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].