key: cord-0940526-tihy9oom
authors: INTISO, Domenico; CENTRA, Antonello Marco; GIORDANO, Antonio; SANTAMATO, Andrea; AMORUSO, Luigi; DI RIENZO, Filomena
title: CRITICAL ILLNESS POLYNEUROPATHY AND FUNCTIONAL OUTCOME IN SUBJECTS WITH COVID-19: REPORT ON FOUR PATIENTS AND A SCOPING REVIEW OF THE LITERATURE
date: 2022-04-07
journal: J Rehabil Med
DOI: 10.2340/jrm.v53.1139
sha: 3500e7170dac40bc1ac5a8a1e2cc2bc449e4548f
doc_id: 940526
cord_uid: tihy9oom

Patients with COVID-19 may develop a range of neurological disorders. We report here 4 COVID-19 subjects with intensive care unit-acquired weakness and their functional outcome. In addition, a scoping review of COVID-19 literature was performed to investigate this issue. Of the post-COVID-19 patients admitted to our Neuro-Rehabilitation Unit, 4 (3 males, 1 female; mean age 59.2 ± 8.62 years) had intensive care unit-acquired weakness, diagnosed with electromyography. Muscle strength and functional evaluation were performed on all patients with Medical Research Council, Disability Rating Scale and Functional Independence Measure, respectively, at admission, discharge and 6-month follow-up after discharge. Electromyography revealed that 3 subjects had critical illness polyneuropathy and 1 had critical illness polyneuropathy/critical illness myopathy. At follow-up, the 3 subjects with critical illness polyneuropathy reached full recovery. The patient with critical illness polyneuropathy/critical illness myopathy showed moderate disability requiring bilateral ankle foot-orthosis and support for ambulation. The scoping review retrieved 11 studies of COVID-19 patients with intensive care unit-acquired weakness, concerning a total of 80 patients: 23 with critical illness myopathy (7 probable), 21 with critical illness polyneuropathy (8 possible), 15 with critical illness polyneuropathy and myopathy (CIPNM) and 21 with intensive care unit-acquired weakness. Of 35 patients who survived, only 3 (8.5%) reached full recovery. All 3 had critical illness myopathy, but 2 of these had a diagnosis of probable critical illness myopathy. Intensive care unit-acquired weakness commonly occurred in subjects with COVID-19. Recovery was variable and a low percentage reached full recovery. However, the heterogeneity of studies did not allow definitive conclusions to be drawn.

(SARS-CoV-2) in China (1) , it has spread rapidly to become a severe worldwide pandemic. To date, epidemiological data show more than 277 million people have been infected and more than 5 million have died (2). COVID-19 is a complex disease that predominantly affects the lungs, producing characteristic interstitial pneumonia with respiratory failure and critical conditions, which can require mechanical ventilation (MV) and admission to the intensive care unit (ICU). The large number of people requiring hospital or ICU admission has produced a health "tsunami", stressing health systems worldwide and resulting in organizational disciplinary changes (3) . A severe effect of the pandemic is the saturation of intensive care capacity.

During ICU stay and after discharge critically ill subjects can develop a common neuromuscular complication, defined as ICU-acquired weakness (ICUAW), which includes a spectrum of disorders including critical illness polyneuropathy (CIP), critical illness myopathy (CIM) and overlapping forms (CIP/CIM or CIPNM) (4) (5) (6) . The occurrence of this neurological complication has been variously detected, with a range of 45-80% (7) (8) . The types of ICUAW show characteristic histological and electrophysiological features, but are clinically indistinguishable, since all forms produce weakness and bilateral limb paresis with an absence of tendon reflexes. Although several studies have been published about the disorders affecting the central nervous system (CNS) and the peripheral nervous system (PNS) in patients with COVID-19 (9) (10) (11) , few reports investigating the occurrence of, and recovery from, ICUAW types have been reported.

The aim of this study is to describe the case reports and functional outcomes of 4 COVID-19 patients with ICUAW admitted to our Neuro-Rehabilitation Unit. In addition, a systematic review of the COVID-19 literature was performed to investigate occurrence of, and recovery from, ICUAW in subjects with COVID-19.

After approval from the local Ethics Committee (Sezione Giovanni Paolo II-IRCCS Casa Sollievo della Sofferenza) and informed consent, patients admitted to our Neuro-Rehabilitation Unit between June 2020 and February 2021 with post-COVID-19 were investigated. Ten post-COVID-19 patients (6 males, 4 females) with neuromuscular disorders were found. Of these, 2 subjects had Guillain-Barré syndrome, 4 had bilateral plexus brachial lesion, and 4 (3 males, 1 female; mean age 59.2 years (standard deviation (SD) 8 

EMG was performed as described previously (13) . Briefly, all patients underwent conventional orthodromic motor and antidromic sensory nerve conduction studies, performed bilaterally on 8 motor nerves (median, ulnar, common peroneal and tibial nerves) Table II .

All post-COVID patients underwent an individualized and tailored rehabilitation treatment for 3 h per day, 6 days a week. The rehabilitation programme comprised joint mobilization, proprioceptive neuromuscular facilitation according to neuro-developmental techniques, flexibility and strength exercises. The patients underwent 2 h of electrical muscular stimulation daily on the lower limbs, by placing surface electrodes on the quadriceps and anterior tibial muscles, bilaterally. Electrical stimuli involved biphasic rectangular square pulses with a 20-ms duration at a rate of 20 Hz every 25 s. Amplitude of pulses was variable and based on the elicitation of visible muscular contraction (100-100 mA) (14) .

At discharge, only 1 subject (patient #1) had reached full recovery and ability in activities of daily living. Two subjects had incomplete recovery with minor disability (patients #2 and #4). Of these, 1 (patient #2) showed persistent left foot drop that required application of a foot-ankle orthosis, and 1 (patient #4) reported fatigue and mild weakness involving the lower limbs that limited performance and endurance in motor activity. However, she was able to ambulate without support. Patient #2 reached independent ambulation after application of the device. All of these subjects had CIP type according to EMG. Patient #3 showed CIP/CIM according to EMG. At discharge, he had moderate disability and motor limitations due to leg paresis with bilateral foot drop that was reduced with foot-ankle orthosis. However, he was able to stand up and to ambulate with bilateral support. At follow-up, 6 months after discharge, 3 subjects (patients #1, #2 and #4) had full recovery and 1 (patient #3) showed bilateral foot drop still requiring ankle foot-orthosis. Strength evaluation and functional scale scores of admission, discharge and follow-up are reported in Table III .

To evaluate COVID-19 subjects with ICUAW, a search of the studies was conducted using MEDLINE/PubMed, CINAHL, EMBASE, Web of Science, Scopus databases and Google Scholar. The search was restricted to English language reports published between 1 December 2019 and 31 March 2021. The search terms included "COVID-19", "critically ill patients", "intensive care unit acquired weakness", "ICUAW", "critical illness polyneuropathy", "CIP", "critical illness myopathy", "CIM", "critical polyneuropathy and myopathy", "CIPNM", "CIP and CIM"; "CIP/CIM", "acute tetraplegia", "functional outcome" and "COVID-19". The search was made either by using MeSH terms, keywords or subject headings. Related terms were combined using the Boolean operators "OR" and "AND". Search limits included only adults. Abstracts/posters or articles that were not peer-reviewed were excluded. The literature search was conducted by 3 independent authors (AMC, AG, and FDR). Inclusion criteria were: patient age ≥ 18 years; COVID-19 diagnosis; COVID-19 subjects with ICUAW, or the following types: CIP, CIM and CIP/CIM. The research was conducted according to the Preferred Reporting Items for Systematic Reviews and the Meta-Analyses (PRISMA) diagram, depicting the selection of articles searched for the study (Fig. 1) .

The review resulted in 11 studies being included, based on inclusion criteria (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (Table IV) . Studies were widely heterogeneous. Of these, 2 were case reports describing single subjects (15) (16) , 5 were case series with small samples ranging from 3 to 11 patients , and 4 cohort studies (22) (23) (24) (25) . Of these, 2 studies investigated neurological manifestations in large cohorts of COVID-19 patients (22-23) and among these, subjects with CIP or CIM were also detected. One was a retrospective study that ascertained COVID-19 subjects with MV who developed ICUAW (24) and 1 study that, with the use of a prospective method design, investigated the incidence of ICUAW in COVID-19 subjects during ICU stay (25) .

A total of 80 patients, age range 51-81 years, was reported. Of these, 23 were diagnosed with CIM (7 probable), 21 with CIP (8 possible), 15 with CIP/CIM, and 21 with ICUAW. Twelve (15%) patients died. ICUAW was diagnosed by EMG in all studies except the study by Van Aerde et al. (24) , in which ICUAW was diagnosed on MRC scale, and the study by Nersesian et al. (22) , in which ICUAW diagnosis was performed clinically. In this study, the authors detected 8 subjects with possible CIP and only 1 was diagnosed by EMG. Biopsy was performed in 1 study (20) involving, globally, 3 subjects. Of these, 1 subject revealed scattered necrotic and regenerative fibres in the absence of inflammatory infiltrates and 2 subjects showed non-specific findings, consisting of very occasional atrophic and regenerative fibres (20) .

Five studies did not report the outcome of COVID-19 subjects with ICUAW because they addressed different issues, such as occurrence (25) , electrophysiological parameters (20, 25) , neurological manifestations of COVID-19 patients (23), or described the clinical phenomenon (15, 16) . Recovery was reported in 6 studies (15, 17, 19, 21, 22, 24) . Of these, 1 was a case report, by Bagnato et al. (15) , who described a 62-year-old woman with COVID-19 diagnosed with CIM. After discharge, she had a mild weakness in the lower limb proximal muscles and was able to walk without assistance. Of the remaining studies, 4 were case series (17, 19, 21, 22) , with samples ranging from 3 to 8 subjects, and 1 was a cohort study that investigated COVID-19 patients with ICUAW compared with no ICUAW (22) , which used mRS, and that by Van Aerde et al. (24) , which used the mobility score and the Barthel scale. Muscle weakness was quantified by the MRC scale in only 2 studies (16, 18) . It was not possible to compare our post-COVID-19 subjects with a matched group of post-COVID-19 patients published in the literature, due to the heterogeneity of enrolled samples, including sitting, timing of neuro-muscular disorder ascertainment, functional measures, demographics (mean age 73.6 ± 8.7 vs 59.2 ± 8.62 years, respectively, in subjects reported in the literature and our sample) and rehabilitative treatment.

ICUAW is a common neurological complication in CO-VID-19 subjects during ICU stay and after discharge, which requires intensive rehabilitation. Recovery was found to be variable, but, unlike the general ICUAW population, a low percentage of COVID-19 patients reached full functional recovery. COVID-19 infection can result in characteristic interstitial pneumonia with severe respiratory failure, which may involve multiorgan systems. An increasing number of studies are being published on the role and pathophysiological mechanisms of COVID-19 (9) in producing and favouring neurological manifestations that affect the central (CNS) and peripheral nervous system (PNS). Among the disorders of PNS, variable conditions and neuropathies have been described, including Guillain-Barré syndrome and its variants (26, 27) , cranial multifocal neuropathy, dysautonomia (28) and brachial plexus lesion (29) . Likewise, neuromuscular disorders, such as myalgia, myositis and, in particular, myasthenia gravis, have also been described (30) . Our experience and the current review show that ICUAW is also a common neurological disorder in critically ill COVID-19 subjects who require ICU stay.

Among COVID-19 patients admitted to neurorehabilitation in our department, we detected 4 subjects with ICUAW. A scoping review of the COVID-19 literature showed that a total of 80 COVID-19 patients with ICUAW were reported in the literature between 1 December 2019 and 31 March 2021. ICUAW can cause variable disabling conditions and, consequently, an important aspect to consider concerns rehabilitation interventions in order to obtain full recovery and a good quality of life (31, 32) . In this respect, despite the lack of treatments and the limitations of rehabilitative strategies (33), subjects with ICUAW can achieve recovery with variable functional outcomes. An extensive literature review of the neuromuscular sequelae of ICU subjects with critical illness revealed that 68.8% made a complete recovery and regained the ability to walk independently (31) . It was reported that the outcome depended on the type of ICUAW, as confirmed by the fact that CIM had an earlier and better functional outcome than CIP (34, 35) . However, the current review shows that the outcome Likewise, whether occurrence of ICUAW in ICU COVID-19 subjects is higher than in the ICU general population also remains unclear. The occurrence of this disorder has been variously detected, and a systematic review reported a median prevalence of 43% (36). Frithiof et al. investigated the occurrence of ICUAW in adult subjects with COVID-19 admitted to ICU between 13 March and 8 June 2020. The ICUAW incidence was higher in COVID-19 patients compared with a general ICU population treated during 2019 (9.9% vs 3.4%). In particular, CIP was more frequent in the COVID-19 ICU cohort (50%) than in the non-COVID-19 ICU cohort (0%, p = 0.008) (25) . On the other hand, Cabañes-Martínez et al. described, out of a total of 225 patients treated in the ICU, 11 patients with a clinical and neurophysiological diagnosis of CIM or CIP, but they stated that it was not possible to calculate the exact incidence of the presence of neuropathy or myopathy (20) . It is well known that several risk factors can result in ICUAW in critically ill patients, including sepsis, ICU length of stay, and multiple organ failure (7, 8) , as well as the use of neuromuscular blocking and several drugs. In this respect, Neresian et al. (22) compared COVID-19 ICU patients with ICUAW to COVID-19 ICU patients without neuromuscular complications. Interestingly, those with ICUAW had a significantly longer stay (median 49.5 vs 23 days, p< 0.001), had been admitted to ICU more frequently (100% vs 40%, p = 0.002), were more often treated with renal replacement therapy (62% vs 14%, p = 0.008), and were more often delirious (75% vs 30%, p = 0.02) (22) . Likewise, Van Aerde et al. noticed that COVID-19 subjects with ICUAW had significantly longer ICU stays (days) (p = 0.008), lower mobility scores at ICU discharge (p < 0.001), compared with those without ICUAW (24) . Therefore, the same risk factors and the severity of systemic disease itself might favour the occurrence of ICUAW in COVID-19 subjects. In this respect, Bax et al. suggested a possible association with the duration of intubation and with increased IL-6 levels at admission (18) .

Another factor to take into account when considering ICUAW in COVID-19 is the possible direct damage to nerves and muscles caused by the virus. It has been reported that some neurological disorders are caused by the direct action of COVID-19 on the brain tissue, such as encephalitis and myelitis (37) . Even without evidence of viral invasion of the nervous system, immunemediated events, through the cytokine or chemokine pathways, may lead to vascular leakage, demyelination, activation of complement and organ damage. Indeed, the dominant characteristics of COVID-19 infection are the excessive immune response of the host to virus invasion of the organs, through the production of inflammation factors, in particular cytokines (38, 39) . Therefore, it is possible that the same underlying pathological conditions in critically ill subjects characterize COVID-19 patients and may represent an environment that favours neuromuscular disorders (20) .

The current study has some limitations. We report here 4 post-COVID-19 patients with ICUAW among those with neuromuscular disorders admitted to a neuro-rehabilitation setting. Therefore, the results concern a single centre and are not generalizable. The review of the COVID-19 literature aimed to determine the occurrence and recovery of ICUAW subjects with COVID-19, but the cohort studies and case series were highly heterogeneous. A further limitation concerns the recovery of subjects with ICUAW types due to the lack of functional measurements and of trials focusing on rehabilitative interventions.

After discharge COVID-19 subjects may have longterm consequences and limitations. A recent study showed that, 6 months after acute infection, COVID-19 survivors were mainly affected by fatigue or muscle weakness, sleep difficulties, and anxiety or depression (40) . Therefore, multi-component rehabilitative interventions and new approach strategies are being applied to address the respiratory, muscular, psychological and affective disorders that can persist in these patients. In this respect, COVID-19 subjects with ICUAW need more intensive rehabilitation, but, at present, rehabilitative interventions and proper investigations concerning ICUAW recovery are scant. Therefore, there is a strong need to find new rehabilitative strategies and plan well-designed studies investigating the efficacy and the benefit of rehabilitation. Further research is needed into the following aspects of neurological manifestations occurring in COVID-19 patients:

• whether the occurrence of ICUAW in COVID- 19 subjects is higher than that in the critically ill population without COVID; • whether COVID-19 causes direct damage to the peripheral nerves, or if such damage is due to inflammation factors that favour nerve lesions; • whether COVID-19 subjects with ICUAW may have a different type of recovery; • rehabilitation interventions and their effect on functional outcome and quality of life.

This review found that ICUAW is common in CO-VID-19 patients, producing disabling conditions for which rehabilitation is required. Recovery is variable, but a low percentage of COVID-19 patients with ICUAW gain a full functional outcome. However, the small size of samples and the heterogeneity of studies in this review do not permit definitive conclusions to be drawn. Rehabilitation interventions and further detailed studies should be carried out to improve functional outcome and to answer unsolved questions.

Funding. The authors received no financial support for the research, authorship, and/or publication of this article.

The authors have no conflicts of interest to declare.

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