2 of illness, and generalized tonic-clonic jerks with up-rolling of eyeballs that persisted for >30 min on day 3 of illness. When the child arrived in the hospital, seizures had already subsided. On examination, the child was febrile (102.7°F), had tachycardia (heart rate 135/min) and tachypnea (respiratory rate 48/min), blood pressure was normal, and the tourniquet test was negative. She was in altered sensorium (E1V2M4), had constricted pupils, and left parotid swelling. There were no rashes, organomegaly, ear discharge, or focal deficits. Fundus examination was normal. Diagnosis of acute encephalitis syndrome with differentials of mumps, dengue, chikungunya, Epstein-Barr Virus (EBV), Japanese Encephalitis (JE), and enterovirus was considered.

The laboratory investigation reported hemoglobin 10.90 g/dL, total leukocyte counts 9370/mL, lymphocytic predominance, and platelets 2.16 lakhs. Cerebrospinal fluid (CSF) was acellular, protein was 60 mg/dL, and glucose was 84 mg/dL (blood sugar 231 mg/dL). Serology for dengue, chikungunya, EBV, JE, and scrub was negative. CSF and blood culture were negative. CSF polymerase chain reaction (PCR) for herpes simplex virus was negative. Serum amylase (310.69 U/L) and lipase (14.45 U/L) were raised. Mumps PCR was positive in the buccal smear but negative in CSF. Ultrasonography of the parotid glands showed inflammation in both parotid glands. A magnetic resonance imaging (MRI) of the brain was done on day 4 of illness that showed normal T1 and subtle cortical-subcortical hyperintensities on T2 and fluid-attenuated inversion recovery sequences; the diffusion-weighted imaging sequence showed bilateral symmetrical diffusion restrictions in supratentorial cortical and subcortical white matter with sparing of the sensorimotor cortex suggestive of a bright tree appearance with central sparing. The apparent diffusion coefficient sequence showed the corresponding changes [Figure 1].

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Figure 1:

(a) Eighteen-month baby with parotid swelling and altered sensorium (white arrow) (b) MRI brain DWI (diffusion-weighted imaging) sequence showing hyperintensity in cortical and subcortical areas (arrow head) with sparing of sensory motor cortex (thin arrow) and (c) corresponding ADC (apparent diffusion coefficient) sequence showing hypointensity in cortical and subcortical areas (arrow head) with sparing of sensory motor cortex (thin arrow), suggestive of acute leukoencephalopathy with restricted diffusion with central sparing pattern.

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Initially, she was treated with levetiracetam, antibiotics, acyclovir, doxycycline, and supportive treatment. She had breakthrough seizures on day 4 of illness, so phenytoin was added. After the neuroimaging findings, a diagnosis of acute leukoencephalopathy with restricted diffusion (ALERD) was considered, and intravenous immunoglobulin (IVIG) (2 g/kg) was started on day 4 of illness over 2 days, followed by a methylprednisolone (MPS) pulse for 5 days. Glasgow Coma Scale improved on day 10 of illness to E4V4M5. She was discharged on oral prednisolone. After 2 weeks of follow-up, the clinical state remained unchanged. At last follow-up after 7 months of discharge, she was seizure free on anti-seizure medication but still non-ambulatory and encephalopathic as she had inconsistent eye contact and no meaningful communication.

DISCUSSION

Our case had bilateral parotitis, prolonged seizure, acute encephalopathy, normal CSF, no evidence of central nervous system (CNS) infection, and characteristic MRI findings of diffusion restrictions with a central sparing pattern (Bright tree appearance), which leads to the diagnosis of clinico-radiological syndrome of ALERD, a phenotype of infection-triggered encephalopathy syndromes (ITES). Although we could not measure CSF cytokine levels, this was a limitation of our study.

Mumps virus is highly neurotropic and can affect the CNS as an “infectious phenomenon” (meningitis, encephalitis), a “post-infectious/autoimmune phenomenon” (acute disseminated encephalomyelitis, myelitis, post-infectious cerebellar ataxia, and Guillain-Barre syndrome) caused by antibodies, or a “para-infectious phenomenon” (acute necrotizing encephalopathy [ANE], mild encephalopathy with a reversible splenial lesion [MERS], and febrile infection-related epilepsy syndrome [FIRES]).^[4] Acute encephalitis syndrome is a common clinical syndrome in pediatric patients. If CSF examination is normal, then para-infectious, autoimmune, and toxic/metabolic etiologies become the possible differentials.

ITES, a para-infectious phenomenon, are defined as an acute-onset fever that rapidly progressed to encephalopathy without any evidence of encephalitis. Specific clinicoradiological phenotypes of ITES are (1) acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), (2) ANE, (3) MERS, (4) acute fulminant cerebral edema, and (5) acute shock with encephalopathy and multiorgan failure, while FIRES is a clinical syndrome. Pathogenesis of ITES is based on cytokine storm, and immunomodulation with MPS, IVIG, and tocilizumab may change the outcome trajectory of these patients.^[5]

AESD is the most common ITES in East Asian countries and usually affects infants. It is a biphasic illness. The first phase is characterized by infection-associated fever and prolonged seizure (early seizure) followed by clinical improvement over the next 2–4 days. The second phase, over the next 3–7 days, has a cluster of seizures (late seizure) with clinical deterioration. MRI brain in the first phase is normal; however, a 2^nd phase MRI shows characteristic cortical and subcortical diffusion restriction (Bright tree appearance). Some cases of AESD are monophasic. For these cases, Kamate and Pawar coined the term ALERD, characterized by acute fever, prolonged seizure, encephalopathy, and diffusion restriction on MRI similar to AESD but without biphasic seizures.^[4] Radiologically, ALERD are two types: Central sparing (sparing of the sensory motor cortex) and diffuse. ALERD may be infectious, toxic/metabolic, or genetic. The prognosis of ALERD is poor as compared to AESD.^[6]

Mumps-associated ALERD is a rare phenomenon . Hazama et al.,^[7] reported the first case of mumps-associated AESD in a 3-year-old child in 2017, presented with a biphasic seizure. The second episode of seizure was followed by encephalopathy. This child had bilateral parotitis, positive immunoglobulin M mumps antibodies, normal CSF, and diffusion restriction on MRI; treated with two courses of IV MPS. On follow-up, developmental quotient was 68.^[7] Saito et al., reported the first case of mumps vaccine-associated AESD in 2022. A 22-month-old boy presented with refractory status epilepticus, MRI showed diffusion restrictions and had neurological sequalae on follow-up.^[8] Our case also had neurological sequalae on short follow-up. This case, to the best of our knowledge, is the first case of mumps-associated ALERD.

CONCLUSION

Mumps infection is a self-limiting disease but can lead to a lot of neurological complications. Para infectious neurological complications like ALERD should be considered if CSF is normal, CSF cytokines are high and the MRI brain has specific biomarkers (Bright tree appearance). All the phenotypes of ITES, including ALERD, are potentially reversible para-infectious complication of mumps if recognized and treated early with immune therapy.