PMC:7445716 / 73138-83676 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7445716","sourcedb":"PMC","sourceid":"7445716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7445716","text":"Discussion\nCOVID-19 pandemic prompts all efforts for the early recognition and treatment of its manifestations. In analogy to other viruses, belonging or not to the coronavirus family [63, 67], neurologic complications in COVID-19 are emerging as one of the most significant clinical chapters of this pandemic. In this regard, peripheral and central nervous system damage in COVID-19 has been postulated to be the consequence of two different mechanisms: 1) hematogenous (infection of endothelial cells or leucocytes) or trans-neuronal (via olfactory tract or other cranial nerves) dissemination to central nervous system in relation with viral neurotropism, and 2) abnormal immune-mediated response causing secondary neurological involvement [62, 68, 69]. The first mechanism is supposed to be responsible for the most common neurological symptoms developed by patients with COVID-19 (e.g., hypogeusia, hyposmia, headache, vertigo, and dizziness). In contrast, the second can lead to severe complications during or after the course of the illness, either dysimmune (e.g., myelitis, encephalitis, GBS) or induced by cytokine overproduction (hypercoagulable state and cerebrovascular events) [68, 69].\nIn the present systematic review, we reviewed clinical features, results of diagnostic investigations, and outcome in 73 cases of COVID-19-associated GBS spectrum [5–56].\nIn the present study, mean age at onset in patients with GBS largely overlapped that of classic COVID-19 subjects [70, 71]. However, pediatric cases with GBS have been increasingly reported in the literature [21, 27, 35, 41], suggesting that, with the spreading of the pandemic, a broader age range might be affected. Moreover, we found a higher prevalence of GBS in males compared to females, as previously reported for Zika virus–GBS [72]. This finding may also reflect the gender epidemiology of SARS-CoV-2. In this regard, males typically show a worse COVID-19 outcome compared to the females [70, 71], possibly due to a generally shorter life expectancy or to higher circulating Angiotensin-Converting-Enzyme 2 (ACE2) levels, the cellular receptor for SARS-CoV-2, in the former compared to the latter [71]. Moreover, given that GBS is a rare disease [57] the epidemiological distribution of the reported cases seems to reflect current worldwide outbreaks, with Europe being the “hottest” spot in March–May 2020 and USA together with Asia in the following period [73, 74]. On another issue, despite a few GBS cases seemed to have a para-infectious profile [10, 37, 38, 40, 55, 56] as described for Zika virus [75], all other reported patients developed neurological symptoms with a typical latency after COVID-19 (median time 14 days). This feature, together with the frequently reported negative nasopharyngeal swab at GBS onset [22, 24, 36, 44, 45, 52] and clinical improvement after IVIG therapy, seems to support the notion of a prominent post-infectious immune-mediated mechanism. However, in this context, the massive release of cytokines in COVID-19 may also contribute to the amplification of the dysimmune process underlying GBS [76, 77]. In this regard, the increase of blood inflammatory markers (e.g., CRP, IL-6, TNF-α, IL-1, etc.) in GBS tested cases may reinforce the hypothesis of a systemic inflammatory storm in COVID-19 [76, 77]. However, given the limited data, we could not perform an accurate analysis of the distribution and, eventually, prognostic value of inflammatory markers in COVID-19-associated GBS. Moreover, we cannot exclude that in cases with GBS developing before or together with COVID-19 symptoms, the disease might have progressed sub-clinically in the early phase to manifest afterwards with its typical systemic clinical picture. Indeed, two cases [10, 12], who tested positive for SARS-CoV-2, never developed COVID-19 respiratory or systemic symptoms and one of them showed an asymptomatic pneumonia at chest-CT [12]. However, only more extensive epidemiological and translational studies, with the aim to compare the characteristics of GBS associated or not with COVID-19, could clarify these issues.\nIn our population, most common clinical manifestations and distribution of clinical variants resemble those of classic GBS confirming the predominance of the sensorimotor syndrome compared to MFS and other rare variants [57–59, 66]. Similarly, the results of CSF analysis reflected typical neurochemical findings in non-COVID-19 GBS. In the latter, elevated CSF proteins and pleocytosis were described in about 50–80% [57, 78] and 11–15% cases, respectively [58, 79, 80], largely overlapping with the percentages in our cohort. In this regard, the mostly normal cell count, together with the absence of SARS-CoV-2 RNA in all tested CSF samples [6–9, 12–14, 16, 21–24, 31, 33, 36, 42, 44, 52, 55], makes the possibility of a direct invasion from SARS-CoV-2 into the nerve roots with intrathecal viral replication less probable. However, a possible bias might rely on the lack of systematic data concerning the latency between symptom onset and CSF sampling in COVID-19 GBS cases. On another issue, in a further case of MFS associated withCOVID-19, who came to our attention, we observed the absence of intrathecal synthesis of SARS-CoV-2 antibodies together with a massive increase of CSF phosphorylated neurofilament heavy chain (pNfH) and serum neurofilament light chain (NfL) proteins, supporting the role of neurochemical markers as easily implementable tools for the detection of nervous system affection in COVID-19-related diseases [81, 82].\nAt variance with CSF findings, we found a discrepancy concerning MRI findings between classic GBS and COVID-19-related GBS. Specifically, while most cases of the former group showed typically spinal root enhancement at MRI [83], in the latter group, in analogy with Zika-associated GBS, the same finding was less frequently reported [84]. However, caution should be warranted in the interpretation of these results, given that MRI findings might have been underestimated, due to lack of a sufficient number of exams in the context of pandemic-imposed restrictions in the routine clinical setting.\nRegarding the distribution of GBS electrophysiological variants, our analysis showed that COVID-19-associated GBS manifests prevalently with AIDP and, to a lesser extent, with AMSAN and AMAN, in line with classic GBS in Western countries [66, 85]. Conversely, the observation of positive anti-GD1b antibodies  in one COVID-19-related MFS patient and negative anti-ganglioside antibodies in other five cases appear in discordance with the high prevalence (≈ 90%) of anti-GQ1b antibodies among non-COVID-19 MFS cases [86], and may suggest different immune-mediated mechanisms. However, these results could not be generalized until a wider population would be tested.\nIn analogy to classic GBS, approximately one-fifth of COVID-19-associated GBS subjects required mechanical ventilation during hospitalisation [87]. In this regard, cases with no improvement or unfavorable outcome showed, in comparison to those with a good prognosis, an older age, confirming similar findings both in classic GBS [58, 88] and in COVID-19 [89], and a slightly higher frequency (without reaching a statistical significance) of past or concurrent COVID-19 pneumonia. However, given the short follow-up time in most cases, we could not reach a definite conclusion on the impact of past or concurrent COVID-19 restrictive syndrome due to pneumonia on the prognosis of GBS patients. Future prospective studies are needed to clarify this issue. Moreover, given that also preceding diarrhea (mostly caused by Campylobacter Jejuni infection) is a strong negative prognostic factor in classic GBS [57, 88], further prospective studies are needed to compare the severity of GBS related to COVID-19 to that associated with C. jejuni. Finally, in the context of respiratory failure and ventilation associated with COVID-19, the differential diagnosis should always take into consideration critical illness neuropathy and myopathy, which tend to develop later during the critical course [90]. Despite these findings, approximately one-third of COVID-19-related GBS patients showed no clinical and/or radiological evidence of pneumonia, providing evidence that GBS may also develop in the context of a paucisymptomatic or even asymptomatic COVID-19. However, given that among the GBS population only two asymptomatic COVID-19 patients were reported to date, we may speculate that, in most cases, a certain degree of lung injury (even minimal) or at least hematic dissemination (e.g., fever underlying significant viral load) is necessary to trigger the immuno-mediated process through lymphocytic recognition of self-antigens or molecular mimicry.\nMajor strengths of our review are the inclusion of a high number of patients, together with an in-depth analysis of the clinical and diagnostic features of COVID-19-associated GBS. We are aware that selection bias might have occurred, given that most reported cases to date have been described mostly in Europe (47 out of 73) and during COVID-19 highest spreading. Therefore, future extensive epidemiological studies are necessary to ascertain the nature of the association between COVID-19 and GBS (causal or coincidental). Moreover, we cannot exclude the possibility that at least some of the cases represent instances of CIDP, given the frequent absence of a follow-up longer than 2 months. On another issue, the low but possible evidence of an epidemiological link between vaccines and GBS development [57, 58] should aware the clinicians of the possible occurrence of GBS after COVID-19 vaccination in the long-term future.\nIn conclusion, based on the systematic review of 73 cases, we showed that the clinical picture of COVID-19-associated GBS seems to resemble that of classic GBS or Zika-associated GBS. Moreover, the chronological evolution, the response to IVIG, and the absence of SARS-CoV-2 RNA in CSF may suggest a prominent post-infectious immune-mediated mechanism rather than a para-infectious one. Although most cases were symptomatic for COVID-19, the preliminary report of a few patients without respiratory or systemic symptoms raises a significant healthcare issue, namely the importance of SARS-CoV-2 testing in all patients with suspected GBS during the pandemic, with the aim to provide an eventual rapid case isolation. Nevertheless, only further analyses on more comprehensive cohorts could help in clarifying better all these 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