Guillain-Barré syndrome in ulcerative colitis and SARS-CoV-2 infection: a case report and literature review

Aim: Guillain-Barré syndrome (GBS) occurrence is rare during inflammatory bowel disease (IBD) and SARS-CoV-2 infection. Its association with thrombotic vascular events, which are common during these two entities, is extremely rare. Case report: We report an exceptional association of GBS and cerebral venous thrombosis in a 28-year-old woman with active ulcerative colitis and no previous history of SARS-CoV-2 vaccination. Mildly symptomatic SARS-CoV-2 infection was diagnosed during etiological investigations of cerebral venous thrombosis. GBS symptoms began 10 days later with clinical and electrical abnormalities consistent with axonal GBS. Other GBS causes were excluded. Favorable outcomes were noted after intravenous immunoglobulin perfusion with full recovery 12 months later. Conclusion: Greater attention should be focused on IBD patients with SARS-CoV-2 infection regardless of its severity.

The occurrence of Guillain Barré syndrome (GBS) is rare during inflammatory bowel disease and SARS-CoV-2 infection.Its association with vascular events commonly observed during these two entities, is extremely rare [1,2].
We report an exceptional association of GBS with cerebral venous thrombosis in a young female patient with active ulcerative colitis.She was treated by corticosteroids and azathioprine therapy, while experiencing paucisymptomatic SARS-CoV-2 infection.

Case report
A 28-year-old woman, with pancolitic ulcerative colitis and ongoing mesalazine therapy, experienced severe acute colitis.There was no relevant family medical history.Favorable outcomes were noted after first line therapy.The patient was discharged on oral corticosteroids (prednisolone 50 mg/day) and azathioprine 100 mg/day after 10 days of hospitalization.Two weeks later, she consulted the emergency department for asthenia, abdominal pain, vomiting and liquid non-bloody diarrhea.
On physical examination, the patient had pale conjunctiva, but no clinical feature of dehydration or fever.Her blood pressure was 90/60 mmHg, heart rate of 104 beats/min and respiratory rate of 16 cycles/min.Rhythmic cardiac sounds were normal with no heart murmurs, and vesicular breath sounds were preserved.The abdomen was soft without palpable masses or organomegaly.Patient reported mild pain upon palpation of the left colic framework with no signs of peritoneal irritation.Bowel sounds were present and digital rectal examination showed normal results.Neurological examination was also normal.
Laboratory findings excluded possible azathioprine side effects as liver enzymes and lipase levels were within normal limits but with increased rate of serum CRP to 85 mg/l.White blood cells count, as well as serum creatinine and electrolytes were normal.
Colonoscopy showed presence of regenerating polyps and superficial ulcerations with healing features ruling out possible ulcerative colitis flare-up.Screening tests for Clostridium difficile and CMV infection were negative.
Abdominal pain and vomiting remained unexplained.Therefore, an abdominal CT scan and cerebral MRI were performed within 3 days from symptom's onset showing a thrombus of the inferior vena cava, a right surrenal hematoma, and bilateral cerebral venous thrombosis of transverse sinuses.Acquired and constitutional thrombophilia were excluded by exhaustive investigations.
Based on the evolving knowledge regarding the SARS-CoV-2 outbreak and its related thromboembolic events, a PCR test for SARS-CoV-2 was performed and reported positive.The patient had not received any SARS-CoV-2 vaccines and did not experience any respiratory complaints or need to oxygen therapy.The diagnosis of digestive manifestation of SARS-CoV-2 infection was made.Treatment with unfractionated heparin and rehydration was conducted for a few days with complete recovery.
Ten days later, the patient presented with progressive generalized weakness predominantly in the lower limbs gradually progressing to inability to walk and paraesthesia.Neurologic examination found weakness in muscular strength evaluated to 2/5 in the lower limbs and 4/5 in the upper limbs with tendon reflex abolition in both lower limbs.There was no cranial nerve involvement, dysautonomia features nor sensory deficit.
Spine MRI was normal.The patient underwent an electro-neuro-myogram 7 days after symptoms' onset revealing reduced amplitudes of action potentials especially in lower limbs and prolonged latencies of F waves without conductions blocks (Table 1).Cerebrospinal fluid (CSF) analysis was performed within 18 days from symptoms' onset.It showed a clear fluid with 1 WBC/mm 3 .CSF glucose level was 4.98 mmol/l and CSF protein level was 0.33 g/l.
Overall, clinical presentation and electrical abnormalities were consistent with axonal form of Guillain-Barré syndrome.Etiologic investigations for GBS were performed excluding viral inflammations, vitamin B12 or B1 deficiency and systemic diseases.
Intravenous immunoglobulin perfusion was prescribed for 5 days at the dose of 0.4 g/kg/day.Improvement was obtained with progressive recovery assessed by muscular testing (3/5 in lower limbs and 5/5 in upper limbs).The patient was discharged with oral corticosteroids, azathioprine, rivaroxaban and physical rehabilitation.Full functional recovery was obtained within 12 months later.

Discussion
In this report, we present a unique case by several aspects.First, it illustrated GBS as a manifestation of SARS-CoV-2 infection in peripheral nervous system.Second, it reported a double neurologic involvement with concomitant GBS and cerebral thrombosis.Third, it presented GBS as a potential extraintestinal manifestation of ulcerative colitis.
While comparing our case to the literature, it's essential to address the practical implications for medical decision making.In our discussion, we will examine potential treatment strategies.
Additionally, we will examine how our case can guide future patient management.Neurologic symptoms during SARS-CoV-2 infection are common, reported up to 84% of hospitalized patients [1].The spectrum of these neurologic symptoms is wide and includes GBS as a rare manifestation.In fact, estimated GBS prevalence was about 15 cases per 100,000 SARS-CoV-2 infections and 147 reported cases to the best of our knowledge [2,3].
It's worth noting that the association of GBS and cerebral thrombosis during SARS-CoV-2 infection is exceptionally rare, with only one prior publication reporting such a case [4].GBS occurred predominately in male patients (65.3%) [3] with a mean age of 52 years and in severely affected patients by SARS-CoV-2 infection requiring intensive care unit admission (44.9%) or mechanical ventilation (38%) [2].However, our case stands out by an earlier age and by the fact that SARS-CoV-2 infection was relatively minor with no respiratory and general symptoms.In this case, young age is likely attributed to the association with ulcerative colitis.
The physiopathological mechanisms of GBS occurrence during SARS-CoV-2 infection are not fully understood and direct and indirect mechanisms have been proposed.Direct mechanism includes the neuroinvasive capacity of SARS-CoV-2 by ACE2 receptor activation.In fact, the coronavirus spike (S) protein attaches to ACE2 receptor for cellular entry [5].ACE2 receptor is otherwise, present in multiple human organs, including nervous system and skeletal muscles.Indirect mechanism is represented by the autoimmune response triggered by a CRS and mediated by the inflammatory response associated with COVID-19 [3].
Clinically, the median time for GBS symptoms onset after infection is about 2 weeks, which is concordant with our case [6].Neurological symptoms were reported in a total of 147 cases summarized in Table 2 [3].It's important to note that muscular weakness must not be confounded with the fatigue and asthenia which are frequent during SARS-CoV-2 infection as well as myalgia, and that clinicians should be also vigilant to minor symptoms like fecal incontinence, which can be easily misdiagnosed in case of concomitant diarrhea as in our case.
GBS showed favorable outcomes with a high survival rate of 78.9%.Intravenous immunoglobulin was the most common used therapy [3].
On the other hand, IBD extra-intestinal manifestations are frequent.Peripheral nervous system involvement seems to be more frequent in UC, with a reported incidence of 1.9% [7].However, it seems that UC presents a lower rate of demyelinating forms as compared with CD [7].For the best of our, only ten cases of GBS and UC association in adults have been published to date knowledge (Table 3), describing GBS in all age spectrum, without sex predilection.Occurrence during active disease was more common.The axonal form of GBS is known to be more frequent in UC while demyelinating form is more prevalent in CD patients [7].
The hypothesis of a common triggering factor of GBS and IBD has been proposed.Since both diseases are considered post-infectious, the role of Campylobacter Jejuni (C.Jejuni) in their respective pathogeneses has been suggested.
On one hand, large population-based cohort studies observed increased hazard rate of IBD among patients with first-time C. Jejuni infection compared with population comparisons [8].This may be related to increased translocation of intestinal microflora because of loss of intestinal epithelial barrier function [9].On the other hand, the role of C. Jejuni in the pathogenesis of GBS, especially the axonal form, as in our patient's case, has been suggested since 30% axonal GBS cases were preceded by C. Jejuni infection.Additionally, antibodies against C. Jejuni's lipo-oligosaccharides (LOS) target also myelin and axons ganglioside molecules of peripheral nerves through molecular mimicry [10].Furthermore, a common immunological pathway of development of GBS and IBD would involve a systemic or local increase in inflammatory cytokines accompanied by Th1/Th2 imbalance.It is thought to be an extra intestinal manifestation of IBD, which is described more frequently with concomitant active disease.
However, it's important to consider potential side effects of medications used in IBD patients to manage the disease.Some drugs like Infliximab and Adalimumab known as anti-TNF-α monoclonal antibodies, have been associated with nerve-related conditions, including acute ones like GBS and chronic immune-mediated conditions [7].In such cases, especially when active disease is present, GBS treatment can be challenging as it remains unclear whether anti-TNF-α therapy should be continued in the absence of a formal link between anti-TNF-α therapy and GBS onset.To remember, our patient had not received any prior anti-TNF-α therapy and symptoms were reported approximatively 1 month after a severe flare-up.This should also rise vigilance among clinicians regarding the possible delay of GBS occurrence while treating IBD flare-ups and especially severe flareups.However, clinicians should actively look for GBS symptoms while monitoring IBD flare-ups and even to educate their patients about these neurological warning signs, which can occur even after hospital discharging.It is important to note that previously reported data has not supported the possibility of SGB induced by corticosteroids or azathioprine therapy, as in our case.
Prognosis of GBS in UC patients appears favorable with no reported fatal issue.Similarly in cases of GBS complicating SARS-CoV-2 infection, intravenous immunoglobulin was the most prescribed treatment, leading to complete recovery in 6/10 of the reported cases.Our patient was treated by intravenous immunoglobulin, initially experiencing partial recovery, with full recovery achieved 12 months later.
When compared with previously published cases, our patient exhibited several common characteristics.However, we observed a unique presentation as the association to SARS-CoV-2 infection as potential triggering factor for GBS in patient with UC has not been reported before.This association appears to trigger also, a life-threatening complication, namely cerebral venous thrombosis.
Thus, it may be reasonable to provide closer follow-up for IBD patients who contract any SARS-CoV-2 infection.An additional vigilance toward neurological signs is highly recommended.After hospital discharge or when hospitalization is not indicated, clinicians should educate their patients about potential alarming neurological signs.Importantly, they should emphasize not confusing these signs with the common symptoms of SARS-CoV-2 infection or IBD flare-ups.Clinicians should encourage their patients to seek consultation in the presence of any doubtful sign in order to promptly detect any potential GBS.

Table 1 .
Values of nerve conduction.

Table 3 .
Summary of published cases of association between UC and GBS compared to our case.