Pembrolizumab-induced Guillain-Barré syndrome in triple-negative breast cancer: A case report

Abstract

BACKGROUND

The programmed cell death protein 1 inhibitor pembrolizumab has become a key treatment for various cancers, including triple-negative breast cancer. However, it is associated with immune-related adverse events, including rare but serious neurological complications such as Guillain-Barré syndrome (GBS). GBS is a potentially life-threatening autoimmune disorder characterized by muscle weakness and paralysis. We present a unique case of pembrolizumab-induced GBS to highlight the importance of recognizing this complication and managing it promptly in patients receiving immune checkpoint inhibitors.

CASE SUMMARY

A 69-year-old woman with a medical history of hypertension, anxiety, depression, and stage IIIB triple-negative breast cancer treated with pembrolizumab, carboplatin, and paclitaxel, presented to the emergency department with a 1-month history of tingling, lower extremity weakness, and shooting pain. Symptoms progressed to global weakness, ascending paralysis, and double vision. Neurological examination revealed significant lower extremity weakness and sensory deficits. Magnetic resonance imaging of the lumbar spine and cerebrospinal fluid analysis confirmed GBS. Initial treatment with intravenous immunoglobulin led to relapse, requiring additional intravenous immunoglobulin and high-dose glucocorticoids. The patient’s condition improved, pembrolizumab therapy was permanently discontinued, and she was discharged to a rehabilitation facility.

CONCLUSION

Pembrolizumab can induce GBS, necessitating early recognition, prompt diagnosis, and multidisciplinary management to prevent serious complications.

Key Words: Pembrolizumab; Guillain-Barré syndrome; Triple-negative breast cancer; Immune-related adverse events; Intravenous immunoglobulin therapy; High-dose steroids; Case report

Core Tip: The immune checkpoint inhibitor pembrolizumab can cause rare immune-related adverse events like Guillain-Barré syndrome. This report details a patient with stage IIIB triple-negative breast cancer who developed Guillain-Barré syndrome after pembrolizumab treatment. Initial treatment with intravenous immunoglobulin was insufficient, but a combination of intravenous immunoglobulin and high-dose steroids led to significant improvement. This case highlights the importance of recognizing neurological complications in patients treated with pembrolizumab and emphasizes the need for timely diagnosis and multidisciplinary management of such complications.

INTRODUCTION

Pembrolizumab is an immune checkpoint inhibitor (ICI) with anti-programmed cell death protein 1 (PD-1) properties known for its effectiveness in treating various types of cancer. It functions by blocking the PD-1 pathway, essentially removing the “off switch” and allowing T cells to remain active. This enables T cells to detect and eliminate cancer cells more effectively. However, it can lead to severe side effects such as cardiotoxicity, pneumonitis, and neurological issues[1]. These ICIs enhance the immune response against cancer but may also cause it to attack healthy tissues, resulting in immune-related adverse events such as Guillain-Barré syndrome (GBS)[2]. GBS is a rare but potentially fatal autoimmune neuropathy characterized by muscle weakness, reduced reflexes, tingling sensations, and in severe cases, respiratory problems[3]. While the condition is usually linked to infections, recent reports have shown that it can also occur as a side effect in patients receiving ICIs like pembrolizumab for cancer treatment[4]. The exact mechanisms behind pembrolizumab-induced GBS are not fully understood, but it is believed to involve immune system activation and autoimmune reactions. Breakdown of immune tolerance, possibly due to shared antigens between the tumor and healthy tissues, may contribute to the development or worsening of GBS when immune checkpoint proteins are blocked[5]. Timely diagnosis and management are crucial. Treatment for GBS typically involves intravenous immunoglobulin (IVIG) administration to modulate the immune response. IVIG may also induce immune tolerance, reducing autoimmune reactions[4,5]. While high-dose steroids are not recommended as a standard treatment for GBS, they have beneficial potential for the acute inflammatory demyelinating polyneuropathy subtype[4-6]. Here, we report a case of severe GBS-like neuropathy in a patient with triple-negative breast carcinoma (TNBC) who was treated with pembrolizumab.

CASE PRESENTATION

Chief complaints

The patient presented with complaints of a tingling sensation in both lower extremities, progressive weakness, shooting pain in the right leg, double vision, and increasing difficulty with mobility.

History of present illness

The patient’s symptoms had begun 1 month prior with a tingling sensation in her legs, which she initially attributed to fatigue. However, the sensation progressed into shooting pain in her right leg, followed by weakness in both lower extremities. Over the following 2 weeks, she developed significant difficulty walking, marked by reduced dexterity and worsening weakness. She had recently begun experiencing double vision, which improved when looking upward or covering one eye. These symptoms began shortly after her last dose of pembrolizumab administered in combination with carboplatin and paclitaxel for TNBC. There was no associated fever, dizziness, or recent infections.

History of past illness

Her medical history was notable for stage IIIB TNBC, for which she was undergoing immunotherapy with pembrolizumab. In addition, she had a history of hypertension, anxiety, and depression, all managed with medications. She denied any previous neurological conditions or significant trauma.

Personal and family history

The patient was a non-smoker and reported being a non-consumer of alcohol. She reported living independently, having partaken in no recent travel, and having no known exposure to toxins. Family history of neurological, autoimmune disorders, and malignancies were unremarkable, other than the patient’s breast cancer.

Physical examination

On admission, the patient appeared fatigued but in no acute distress. Her vital signs were stable with a blood pressure of 102 mmHg/55 mmHg, a heart rate of 80 beats per minute, and a respiratory rate of 20 breaths per minute. Neurological examination revealed 4/5 muscle strength in the upper extremities, but significant weakness in the lower extremities, graded 2/5. The patient demonstrated impaired dexterity in her legs and had decreased reflexes in both lower limbs. Sensory testing revealed diminished vibratory sensation in her toes and fingers, with reduced light touch and pinprick sensation in her distal extremities. Cranial nerve examination was largely normal, except for persistent diagonal double vision. No signs of respiratory compromise were noted.

Laboratory examinations

Routine blood tests, including a complete blood count and comprehensive metabolic panel, were within normal limits. Markers of inflammation, including C-reactive protein and erythrocyte sedimentation rate, were mildly elevated but nonspecific. Thyroid-stimulating hormone, 25-hydroxyvitamin D, vitamin B12, and folate levels were all normal. Urinalysis and routine fecal tests yielded unremarkable findings. There was no evidence of infection based on standard immune and infection indices.

Imaging examinations

Magnetic resonance imaging of the lumbar spine (Figure 1) revealed smooth enhancement along the conus medullaris, extending to the nerve roots of the cauda equina, suggesting an inflammatory demyelinating process consistent with GBS. No abnormalities were found on chest or abdominal imaging, and there was no indication of metastatic disease or significant changes related to her breast cancer. A lumbar puncture showed elevated protein levels and mild pleocytosis, further supporting the diagnosis of GBS.

Figure 1 Magnetic resonance imaging of the lumbar spine. A: Abnormal enhancement and clumping of the cauda equina nerve roots suggested inflammatory pathology, and given the patient’s history, arrow: Guillain-Barré syndrome; B: Abnormal cauda equina nerve root enhancement suggested inflammatory pathology, and given the patient’s history, arrow: Guillain-Barré syndrome.

MULTIDISCIPLINARY EXPERT CONSULTATION

Neurologist consult determined suspected GBS due to pembrolizumab and recommended IVIG and close monitoring for progression. In addition, the need for ongoing neuroimaging and lumbar puncture results were emphasized to confirm the diagnosis and rule out alternative causes such as paraneoplastic syndromes. Oncologist consult confirmed pembrolizumab-induced GBS and culminated in advisement of permanent discontinuation of pembrolizumab and adjustment of cancer treatment. Rheumatologist consult suggested high-dose glucocorticoids with IVIG to manage the autoimmune response and inflammation. physical medicine and rehabilitation consult developed a post-hospital rehabilitation plan focusing on strength, mobility, and functional recovery. Ophthalmology consult led to evaluation of the new-onset double vision linked to GBS-related cranial nerve involvement and recommended conservative management.

FINAL DIAGNOSIS

This patient was therefore diagnosed with GBS.

TREATMENT

The patient was initially treated with 2 g/kg IVIG over 4 days, the standard treatment for GBS. Despite partial improvement, she experienced a relapse with worsening upper extremity weakness and persistent double vision. In response to the relapse, a second course of IVIG was initiated at 0.4 g/kg/day for 4 days. High-dose glucocorticoids (intravenous methylprednisolone, 1 g daily for 5 days) were also added to reduce inflammation and modulate the immune system. The combination of IVIG and steroids resulted in a marked improvement in motor strength, especially in the lower extremities, where her strength improved from 2/5 to 4/5. After her condition stabilized, she was transitioned to oral prednisone (50 mg twice daily) for 7 days, followed by a slow taper to minimize the risk of recurrence.

OUTCOME AND FOLLOW-UP

The patient showed significant neurological improvement following the second course of IVIG and glucocorticoid therapy. Her motor strength in the upper extremities returned to near normal, while lower extremity weakness improved, allowing assisted standing and walking. Sensory deficits and double vision gradually resolved. She was transferred to an inpatient rehabilitation facility for continued recovery. At a 6-week follow-up, the patient exhibited further strength improvement and was able to walk independently. She continued weekly physical therapy and had regular multidisciplinary outpatient follow-up with neurology and oncology. Pembrolizumab was permanently discontinued, and her cancer treatment plan was reassessed. Continued follow-up was arranged to monitor for GBS relapse or long-term effects.

DISCUSSION

Pembrolizumab is a United States Food and Drug Administration-approved monoclonal antibody that targets PD-1. It is used to treat various cancers including metastatic melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, TNBC, renal cell carcinoma, urothelial cell carcinoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, microsatellite instability-high cancer, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, and small cell lung cancer[7]. The PD-1 receptor on lymphocytes serves as an important “immune checkpoint” that helps prevent the immune system from attacking healthy cells[7]. Programmed death receptor-ligand 1 (PD-L1) is overexpressed in several types of tumors. When PD-L1 interacts with PD-1 in lymphocytes, it suppresses T cell activity. Pembrolizumab works by blocking the formation of the PD-1: PD-L1 complex, which enhances T cell-mediated killing[8,9]. In patients with advanced TNBC with PD-L1 expression, combining pembrolizumab with chemotherapy led to notably extended overall survival compared to chemotherapy alone[10]. Once diagnosed with TNBC, our patient was started on pembrolizumab, carboplatin, and paclitaxel.

Pembrolizumab is a relatively newer drug, and its additional side effects continue to emerge and are documented in the literature. Significant adverse reactions observed thus far include adverse skin reactions, endocrinopathies, colitis, pneumonitis, hepatotoxicity, renal injury, infusion-related reactions such as anaphylaxis or hypersensitivity, as well as headache, back pain, arthralgia, decreased appetite, weight loss, and hyponatremia[7]. Skin-related adverse events, like mild itching or rash, are the most common, followed by gastrointestinal toxicity, often presenting as diarrhea and colitis. Endocrine adverse events, including thyroid dysfunction, pituitary inflammation, and adrenal insufficiency, rank third in frequency. Musculoskeletal toxicity, such as mild joint or muscle pain, and ocular toxicity, like mild dry eye syndrome and uveitis, are also commonly reported[10]. One of the lesser reported but potentially life-threatening side effects of pembrolizumab is the adverse neurologic effects. The incidence of adverse neurological effects has been reported to be approximately 6.1% for anti-PD-1/PD-L1[1].

GBS is a rare and severe post-infectious neuropathy characterized by autoimmune nerve destruction, leading to symptoms such as numbness, tingling, weakness, and potential paralysis. Human immunodeficiency virus, mycoplasma, Haemophilus influenza, Campylobacter jejuni, Epstein-Barr, influenza virus, and cytomegalovirus are examples of common pathogens that can lead to GBS[2]. Despite its relatively low incidence of 0.4 cases to 2 cases per 100000 individuals, the medical expenses associated with GBS significantly contribute to an estimated annual treatment cost of 1.7 billion dollars[11]. In 60% of GBS patients, autoantibodies against glycolipids are the primary pathogenic factors. These antibodies often arise due to an immune response against glycoconjugates in pathogens from previous infections, a mechanism known as the “molecular mimicry theory”[12]. There have been a few reported cases of GBS as a side effect following the use of pembrolizumab. According to a comprehensive evaluation by Li et al[1] of 33 cases of GBS-like polyneuropathy with ICI use, symptoms usually started 8.2 weeks after the ICI treatment began. Regulatory T (Treg) cells modulate immune responses, maintain tolerance to self-antigens, and prevent autoimmune diseases. PD-1 is a transmembrane receptor located on the surface of T lymphocytes, suppressing T cell activation. Interaction between PD-1 and its ligands PD-L1/PD-L2 leads to Treg cell-mediated suppression of anti-tumor immunity. Pembrolizumab inhibits the formation of the PD-1: PD-L1 complex, thereby boosting T cell activity and leading to strong T cell activation, improving T cell-mediated killing. Additionally, pembrolizumab not only strengthens anti-tumor immunity but also reduces the generation of Treg cells in normal tissues, which may potentially lead to autoimmune adverse effects. This disruption in immune balance may lead to GBS[2]. According to the Chinese Society of Clinical Oncology 2021 guideline on ICI-associated toxicity, conventional therapies for GBS include corticosteroids and IVIG. The combined use of these treatments has been shown to alleviate clinical symptoms in GBS patients by 73%[4]. Plasma exchange is a secondary option if the patient’s condition deteriorates or the initial treatment proves ineffective. However, several network meta-analyses indicated that plasma exchange or IVIG might be more efficacious for GBS compared to corticosteroids[13,14]. In our patient, the first attempt to treat with IVIG was not successful and provided very limited benefits. However, a subsequent treatment with IVIG combined with high-dose glucocorticoids led to significant improvement in the patient’s condition. Her muscle strength, which had been severely compromised, showed a remarkable improvement from grade 2 to grade 4 motor strength in her bilateral lower extremities.

In this case, the patient did not show any signs of pre-existing infection. Comprehensive laboratory tests, including thyroid-stimulating hormone, 25-hydroxyvitamin D, vitamin B12, folate, and metabolic panel, all came back normal. Magnetic resonance imaging scans ruled out spinal cord issues but showed enhancement along the conus, suggesting GBS or chronic inflammatory demyelinating polyradiculopathy. A lumbar puncture confirmed GBS with elevated protein levels and mild pleocytosis. It was noted that the chemotherapy administered for the patient’s cancer treatment can induce neuropathy. However, based on the typical symptoms of GBS, the timing of the onset of symptoms, and the lumbar puncture findings, it was concluded that the symptoms were likely caused by pembrolizumab-induced GBS. We have reviewed several case reports documenting GBS or GBS-like neuropathy occurring in patients treated with pembrolizumab for various cancers such as melanoma, lung cancer, renal cell carcinoma, and urothelial carcinoma. The treatment typically involves IVIG and high-dose corticosteroids, with varying degrees of improvement reported. However, some cases have resulted in respiratory failure or death despite treatment. The findings are summarized in Table 1.

Table 1 Review of literature on cases of pembrolizumab-induced Guillain-Barré syndrome.

Ref.	Age	Sex	Cancer type	Associated treatment	Onset of GBS after the initiation of treatment in weeks	Treatment of GBS	Neurologic recovery
Han et al[2]	55	Male	Advanced renal cell carcinoma with sarcomatoid differentiation	Sunitinib	16	Oral dexamethasone and then switched to IVIG 0.4 g/kg for 5 days along with prednisone 1 mg/kg per day followed by a taper	Symptoms improved during 1 week of treatment; after 1 month, walking and standing was normal
Ding et al[15]	58	Male	Squamous cell carcinoma of the lung	KN046, a PD-L1/CTLA-4 bispecific antibody	3	Methylprednisolone 500 mg plus IVIG 0.4 g/kg/day for 3 days with no improvement; MM capsules 500 mg twice a day for 3 days with significant improvement	Favorable
Perrod et al[16]	69	Male	Advanced duodenal adenocarcinoma	None	4	IVIG 2 mg/kg for 3 days and IV methylprednisolone 240 mg for 5 days, followed by oral prednisolone 80 mg per day	Favorable
Brzezinska et al[17]	72	Female	Endometrial adenocarcinoma	Lenvatinib	1	Methylprednisolone 1 g IV daily for 5 days and IVIG 2 g/kg over 5 days	Favorable
Oguri et al[18]	76	Male	Stage IV lung adenocarcinoma	None	3	Prednisolone 1 mg/kg followed by IVIG therapy 400 mg/kg/day	Death from respiratory failure on day 53
Sangani et al[19]	80	Male	Metastatic bladder cancer to bones and retroperitoneal lymph nodes	None	1	IVIG for 5 days plus continued physical therapy	Favorable
Aoki et al[20]	85	Female	Metastatic urothelial carcinoma	None	18	Methylprednisolone 80 mg/day followed by oral prednisolone 30 mg/day taper	Favorable
Muralikrishnan et al[21]	65	Female	Malignant melanoma	None	4	IVIG over 5 days for the first time; PE for 7 days and solumedrol for 5 days instead of IVIG for reoccurrence	Relapsed, ongoing bilateral leg tingling and diarrhea
Arora et al[22]	70	Male	Melanoma and prostate cancer	None	12	Dexamethasone for 6 days and IVIG for 5 days	Hydrocephalus, ventricular enlargement; bed-bound; death upon withdrawal from life support
Ong et al[23]	66	Male	Lung adenocarcinoma	None	6.5	Methylprednisone and IVIG, prednisone	Favorable; mild residual paresthesia of the feet
Manam et al[24]	73	Male	Lung adenocarcinoma	None	3	Methylprednisolone along with IVIG, PE	Favorable
Manam et al[24]	81	Male	Melanoma	None	10	Methylprednisolone along with IVIG for 5 days, PE	Death from respiratory failure
de Maleissye et al[25]	85	Female	Metastatic melanoma	None	9	Prednisolone, IVIG	Favorable
Janssen et al[4]	74	Male	Prostate cancer	None	6	Prednisolone, IVIG PE	Death from pneumonia
Janssen et al[4]	55	Male	Melanoma	None	16	Prednisolone, IVIG, methylprednisolone	Mild persistent weakness of feet extensors and mild sensory loss and ataxia
Hashimoto et al[26]	72	Male	Non-small cell lung cancer	None	1.5	Corticosteroids and immunoglobulin therapy	Undescribed
Pomerantz et al[27]	58	Male	Squamous cell carcinoma of the lung	Nivolumab	8.4	IVIG for 5 days	Rehabilitation; no other potential agents were given; patient was alive 6 months after the use of last immunotherapies

GBS: Guillain-Barré syndrome; IVIG: Intravenous immunoglobulin; PD-L1: Programmed death receptor-ligand 1; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; IV: Intravenous; MM: Mycophenolate mofetil; PE: Plasma exchange.

CONCLUSION

In summary, we described a rare case of pembrolizumab-induced GBS in a patient with TNBC. Pembrolizumab, an immune ICI, can lead to various adverse effects, including rare neurological complications such as GBS. This case emphasizes the importance of conducting a thorough neurological assessment, which led to the suspicion of GBS in our patient. GBS induced by immune ICIs can have serious and potentially life-threatening consequences if not promptly identified. Clinicians should be aware of the neurotoxic effects associated with pembrolizumab therapy, requiring a multidisciplinary approach to patient management to prevent morbidity and mortality.