key: cord-1009516-2gwl260z authors: Khan, Afreen; Chakravarty, Aparna; Jain, Abhinav; Harish, Rekha; Naqishbandi, Rizwan; Ishani, Twisha title: Clinical spectrum of neurological manifestations in pediatric Covid-19 illness: a case series date: 2021-07-10 journal: J Trop Pediatr DOI: 10.1093/tropej/fmab059 sha: 8fd9da664c75d3ad7050239375165565d9c5c6d5 doc_id: 1009516 cord_uid: 2gwl260z We describe a cohort of three patients with variable neurological presentations by SARS COV-2 infection. It includes one case each of Acute Cerebellitis, Acute encephalomyelitis and Arterial Ischemic Stroke. To the best of our knowledge we report the first pediatric case of acute cerebellitis due to SARS CoV-2 infection. All critically ill patients were treated with methylprednisolone pulse therapy and dexamethasone. Patient with acute cerebellitis in addition required Intravenous Immunoglobulin infusion. All the patients responded to the treatment with complete neurological recovery. Since the emergence of COVID -19 pandemic, varied clinical manifestations are reported which further broaden the spectrum of illness caused by SARS CoV-2 infection. In the early phase of the pandemic most published data were on adults with SARS CoV-2 infection. Only mild symptoms like fever, cough, headache, rhinorrhoea, myalgia, sore throat etc. were reported in children [1] . It was therefore presumed that children had only mild symptoms with less hospitalisation, until April 2020 when reports from the United Kingdom described the features suggestive of incomplete Kawasaki Disease and Toxic shock syndrome in association with SARS CoV-2 infection [2] . Since then, similar presentations have been reported in children across the globe and have been termed as Multisystem Inflammatory syndrome in children (MIS-C) [3] [4] [5] [6] [7] . It incorporates a spectrum of presentations from mild symptoms to severe life threatening complications like respiratory failure, shock, disseminated intravascular coagulation, renal failure etc [8] . Data on pediatric neurological complications following COVID 19 is scarce and they are either reported as a part of large studies or as individual case reports. Here we report three cases with different neurological manifestations of SARS CoV-2 infection and also the first case of acute cerebellitis in pediatric age group. Consent was taken from the parents of all the cases. CASE SERIES: 1. Acute cerebellitis (Case 1) Eleven year old male child presented to the Emergency Department with two episodes of generalised tonic-clonic seizures. There was a history of fever, headache, vomiting and abdominal pain for last three days. On examination the child was delirious and had horizontal nystagmus, dysarthria, nuchal rigidity, features of raised intracranial tension (ICT) and shock. In view of raised ICT 3% normal saline was infused. Broad spectrum antibiotics (Ceftriaxone and Acyclovir) along with intravenous fluids, inotropes were administered. Contrast enhanced magnetic Resonance Imaging (CEMRI) brain revealed features of acute cerebellitis (Figure 1a and 1b) . Initial laboratory investigations were unremarkable. Intravenous Methylprednisolone pulse therapy (30 mg/kg/day for 3 days) was started. On third day the child deteriorated neurologically however his hemodynamical parameters stabilized and was weaned off the inotropic infusion. Serial MRI revealed increasing cerebellar edema. Further laboratory evaluation showed elevated inflammatory markers along with positive COVID serology, fulfilling the criteria for MIS-C (Table-1 ). Other laboratory investigations were not suggestive of any viral, bacterial or immunological abnormality (Table1).CSF analysis could not be performed due to persistent raised ICT. Intravenous Immunoglobulin (IVIG) infusion (2gm/kg of body weight single dose), mannitol and steroids (intravenous Dexamethasone 0.15mg/kg/dose 6 hourly) were added. Child improved gradually. Cognition improved in next four days but cerebellar signs -ataxia, dysarthria and nystagmus persisted. CEMRI brain performed on Day 7 also displayed slow resolution of cerebellar edema. Oral steroids (Prednisolone 2mg/kg/day), antiepileptic drugs, osmotic agents along with physiotherapy were continued. Steroids were gradually tapered over a period of 6-8 weeks. On follow up at four months child is stable with normal neurological examination and neuroimaging demonstrated complete resolution. Seven year old female, known case of right temporal epilepsy on multiple antiepileptic drugs since 5 years of age presented with a history of high grade fever, loose stools, vomiting and throat pain for four days. On examination she was sick, febrile with generalized erythematous rash, swollen lips and non suppurative tonsillo-pharyngitis. She was hemodynamically stable with normal systemic examination. Intravenous antibiotics -Injection Ceftriaxone 100 mg/kg/day and Clindamycin-30 mg/kg/day) along with symptomatic treatment were started. SARS CoV-2 RT PCR was negative and initial laboratory parameters were normal except renal profile suggestive of prerenal AKI. Next day she developed toxic shock syndrome. Significant laboratory parameters were leucocytosis, thrombocytopenia, raised inflammatory markers with slightly deranged renal profile and hypo-albuminemia (Table 1) . Child was shifted to Pediatric Intensive Care Unit, started on inotrope (Norepinephrine @1 µg/kg/min) and antibiotics were upgraded to injection Meropenem @ 60 mg/kg/day and Vancomycin @45 mg/kg/day. Over next 36 hours the body rash and pharyngitis improved. However on day 4, there was a sudden neurological deterioration with Glasgow Coma Scale of 5/15 and poor respiratory efforts, and thus was mechanically ventilated. Chest X-ray was normal. CSF analysis was performed which did not reveal any evidence of viral/bacterial meningitis and RT PCR for COVID-19 was also negative. However, CEMRI brain suggested possibility of encephalitis with myelitis ( Figure 2a and 2b) and serology for SARS CoV-2 was positive. Child met all the criteria of Multisystem Inflammatory Response Syndrome-Children (toxic shock syndrome, multisystem involvement, raised inflammatory markers, no other obvious cause of inflammation, positive SARS CoV-2 serology). In setting of MIS-C with no other explainable cause for neurological involvement it was attributed to SARS CoV-2 infection. Pulse methylprednisolone therapy (30 mg/kg/day) for 5 days followed by intravenous dexamethasone 0.15mg/kg/dose 6 hourly was started. Child was extubated after two days of ventilation. After receiving pulse methylprednisolone therapy she developed hypertension which was managed with antihypertensive drugs. She responded well to the therapy and was discharged after 16 days on oral steroids which were continued 6 weeks and stopped after tapering. At two month follow up patient had no neurological deficit. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Fifteen years old female with no chronic medical history presented to Emergency Department with brief history of headache and multiple episodes of generalized tonic clonic seizures in the last 24 hours. On examination child was apprehensive, sick looking, conscious and had respiratory distress. The saturation on oxygen by mask @ 6 L/min was 86%. Initial stabilization started with administration of high flow oxygen by mask with reservoir bag, intravenous fluids and antiepileptic drug. Her condition soon deteriorated and patient had gasping respiration for which she was mechanically ventilated. A probable diagnosis of severe acute respiratory infection was made. Initially the seizures were attributed to hypoxia. Complete neurological examination could not be performed as child was sedated during ventilation. Empirical antibiotics Ceftriaxone, vancomycin and Oseltamivir were started. Initial laboratory values showed total normal leucocyte count with lymphocytopenia and raised inflammatory markers (CRP, ESR, Ferritin and D-Dimer). Chest X-ray was consistent with acute respiratory distress syndrome (bilateral coalescent opacities predominantly in the lower zones and parahilar location) but 3 subsequent samples from nasopharynx and tracheal aspirate were negative for SARS CoV-2 RT PCR. She was gradually weaned off the ventilator support and shifted to Bilevel Positive Airway Pressure (BiPAP) mode of NIV after 5 days of admission. Post extubation, on neurological examination she had tremulousness of tongue and horizontal nystagmus. Neuro-imaging showed a small hypodense area involving subcortical white matter in the right frontal lobe suggestive of infarct( Figure 3 ) and a small intra-cerebral hematoma in left frontal lobe with mild peri-lesional edema. Her antibody titres for COVID were significantly raised with raised inflammatory markers. A diagnosis of MIS-C was made. She was started on IV dexamethasone (0.15mg/kg/dose 6 hourly) followed by oral steroids for one week. Child also had hypertension for period of two days the cause of which could not be ascertained. She gradually improved and was discharged after 17 days. A follow up at 4 month showed no neurological deficit. We report a cohort of three patients with distinct neurological involvement due to SARS CoV-2 infection:One case each of acute cerebellitis, arterial ischemic stroke and encephalomyelitis. Evidence of infection was positive antibodies against SARS-CoV-2 in all. The IgG antibodies were measured in patients serum by using indirect chemiluminescence immunoassay(CLIA) technology for the quantitative determination of Anti-S1 and Anti -S2 specific IgG antibodies to SARS CoV-2, a value of more than 15AU/ml was considered positive. Recent studies have suggested that COVID serology has high sensitivity and specificity in COVID-19 detection [9, 10] . A meta-analysis performed by Zhang et al to study the diagnostic efficacy of anti SARS-CoV-2 IgG/IgM test for COVID 19 reported pooled sensitivity and specificity of 0.85(95% CI 0.79-0.90) and 0.99 (95% CI 0.98-1.0) [9] . The diagnosis of MIS-C was made when all the criteria suggested by CDC or WHO were fulfilled [11, 12] . In the current series all three patients had specific neurological complications, were seriously ill, had MIS-C and definite neuroimaging finding. It was 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 consistent with the reports showing association of specific neurological complications with seriously ill patients [13, 14] . In adults, cerebrovascular problems due to thrombotic complications are the most common neurological sequel followed by meningitis and encephalitis [15] . There is limited information about detailed neurological involvement by SARS COV-2 virus in children and no large case series or studies on the same are available till date. They are also underreported in preverbal and critically ill children. To study these complications, Panda et al conducted a systematic review and meta-analysis. They included all articles published from December 2019 to July 2020 in children < 18 years with confirmed neurological complications due to COVID-19. The review showed that amongst 41 children with COVID -19 associated definite neurological complications, encephalopathy was a predominant neurological manifestation (25 children) followed by meningeal signs (17 children) and seizures (12 children) [13] . Similarly encephalopathy was the most common finding in the present series. In the review by Panda et al neuroimaging findings were available only for few patients but most of them were normal [13] . In contrast to this Lindan et al described post infectious immune mediated acute disseminated encephalomyelitis as the most common neuroimaging abnormality followed by myelitis and neural enhancement in 38 children with neurological disease related to SARS CoV-2 infection [16] .However we cannot assign such ranks to our findings due to small cohort with three different neuroimaging findings. At the time of presentation one patient had no respiratory involvement, one presented with SARI (severe acute respiratory infection) and other with pharyngitis that later developed pneumonia. This is consistent with the study by Ahmad et al. They suggested that neurological symptoms may precede respiratory symptoms or may be the only symptom of COVID 19 [14] . Till date only few cases of arterial ischemic stroke were reported in children whereas none of acute cerebellitis and acute hemorrhagic encephalopathy [13, [16] [17] [18] [19] . To the best of our knowledge we here report the first case of acute cerebellitis associated with SARS CoV-2 in children. After the onset of COVID pandemic, only ten cases of cerebellar symptoms, associated with SARS COV-2 infection have been reported. All patients were adult males and only one had serious neurocognitive impairment. Abnormal neuroimaging (bilateral cerebellar edema) was present only in one patient. Seven patients were treated with combination of IVIG and steroids or either of them whereas three patients did not receive any specific therapy. There was mortality of one patient who had severe respiratory involvement. Rest recovered completely within a short duration. [20] [21] [22] [23] [24] [25] [26] . In contrast to these reported patients with cerebellar symptoms, our patient was an adolescent male who had serious neurological involvement with significant MRI changes. He was treated with IVIG and steroids. Though he responded gradually but recovered completely. In adults cerebrovascular accidents (CVA) are more commonly seen neurological complication of SARS CoV-2. CVA is rarely seen in children. Only few case reports are available till date in pediatric age group [19, 27, 28] . Lauren et al performed a survey including 61 international sites with pediatric stroke expertise and found that 4.6% of all the patients who had stroke were found to be positive for SARSCoV-2 however most of them 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 had additional established risk factor [29] . No such risk factors suggestive of thrombophilia were found in our patient. The main presenting complaints in previous reports were headache, vomiting and weakness of extremities but in our patient with AIS (Arterial Ischemic Stroke) had no previous history and presented with seizures and severe respiratory distress. In this series all patients were treated with intravenous dexamethasone and pulse methylprednisolone therapy while one patient with acute cerebellitis required intravenous immunoglobulin (IVIG). These patients responded gradually to the treatment. On follow up visits none had any neurological deficits. Recent studies have also shown that steroids, IVIG and supportive therapy are mainstay of management [30] . Various pathogenic mechanisms have been proposed but nothing confirmatory has been known so far. ACE2 receptors present on glial cells in brain and spinal neurons serve as a target receptor for attachment and internalization of virus followed by multiplication and damage. The virus enters the brain either through the circulatory or neuronal pathway. The cytokines disrupt the blood brain barrier during the cytokine storm through enabling the virus brain entry. Virus can also reach the brain through the nasal epithelium via olfactory neurons and olfactory bulb or through peripheral nervous system in a retrograde manner through neurons. Virus damages the cells either directly or through post infectious autoimmune process. The above two mechanisms can explain the occurrence of encephalitis, ADEM (autoimmune disseminated encephalomyelitis) etc. [31] [32] [33] . In our series, both patients with cerebellitis and encephalomyelitis had negative SARS CoV-2 RT PCR, positive serology, elevated inflammatory markers and responded to the immunosuppressive therapy, which favors an immune-mediated phenomenon. Cerebrovascular complications have resulted from thrombotic events supported by various studies demonstrating a hypercoagulable state in COVID; the cause of which is multifactorial like endothelial dysfunction, inflammation, hypoxia etc [34, 35] . Binding to ACE-2 receptors may also cause abnormally elevated blood pressure which increases the risk of cerebral hemorrhage. In three of our patients who were seriously ill transient hypertension was present. In patient with acute cerebellitis it was attributed to raise intracranial tension but in other two patients it could be explained by either steroids or abovementioned mechanism. Detailed studies can help to analyze the association of hypertension with SARS CoV-2 infection. In conclusion, though the vaccine has been introduced in many countries across the globe, it is not yet recommended in children < 18 years of age [36] . Even after recommendation follow up studies are required to assess the neuro-protective efficacy. Poor immunization coverage especially in resource limited countries and emergence of new mutant strains are other potential challenges. Identifying a neurological disease associated with SARS CoV-2 in patients with mild or no respiratory involvement is often difficult. We hereby emphasize that any neurological symptom in a SARS CoV-2 infections needs to be investigated appropriately and reported in detail to create a better understanding of the disease spectrum. This will enable treating physician for timely diagnosis and management failure of which might leave patients with severe neurological sequelae. 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