Refractory Crohn's disease complicated with Guillain-Barré syndrome: A case report

Abstract

BACKGROUND

Inflammatory bowel disease (IBD) comprises a group of chronic inflammatory gastrointestinal disorders, including Crohn's disease (CD) and ulcerative colitis, with uncertain etiologies. The natural course of IBD can be accompanied by extraintestinal manifestations involving the skin, mucous membranes, musculoskeletal structures, eyes, cardiovascular system and nervous system. Guillain-Barré syndrome (GBS) is a type of peripheral neuropathy. However, the etiology and pathogenesis of IBD combined with GBS are unclear, and only a few clinical cases have been reported. Here, we report a case of refractory CD complicated by GBS and review the previous literature to improve the understanding of these diseases.

CASE SUMMARY

A 34-year-old man had a 9-year history of refractory CD. He became unresponsive to multiple drugs and experienced recurrent intestinal fistulas. After several abdominal surgeries and treatment with ustekinumab, he achieved clinical remission. Unfortunately, he developed GBS during maintenance treatment with ustekinumab. According to previous reports, in some patients with IBD combined with GBS, GBS may be a comorbidity, an extraintestinal manifestation of IBD, or an adverse reaction to IBD therapeutic drugs. After a comprehensive evaluation, we suspected that GBS might have been a comorbidity in this patient. To avoid fatal disease relapse after medication discontinuation, we concluded that ustekinumab should not be withdrawn. On the basis of a joint decision between doctors and the patient, we decided to continue maintenance treatment with ustekinumab along with intravenous immunoglobulin, dexamethasone and traditional Chinese medicine acupuncture, which resulted in a steady improvement in his GBS symptoms and sustained remission of CD.

CONCLUSION

When IBD is complicated by a neurological disease, it is first necessary to analyze the patient's condition and then choose the corresponding treatment strategy. If the neurological disease is a specific comorbidity, treatment of both IBD and the comorbid disease should be considered. For IBD patients with extraintestinal manifestations involving the nervous system, neurological manifestations tend to resolve when the active IBD is controlled. When an adverse drug reaction is suspected, the medication should be discontinued, and symptomatic treatment should be administered.

Key Words: Inflammatory bowel disease; Crohn's disease; Ulcerative colitis; Guillain-Barré syndrome; Biological agents; Case report

Core Tip: Inflammatory bowel disease (IBD) comprises a group of chronic inflammatory gastrointestinal disorders, including Crohn's disease (CD) and ulcerative colitis. The natural course of IBD can be accompanied by several extraintestinal manifestations. IBD combined with Guillain-Barré syndrome (GBS) has rarely been reported. Here, we describe a patient with refractory CD who stopped responding to multiple drugs and experienced recurrent complicated intestinal fistulas. After several abdominal surgeries and treatment with ustekinumab, he achieved clinical remission. Unfortunately, he developed GBS during maintenance therapy. In patients with IBD combined with GBS, GBS may be a comorbidity, an extraintestinal manifestation of IBD, or an adverse reaction to IBD therapeutic drugs. We suspected that GBS might have been a comorbidity in this patient; therefore, we decided to continue maintenance treatment with ustekinumab along with intravenous immunoglobulin, dexamethasone and traditional Chinese medicine acupuncture, which resulted in a steady improvement in his GBS symptoms and sustained remission of CD.

INTRODUCTION

In recent years, the prevalence of inflammatory bowel disease (IBD) has increased in China[1]. IBD is often accompanied by extraintestinal manifestations, and these extraintestinal disorders can influence the diagnosis of and treatment strategy for IBD. Extraintestinal involvement in IBD frequently affects organs and tissues such as the skin and mucous membranes, the musculoskeletal system, the eyes, the liver and bile ducts, and the cardiovascular and nervous systems. IBD complicated by neurological diseases, including central nervous and peripheral nervous system diseases, may have a poor prognosis, as evidenced by limited neurological function recovery, which has a harmful effect on quality of life[2]. The prevalence of neurological manifestations or complications of IBD is heterogeneous and varies between 0.2% and 36%, with peripheral neuropathy being especially frequent[3]. Guillain-Barré syndrome (GBS) is an immune-mediated acute inflammatory peripheral neuropathy with an annual incidence of 0.81-1.89 per 100000 people and a male-to-female incidence ratio of approximately 3:2[4]. GBS is characterized mainly by symmetric weakness of the limbs, weakened or absent tendon reflexes, decreased or abnormal sensation of the distal limbs, and albuminocytologic dissociation in cerebrospinal fluid (CSF) in some patients. Furthermore, GBS can be life-threatening in some severe cases[5-7]; thus, early diagnosis and appropriate treatment are extremely important.

CASE PRESENTATION

Chief complaints

A 34-year-old male presented with intermittent abdominal pain and diarrhea for more than 9 years and weakness of the limbs for 3 days.

History of present illness

The patient was clinically diagnosed with acute appendicitis and underwent appendectomy at his local hospital in June 2014. In July 2015, the patient experienced recurrent right lower abdominal pain with diarrhea. An abdominal computed tomography (CT) scan revealed irregular thickening and swelling of the transverse and hepatic flexure of the colon and ileocecal region. Colonoscopy revealed a cobblestone-like appearance with ulceration and polypoid hyperplasia in the transverse colon and ileocecal region. Single-balloon enteroscopy revealed a longitudinal ulcer in the distal ileum. The subsequent esophagogastroduodenoscopy examination revealed normal findings. Histological analysis of the colon and ileal biopsy samples revealed chronic active inflammation with ulceration in the transverse colon and ileocecal and terminal ileum. Zeihel-Nelson staining was negative for acid-fast bacilli, and the results of skin testing for pure protein derivatives of tuberculin were negative. On the basis of the above clinical, imaging, endoscopic and histological findings, the final diagnosis of the patient was active Crohn's disease (CD) (A2 L3B3). Oral prednisone at 40 mg/day was then administered for 10 days. All of his symptoms were ameliorated one month later. Oral prednisone was maintained for 5 months with 5 mg tapering at 2-week intervals and combined with 75 mg/day azathioprine. The patient's clinical symptoms were relieved, and his C-reactive protein (CRP) level and erythrocyte sedimentation rate returned to normal. In January 2019, the patient underwent intestinal adhesion relaxation; partial resection of the transverse colon, ileum and duodenum; ileal valve repair; and duodenum-ileo-transverse colon lateral anastomosis due to recurrent intestinal obstruction and ileal transverse colon anastomosis-duodenal fistula. After the operation, the patient experienced recurrent abdominal pain, fever, an incision fistula and a right lower abdominal intestinal fistula. Treatment, such as anti-infection and nutritional therapies, was provided. In October 2019, intravenous infusion of infliximab was initiated (250 mg at 0, 2 and 6 weeks during the induction period and every 8 weeks during the maintenance period). In July 2020, the treatment was switched to ustekinumab (first 260 mg IV and subsequently 90 mg injected subcutaneously every 8 weeks) because the patient was unresponsive to infliximab. In July 2022, he underwent duodenal and jejunal fistula repair, partial colectomy, partial ileectomy, ileum–ileum anastomosis and ileum–descending colon anastomosis. At this point, a continuous digestive tract was finally achieved, and the patient gradually transitioned to a normal diet. With regular postoperative ustekinumab treatment, the patient remained in clinical remission. Unfortunately, he subsequently experienced limb weakness, unstable holding of objects, and difficulty standing and walking for no apparent reason in December 2022.

History of past illness

The patient had a 10-year history of hepatitis B virus infection and had taken the oral antiviral drug entecavir for 7 years.

Personal and family history

The patient had no related personal or family history.

Physical examination

On examination, several scars were found on the skin of the patient’s abdominal wall and right lower limb. He was clear and mentally alert, his advanced cognitive function and cranial nerve examination results were normal, and he had normal superficial sensation and limb muscular tension. The patient’s limb muscle strength was weak, with upper and lower limb muscle strengths of level 3 and 2, respectively. Limb tendon reflexes were weak, physiological reflexes were normal, and pathological reflexes were negative.

Laboratory examinations

Blood cell analysis revealed increased white blood cell and neutrophilic granulocyte counts of 10.78 × 10⁹/L (normal range 3.5 × 10⁹-9.5 × 10⁹/L) and 8.25 × 10⁹/L (normal range 1.8 × 10⁹-6.3 × 10⁹/L), respectively. The CRP level was 5.23 mg/L (normal range 0-3 mg/L). A hepatitis panel was positive for hepatitis B surface antigen and hepatitis B core antibody. Hepatitis B viral DNA test results were negative. CSF routine and biochemical test results and tuberculosis smear results were negative. The results of routine stool tests, occult blood analysis, and bacterial cultures were negative.

Imaging examination

Head magnetic resonance imaging (MRI) and CT findings were normal. Abdominal X-ray revealed some gas and fecal shadows in the intestine, a small amount of liquid and gas in the middle and lower abdomen and chain-shaped dense shadows on both sides of the middle and lower abdomen.

Nerve conduction velocity

Nerve conduction velocity revealed demyelination in the motor nerve axons of the limbs. No F waves were observed in either upper limb, indicating demyelination changes in the proximal portion of both upper limbs. The H-reflexes of both upper limbs were normal.

Electromyography

When the right gastrocnemius and quadriceps muscles contracted, the average wave amplitude increased, indicating the presence of neurogenic damage in these muscles.

FINAL DIAGNOSIS

(1) CD (A2 L3 + L4B3) complicated by duodenal fistula, jejunal fistula, colonic fistula, ileostomy closure, partial resection of the small intestine and partial resection of the colon; (2) GBS; and (3) Chronic hepatitis B.

TREATMENT

Dexamethasone sodium phosphate (10 mg/day) and immunoglobulin (17.5 g/day) were intravenously administered for 7 days in combination with traditional Chinese medicine acupuncture and rehabilitation training.

OUTCOME AND FOLLOW-UP

The patient's limb muscle strength gradually recovered. His limb muscle strength returned to normal, and he was able to hold objects, move, and walk independently at the 16-month follow-up. During this period, subcutaneous injections of ustekinumab 90 mg/8 weeks were administered regularly, and the patient achieved clinical remission. On April 2, 2024, a repeat colonoscopy revealed an anastomosis 35 cm away from the anus and a 0.6 cm × 0.3 cm longitudinal ulcer in the proximal intestine 60 cm away from the anastomosis.

DISCUSSION

The etiology and pathogenesis of GBS are not fully understood, and GBS is currently believed to be related to factors such as genetic susceptibility, infection and immune abnormalities. GBS is a typical postinfection disease. At onset, approximately two-thirds of GBS patients have a history of respiratory or gastrointestinal infections. Eighty-five percent of patients with diarrhea as a precursor symptom were previously infected with Campylobacter jejuni. Other related pathogens include cytomegalovirus, EB virus, Mycoplasma pneumoniae, hepatitis B virus, human immunodeficiency virus and Zika virus[8-10]. Vaccination may also be associated with the onset of GBS, but controversies regarding this association still exist. Furthermore, polymorphisms in immune-related genes lead to differences in the recognition of specific antigen substances and the intensity of immune responses among individuals, thereby affecting their susceptibility to diseases. However, the genes associated with susceptibility to GBS have not yet been identified. Other studies have revealed that leukemia, lymphoma, the use of immunosuppressants after organ transplantation, and autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis are frequently associated with GBS, suggesting that immunological disorders are associated with the pathogenesis of GBS[11-14]. IBD is caused by the interaction of various factors, such as environmental, genetic, infection and immune factors. Up to 50% of IBD patients have extraintestinal manifestations[3], whereas the combination of IBD and GBS is uncommon, with only a few cases reported.

It may be difficult to determine whether GBS is due to medications used to treat IBD, IBD itself, or both. We searched recent English literature and found 10 case reports of IBD combined with GBS (6 patients with CD and 4 patients ulcerative colitis (UC), as shown in Table 1). Among these ten patients with IBD complicated by GBS, one first presented with GBS symptoms. After intravenous immunoglobulin (IVIG) therapy, his GBS symptoms gradually ameliorated. Two weeks after the onset of GBS, the patient developed abdominal pain, diarrhea and bloody stools. Subsequent colonoscopy and histological changes suggested UC. In this case, UC and GBS were difficult to distinguish between primary and secondary cases, and each disease course did not influence the other, suggesting that when GBS occurs in combination with IBD, it is a special comorbidity[15]. Three of the 10 patients were diagnosed with UC and were treated with 5-ASA, prednisolone or azathioprine. All three patients presented with symptoms of GBS during the course of UC[16-18]. Furthermore, a study revealed that, in 33% of CD patients and 40% of UC patients, peripheral neuropathy was related to the exacerbation of IBD, suggesting that the development of peripheral neuropathy is mediated by immune factors. Therefore, GBS may be an extraintestinal manifestation of IBD[19]. Another 5/10 patients were diagnosed with CD; three of them received adalimumab[20-22], and the other two received vedolizumab[23] and ustekinumab[24]. GBS symptoms appeared during biological treatment in these 5 patients. The authors suspected that the presence of GBS during the course of CD may be related to these biologics. Therefore, biologics were discontinued, and IVIG was administered upon GBS symptom onset. In addition to IBD, GBS has also been related to other immune-related disorders and treatment with biologics. Cases of psoriasis and ankylosing spondylitis combined with GBS were reported by Natividade et al[25] and Bouchra et al[26]. The 2 patients in these reports were treated with adalimumab and infliximab. After the onset of GBS symptoms, the biologics were discontinued, IVIG and other treatments were administered, and the GBS symptoms were relieved. Therefore, in these patients, GBS may have been an adverse reaction to IBD therapeutic drugs. The remaining 1/10 patients developed GBS after treatment with adalimumab[27]. Because the patient had active CD and was willing, adalimumab injection was continued along with IVIG therapy, and the GBS symptoms were gradually alleviated. On the basis of the above reports, there may be several possibilities for the occurrence of neurological manifestations in patients with IBD: (1) Special neurological comorbidities occur along with IBD; (2) Extraintestinal manifestations of IBD involving the nervous system occur; and (3) Neurological manifestations occur as a complication of IBD or as adverse nervous system reactions to IBD therapeutic drugs.

Table 1 Treatment and prognosis of inflammatory bowel disease combined with Guillain-Barré syndrome.

Ref.	Age/sex	Diagnosis	Drug	Medication and symptoms interval	Treatment	Prognosis
Tominaga et al[15]	39/M	UC	None	None	IVIG	CR
Jayasundara et al[16]	24/M	UC	AZA + prednisolone	Not mentioned	IVIG	PR
Krystallis et al[17]	59/M	UC	Prednisolone + 5-ASA	Not mentioned	IVIG + prednisolone	CR
Liu et al[18]	31/F	UC	5-ASA	Not mentioned	Methylprednisolone	CR
Cesarini et al[20]	72/M	CD	Adalimumab	1 month	IVIG + methylprednisolone	PR
Cançado et al[21]	64/M	CD	Adalimumab	2 weeks	Prednisone	CR
Patwala et al[22]	37/M	CD	Adalimumab	9 months	IVIG	PR
De Azevedo et al[23]	31/M	CD	Vedolizumab	2 weeks	IVIG	Not mentioned
Fukushima et al[24]	32/M	CD	Ustekinumab	1 year	IVIG	PR
Natividade et al[25]	45/M	Psoriasis	Adalimumab	1 year	IVIG	PR
Bouchra et al[26]	47/F	AS	Infliximab	2 months	IVIG	CR
Lee et al[27]	33/F	CD	Adalimumab	2 months	Adalimumab + IVIG	CR

CD: Crohn's disease; UC: Ulcerative colitis; IVIG: Intravenous immunoglobulin; AS: Ankylosing spondylitis; 5-ASA: 5-aminosalicylate; AZA: Azathioprine; CR: Complete remission; PR: Partial remission.

In this study, our patient had a 9-year history of refractory CD and discontinued the use of multiple drugs because of poor treatment efficacy or secondary unresponsiveness. After several surgeries and treatment with ustekinumab, he achieved clinical remission. Unfortunately, he developed GBS during maintenance treatment with ustekinumab. Considering that GBS may be a comorbidity in this patient, we continued maintenance treatment with ustekinumab along with IVIG, dexamethasone and traditional Chinese medicine acupuncture, which resulted in a steady improvement in his GBS symptoms and sustained remission of CD.

CONCLUSION

With the increasing prevalence of IBD in China, the number of patients with IBD combined with extraintestinal manifestations, such as neurological diseases, may gradually increase. When an IBD case is complicated by a neurological disease, it is first necessary to analyze the patient's condition and then choose the corresponding treatment strategy. If the neurological disease is a specific comorbidity, treatment of both IBD and the comorbidity should be considered. For IBD patients with extraintestinal manifestations involving the nervous system, neurological manifestations tend to resolve when the active IBD is controlled. When an adverse drug reaction is suspected, the medication should be discontinued, and symptomatic treatment should be administered. The underlying mechanism of IBD combined with neurological diseases is still not fully understood, and some neurological diseases can lead to poor outcomes or even death. Therefore, it is necessary to identify IBD and neurological diseases as early as possible and provide reasonable treatments to improve the prognosis.