Epilepsia Partialis Continua as a Sequelae of Measles Infection in Children With Hematolymphoid Malignancies

Abstract

PURPOSE

To share our clinical experience with the diagnosis and management of children with hematolymphoid malignancies presenting with epilepsia partialis continua (EPC) as a sequelae of measles infection.

MATERIALS AND METHODS

In December 2022, a series of children in our hemato-oncology unit presented with focal status epilepticus with no conclusive evidence pointing toward any underlying etiology. One such child had a typical measles rash a few weeks before the onset of this focal status epilepticus. After a series of cases with a similar presentation, a clinical pattern suspicious for measles became evident. cerebrospinal fluid polymerase chain reaction was positive for measles virus with measles immunoglobin M detected in the serum. This led to the diagnosis of measles inclusion-body encephalitis in a series of children who presented with EPC over a period of 3 months. EPC is a rare manifestation of measles that is seen only in immunocompromised patients.

RESULTS

Among the 18 children reported in this series, only 10 had a history of rashes. The rash was mostly transient and elicited only on retrospective history taking. Five of the 18 children who did not lose consciousness during the prolonged seizure episode survived the disease but had residual neurologic sequelae. Among the 18 children, two were unimmunized and immunization status could not be confirmed in three other children.

CONCLUSION

This case series highlights the threats posed by measles infection in children with cancer who are immunosuppressed because of the underlying disease and ongoing chemotherapy. Loss of herd immunity because of declining measles immunization rates secondary to vaccine hesitancy and COVID-19 lockdown pose a greater risk of measles infection and its complications for patients with deficient immune systems.

Presentation of measles in an immunocompromised child can go unnoticed. Measles related complications like measles inclusion body encephalitis (MIBE) presenting as epilepsia partialis continua (EPC) or pneumonia might be the initial manifestation of the disease

INTRODUCTION

Epilepsia partialis continua (EPC) is a rare condition defined clinically as a syndrome of continuous focal jerking of a body part, usually localized to a distal limb, occurring over hours, days, or years.¹ Facial and distal limb muscles are preferentially involved. Consciousness is retained, but manifestations are varied and progressive cognitive and neurologic decline can occur.² The myoclonic jerks are often unresponsive to antiepileptic medications. Various causes, including architectural damage, cortical dysplasia, metabolic or electrolyte disturbances, neoplasia, autoimmune phenomena, or infections, can present with EPC.^3,4 In our series, the underlying etiology was subacute measles encephalitis, also known as measles inclusion-body encephalitis (MIBE). As there is only anecdotal evidence of this entity in the literature, mostly in the prevaccination era, we describe in detail the clinical presentation and workup for children presenting with measles encephalitis.

CONTEXT

• Key Objective

• To share the clinical challenges we faced in the diagnosis and management of measles related complications in children with hematolymphoid malignancies.

• Knowledge Generated

• Measles infection might go unnoticed in children with hematolymphoid malignancies due to transient nature of the fever and rash. Epilepsia partialis continua (EPC) is a presentation of measles inclusion body encephalitis (MIBE) that occurs as a sequelae of measles infection in an immunocompromised host. Vitamin A, intravenous immunoglobin and oral ribavirin failed to prevent progression of EPC. Deficient cell mediated immunity might play a major role in development of MIBE.

• Relevance

• Measles infection poses a threat to children with hematolymphoid malignancies undergoing chemotherapy in light of declining immunization rates secondary to vaccine hesitancy and COVID-19 lockdowns. Protection by herd immunity is the best way to prevent measles-related complications.

Measles is a major cause of mortality in children with hematolymphoid malignancies. Herd immunity from measles vaccination has been a protective shield against measles outbreaks, especially in immunocompromised children.^5,6 COVID-19 lockdowns with a fall in immunization coverage have led to a chink in this armor, resulting in an outbreak of measles. During the autumn months of 2022, the city of Mumbai experienced one such measles epidemic. Few children at our pediatric oncology unit presented with a florid rash, typical of measles. A majority of patients reported an episode of fever, but the rash was transient or absent. After appropriate treatment with oral ribavirin, treatment for their hematolymphoid malignancy was resumed. About a month after the onset of rash, some of these children presented with EPC progressing to refractory seizures with status epilepticus and altered mental status.

MATERIALS AND METHODS

This is a retrospective chart review of data that were collected prospectively when a series of patients presented with EPC in the Pediatric Oncology unit at a tertiary care center in India.

All children who presented with EPC were investigated for the cause of seizures.

Cerebrospinal fluid (CSF) studies included cell count, cytology, FILMARRAY multiplex polymerase chain reaction (PCR), and paired CSF and serum samples for glucose and protein. The CSF was sent to the national reference laboratory at the National Institute of Virology, Pune, for identification of encephalitis-causing viruses, including Japanese encephalitis virus, Chandipura vesiculovirus, and Herpes simplex virus.

After informed consent was obtained, a brain biopsy was performed for one patient on day 19 of seizure and histopathology was performed to look for measles inclusion bodies.

CSF was also tested for CSF:serum measles immunoglobin G (IgG) quotient. CSF:serum quotient is a ratio of CSF:serum measles-specific IgG quotient to CSF:serum total IgG quotient. The test discriminates blood-derived and CSF-derived proteins on a nonlinear (hyperbolic) functional relationship, which takes into account the molecular flux, CSF flow rate, IgG (total and pathogen-specific), and albumin quotient across the blood brain barrier. Described in detail by Reiber and Lange,⁷ CSF:serum quotient reference of more than 1.5 is considered to be indicative of measles-specific antibody production in CNS.

CSF samples were sent to the Autoimmune Laboratory at the National Institute of Mental Health and Neurosciences, Bengaluru. CSF was tested using indirect immunofluorescence assay on transfected cell lines for quantitative determination of human antibodies against glutamate receptors (NMDA, AMPA1, and AMPA2), CASPR (contactin-associated protein 2), and LGI-1 (leucine-rich glioma-inactivated protein 1). CSF was also tested for antibodies against GABA_B receptor GABAB1 and B2.

RESULTS

Clinical Presentation of Subacute Measles Encephalitis

Within the 3-month period, 18 children age 2-18 years presented with intractable seizures or ataxia. The median age was 7 years, and the male to female ratio was 5:1. All 18 children had a hematolymphoid malignancy. Children with solid tumors, treated in the same unit, did not present with EPC although many also had clinical features suggestive of measles. EPC was the presenting feature in 11 children; two presented predominantly with ataxia, and five presented with generalized tonic-clonic seizures. All children had a hematolymphoid malignancy undergoing treatment: seven on intensive chemotherapy and 11 on maintenance therapy. Ten children had a history of fever with a rash between 5 and 49 days before the onset of seizures with a median of 28 days. Among the 10 children with history of rash, only four had typical measles-like rash that was documented by the treating physician and received ribavirin for approximately 7-10 days. The rash and fever subsided at the time of presentation of the seizure.

All 11 children with intractable partial seizures had intact sensorium at presentation. In five children, parents noticed tremors, mutism, behavioral changes, irrelevant talking, or ataxia a few days before the seizures. At the onset of EPC, involvement could be twitching of one finger, eyelid, facial muscles, or a proximal or distal muscle group of the lower or upper extremity. The partial epilepsy then shifted focus from one extremity to the other or progressed with a Jacksonian march with involvement of the other extremities. Four children who presented with a generalized seizure recovered from the postictal phase and were observed to have intractable focal myoclonic jerks.

Multiple antiepileptic medications were initiated and escalated to include levetiracetam, lacosamide, valproate, phenytoin, carbamazepine, clobazam, and vigabatrin with no effect on the myoclonic jerks. Therapeutic drug monitoring was used to adjust the dose of antiepileptics. On multiple antiepileptics, the children were drowsy, but arousable. Midazolam-ketamine drip was started on four children, and they were intubated electively. On midazolam-ketamine drip, the seizures were aborted, but on weaning the drip gradually, the seizures returned. Once it became evident that the midazolam-ketamine drip had only a temporary effect, intubation was delayed until airway protection was necessary. However, a few days after the onset of seizures, ranging from 2 to 5 days, these children were eventually intubated for airway protection as their sensorium deteriorated. All children received intravenous immunoglobulin (IVIG) at 2 g/kg within 72 hours of seizure onset, with no improvement in seizure control. Four children also received methyl prednisolone with no response.

After a period of 1 1/2-2 months, 11 children eventually succumbed because of secondary bacterial infections or ventilator-associated pneumonia. One child was palliated and sent home on a tracheostomy tube and oxygen concentrator but eventually expired at home. Two children were discharged against medical advice.

Approximately 27% (5 of 18) of the children eventually survived with residual neurologic deficits in the form of ataxia or weakness of the affected extremity. Among the five survivors, two children had ataxia and three presented with partial seizures and did not require intubation. Refer to Table 1 for clinical characteristics.

TABLE 1.

Baseline Characteristics and Clinical Presentation

Patient No.	Age, Years	Sex	Diagnosis	Phase of Treatment	H/o Fever and Rash	Neurologic Presentation	Time to Presentation From the Onset of Rash, Days	Vaccination Status
1	7	Male	Mixed phenotype acute leukemia	Consolidation	Yes	Focal → GTCS	10	Immunized
2	10	Female	Intermediate-risk B ALL	Maintenance cycle 1	Yes	GTCS → Focal	37	Immunized
3	4	Male	High-risk B ALL	Interim maintenance	Yes	Focal → GTCS	39	Unimmunized
4	8	Male	Intermediate-risk B ALL	Maintenance cycle 2	No	GTCS → Focal	—	Unimmunized
5	2	Male	Intermediate-risk B ALL	Consolidation	Yes	Focal	23	Could not be confirmed
6	6	Male	High-risk B ALL	Maintenance cycle 1	No	GTCS → encephalopathy	—	Could not be confirmed
7	8	Male	T ALL	Maintenance cycle 1	Yes	Focal	48	Immunized
8	13	Male	T ALL	Maintenance cycle 2	No	GTCS → Focal	—	Immunized
9	9	Female	AML	End of therapy on maintenance	No	Focal	—	Immunized
10	7	Male	AML	End of therapy on maintenance	Yes	Focal	5	Immunized
11	6	Male	High-risk B ALL	Maintenance cycle 4	Yes	Ataxia	11	Could not be confirmed
12	6	Male	Burkitt lymphoma	Intensive chemotherapy	Yes	Focal	28	Immunized
13	17	Male	Hodgkin lymphoma	Intensive chemotherapy	Yes	GTCS → Focal	13	Immunized
14	6	Male	High-risk B ALL	Maintenance cycle 8	No	Focal	—	Immunized
15	10	Female	T ALL	Maintenance cycle 2	Yes	Focal	49	Immunized
16	18	Male	B ALL in CR2 post-transplant conditioning	Postconditioning	No	Focal	—	Immunized
17	4	Male	High-risk B ALL	Maintenance cycle 4	No	Focal	—	Immunized
18	4	Male	ALK-positive ALCL	End of therapy maintenance	No	Ataxia	—	Immunized

NOTE. Neurologic presentation ranged from GTCS that progressed to focal seizures or focal seizures to GTCS or encephalopathy.

Abbreviations: ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; GTCS, generalized tonic clonic seizure; H/o, history of.

Clinical Investigations

The cause of seizures was investigated extensively until a clinical pattern was evident. Table 2 shows the results of the investigations and outcomes. CSF examination showed normal glucose, near-normal proteins, and none or few cells. Serum immunoglobin M (IgM) was positive in six of eight children tested. The CSF:serum measles IgG quotient was >1.5 in all nine of nine who were tested. CSF measles PCR was positive in three of the six children who were tested. CSF multiplex PCR was negative for common encephalitis-causing viruses including herpes simplex virus (HSV), Japanese encephalitis virus, and varicella. Orientia tsutsugamushi PCR for scrub typhus was also negative when tested in one patient. Brain biopsy was performed in one patient, as described above, and was positive for measles PCR (Fig 1). The D8 genotype of measles virus (MeV) was detected in the brain biopsy specimen and CSF and throat swabs.

TABLE 2.

Investigations and Outcomes

Pt No.	Age, Years	Sex	CSF Studies	CSF Cytology	Autoimmune Panel	Measles Serum IgM	CSF/Serum Measles IgG Quotient	CSF Measles PCR	ALC	Final Outcome
1	7	Male	Sugar 86/protein 30	No cells	—	—	12.8	—	0.65	Recovered with residual neurologic deficit
2	10	Female	Sugar 60/protein 53	No cells	Negative	Equivocal	8.62	Negative	0.44	Expired
3	4	Male	Sugar 70/protein 53	No cells	Negative	Positive	16.9	—	0.52	Expired
4	8	Male	Sugar 85/protein 82	No cells	Negative	Positive	1.91	Weak positive	0.3	Expired
5	2	Male	Sugar 50/protein 54	No cells	Negative	Positive	1.9	—	0.11	Expired
6	6	Male	Sugar 51/protein 38	Numerous small cells	Negative	—	—	—	0.73	Recovered with residual neurologic deficit
7	8	Male	—		—	—	—	—	0.43	Expired
8	13	Male	Sugar 59/protein 101	Seven cells	—	—	—	—	—	Expired
9	9	Female	Sugar 68/protein 72	No cells	—	—	—	—	1.02	Expired
10	7	Male	Sugar 67/protein 59	No cells	—	—	1.6	—	0.14	Expired
11	6	Male	Sugar 67/protein 10.4	No cells	Negative	—	8.15	—	0.33	Recovering with residual ataxia
12	6	Male	Sugar 57/protein 67		Negative	—	—	Positive	0.08	Expired
13	17	Male	Sugar 67/protein 29	Three lymphocytes	Negative	Negative	—	—	—	Expired
14	6	Male	Sugar 74/protein 10	Four lymphocytes	Negative	—	—	—	0.26	Expired
15	10	Female	Sugar 88/protein 59	No cell	—	Positive	6.14	—	0.37	Alive
16	18	Male	—	—	—	—	—	—	—	Expired
17	4	Male	Sugar 51/protein 59	16 neutrophils	—	Positive	—	Negative	2.03	Recovered with residual neurologic deficit
18	4	Male	Sugar 58/protein 49.3	—	—	Positive	17.8	—	—	Recovered with residual neurologic deficit

Abbreviations: ALC, absolute lymphocyte count; CSF, cerebrospinal fluid; IgG, immunoglobin G; IgM, immunoglobin M; PCR, polymerase chain reaction.

FIG 1.

Representative photomicrographs show brain parenchyma with an increase in cellularity by singly scattered cells of lymphoid cells and microglial-like morphology and an increase in small vessel type of vascularity ((A) HE × 40; (B) HE × 100; (C) HE × 200). The lymphoid cells are immunopositive for CD3 ((D) IHC × 200) with an almost equal proportion of CD4-positive ((E) IHC × 200) and CD8-positive ((F) IHC × 200) cells. No significant CD20-positive B-lymphoid cells are seen ((G) IHC × 200). Few scattered plasma cells are also seen, as highlighted immunopositivity for CD138 ((H) IHC × 200), and the microglial-like cells are highlighted by CD163. ((I) IHC × 200). HE, hematoxylin and eosin stain; IHC, immunohistochemistry.

Magnetic Resonance Imaging Findings

Brain imaging performed early in the course of seizures was normal in most patients. Repeat imaging performed 2 weeks or later showed multifocal cortical and subcortical gray matter hyperintense lesions on T2. Basal ganglia and thalamus were also involved in some patients.

Because of atypical findings, postictal changes or acute disseminated encephalomyelitis were considered as differential diagnoses (Figs 2 and 3).

FIG 2.

FLAIR axial images (patient 10) reveal focal asymmetric abnormal hyperintense signals involving (A) the bilateral precentral and adjacent middle frontal cortex (arrow), cortex, and subcortical white matter of left parietal and superior frontal gyrus, (B) left lentiform nucleus and thalamus (arrow), and (C) left hippocampus (arrow). (D) No abnormal meningeal or parenchymal enhancement or (E) restricted diffusion was seen. FLAIR, fluid attenuated inversion recovery sequence.

FIG 3.

(Patient 2) Axial FLAIR images demonstrate subtle abnormal hyperintense signals in (B and C) the left parietal gyrus and (C and D) left insular cortex and temporal lobe and left thalamus with (E) patchy meningeal enhancement in the parietal region and (F) minimal restricted diffusion. Follow-up MRI after 15 days shows a significant increase in abnormal FLAIR hyperintense signals involving the (A) left superior and middle frontal gyrus and (B) left inferior parietal lobule and (C and D) peri-Sylvian region with gyral swelling. (C) The abnormal signal of left thalamus shows increase. (C) Involvement of the caudate and lentiform nucleus was also seen. (E) Mild patchy meningeal enhancement in the parietal region was present with (F) no areas of restricted diffusion. FLAIR, fluid attenuated inversion recovery sequence; MRI, magnetic resonance imaging.

EEG Findings

The EEG findings in this cohort varied from frequent interictal epileptiform discharges corresponding to the area of cortical involvement to increasingly severe grades of encephalopathy. Nonconvulsive status epilepticus was noted in one patient, and burst suppression was attained and retained for 24 hours before tapering of general anesthesia. However, further deterioration occurred, and EEG showed generalized delta-grade slowing (Figs 4 and 5).

FIG 4.

EEG showing frequent bilateral frontocentral epileptiform spike wave discharges.

FIG 5.

Electroencephalogram recorded in longitudinal bipolar montage showing severe delta-range slowing of background activity.

DISCUSSION

Measles is one of the most contagious human pathogens with an airborne transmission and a secondary attack rate of 90%. It is generally seen in children with a prodrome of cough, coryza, and conjunctivitis followed by fever and rash. The rash typically starts on the face or at the hairline behind the ears and spreads over the trunk and extremities.⁶

The presentation of measles is atypical in an immunocompromised host. The rash can be transient or evanescent, has an atypical pattern of distribution, and is sometimes absent.^8-10 In our series, approximately 55% of the children did not notice a rash. This was higher than the 20% reported in the UK experience^10-12 and could be because the rash went unnoticed on a darker skin.

Measles infection in children with cancer might go undetected until they present with complications, such as pneumonitis or encephalitis.^10-13 This was the case in this study. We arrived at a diagnosis of MIBE once we noticed that a few children with EPC had a preceding history of fever and rash. We also had a series of children who succumbed to pneumonitis and acute respiratory distress syndrome but were not labeled as measles in the absence of a measles probe in the BioFire pneumonia panel.¹⁴ Four children in our series with EPC were previously admitted for respiratory support for viral pneumonia around the time they had fever and rash. Seizures occurred between 10 and 37 days after the onset of the rash in these patients. This suggests that they were able to overcome the viral infection, but there was persistence of measles virus in the brain. Not all children with measles presented with seizures, suggesting that viral and host factors might contribute to the development of encephalitis.

The pathogenesis of MIBE is not yet fully understood. Previous reports have suggested that mutations in the F protein of MeV might contribute to the hyperfusogenicity of the virus, facilitating its CNS invasion.^15-18 It has been postulated that the lack of cell-mediated immunity, specifically deficiency of CD8⁺ T cells, leads to persistence of the virus in the CNS, leading to MIBE.¹⁹ Approximately 60% of children in our series were in the maintenance phase and were not on intensive chemotherapy but on immunosuppressive medications such as oral 6-mercaptopurine once daily and methotrexate once a week. At the time of presentation with seizures, the absolute lymphocyte count (ALC) was low ranging from 80 to 2,030 cells/μL with a median of 370 cells/μL. The low ALC could be due to postmeasles myelosuppression accentuated by continuation of the immunosuppressive medications. Five of the 10 patients who underwent a throat swab showed persistence of MeV by PCR at the time of seizures, well after the onset of measles infection. Thus, cell-mediated immunity, specifically T-cell–mediated immunity, is essential for viral control.¹⁹

Neurologic complications of measles are varied and range from an acute encephalitis-like picture to neurodegenerative disorder. Acute encephalitis can present as (1) primary measles encephalitis (PME) or (2) immune-mediated, acute postinfectious measles encephalomyelitis (APME). The neurodegenerative diseases because of persistence of the virus in the CNS present as (3) MIBE and (4) subacute sclerosing pan encephalitis (SSPE).^20-22

PME occurs in unimmunized, immunocompetent children during the exanthema phase or within a week of the measles prodrome. On the other hand, APME is immune-mediated, with circulating antibodies to myelin basic protein of oligodendrocytes causing inflammation and demyelination.^21,22 MIBE and SSPE are a sequelae of viral persistence and replication in the CNS. MIBE occurs early after an episode of measles, whereas SSPE has a latency period of 7-10 years.

In our series, all children were immunocompromised, did not have CSF pleocytosis or elevated protein, and presented at a median of 28 days (5-49 days) after resolution of rash, favoring a diagnosis of MIBE.

MIBE has been classically reported in immunocompromised children and adults, mostly in the form of case reports and case series in the pre- and early vaccination era.^2,9-13 MIBE has also been reported in immunocompromised individuals as a result of HIV, hematologic malignancies, or immunosuppressive medications.^23-26

Measles as a cause of EPC in immunosuppressed hosts was identified in previous reports by the demonstration of measles inclusion bodies (intranuclear inclusions of paramyxovirus nucleocapsid) by electron microscopy or the presence of measles antigen using fluorescent-labeled antibody probes in the brain and recently using PCR techniques.²⁷ In our case, the D8 genotype was detected in the brain biopsy and CSF and was consistent with the virus identified during the measles outbreak in the city in November 2022.^28,29

In MIBE, viral replication occurs in the CNS, leading to the intrathecal synthesis of antibodies.^7,18,21 Virus-specific antibody synthesis in the brain can be detected with high sensitivity and specificity using an enzyme immunoassay to calculate the virus-specific antibody index, as described in the Methods section.⁷ A ratio of >1.5 was detected in nine of nine children tested, suggestive of intrathecal synthesis of antimeasles antibodies. The high antibody titers in the CSF along with the presence of clinicoradiologic correlation pointed toward measles virus replication in the brain, confirming the diagnosis of MIBE. Measles is not the only cause of EPC. Other viruses have also been reported to be associated with EPC. We reported a series of children with EPC presenting in early 2018 where HSV was isolated from the CSF.³⁰

During the course of 3 months, no therapy to prevent EPC seemed to be effective. IVIG was ineffective in preventing the progression of seizures, nor did it prevent the development of MIBE when administered prophylactically after an episode of measles. Nine children with measles like rash received IVIG and vitamin A, one went on to develop EPC, and two progressed to develop measles pneumonia, suggesting no definitive role of IVIG in preventing measles-related complications. The UK Medical Research Council reported a similar finding in the UKALL V trial. IVIG was ineffective in preventing progression to EPC in children with acute leukemia who developed measles.³¹ During the initial phase of the outbreak, we also considered the possibility of immune-mediated APME and gave a trial of high-dose methylprednisolone with no improvement.^7,20

Currently, there is no proven therapy to prevent the progression of measles to MIBE, and prevention of measles infection appears to be the best strategy against EPC. From the reported literature on SSPE and MIBE, there has been some response to isoprinosine and intravenous (IV) ribavirin.^32-34 However, IV ribavirin is not US Food and Drug Administration–approved and we could not access IV ribavirin.

The measles vaccine is a live vaccine. Children with acute leukemia receiving measles vaccine progressed to frank measles and death.^35,36 Therefore, pre-exposure vaccine prophylaxis cannot be used as a strategy in children with leukemia to prevent measles. Children undergoing chemotherapy for acute leukemia, who have received childhood vaccinations, demonstrate loss of vaccine-acquired humoral immunity. A recent study in children who completed chemotherapy for hematolymphoid malignancies showed loss of vaccine-acquired immunity, with >57% of children showing seronegativity for measles.³⁷ Therefore, irrespective of previous vaccine status, children with hematolymphoid malignancies are susceptible to measles because of their immunosuppressed state. Protection by offering herd immunity is the best way to prevent measles in children receiving immunosuppressive therapy.

The national immunization program and its implementation play a major role in providing herd immunity. The Indian immunization program recommends two doses of the measles vaccine. The first dose is administered at 9-12 months, whereas the second dose is recommended at age 16-24 months. Immunization rates were low during COVID-19 disease in India where we had one of the most restrictive lockdowns in the world that lasted for approximately 4 months. With most of the country's health care machinery busy with COVID-19 disease, there were delays and disruptions in childhood vaccination program and a decline in coverage. WHO estimates that about 1.1 million children in India missed their first dose of measles vaccine because of pandemic setbacks in 2022.³⁸ The Ministry of Health and Family Welfare (MoHFW) has conducted special immunization drives as an outbreak response. With the aim of eliminating measles and rubella, the MoHFW has administered an extra dose of the measles-rubella vaccine in schools to children younger than 15 years in addition to the routine immunization schedule. Achieving immunization rates >95% is the best way to protect children from measles-related complications.

AUTHOR CONTRIBUTIONS

Conception and design: Sudivya Sharma, Chetan Dhamne, Girish Chinnaswamy, Sunil Vaidya, Shripad Banavali

Provision of study materials or patients: All authors

Collection and assembly of data: Sudivya Sharma, Chetan Dhamne, Shilpushp Bhosale, Badira Parambil, Jigeeshu Divatia, Girish Chinnaswamy, Vasundhara Patil, Anita Mahadevan, Sunil Vaidya, Shilpa Kulkarni, Atul Kulkarni, Vijaya Patil, Shyam Srinivasan, Venkata Rama Mohan Gollamudi, Nirmalya Roy Moulik, Maya Prasad, Gaurav Narula, Shripad Banavali

Data analysis and interpretation: Sudivya Sharma, Chetan Dhamne, Vasundhara Patil, Rishikesh Joshi, Sridhar Epari, Anita Mahadevan, Sunil Vaidya

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

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