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Abstract

Neurological manifestations related to SARS-CoV-2 infection in adults have been largely reported since the beginning of the pandemic. Subsequent large-scale studies involving children confirmed the occurrence of neurological symptoms associated with SARS-CoV-2 infection also among paediatric patients, especially in the context of paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS). At this regard, we report the challenging case of a 10-month-old baby with PIMS-TS complicated by acute cerebral oedema successfully treated with intravenous immunoglobulins, corticosteroids and anakinra. Our results, combined with the evidence of larger case series suggest that higher inflammatory burden is more frequent in patients with neuro PIMS-TS. As regards neuroimaging, neuroimmune disorders are found to be more common during acute COVID-19, MERS is more frequent during PIMS-TS. Distinct immune mechanisms may underlie these different types of neurological involvement, which are yet to be understood. Further studies are required to better define the physiopathology of neuro PIMS-TS and its possible therapeutical implications.

Keywords

Kawasaki disease MIS-C neurological manifestations PIMS-TS

Introduction

Since the outbreak of coronavirus disease 2019 (COVID-19) pandemic, it was clear that children had an asymptomatic or mild infection course, with minimal hospitalization rate and mortality.^1,2

However, starting from April 2020, several countries reported on children with an acute critical condition subsequent to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This new clinical entity was quite similar to other known inflammatory diseases [i.e. Kawasaki disease (KD), septic shock and toxic shock syndrome],^3,4 although with peculiar findings. This condition was labelled paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS) by the Royal College of Paediatrics and Child Health.⁵ Subsequently, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) referred to this condition as Multisystem inflammatory syndrome in children (MIS-C).^6,7

Neurological manifestations related to SARS-CoV-2 infection in adults have been largely reported since the beginning of the pandemic.⁸ Subsequent large-scale studies involving children confirmed the occurrence of neurological symptoms associated to SARS-CoV-2 infection also among paediatric patients, especially in the context of PIMS-TS.⁹

LaRovere et al.¹⁰ reported that 22% of 1695 children with acute COVID-19 or PIMS-TS in the United States presented a neurological involvement. PIMS-TS patients did not show a higher rate of neurological involvement (35% versus 37%) or life-threatening events (47% versus 53%) than acute COVID-19 patients. Transient symptoms (88%) such as fatigue, confusion, headache, loss of smell or taste and seizures were the most frequently reported (88%). Therefore, a minority of patients (12%) experienced life-threatening conditions: severe encephalopathy (34.9%), ischemic or haemorrhagic stroke (27.9%), acute central nervous system infection or acute disseminated encephalomyelitis (ADEM; 18.6%), acute fulminant cerebral oedema (9.3%) and Guillain–Barré syndrome (9.3%). These symptoms were more frequent in patients with underlying neurologic disorders and an unfavourable outcome, including death or neurological disability at discharge, was observed in 65% of patients with severe manifestations.

A further prospective cohort study conducted in the United Kingdom involving 1334 patients¹¹ detected a much lower rate of neurological manifestations (3.8%) among children with acute COVID-19 and PIMS-TS. In the PIMS-TS subgroup (25 patients) encephalopathy (88%), peripheral nervous system involvement (40%), headache or meningism (40%) behavioural changes (36%), hallucinations (24%) and seizures (16%) were observed. Abnormal neuroimaging consistent with mild encephalopathy with reversible splenial lesion (MERS) was detected in 28% of patients. Neuroimmune disorders were more frequently observed in the COVID-19 group (48%) compared with the PIMS-TS one (<1%).

At this regard, we report the challenging case of a 10-month-old baby with PIMS-TS complicated by acute cerebral oedema. Furthermore, we performed a narrative literature review of PIMS-TS cases with neurological involvement, in order to characterize the spectrum of neurological manifestations of this critical condition, to establish the temporal association between PIMS-TS and neurological symptoms as well as to understand the potential underlying mechanisms of neurological involvement during PIMS-TS clinical course.

Materials and methods

A written informed consent for patients’ information and images to be published and written consent to treatment were provided by the legally authorized representatives. CARE guidelines were followed for the case report drafting.¹²

As regards the narrative review of PIMS-TS cases with neurological involvement, the search strategy was carried out in PubMed/Medline and Embase databases using in all fields the key terms [ ‘Paediatric inflammatory multisystem syndrome temporally associated with COVID-19’ OR ‘PIMS-TS’ OR ‘Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2’ OR ‘MIS-C’] AND [ ‘Neurological’ AND ‘Nervous’ AND ‘encephalopathy’ AND ‘seizures’ AND ‘papilledema’ AND ‘stroke’ AND ‘headache’ AND ‘hallucination’ AND ‘intracranial hypertension’]. The review includes retrospective cohort, prospective cohort studies, case series and case reports. Only articles published in English were included. Studies reporting poor or not-extractable data were excluded, as well as papers published before May 2020 (first PIMS-TS reported case). Double-reported patients were excluded from the total account.

Case report

A previously healthy 10-month-old African infant developed high-grade fever and emesis with a subsequent widespread urticarial rash and bilateral non-secretive conjunctivitis.

He was admitted to our tertiary care hospital after 4 days of persistent fever. At the physical examination, the infant presented marked irritability with tense, wide and bulging anterior fontanelle, shallow breathing and a widespread macular erythematous rash on trunk and limbs. Brain ultrasounds did not detect intracranial bleeding or meningitis signs. Blood tests evidenced a remarkable increase of inflammatory markers [C-reactive protein (CRP) 32.08 mg/dl, procalcitonin (PCT) 97.7 ng/ml], neutrophilic leucocytosis, NT-pro-BNP (92,230 pg/ml) and D-dimer (2547 ug/l FEU) elevation, and a high ferritin value (810 ng/ml). SARS-CoV-2 IgG antibodies were positive, while RT-PCR for SARS-CoV-2 on nasopharyngeal swab was negative. Echocardiography evidenced slight coronary arteries dilatation and hyperkinetic left ventricle, with normal systolic function. Empiric antibiotic and antiviral treatment was started. Clinical and laboratory findings suggested a PIMS-TS diagnosis. Therefore, a single 2 g/kg dose of intravenous immunoglobulin (IVIG) was administered, followed by intravenous continuous infusion of anakinra (10 mg/kg qd). Moreover, a prophylactic antithrombotic therapy with enoxaparine at 100 UI/kg qd was started because of D-dimer elevation and initial coronary arteries dilatation, according to American College of Rheumatology clinical guidelines for PIMS-TS.¹³

Despite this prompt intervention, 24 h after admission, a neurological deterioration was observed with drowsiness alternating with extreme irritability. Brain computed tomography (CT) reported an initial cerebral oedema, with meningeal and cerebral herniation from the anterior fontanelle. The patient continued to get worse and severe hypotension rapidly occurred requiring the admission to the intensive care unit (ICU), hemodynamic support with amines and mechanical ventilation. In order to treat cerebral oedema, dexamethasone and mannitol were administered intravenously. Subsequent cardiological evaluation described increased coronary arteries ectasia.

On day 7 from admission, a new fever rise, and a leucocytosis rebound occurred during the slow tapering of anakinra, therefore, the immunomodulatory regimen was re-intensified. A second 2 g/kg dose of IVIG followed by three boluses of methylprednisolone was administered.

After the maximization of treatment, patient’s clinical conditions gradually improved. He was weaned from ventilation, sedation and vasoactive support. Antibiotics and antiviral therapy were discontinued since all infectious tests resulted negative (aerobic and anaerobic bacteria and fungal blood cultures; Cytomegalovirus, Epstein-Barr virus, Adenovirus, Neisseria meningitidis, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, Listeria monocytogenes, Streptococcus agalactiae, Haemophilus influentiae, Human Herpesvirus-6, Human Herpesvirus-7, Enterovirus, Herpes Simplex virus-1, Herpes Simplex virus-2, Parvovirus on blood samples by real-time polymerase chain reaction (RT-PCR); QuantiFERON for the detection of Mycobacterium tuberculosis).

On day 10, the boy was back at his neurological baseline, with a normal anterior fontanelle. He was persistently afebrile, and the rash completely disappeared. Inflammation indexes slowly decreased, and the patient was moved to the paediatric ward. Dexamethasone regimen was suspended. Two weeks after the admission, the baby presented peeling of the extremities and remarkable thrombocytosis. Right coronary artery (RCA) demonstrated a residual deep aneurismatic remodelling (+5.5 SD). Anti-platelet therapy was started, while enoxaparin was discontinued. Anakinra was slowly tapered and shifted to subcutaneous administration, with no fever relapse.

Brain magnetic resonance imaging (MRI), performed on day 14, showed periventricular hyperintensities without restricted diffusion (Figure 1). Slight cerebral and cerebellar trophism reduction was observed, with mild peri encephalic subarachnoid spaces enlargement. Angiography, venography and post-contrast scan were normal.

Figure 1.

Radiological findings in our neuro PIMS-TS patient: (a) brain CT reporting cerebral oedema, with meningeal and cerebral herniation from the anterior fontanelle, (b) brain MRI showing periventricular hyperintensities without restricted diffusion, (c) and (d) left and right coronary artery ectasia, respectively.

Coronary arteries dilatation regressed at its normal size (proximal RCA: +2.2 DS; common trunk of left coronary artery +2 DS; proximal anterior interventricular coronary artery: +1.32 DS; circumflex branch of left coronary artery +1.2 DS) within 2 weeks after its peak (Figure 2). As regards neurological status, the infant presented a regular development without sequelae.

Figure 2.

Timeline of patient course.

Results

We retrospectively reviewed the clinical history of 75 patients with neuro PIMS-TS reported in literature. We collected epidemiological, clinical, therapeutical, laboratory and instrumental data (Table 1).

Table 1.

Neuro PIMS-TS previously reported cases.

Study	AgeSex	Ethnicity	SARS-CoV-2 tests	Blood tests	Neurological manifestations	Cardiovascular findings	Other symptoms and sings	Neuro-Imaging	Lumbar puncture	Therapy	Outcome
Abel et al.¹⁴	33 months M	NA	RT-PCR: negative/indeterminate Serology: positive	PLT 23,000/ul CRP 25.2 mg/dl Ferritin 2000 ng/ml NT-pro-BNP 29,447 pg/ml	CNS Irritability Somnolence Hypotonia PNS None EEG: moderate background slowing	ECG: Sinus tachycardia	Fever Emesis Rash	CT: normal MRI (day 7): restricted diffusion in the bilateral lateral thalamic nuclei without T2/FLAIR changes MRI (day 15): normal	Normal	Antibiotics Anakinra Methylprednisolone Anticoagulants	Mild residual weakness requiring physical therapy
Baccarella et al.¹⁵	9 years M	NA	RT-PCR: negative Serology: positive	NA	CNS Headache Diplopia Right abducens palsy PNS None	NA	Fever Abdominal pain	MRI and venography: normal	Elevated opening pressure: 34 cm H₂O Sars-CoV-2 RT-PCR: negative Other CSF studies: normal	PIMS-TS protocol Acetazolamide	Complete recovery
	6 yearsM	NA	RT-PCR: positiveSerology: positive	NA	CNSHeadacheDiplopiaRight abducens palsyBilateral papilledemaPNSNone	NA	No other signs	MRI: kinking and distention of both optic nerve sheaths with protrusionof the optic discs into the globes	Normal opening pressure: 14 cm H₂OSars-CoV-2 RT-PCR: negativeOther CSF studies: normal	PIMS-TS protocolIntensive care unit admissionVasopressor support	Recovery of papilledema after 5 months
Becker et al.¹⁶	14 yearsF	NA	RT-PCR: negativeSerology: positive	WBC 16,700/ulN 86%L 1%PLT 150,000/ulCRP 34.3 mg/dlESR 55 mm/hPCT 15.3 ng/mlNa 125 mEq/lCreatinine 2.5 mg/dl	CNSBlurry visionAbducens palsyBilateral papilledemaPNSNone	TachycardiaHypotensionUS:—Left ventricular dysfunction—Right coronary artery dilatation (day 7): Z score 3.15	FeverDyspneaHeadacheEmesisDiarrhoeaRash	MRI: restricted diffusion of optic nerve sheaths, flattening of the posterior sclera, and eversion of the optic discsVenography: flattening of the left transverse and sigmoid sinuses	Elevated opening pressure: > 36 cm H₂OOligoclonal bands	CefepimeDoxyciclineEpinephrineNorepinephrineHydrocortisoneIVIGMethylprednisoloneAcetazolamideAspirin	Right coronary artery dilatation and bilateral papilledema resolved at 2 months follow-up; back at neurological baseline
	6 yearsF	NA	RT-PCR: negative (day1)/positive (day 2) low viral loadSerology: positive	WBC 9100/ulN 80%L 10%PLT 98,000/ulCRP 16.8 mg/dlESR 105 mm/hPCT 70 ng/mlNT-pro-BNP 606.3 pg/mlTroponin: normalNa 129 mEq/l	CNSAltered mental statusIrritabilityNucal rigidityPNSNoneEEG: no seizures	US:—Moderate left ventricular dysfunction	FeverRashConjunctivitisEmesisDiarrhoea	CT: cerebral oedema	Elevated opening pressure: 31 cm H₂OSars-CoV-2 RT-PCR: negativePleocytosis	IVIGAnakinraMethylprednisoloneEpinephrineNorepinephrineMilrinoneAspirin	Discharged on day 12 at neurological baseline
	13 yearsF	NA	RT-PCR: negativeSerology: positive	WBC 13,300/ulN 94.8%L 3.5%PLT 107,000/ulCRP 23.2 mg/dlPCT 1.5 ng/mlNT-pro-BNP: normalTroponin: normal	CNSHeadacheNeck painWaning mental statusNuchal rigidityEncefalopathyIntracranial hypertensionPNSNoneEEG: no seizures	TachycardiaHypotensionUS:—Progressive biventricular dysfunction	FeverEmesisAbdominal painHepatosplenomegaly (US)Pelvic fluid (US)	CT: normalMRI: normal	Elevated opening pressure: > 38 cm H₂OPleocytosisElevated protein	CeftazidimeDoxyciclineHypertonic salineIVIGHydrocortisoneMethylprednisoloneTocilizumabEpinephrineNorepinephrineVasopressinMilrinoneEnoxaparinAspirin	Discharged on day 27 at neurological baseline
	12 yearsM	NA	RT-PCR: negativeSerology: positive	WBC 10,300/ulN 84.6%L 6.7%PLT 204,000/ulCRP 22.4 mg/dlESR 62 mm/hPCT 38.1 ng/mlNT-pro-BNP 230 pg/mlTroponin 4.4 ng/mlNa 123 mEq/l	CNSWaning mental statusNuchal rigidityPNSNoneEEG: diffuse slowing, no seizures	TachycardiaHypotensionUS:—Biventricular dysfunction	FeverEmesisDiarrhoeaConjunctivitisHepatomegalyS4 gallop	CT: normal	Elevated opening pressure: 34 cm H₂O	EpinephrineMilrinoneIVIGMethylprednisoloneEnoxaparinAspirin	Discharged on day 16 at neurological baseline
Tiwari et al.¹⁷	9 yearsF	NA	RT-PCR: positiveSerology: positive (week 4 of admission)	PLT 250,000/ulCRP 6.49 mg/dlESR 50 mm/hFerritin 614 ng/mlD-dimer 3570 ng/mlTroponin I: normalNa 132 mEq/lALT 126 UI/lLDH 1000 UI/l	CNSRight facial nerve palsyFrontal headacheRight hemiparesisBrisk deep tendon reflexesExtensor right plantar responseWorsening GCS (day 3)PNSNone	HypertensionBradycardiaCardiac arrestUS: normalECG: normal	Fever (14 days)EmesisConjunctivitis	CT: infarcts in the genu and adjacent body of corpus callosum, left basal ganglia and bilateralthalami; mild oedema and mild mass effect over the lateral ventricleCT angiography:multifocal smooth stenosis of both intracranial internal carotid arteries, right middle cerebral artery, and anterior cerebral arteries. Diffuse narrowing of the M2 and M3 segment branches of both middle cerebral arteries	Sars-CoV-2 RT-PCR: negativePleocytosis (80% lymphocytes)Slightly increased protein	Mechanic ventilationSedationHead elevation (30°)Glycerol 3%Hypertonic salineMannitolSupportive careCeftriaxoneVancomicinAzithromycinIVIGMethylprednisoloneDexamethasoneRemdesevirLMWH	GCS 13 power: 2–3/5On psychomotor rehabilitation
Kim et al.¹⁸	7 yearsM	NA	RT-PCR: positive(his parents had positive nasopharyngeal swab 4 weeks before)	CRP 22 mg/dlESR 38 mm/hPCT 6.68 ng/mlFerritin: 1601.2 ug/lD-dimer 17,650 ng/ml	CNSHeadacheNeck painAltered mental statusExpressive aphasiaPinpoint pupilsLeft gaze deviationBrudzinski signExtensor posturingFixed and dilated pupilsAbsent brainstem reflexesPNSNoneEEG:bilateral generalized voltage attenuation	ECG: normal	FeverEmesisAbdominal pain	CT angiography: negativeCT scan: diffuse cerebral oedema	Elevated opening pressure: 103.3 cm H₂O	LevetiracetamLorazepamVancomyicinCeftriaxone	Brain death
Shenker et al.¹⁹	12 yearsM	NA	RT-PCR: positiveSerology: positive (day 9)	WBC: 28,000/ulPLT 109,000/ulCRP 42.14 mg/dlFerritin 633 ng/mlD-dimer 816 ng/mlNT-pro-BNP 1067 pg/mlTroponin: negative	CNSHyperactivityEmotional labilityTangential speechAltered mental statusDecreased level of consciousnessPNSNoneEEG: focal epilepsy arising in the central regionwith diffuse bifrontal spread	TachycardiaHypotension	FeverRight-sided neck swellingConjunctivitisAbdominal rashTrismus	Neck CT: retropharyngeal fluid collectionHead CT: normalMRI: normalMR angiography: normal	NormalSars-CoV-2 RT-PCR: negative	EnoxaparinClindamycinAmpicillin-sulbactamVancomycinFurosemideIVIGEpinephrineRemdesevirAnakinraLevetiracetamLorazepamFosphenytoinOxcarbazepine	Discharged on day 26 at neurological baseline
Abdel-Mannan et al.²⁰	8 yearsM	South Asian	RT-PCR: positive	CRP 44.8 mg/dlFerritin 1414 ng/mlD-dimer 1,625,400 ng/mlLDH 1016 UI/l	CNSAgitationMeningismHeadacheGeneralized proximal weaknessPNSNoneEEG: mild diffuse slowingEMG: patchy myopathic changes	Circulatory shockUS:—Mild tomoderate left ventricular dysfunctionECG: pericarditis	FeverAbdominal painPalmar rashEmesis	CT (day 5): hypodensity of the splenium of the corpus callosum (SCC)T2 MRI: persistent signal changes in the genu and SCC without restricted diffusion	Sars-CoV-2 RT-PCR: negativeWBC 8.000 cells/ulProtein 2 g/dl	ICU admissionIVIGDexamethasoneMethylprednisoloneAnakinra	Encephalopathy resolved, wheelchair bound
	9 yearsM	Afro-Caribbean	RT-PCR: positive	CRP 31.3 mg/dlFerritin 1192 ng/mlD-dimer 494,500 ng/mlNa 129 mEq/lLDH 900 UI/l	CNSConfusionAtaxiaDysarthriaDysphagiaBilateral proximal leg weaknessUrinary retentionPNSNoneEEG: diffuse slow activity	Circulatory shockUS:—Mitral regurgitationECG:—Supraventricular—Ectopics	FeverPalmar rashEmesis	T2 MRI (day 1): signal changes of the genu and SCC and bilateral centrum semiovale with restricted diffusion	Sars-CoV-2 RT-PCR: negativeWBC: 2.000 cells/ulProtein: 1,9 g/dl	ICU admission	Discharged on day 11 at neurological baseline
	15 yearsF	South Asian	RT-PCR: positiveSerology: positive	CRP 28.9 mg/dlFerritin 48,142 ng/mlD-dimer 1,479,800 ng/mlLDH 4331 UI/l	CNSConfusionDysarthriaDysphagiaGlobal flaccid weaknessReduced reflexesPNSNoneEEG: mild excess of slow activity over the anterior regionEMG: mild myopathic or neuropathic changes	Circulatory shockUS:—Mild pericardial effusion	FeverDyspneaEmesisRash	T2 MRI (day 21): hyperintensities and restricted diffusione in the SCC and bilateral celtrum semiovale	NA	ICU admissionAnakinraDexamethasoneMethylprednisoloneRituximab	Encephalopathy resolved, wheelchair bound
	15 yearsF	Afro-Caribbean	RT-PCR: positiveSerology: positive	CRP 32.8 mg/dlFerritin 1218 ng/mlD-dimer 1,248,600 ng/mlLDH 1168 UI/l	CNSConfusionDisorientationHeadacheGlobal proximal weaknessReduced reflexesPNSNoneEMG: mild myopathic changes	Circulatory shock	FeverDyspneaEmesisRash	T2 MRI: signal changes in the SCC with mild restricted diffusion	NA	ICU admissionIVIG	Discharged on day 18 at neurological baseline
Bektaş et al.²¹	10 yearsM	NA	RT-PCR: negativeSerology: positive 1 week after discharge	PLT 124,000/ulCRP 39.2 mg/dlPCT 114 ng/mlFerritin 341 ng/mlD-dimer 595 ng/mlNT-pro-BNP 13,800 pg/mlTroponin I 324 ng/mlNa 131 mmol/l	CNSHallucinationsAgitationDisorientationPersonality changesPNSNoneEEG: diffuse slowing	TachycardiaHypotensionUS:—Left ventricular dysfunction—Mitral regurgitation	FeverDiarrhoeaDiffuse rashSwelling in hands and feetDyspnoeaTachypnoea	T2 MRI: hyperintensities in the SCC with restricted diffusionMRI (day 7): normal	NormalOligoclonal bands test: negative	IVIGMethylprednisolone	Discharged on day 11 at neurological baseline
	11 years	NA	RT-PCR: negativeSerology: positive	PLT 113,000/ulCRP 45.6 mg/dlPCT 32 ng/mlFerritin 533 ng/mlD-dimer 850 ng/mlNT-pro-BNP 35,000 pg/mlTroponin I 182 ng/mlNa 132 mmol/l	CNSAgitationPersonality changesPNSNoneEEG: diffuse slowing	TachycardiaHypotensionUS:—Ventricular dysfunction—Mitral regurgitation	FeverDiarrhoeaRashConjunctivitisDecreased breath sounds on lung bases	T2 MRI: hyperintensities in the SCC with restricted diffusionMRI (day 7): normal	NA	IVIGMethylprednisoloneMilrinoneNoradrenaline	Discharged on day 10 at neurological baseline
Sa et al.²²	14 yearsM	African-American	RT-PCR: negative	CRP 30.8 mg/dlESR 53 mm/hFerritin 1753 ng/mlD-dimer >20,000 ng/mlCreatinine 1.4 mg/dl	CNSRestlessnessAgitationConfusionIntermittent sleepingAggressivenessAttention impairmentPNSNone	TachycardiaHypotensionCirculatory shockUS:—Mild coronary arteries dilation (Z score < 2.5)—Left ventricular dysfunction (LVEF 42%)	FeverAbdominal painTruncal rashTachypnoea	MRI: normal	NA	AntibioticsFluid resuscitationNorepinephrineKetamineMidazolamDexmedetomidineLMWHMethylprednisoloneHFNCAnakinraMilrinoneHaloperidolLorazepamOlanzapineIVIG	Discharged on day 12 at neurological baseline
	2 yearsF	Afro-Caribbean	RT-PCR: positiveSerology: positive	CRP 18.9 mg/dlPCT 4.72 ng/mlFerritin 275 ng/mlD-dimers: 12,860 ng/mlFibrinogen: 860 mg/dl	Altered consciousnessPNSNoneEEG: fluctuating encephalopathy	US:—Mild left ventricular dysfunction—Coronary aneurism	FeverLymphadenopathyPeriorbital and lip oedemaAbdominal painAltered consciousness	CT: normalMRI: normal	NormalSars-CoV-2 RT-PCR: negative	IVIG Methylprednisolone	Complete recovery at 3 months follow-up
	4 yearsM	Caucasian	RT-PCR: negativeSerology: negative	CRP 28.3 mg/dlPCT 4.98 ng/mlFerritin: 172 ng/mlD-dimers: 10,600 ng/mlFibrinogen 680 mg/dl	CNSAltered consciousness;behavioural changesPNSNoneEEG: normal	US:—Hyperechogenicity of coronary arteries—Ectasia of left anterior descending coronary artery	FeverAbdominal painDiarrhoeaVomitsAltered consciousnessBehavioural changes	MRI: normal	CSF: mixedoligoclonal bands(serum and CSF)	IVIGMethylprednisolone	Behavioural changes at 3 months follow-up
	6 yearsF	Asian	RT-PCR: positiveSerology: positive	CRP: 8 mg/dlD-dimers: 1200 ng/mlFerritin: 74 ng/mlFibrinogen: 410 mg/dl	CNSSevere behavioural changesPNSNone	US:—Coronary aneurysm	FeverRashFace and feetOedemaAbdominal pain vomitsSevere behaviouralchanges	NA	NA	Oral prednisolone	Complete recovery at 4 months follow-up
	8 yearsF	Afro-Caribbean	RT-PCR: negativeSerology: positive	CRP 47 mg/dlPCT 56.15 ng/mlFerritin: 642 ng/mlD-dimers: 10,360 ng/mlFibrinogen 680 mg/dl	CNSAltered consciousness; visual hallucinationsPNSNone	Circulatory shockUS:—Ventricular dysfunction	FeverSore throatVomitsDiarrhoea	MRI: normal	NA	IVIGMethylprednisolone	Complete recovery at 4 months follow-up
	12 yearsM	Caucasian	RT-PCR: negativeSerology: negative	CRP 9.4 mg/dlPCT 1.19 ng/mlFerritin: 136 ng/mlD-dimers: 1050 ng/mlFibrinogen 140 mg/dl	CNSPersistent severe headacheSleepinessPNSNone	HypotensionUS:—Hyperechogenicity of coronary arteries	FeverRashPedal oedemaConjunctivitisAbdominal painVomitsPersistent severeHeadachesSleepiness	CT: normalMRI: normal	NA	IVIGMethylprednisolone	Complete recovery at 3 months follow-up
	12 yearsF	Afro-Caribbean	RT-PCR: negativeSerology: positive	CRP 34.3 mg/dlPCT 77.6 ng/mlFerritin: 4815 ng/mlD-dimers: 69,760 ng/mlFibrinogen 680 mg/dl	CNSBehavioural changesCognitive deteriorationPNSNoneEEG: reduced left posterior background rhythms	Circulatory shockUS:—Coronary aneurysms—Ventricular dysfunction	FeverRashCracked lipsConjunctivitisLymphadenopathyARDSAbdominal painDiarrhoeaVomits	MRI: subtlecortical changes	NA	IVIGMethylprednisoloneInfliximab	Mildbehaviouralchanges/lowmood at 4 monthsfollow-up
	14 yearsM	Afro-Caribbean	RT-PCR: positiveSerology: positive	CRP 55.6 mg/dlPCT > 100 ng/mlFerritin: 4220 ng/mlD-dimers: 13,490 ng/mlFibrinogen 1080 mg/dl	CNSHeadachesFocal neurology with asymmetric pupils (stroke)PNSNone	Circulatory shockUS:—Ventricular dysfunction	FeverARDSDiarrhoea	CT: acute right anterior circulation infarct	NA	No treatment	Death
	15 yearsF	Afro-Caribbean	RT-PCR: negativeSerology: negative	CRP 9.9 mg/dlPCT 0.22 ng/mlFerritin: 640 ng/mlD-dimers: 28,790 ng/mlFibrinogen 680 mg/dl	CNSBehavioural changesVisualand auditoryhallucinationsSeizuresPNSNoneEEG: focal spikewavedischarges	Circulatory shockUS:—Ventricular dysfunction	FeverARDS	MRI: splenium of corpus callosum and hippocampal mild diffusion restriction	NormalRT-PCR Sars-CoV-2: negative	IVIGMethylprednisolone	Mild memory difficulties at 3 months follow-up
	10 yearsM	Afro-Caribbean	RT-PCR: negativeSerology: positive	CRP 29.6 mg/dlPCT 0.34 ng/mlFerritin: 1572 ng/mlD-dimers: 29,080 ng/mlFibrinogen 730 mg/dl	CNSLeft-sidedfacial weaknessHypertension andbradycardia (raised intracranial pressure): strokePNSNone	Hypertension bradycardia (raised intracranial pressure: stroke)	FeverDorsal, chest, andthighs pain (sicklecell crisis)Abdominal painVomits	CT/MRI: right frontal intraparenchymal haemorrhage and infarction	NA	IVIGMethylprednisoloneTocilizumab	Left hemiparesis
Laçinel Gürlevik et al.²³	3 yearsM	NA	RT-PCR: negativeSerology: positive	NA	CNSIrritabilityLethargyHeadacheMeningismVisual hallucinationsPNSNone	Hypotension	FeverRashConjunctivitisHepatosplenomegaly	CT: normal	Glucose: 58 mg/dlProtein: 40 mg/dlDirect microscopic examination: no cellCSF culture: negativeViral encephalitis panel: negative	IVIGSteroidsImmunomodulatorsPlasma exchangeProphylactic anticoagulationAntiviral	Complete recovery
	14 yearsF	NA	RT-PCR: negativeSerology: positive	NA	CNSVisual and auditory hallucinationsDeliriumFluctuating attention and cognitionBlurred visionPNSNone	Hemodynamic impairment	FeverRashConjunctivitisDiarrhoeaAbdominal pain	MRI (day 26): multiple microhemorrages and bilateral MCA stenosis consistent with small- and medium-vessel vasculitisMRI (day 36): PRESMRI (day 54): PRES regression	NA	IVIGSteroidsImmunomodulatorsPlasma exchangeECMOProphylactic anticoagulationAntiviral	Discharged with moderate muscle strength loss and need assistance for walkingDifficulty in climbing stairs and tremors on up to 6 months follow-up
	15 yearsF	NA	RT-PCR: negativeSerology: positive	NA	CNSVisual and tactile hallucinationsFluctuating cognitionAgitationDeliriumPNSNoneEEG (1 month later): normal	Hypotension	FeverAbdominal painDiarrhoeaRash	NA	NA	IVIGSteroidsImmunomodulatorsProphylactic anticoagulationAntiviral	Complete recovery
	6 yearsF	NA	RT-PCR: negativeSerology: positive	NA	CNSIrritabilityVisual hallucinationsFluctuating cognitionWeakness (upper and lower limb, 2/5)PNSNoneEMG: myopathic changes	NA	FeverRashAbdominal painConjunctivitis	CT: normal	NA	IVIGSteroidsImmunomodulatorsPlasma exchangeProphylactic anticoagulationAntiviral	Discharged with mild muscle strength loss and need assistance for walking
	17 yearsM	NA	RT-PCR: negativeSerology: positive	NA	CNSHeadacheIrritabilityLethargyFluctuating cognitionMeningismOn extubation (26th day): weakness lower > upper limbs, muscle atrophyPNSEMG (2 months later): motor axonal polyneuropathy in lower extremities	HypotensionTachycardia	EmesisFeverHepatosplenomegaly	CT: normalCT angiography: stenosis in the upper truncus of the right MCA and paucity of distal branches of the MCA	Glucose: 58 mg/dlProtein: 23 mg/dlDirect microscopic examination: no cellCSF culture: negative	IVIGSteroidsImmunomodulatorsPlasma exchangeProphylactic anticoagulationAntiviral	Discharged with moderate muscle strength loss and need assistance for walking, steppage gait, impaired vibration sensation in the lower limbs on up to 5 months follow-up
	13 yearsM	NA	RT-PCR: negativeSerology: positive	NA	CNSNonePNSTingling and pain in the hands and feetHyperesthesiaEMG (at admission): normal	NA	FeverRashConjunctivitisDiarrhoeaAbdominal pain	NA	NA	IVIGSteroidsImmunomodulatorsProphylactic anticoagulationAntiviral	Recovered with gabapentin
Olivotto et al.²⁴	5 yearsM	NA	Serology: positive	↑ CRP↑ PCT↑ ESR↑ ferritin↑ D-dimer↑ NT-pro BNPTroponin T: normal↑ IL-6↓ PLTHypoalbuminemiaHyponatremiaLymphocytopenia	CNSHeadacheDrowsinessIrritabilityMood deflectionSleep disorderPhotophobiaDiffuse limb painLower limb weakness and areflexiaGait disorderSpeech disorderOculomotor apraxiaPNSNoneEEG: diffuse delta slow activity	Mild dysfunction (EF 49–50%)	FeverAstheniaAbdominal painEmesisDiarrhoea	Brain MRI: normalSpinal MRI: enhancement of the anterior roots of the cauda equina	Normal	IVIGMethylprednisolone	Full recovery
	3 yearsF	NA	Serology: positive	↑ CRP↑ PCT↑ ESR↑ Ferritin↑ IL-6↓ PLTHypoalbuminemiaHyponatremiaLymphocytopeniaProteinuria	CNSIrritabilityMood deflectionDrowsinessPNSNoneEEG: focal posterior slowing	None	FeverRashConjunctivitisLower limb oedema	MRI: normal	Normal	IVIGMethylprednisolone	Full recovery
	3 yearsF	NA	RT-PCR: positiveSerology: positive	↑ D-dimer↑ NT-pro BNP↑ Troponin T↑ PLTNeutrophiliaHypoalbuminemiaHyponatremia	CNSGeneralized tonic-clonic seizuresIrritabilityDrowsinessHyporeactivityMood deflectionPNSNoneEEG: diffuse delta slow activity	Severe dysfunction (EF < 35%)	FeverAbdominal painDiarrhoeaFemoral artery thrombosisSubpleural thickenings and pleural effusion	MRI: normal	Normal	ICU admissionIVIGMethylprednisolone	Full recovery
	7 yearsF	NA	Serology: positive	↑ CRPNeutrophilia↑ ferritin↓ PLT	CNSIrritabilityMood deflectionHeadacheDiffuse limb painSpeech disorderPhotophobiaMeningismDrowsinessPNSNoneEEG: diffuse theta slow activity	None	FeverAstheniaAbdominal painDiarrhoeaRash	MRI: normal	Normal	IVIGMethylprednisolone	Full recovery
	10 yearsM	NA	RT-PCR: positiveSerology: positive	↑ NT-pro BNPTroponin T: normal↓ PLT	CNSHeadacheDrowsinessIrritabilityMood deflectionPNSNoneEEG: 8 Hz posterior dominant rhythm	Mild dysfunction (EF 48%)	FeverAstheniaAbdominal painNauseaConjunctivitis	NA	NA	IVIGMethylprednisoloneICU admission	Full recovery
	8 yearsM	NA	RT-PCR: positiveSerology: positive	↑ CRPNeutrophilia↓ PLTLymphocytopenia↑ ferritin	CNSIrritabilityDrowsinessMood deflectionPNSNoneEEG: 8 Hz posterior dominant rhythm	None	FeverEmesisAbdominal painMild subpleural thickenings	NA	NA	IVIGMethylprednisolone	Full recovery
	8 yearsF	NA	RT-PCR: positiveSerology: positive	↑ CRP↑ PCT↑ D-dimer↑ NT-pro BNP↑ Troponin T↑ IL-6↓ PLTHyperglycemiaNeutrophiliaLymphocytopenia	CNSIrritabilityDrowsinessMood deflectionPNSNoneEEG: slow delta waves mixed with posterior dominant rhythm (8 Hz)	Mild dysfunction (EF 48%)	FeverAbdominal painEmesisDiarrhoeaConjunctivitisSubpleural thickenings	NA	NA	IVIGMethylprednisoloneICU admission	Full recovery
Ray et al.¹¹	25 PIMS-TS patients10 (1–17) years	White (3/25, 12%)Black (14/25, 56%)Asian (8/25, 32%)	RT-PCR positive: 11/25 (44%)Serology positive: 19/25 (76%)	CRP: 29 mg/dl (8–55.6)Elevated acute-phase reactants: 25/25 (100%)WBC 20,000/ul (3000–44,400)	CNSEncephalopathy: 22/25 (88%)Seizures: 4/25 (16%)Headache or meningism: 10/25 (40%)Behavioural changes: 9/25 (36%)Hallucinations: 6/25 (24%)Ataxia: 3/25 (12%)Stroke: 2/25 (8%)ADEM: 1/25 (4%)PNSPeripheral nervous system involvement: 10/25 (40%)	Cardiovascular shock: 9/25 (36%)	Systemic features (fever, rash, hypotension or shock) 25/25 (100%)Respiratory involvement: 6/25 (24%)	CT or MRI: 23/25 (92%)Abnormal neuroimaging: 17/23 (74%)—MERS: 7/25 (28 %)—Stroke: 2/25 (8%)EEG: non-specific focal or generalized background slowing: 13/25 (52%)	Pleocytosis: 3/25 (12%)	PICU admission: 20/25 (80%)Inotropic support: 13/25 (52%)Immunomodulation: 22/25 (88%)	Disability: 7/25 (28%)Death: 1/25 (4%)
Lindan et al.²⁵	11 PIMS-TS patients	NA	NA	NA	CNSNAPNSNA	NA	NA	7/11 (64%): splenial lesion of the corpus callosum4/11 (36%): enhancing myositis of the facial or neck musculature2/11 (18%) cranial nerve enhancement1/11 (9%): cauda equina enhancement1/11 (9%): myelitis1/11 (9%): multiple microthrombi	NA	NA	5/11 (45%): clinically normal at hospital discharge6/11 (55%): clinically improved at hospital discharge

ADEM, acute disseminated encephalomyelitis; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; CT, computer tomography; ECG, electrocardiography; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalography; EF, ejection fraction; EMG, electromyography; ESR, erythrocyte sedimentation rate; FLAIR, fluid-attenuated inversion recovery; GCS, glasgow coma scale; HFNC, high flow nasal cannula; ICU, intensive care unit; IVIG, intravenous immunoglobulin; L, lymphocytes; LDH, lactate dehydrogenase; LMWH, low molecular weight heparin; MCA, middle cerebral artery; MERS, Mild Encephalitis/Encephalopathy with Reversible Splenial Lesion; MRI, magnetic resonance imaging; N, neutrophils; Na, sodium; NA, not available; NT-pro-BNP, brain natriuretic peptide; PCT, procalcitonin; PICU, paediatric intensive care unit; PIMS-TS, pediatric inflammatory multisystem syndrome tempo rally associated with COVID-19; PLT, platelets; PNS, peripheral nervous system; PRES, posterior reversible encephalopathy syndrome; RT-PCR, real time polymerase chain reaction; US, ultrasonography; WBC, white blood cells.

Epidemiology

51.6% of patients (33/64) were male. The median age was 9 years. Among those with known ethnicity, the majority (59%, 23/39) were African descent. 28.2% was Asian (11/39); only 12.8% was Caucasian (5/39).

SARS-CoV-2 tests

85% of the patients (51/60) who underwent SARS-CoV-2 serology testing resulted positive, while RT-PCR on nasopharyngeal swab resulted positive in 42.6% of patients (26/61).

Signs and symptoms

Among neuro-PIMS-TS reported patients, fever was the most common finding (97.4%, 38/39). Vomiting (53.8%, 23/39), abdominal pain (53.8%, 21/39), and diarrhoea (41%, 16/39) were also frequent clinical signs, together with skin rash (53.8%, 21/39) and conjunctivitis (33.3%, 13/39). Dyspnoea was reported in 20.5% of these patients (8/39).

Blood tests

Among neuro PIMS-TS patients reported in case reports and case series, 75% (18/24) showed a CRP value higher than 20 mg/dl; a CRP value higher than 30 mg/dl was detected in 45.8% of cases (11/24). 46.6% (7/15) showed a PCT value higher than 30 ng/ml.

Ferritin levels resulted higher than 1000 ng/ml in 50% of these patients (10/20); a D-dimer elevation above 2500 ng/ml was reported in 73.7% of them (14/19).

NT-pro BNP was not routinely performed in neuro PIMS-TS children; 26.9% of cases reported a NT-pro BNP determination during the clinical course with a median value of 13,358 pg/ml.

Neurological manifestations

Encephalopathy was the most common neurological finding, involving 82.8% of neuro PIMS-TS patients (53/64). 43.8% of patients (28/64) experienced headache and/or meningism. Behavioural changes were described in 37.5% (24/64) and hallucinations in 21.9% of cases (14/64). Seizures were documented in 9.4% of patients (6/64). 4 stroke episodes (9.4%, 6/64) were also reported.

Signs of intracranial hypertension (abducens palsy 3/39, papilledema 2/39) were described in a minority of cases. Proximal and/or global weakness was sometimes reported, involving 18% of children (7/39). However, Ray et al. reported a higher rate of peripheral nervous system involvement among their patients (40%, 10/25).

Cardiac manifestations

Among neuro PIMS-TS patients, 30% (9/30) presented with tachycardia and 52.7% (29/55) with hypotension and/or shock. Indirect cardiovascular signs of intracranial hypertension (hypertension and bradycardia) were reported in two cases.

Coronary arteries dilatation and/or aneurysm were described in 25% of patients (6/24); ventricular dysfunction was reported in 48.6% of cases (18/37).

Neuro-imaging findings

Signal changes in the genu and/or splenium of the corpus callosum (consistent with MERS) were the most common imaging findings among all neuro PIMS-TS patients, accounting on 30.4% of cases (21/69). 11.6% of them presented with radiological signs of stroke (8/69).

Among neuro PIMS-TS patients reported in case reports and case series, normal brain imaging was quite frequent, being documented in 42.4% of patients (14/33). Cerebral oedema and anomalies of optic nerves were both described in 2 cases. Lindan et al. also reported two cases of cranial nerve enhancement (18.2%, 2/11) among their patients; myositis of the facial or neck musculature was a common finding, involving 36.4% of children (4/11).

Treatment

A first-line immunomodulatory treatment with IVIG and methylprednisolone was received by 84.6% (33/39) of neuro PIMS-TS patients. 23.1% of them (6/26) also required the recourse to anakinra. Antibiotics were administered in 18% of patients (7/39). Vasoactive support was necessary in 34.3% of cases (9/26). 30.8% of patients (12/39) underwent anticoagulant treatment, while aspirin was administered in 10.3% (4/39).

Ray et al. reported a high rate of paediatric intensive care unit admission (80%, 20/25), with inotropic support in 52% of cases (13/25) and immunomodulatory treatment in 88% of patients (22/25).

Outcomes

A complete recovery without sequelae was reported in most cases (64%, 48/75). However, a variable degree of residual disability was observed, involving 32% of patients (24/75) and ranging from hemiparesis and wheelchair bounding to mild behavioural changes. Death was a rare adverse event (4%, 3/62).

Discussion

To the best of our knowledge, we reported the youngest PIMS-TS patient presenting a neurological involvement. Four case reports, five case series, one prospective cohort study and one multicentre study have previously described neuro PIMS-TS patients, recording a total amount of 75 children, with a median age of 9 years (Table 1).

As regards ethnicity, our infant was of African descent. It is well known that most of the PIMS-TS patients are African/Afro-Caribbean, Hispanic and South Asian, mainly in Western countries.²⁶ Only few cases were described in East Asia, probably because of the lack of knowledge of this new clinical entity at the beginning of pandemic.²⁶ African ancestry was also one of the most represented in neuro PIMS-TS.

Our patient presented a positive SARS-CoV-2 serology, with negative RT-PCR on nasopharyngeal swab. LaRovere et al. described a 22% of patients reporting neurological symptoms between COVID-19 and PIMS-TS patients and a concomitant positivity of both serology and RT-PCR was often reported^10,11 making difficult to distinguish between acute hyperinflammatory COVID-19 and PIMS-TS. Patients with and without neurological involvement presented a similar rate of PIMS-TS diagnosis and life-threatening neurologic events did not show a predominance among PIMS-TS cases.

Considering clinical features, our patient presented high-grade fever, emesis and widespread skin rash as reported in previous cases.

In this group of patients, a severe neurological involvement was associated to a remarkable inflammatory state,^10,11 similarly to KD patients.²⁷ Our infant presented with acute cerebral oedema and deep increase of inflammatory markers. A CRP value >30 mg/dl, a PCT value >30 ng/ml and a ferritin level >1000 ng/ml were observed in about half of the reported neuro PIMS-TS cases.

Our infant presented with wide, tense and bulging anterior fontanelle, with a rapid subsequent neurological impairment and a deep increase of NT-pro BNP (92,230 pg/ml) at the clinical onset, without any sign of myocardial dysfunction. NT-pro BNP represents a marker of left ventricular dysfunction in heart failure patients since it regulates systemic fluid volume through vasodilatation and natriuresis.²⁸ However, the wide distribution of BNP receptors in the brain may suggest a novel pathway between heart and brain and a potential additional role for NT-pro BNP in the development of cerebral oedema.^29,30

As regards the pathogenesis of the neurological involvement observed in our case and in the most of the neuro-PIMS-TS patients, it is reasonable to suppose that is due to an immune-mediated pathophysiological mechanism triggered by previous SARS-CoV-2 infection rather than a direct viral invasion. This hypothesis is supported by the fact that the neurological symptoms occurred during a post-infectious multisystem inflammatory condition. Moreover, cytopathological evaluation of cerebrospinal fluid samples of previous neuro-PIMS-TS cases were negative for SARS-CoV-2 RNA by RT-PCR and reported increased numbers of lymphocytes and macrophages suggesting that the production of cytokines induced by the inflammatory response is responsible of the neurological manifestations. This hypothesis is also supported by the excellent response to immunomodulatory treatment for neurological complications in this group of patients.^23,24

Encephalopathy, headache and/or meningism and behavioural changes (33.3%) were the most reported symptoms in neuro PIMS-TS patients. Signs of intracranial hypertension (abducens nerve palsy, papilledema) and cerebral oedema were observed in a minority of cases.

A clinical hallmark was the concomitant presence of myocardial disfunction. Cardiovascular impairment frequently coexists with neurological symptoms since hypotension and/or shock and ventricular dysfunction were frequently observed. Coronary arteries ectasia and/or aneurysm were also reported even if typically transient, usually occurring at the onset of fever and rarely progressing to aneurysms.^31–33

As regards neuroimaging, a non-specific periventricular hyperintensities and a slight cerebral and cerebellar trophism reduction was observed in our patient. According to previous data, MERS is a common finding in neuro PIMS-TS patients.¹¹ MERS is a distinct radiological entity characterized by hyperintensities of the genu and/or the splenium of corpus callosum on MRI T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted images.³⁴ MERS may have different causes; primarily viral infections as most frequent triggers,³⁴ although its exact pathophysiology is still unknown. The most accredited hypothesis is that pro-inflammatory cytokines lead to glutamate release and oxidative stress in neurons, resulting in cytotoxic oedema.³⁴ MERS cases following SARS-CoV-2 infection have been reported.³⁵ Similarly, anecdotal cases of KD-associated MERS have reported,^25,36 strengthening the hypothesis that MERS may be a consequence of systemic hyper-inflammation.

Lindan et al.²⁵ collected 38 cases of neuroimaging abnormalities in COVID-19 and PIMS-TS children. In the acute COVID-19 subgroup, 50% of patients presented a neuroimmune disorder (ADEM-like and neuritis); 33.3% had fulminant co-infections (tuberculosis, chickenpox, bacterial sepsis) and rapidly died; one patient (8.3%) showed an aggressive necrotizing myelitis; a 27-weeks pregnant adolescent girl presented with posterior reversible encephalopathy syndrome and occipital infarction. In the PIMS-TS subgroup, 64% of patients presented splenial lesions; two patients (18%) had cranial nerve enhancement; one patient (9%) reported cauda equina enhancement and myelitis was observed in one case (9%). Four patients (36%) had enhancing myositis of the facial and neck muscles; one patient (9%) reported multiple brain microthrombi.

These results suggest that neuroimmune disorders (i.e. ADEM-like changes, neuritis, Guillain Barrè syndrome) may be more frequently observed during acute COVID-19 and neurological symptoms during COVID-19 and PIMS-TS may be caused by different immune mechanisms.

Focusing on treatment, our patient presented with a refractory disease and maximal therapy was performed, including IVIG, steroids and anakinra. Considering previous data, IVIG and methylprednisolone were the most common adopted treatment. Anakinra was administered in 23% of these patients, mostly in case of first-line treatment-resistant cases.

As regards thromboprophylaxis, our patient was treated with enoxaparine, while in the subacute phase anti-platelet regimen was started. Anticoagulants were used in 23% of neuro-PIMS-TS patients, while aspirin was used in 15.3% of cases.

Despite being a life-threatening condition with high rates of ICU admission,^10,11 PIMS-TS patients, if promptly treated, report a complete recovery. As regards neuro PIMS-TS subgroup, a complete recovery was observed in most of the patients although a significant rate of disability (32%) was reported, thus underlying the importance of a timely diagnosis and treatment.

In conclusion, neurological involvement may be frequent in PIMS-TS patients as expression of the hyperinflammatory state. Symptoms are acute and reversible in most of the patients with a favourable response to immunomodulatory treatment. Available data suggest that paediatric patients experience different types of neurological involvement during acute COVID-19 and PIMS-TS. Further studies are needed to better characterize these different neurological manifestations related to SARS-CoV-2 infection suggesting the opportunity of different patient-tailored therapeutical strategies.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Maria Vincenza Mastrolia

Gabriele Simonini

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