key: cord-0996239-mt74n52l
authors: Avila-Smirnow, Daniela; Céspedes, Pamela; Reyes, Felipe; Angulo, Jenniffer; Cavagnaro, Agustín; Wegner, Adriana
title: Neuromuscular complications of severe COVID-19 in paediatric patients: medium-term follow-up
date: 2022-04-09
journal: Neuromuscul Disord
DOI: 10.1016/j.nmd.2022.04.001
sha: 6f26a7e8629f5c5179667aee96695051b2d390b2
doc_id: 996239
cord_uid: mt74n52l

Neuromuscular complications in paediatric patients with severe coronavirus disease 2019 (COVID-19) are poorly characterised. However, adult patients with severe COVID-19 reportedly present with frequent neuromuscular complications that mainly include critical illness neuropathy (CIN), critical illness myopathy (CIM), and focal neuropathies. We examined the records of all paediatric patients with severe COVID-19 who were mechanically ventilated and experienced neuromuscular complications from our single tertiary centre between March 2020 and August 2021. During this period, 4/36 (11%) patients admitted to the paediatric ICU who were mechanically ventilated experienced neuromuscular complications (one CIM, two focal neuropathies, and one CIN associated with plexopathy). In three of them, the gamma genetic variant of SARS-CoV-2 was identified. At the 4–5 month follow-up, three of our patients exhibited slight clinical improvement. We conclude that paediatric patients with severe COVID-19 may present neuromuscular complications similar to adults (11%), and their medium-term prognosis seems unfavourable.

Patients with severe coronavirus disease 19 , like other patients hospitalised in the Intensive Care Unit (ICU), can present with specific neuromuscular (NM) complications, with critical illness neuropathy (CIN) and myopathy (CIM) being the most common [1] . In adults, severe COVID-19 is also reportedly associated with focal neuropathies and plexopathies at a significantly higher frequency than expected [2] . CIN and CIM have been reported in up to half the adults presenting with severe COVID-19 [1] . A prospective study observed that CIN was more frequent in patients who suffered COVID-19 than in a control group of critically ill patients [3] . Conversely, focal neuropathies and plexopathies have been observed in 5-15% of adult patients with COVID-19 who were hospitalised in the ICU [4, 5] . These findings suggest that there is an association between severe COVID-19 and peripheral nerve involvement, at least in adults (Table 1) .

However, in paediatric patients, it has been reported that patients hospitalised for COVID-19 may present with flaccid tetraparesis [6, 7] , characterised by variable myopathic and neuropathic signs in electrophysiological studies. Nevertheless, we found no reports of focal neuropathy or plexopathy in children with severe COVID-19 [8] .

Between March 2020 and August 2021, 11% (4/36) of the children under the age of 18 years admitted to the paediatric ICU of the Sótero del Río Hospital for severe COVID-19 with mechanical ventilation (MV) requirement experienced NM complications. Given that NM complications associated with severe COVID-19 in paediatric patients have been poorly characterised, here, we report the details of these four patients in our centre ( Figure   1 ). This study was approved by the local ethics review board (Comité Etico Científico del Servicio de Salud Metropolitano Sur Oriente). Owing to the retrospective nature of this study, the requirement for informed consent was waived.

These four patients were admitted to the ICU between May and June 2021, with the diagnosis of acute respiratory distress syndrome due to COVID-19 and were treated with a dexamethasone and anticoagulation scheme for 10 days , according to our protocol. No other anti-inflammatory or immunomodulatory drugs were used as part of this protocol. The SARS-CoV-2 virus gamma variant was identified in three patients. The characteristics of each patient are presented in Tables 2 and 3 .

Three of the four patients with NM complications were ventilated in prone position for a mean period of 80 h. In contrast, only two of the 32 patients who did not have NM complications were ventilated in a prone position for a mean period of 54 h. Additionally, all the patients with NM complications were obese, with a mean BMI of 35, but only 15 of the 32 patients without NM complications were obese, having a mean BMI of 31.

A 17-year-old boy with type III obesity was admitted to the ICU, intubated, and placed in the prone position. On the second day after admission, an acute myocardial infarction was suspected, because ultrasensitive troponine I increased up to 1005 pg/mL (normal value<34 pg/mL). Therefore, salicylic acetyl acid and atorvastatin were initiated, and cardiac ultrasound was performed and showed normal findings. Posteriorly, troponin declined to 10 pg/mL, on day eleven after admission, while a progressive elevation of CK was observed during atorvastatin treatment, reaching up to 3.400 UI/L (normal value 30-200 UI/L) on day 10 after admission. We did not measure myoglobin, as it was not available at our laboratory at that moment. Atorvastatin-induced myositis was then suspected. Hence, we decided to stop this medication, and CK normalized posteriorly. A final diagnosis of myocarditis was made, but the patient did not meet other MIS-C criteria.

He required invasive MV (IMV) for 17 days, was prone for 55 h, and paralysed for 7 days.

On the 21st day post-admission, after extubation and several days of suspended sedation and paralysis, the patient presented with tetraplegia. On examination, he was awake-with preserved occulomotility and facial mimicry-but also had tetraplegia and Achilles areflexia, with a Medical Research Council (MRC) sum score [9] of 6/60. An electrophysiology study showed a decrease in the amplitude of CMAPs (compound muscle action potentials) and SNAPs (sensitive nerve action potentials), with signs of active denervation without voluntary muscle activation, which is suggestive of CIN. His mobility recovered over time, but on admission day 55, as he regained muscle strength, asymmetry was observed in the mobility of the upper limbs with paresis of the left upper limb, for which brain CT and angio-CT were requested. No abnormalities were noted on the images.

On re-examination, hypotonia of the left upper limb was observed, with the upper limb adducted and extended. Thus, left brachial plexopathy was suspected. The electrophysiology study was repeated and the clinical diagnosis was confirmed, suggesting a compromise of the upper trunk. At the last follow-up, 5 months after ICU admission, the patient could stand independently for 30 s and had recovered partial mobility of the left upper limb, with a strength score of 2/5 on the MRC scale in the most affected muscles.

The electrophysiological study was repeated, and signs of re-innervation in the affected muscles were observed.

A 15-year-old girl with a history of obesity was admitted to the ICU, requiring non- Electroneuromyography performed 4 months after her ICU admission showed ulnar neuropathy at the elbow level. At the last follow-up, the patient still experienced persistent weakness and hypoesthesia but was able to perform her daily living activities.

An obese 10-month-old female infant was admitted to the ICU, requiring IMV for 16 days, nine of which she was ventilated in the prone position. On day 19 of the disease-after extubation and suspension of sedation and paralysis, while she was with NIMV-weakness of the four extremities was observed and an MRC sum score of 28/60 was observed on neurological examination. A myopathic process was suspected and subsequently confirmed by an electrophysiological study. She progressively improved; at 3 months after ICU admission, the patient had returned to her neurological baseline. At the last follow-up, 4 months after admission, neurological examination showed a normal strength MRC sum score of 60/60, and she was able to walk with assistance.

A 15-year-old girl with a history of type III obesity was admitted to the ICU and was She was pain-free in the pregabalin suspension phase, and could walk 4 months after ICU admission; unfortunately, the foot drop remained and motor examination revealed no clinical improvement.

Here, we presented four cases of paediatric patients with severe respiratory distress syndrome due to COVID-19 and serious complications of the peripheral nervous system. Three cases were adolescents with focal lesions of the peripheral nerves and plexuses, and one patient also had a CIN. One patient was an infant with CIM. Notably, three of the four cases were associated with the gamma genetic variant, required IMV, and experienced more severe motor impairment.

adults and children [10, 11] . Among them, milder NM manifestations and complications include anosmia, ageusia, and myalgia. [2, 12] . Patients with severe COVID-19 generally present with more severe NM sequelae-mainly CIN and CIM [1, 13] , focal neuropathies, and plexopathies [4, 5, 14] .

In adults, the NM complications of COVID-19 have been better described and appear to be more frequent than in children. CIN and CIM have been observed in 10-40% of ICU patients with COVID-19 [1, 3, 13] . One study identified that CIN was more frequent than CIM in patients with severe COVID-19, and an early elevation of neuronal damage markers, neurofilament light chain and fibrillary acidic protein, suggested that there was an association between COVID-19 and nerve damage [3] . Additionally, there are several case reports of adult patients over 40 years of age who developed focal polyneuropathies and plexopathies [4, 5, 14] . In these patients, ulnar, sciatic, and brachial plexus nerve involvement were more frequently observed, similar to our paediatric patients.

After several months of the pandemic, we are observing the consequences of COVID-19 at the muscular level [15] [16] [17] . A longitudinal study of 1,655 adult patients reported that at 6month follow-up, the most frequent symptom post COVID-19 was muscle weakness (63% of cases) [18] . Patients with the highest risk of presenting this motor sequela were those with more severe respiratory compromise during hospitalisation.

Several case series have detailed paediatric patients presenting with neurological complications associated with COVID-19, including NM ones. One study reported that 13% [7] of paediatric patients hospitalised for COVID-19 presented with neurological complications and of those, 60% experienced complications of the peripheral nervous system-mainly Guillain Barré syndrome and flaccid tetraparesis [7] . However, pure muscle involvement in children with severe COVID-19 appears to be rare. We found only one case report of a child with myositis after hospitalisation requiring IMV [19] . In our group of patients, only patient 3 presented with a myopathic condition, which was classified as CIM and associated with a moderate elevation of creatine kinase.

All patients who had serious NM complications were obese, and the most severe complications were observed in the two children who had type III obesity and were also carriers of the gamma variant. Further, there was a temporal association between the predominance of gamma variants in SARS-CoV-2 in our country (Chile) and the described cases. These cases were registered in May and June 2021, during the largest wave so far in Chile, with the highest incidence paediatric ICU admission due to COVID-19. A Brazilian study also reported that there was a higher proportion of young adults with severe COVID-19, associated with the circulation of the gamma variant [20] . Due to the greater severity of COVID-19 in younger people, a greater risk of NM complications that seem to be related to the severity of respiratory condition can be expected. The greater severity of gamma variant infection in these patients could be explained by a reduced neutralising reaction to SARS-CoV-2 [21] .

The underlying mechanisms of focal neuropathies in patients with severe COVID-19 have been attributed to prone ventilation, including compression and traction, although some authors have proposed that inflammatory mechanisms may also be contributing factors [4, 5] . An inflammatory mechanism is postulated since neuropathies associated with mild COVID-19, whose parainfectious origin is known, such as Parsonage Turner Syndrome, have been observed [22] . Moreover, a clinical series observed electrophysiological signs suggestive of multiple mononeuritis in patients with COVID-19 [4] . In patients with COVID-19 and CIN/CIM risk factors, such as a longer stay in the ICU, more thromboembolic events, and IMV for more than 2 weeks, have been recognised [18] . In the future, prospective and multicentre studies should examine a larger number of patients to help clarify the mechanisms underlying NM complications. It remains unclear whether these complications are only a consequence of the severity of the disease or whether an inflammatory mechanism associated with COVID-19 is also involved; obesity seems to be a predominant comorbidity in this series. Similarly, it is crucial to understand the long-term prognosis of neuropathies, since in our series, the prognosis was unfavourable.

This is the first report to include neuropathies and plexopathies as NM complications in paediatric patients with severe COVID-19, which is why we believe it is important that we provide detailed descriptions of the clinical presentation and medium-term outcomes of these cases. We recommend being aware of these possibly serious complications in paediatric patients and observing their disease course and possible sequelae accordingly.

We conclude that paediatric patients with severe COVID-19 may present neuromuscular complications similar to adults and that their medium-term prognosis seems unfavourable. 

The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings

Critical illness polyneuropathy, myopathy and neuronal biomarkers in COVID-19 patients: A prospective study

Mononeuritis multiplex: an unexpectedly frequent feature of severe COVID-19

Nerve compression injuries after prolonged prone position ventilation in patients with SARS-CoV-2: A case series

Neurologic and radiographic findings associated with COVID-19 infection in children

Neurologic features associated with SARS-CoV-2 infection in children: A case series report

Coronavirus infections in the nervous system of children: A scoping review making the case for long-term neurodevelopmental surveillance

Medical Research Council-sumscore: A tool for evaluating muscle weakness in patients with post-intensive care syndrome

Neurological complications in patients with SARS-CoV-2 infection: A systematic review

Neurological complications of SARS-CoV-2 infection in children: A systematic review and metaanalysis

Central and peripheral nervous system involvement by COVID-19: A systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings

Clinical and neurophysiological characterization of muscular weakness in severe COVID-19

Brachial plexus neuropathies during the COVID-19 pandemic: A retrospective case series of 15 patients in critical care

Assessment of the frequency and variety of persistent symptoms among patients with COVID-19: A systematic review

Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection

Muscle weakness, functional capacities and recovery for COVID-19 ICU survivors

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study

Children's multisystem inflammatory syndrome with myopathy

SARS-CoV-2 variant of concern P.1 (Gamma) infection in young and middleaged patients admitted to the intensive care units of a single hospital in Salvador

The biological and clinical significance of emerging SARS-CoV-2 variants

Parsonage-turner syndrome associated with SARS-CoV2 (COVID-19) infection

Figure 1: Selection flowchart of 36 pediatric patients with severe COVID-19

Thirty-six patients were hospitalized in the ICU. Six of them had sensitive or motor deficits, but only four of them had motor and EMG findings, which were confirmatory of a neuromuscular complication

The authors want to thank the clinicians who referred the four patients reported here.Funding Sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author Contributions: Pamela Céspedes, Agustín Cavagnaro, and Adriana Wegner were responsible for the intensive care management of the patients. Jenniffer Angulo and Felipe Reyes we responsible for the analysis of SARS-CoV-2 variants. Daniela Avila-Smirnow was responsible of the neurological and electrophysiological assessment of the patients and data analysis. All authors contributed to the writing of the manuscript and have approved the final version.

Adm admission, ALC absolute lymphocyte count, ANC absolute neutrophil count, BMI: body mass index, CRP: C reactive protein, IMV invasive mechanical ventilation, NIMV non-invasive mechanical ventilation, P: patient, WBC white blood cell count,