Discussion
The incidence of GBS is between 1.1/100,000/year and 1.8/100,000/year with lower rates reported in children (<16 years) of around 0.6/100,000/year according to a systematic literature review conducted in 2009 [7]. More recently, a one-year observational multicenter study in Northern Italy found that the cumulative incidence of GBS increased by 59% in the period of March 2020 to March 2021, with COVID-19-positive GBS patients representing 50% of the total GBS cases [8]. To our knowledge, a strength of our study is that this is the first reported case of rapidly progressive neurologic deterioration resistant to PLEX therapy in a patient whose COVID symptoms started three days prior to manifestation of neurological symptoms.
In a recent systematic review of 79 COVID-19-associated GBS cases, clinicians used PLEX therapy in 10 cases, 4 of the 10 also received intravenous immunoglobulin (IVIG). Compared to our case of a time to onset of neurologic symptoms, there was three-day lag between the onset of COVID-19 symptoms and the onset of neurological symptoms, whereas the patients reported in this study had days ranging from 7 to 21 days [9]. Therefore, to our knowledge, this is the first reported case of PLEX therapy given to a patient with the shortest time to onset of GBS neurological symptoms. Interestingly, of all the patients in this review, there was one case of a patient with GBS who was asymptomatic for COVID-19, with the exception of a low-grade fever, who responded well to PLEX therapy [10].
In addition to this case, six other COVID-positive patients presented without COVID symptoms or within six days of neurologic manifestations. Altogether, this indicates a para-infectious process. On the other hand, the majority of patients developed GBS symptoms with a mean of 11±6.5 days, with a range of 3-28 days supporting the notion that GBS is a post-infectious process in COVID-19 patients [9]. Similar results were found in a review of 37 published cases of GBS associated with COVID-19, which reported the median time of onset of neurologic symptoms to be 12.2 days with a reported male to female ratio of 2.5:1 [11].
Considering the wide variability in time to onset of GBS symptoms in some COVID-19 patients, it may be theorized that a threshold of inflammation, rather than a cytokine storm, must be reached in combination with immune dysregulation to produce peripheral nervous injury albeit through direct cytokine-induced macrophage activation or molecular mimicry, respectively [12,13]. Therefore, reaching this threshold is not associated with symptoms but rather may be a time-dependent process, which would explain the variability in onset of GBS symptoms. This is supported by the fact that even asymptomatic COVID-19 patients develop GBS neurologic symptoms indicating that perhaps their threshold level of inflammation is so low that they do not produce symptoms. However, even at this low threshold they still develop neurological features of GBS.
PLEX therapy is suggested as a viable treatment for COVID-19 induced cytokine storm given its direct removal of cytokines such as interleukins-3, 6, 8, 10, interferon-gamma, tumor necrosis factor-alpha, and various immunoglobulins of the IgG class. In theory the rationale for using PLEX is to promote an anti-inflammatory state that adequately suppresses thrombo-inflammation and therefore the ensuing microangiopathy [14]. Given that PLEX therapy’s efficacy is in its ability to reduced cytokine-induced inflammation, the central question is to what degree we can attribute GBS symptoms in COVID patients to inflammatory damage alone versus genetic predisposition or molecular mimicry. Considering IVIG has been efficacious, perhaps the pathophysiology of neurological damage in the setting of COVID-19 is related to multiple different pathological processes. However, this theory has limitations. We cannot definitively rule out the possibility that in some cases of GBS developing before or concurrently with COVID-19 symptoms, the disease might have progressed sub-clinically in the early phase to manifest afterwards with its typical clinical picture [9]. Lastly, the possibility of a host immunogenic background adds an additional point of consideration. Considering HLA polymorphisms, this may explain the increased rates of COVID-19 related GBS in Italy, per a recent systematic review of 99 GBS with confirmed COVID-19 cases found one third of cases were Italian [11].
When treated with IVIG, or PLEX and steroid, a majority of patients show clinical improvement with partial or complete remission. Little improvement or poor outcomes is associated significantly associated with advanced age. Sex, electrophysiological subtypes, COVID pneumonia, and latency between COVID-19 and GBS were less associated with better outcomes [9]. However, up to 30% of patients with GBS progress to respiratory failure [15]. Patients treated with IVIG have a significantly lower probability and shorter overall duration of mechanical ventilation compared to those treated by PLEX [16].
Current literature is highly contentious as to the correlation between COVID-19 and GBS. However, in a large population-based study investigating the neurologic adverse events and SARS-CoV-2 infection, Patone et al found the highest risk of GBS in the one to 28-day period after a SARS-CoV-2-positive test, with the highest rate of hospital admission or death from acute CNS demyelinating events on the day of the positive SARS-CoV-2 test, which attributed all neurologic conditions to SARS-CoV-2 itself in either vaccine or viral entity [17]. The purpose of disseminating this case report is to propose a possible mechanism linking COVID-19 with the neurological symptoms of GBS, and to highlight the necessity of immediate treatment with PLEX or IVIG. Our case of a 60-year-old-male is consistent with current literature supporting the average mean age at onset of COVID-19 and GBS to be over 50 years of age [13].