Nivolumab-induced sensory ganglionopathy

Introduction

Nivolumab is a monoclonal antibody targeting the programed cell death-1 protein (PD-1) on T cells. As an immune checkpoint inhibitor (ICI), it blocks the relation between the PD-1 receptor and its ligands. ¹ Nivolumab has come up as a successful therapy for advanced cancers, including melanoma, non-small cell lung cancer, Hodgkin lymphoma, head and neck cancer, urothelial cancer, advanced renal cell carcinoma, colorectal cancer, and esophageal cancer. Moreover, it can be effective in some rare cancers such as Merkel cell carcinoma (MCC). ²

ICI-related neurologic side effects have been previously documented such as peripheral neuropathy, Guillain–Barré syndrome, transverse myelitis, myasthenia gravis, encephalitis, meningitis, encephalopathy and paraneoplastic syndromes (PNSs).^3–8 In addition, paraneoplastic cerebellar degeneration, necrotizing myopathy, Lambert-Eaton myasthenic syndrome (LEMS), encephalomyelitis with ataxia were identified as MCC-related paraneoplastic neurological syndromes (PNSs). ⁹ Here we present the rare toxicity of the drug.

Case report

A 63-year-old male presented to a local clinic with localized swelling in the inguinal region He was diagnosed with MCC based on an excisional biopsy in April 2019. He received adjuvant radiotherapy treatment. Nine-month follow-up, the operation was performed for the second time due to local recurrence. After the operation, residual cancer tissue was detected in the patient, and nivolumab immunotherapy 3 mg/kg² weekly was initiated. Following the third dose of the treatment, he developed tingling in the hands and feet and difficulty in walking. Additionally, he suffered from frequent urination, which began during this period. When he came to our clinic, his vital signs and other than neurologic examination findings were within normal limits. Motor examination demonstrated normal bulk and tone in bilateral upper extremities, however, he had bilateral drop foot. On Medical Research Council (MRC) muscle scale; strength in the upper-proximal right, upper-proximal left, upper-distal right, upper-distal left extremities were scored 4/5, 5/5, 3/5, and 3/5, respectively. Muscle response in lower-proximal right, lower-proximal left, lower-distal right, and lower distal-left extremities were all noted to be 3/5. There were normal plantar reflexes and abolic deep tendon reflexes. Cerebellar function tests could not be performed due to loss of strength. The patient reported bilateral glove and sock-patterned paraesthesias, and loss of joint position sense in distal limbs. Other examinations, including his sense of touch and laboratory results, were within normal limits.

An electomyography (EMG) revealed polyneuropathic involvement characterized by severe axon loss in upper and lower extremity sensory fibers. The results are consistent with the clinical picture of sensory ganglionopathy. No motor neuropathic involvement and no findings suggestive of demyelinating neuropathy were detected (Figure 1 represents Table 2 and Table 3 ; Figure 2 represents Table 4, Table 5, and Table 6). Needle EMG, nerve conduction studies, and repetitive EMG were all within normal limits. Cranial and cervical magnetic resonance imaging with contrast reported ischemic gliotic changes secondary to chronic microangiopathies, cerebral cortical atrophy. Central posterior protrusion is observed in the C4-5 intervertebral disc. C5-6 disc space is narrowed. Bulging is observed in the C6-7 intervertebral disc, no other significant finding is detected.

OPEN IN VIEWER

Figure 1.

The results of the patient's motor nerve condition studies.

OPEN IN VIEWER

Figure 2.

The results of the patient's sensorial nerve condition studies.

OPEN IN VIEWER

Table 1.

Selected case reports reporting the details of potentially Immune-related neurologic toxicities with immune checkpoint inhibitors.

Case report	Patient characteristic	Nivolumab dosage	Pattern of neurologic toxicities	Treatment
Sakoh et al. 5	A 72-year-old man with non-small cell lung carcinoma	3 mg/kg Nivolumab at the 13th cycle	Ataxic sensory neuropathy and Ramsey Hunt syndrome	1 mg/kg methylprednisolone followed by that intravenous immunoglobulin 400 mg/kg/day for 5 days
Simsek et al. 6	A-58-year-old male with renal cell carcinoma	Nivolumab 3 mg/kg (total dose of 225 mg) at the 6th round	Peripheral neuropathy	1 mg/kg methylprednisolone
Larkin et al. 7	A 57-year-old man with advanced melanoma	Ipilimumab and nivolumab combination therapy with unknown dosage	Numbness of bilateral lower extremitiesand optic neuritis	1 gram intravenous methylprednisolone followed by oral prednisone
Sakai et al. 8	A 81-year-old male with mediastinal melanoma	3 mg/kg nivolumab at the first cycle	Mononeuropathy multiplex	1 g/day IV methylprednisolone for 3 days, followed by oral prednisolone

OPEN IN VIEWER

Table 2.

Right peroneus motor.

	Latency	Amplitude
	ms	mV	m/s
BI.Knee-Ankle	11.1	3.1	40.5

ms: millisecond; mV: signal amplitude; m/s: meters/second.

OPEN IN VIEWER

Table 3.

Right Radialis motor.

	Latency	Amplitude	Rate
	ms	mV	m/s
Ab. Elbow-Forearm	6.77	1.86	50.0

ms: millisecond; mV: signal amplitude; m/s: meters/second.

OPEN IN VIEWER

Table 4.

Right peroneus superfic sensory.

	Latency	Amplitude	Rate
	ms	µV	m/s
Calf – Med. Dor. Cutan	–	–

ms: millisecond; µV: voltage; m/s: meters/second.

OPEN IN VIEWER

Table 5.

Right radials sensory.

	Latency	Amplitude
	ms	µV	m/s
EPL tendon—Wrist	–	–

ms: millisecond; µV: voltage; ***m/s: meters/second.

OPEN IN VIEWER

Table 6.

Right Suralles sensory.

	Latency	Amplitude
	ms	µV	m/s
Mid. lower leg—Lat. Malleous	–	–

ms: millisecond; µV: voltage; m/s: meters/second.

A variety of diagnostic tests have been performed to elucidate the etiology of sensory ganglionopathy. Antineoplastic panel including; anti-amphiphysin, Anti-CV2, Anti-Ma2/Ta, Anti-Ri/ANNA-2, Anti-Yo/Anti-Purkinje Cell Antibodies-1, Anti Hu/Antineuronal Nuclear Antibody-1, Anti-recoverin Ab, SOX1 Ab, Zic4, Glutamate Decarboxylase Antibodies, Anti-Tr/DNER, Anti-TITINE Ab, Voltage-dependent Ca channel Ab were negative. Some rheumatological tests including extractable nuclear antigen antibodies, anti-nuclear antibodies, and rheumatoid factor were within normal limits. The results of screening for human immune deficiency virus, Epstein–Barr virus (EBV) antibodies, and viral deoxyribonucleic acid to EBV, human T-lymphotropic virus (HTLV-1) antibody for HTLV-1 were all negative. Furthermore, the case had no vitamin B12, folic acid, or iron deficiency. He did not consent to the spinal tap procedure. The Naranjo score was 6, suggesting a probable adverse drug effect. ¹⁰ Methylprednisolone 1 mg/kg/day treatment was initiated. After 1 month, the patient reported a 50% improvement in his condition.

The patient presented with symptoms of hoarseness and concurrently displayed an inability to ambulate without external support, possibly due to a reduction in sensory perception in the lower extremities. Except for the loss of the joint position sense in the left upper and right lower extremity and general superficial stocking and glove neuropathy other neurological findings were normal. Strength improved by one-fifth in all upper proximal and distal extremities. The steroid dose was reduced from 16 mg to 5 mg every other day. In the third month, a positron emission tomography-computed tomography showed significant tumoral regression, and he healed by approximately 85%. There were significant improvements in his strength which went up from MRC grade 3 to maximum level in all distal extremities. Methylprednisolone treatment was reduced to 4 mg every other day.

Discussion

We describe a rare sensory ganglionopathy side effect of nivolumab. The clinical manifestations of sensory ganglionopathy include hypoesthesia, vibratory perception, proprioception; pseudoathetoid posturing, Romberg's sign, and absent tendon reflexes. Moreover, sensory features can begin in any or all territories innervated by sensory neurons, especially the face, oral mucosa, trunk, and proximal extremities. ¹¹

The major adverse effects of ICIs include diarrhea, hepatitis, colitis, skin toxicities, neuropathies, and endocrinopathies such as hypophysitis, and thyroiditis. ¹² Dubey et al., ¹³ defined neuropathies related to ICIs with the vast majority being cranial neuropathies. These drugs may rarely cause damage to the sensory ganglia, a condition called sensory ganglionopathy. Some case reports about the sensory manifestations of nivolumab exposure are presented in Table 1. Magnetic resonance imaging, EMG, and nerve biopsy can be used for diagnosis. There are some therapies that have been used for sensory ganglionopathies such as glucocorticoids, immunosuppressive agents, rituximab, plasma exchange, and intravenous immune globulin. ¹¹

Some neurons and ganglia structures are unlikely to recover due to the irreversible destruction of cells. In a case series, the patients who suffered from sensory neural symptoms and were treated in the first 2 months showed improvement, while others treated in 8 months did not show a marked improvement. ¹⁴ PNSs are defined as signs and symptoms that are not directly related to a tumor or metastases, are distant from the tumor site, are dependent on the presence of the tumor and therefore regress after removal of the tumor. Small cell lung cancer (SCLC), breast, gynecological, and hematological malignancies, and neuroendocrine tumors may be associated with PNSs. ¹⁵

The rate of PNSs accompanying cancer is 8%, of which 20% is SCLC. ¹⁶ MCC is a neuroendocrine cancer that histologically resembles SCLC. Therefore, patients with MCC may present with similar PNSs, including LEMS and paraneoplastic cerebellar degeneration. ⁹ The anti-Hu antibody syndrome with limbic encephalitis has been described in MCC as a paraneoplastic neurologic syndrome. ¹⁷ With the approval of ICI nivolumab, the prognosis of metastatic MCC has significantly improved. ¹⁸

ICIs may increase the risk of developing PNSs. Paraneoplastic manifestations of ICIs are limbic encephalitis, autoimmune demyelinating polyneuropathies, myasthenia gravis, and other neurologic findings. ¹⁹

It is hard to distinguish the difference whether a neurologic problem is related to the paraneoplastic event or an ICI-activated syndrome. PNSs develop gradually, while ICIs toxicity can be rapidly seen at any time after initiation of ICI therapies. ²⁰ We believe that our case is sensory ganglionopathy as a side effect of nivolumab. However, we cannot definitely say that it is an undocumented PNS of MCC. The ganglionopathy may have occurred as a PNS and disappeared after the effective tumor response of nivolumab. We will likely be sure about the diagnosis after follow-up.

In summary, immune checkpoints’ usage has increased worldwide, therefore we can experience the side effects widespread. Besides common toxicities, rare conditions such as sensory ganglionopathy can be seen. In order to increase the success of treatment, it is essential to emphasize the need for early diagnosis of side effects in those patients.

Supplemental Material