Myasthenia-like paraneoplastic syndrome with multiple cranial nerve tumor infiltration: A case report and literature review : Medicine

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Research Article: Clinical Case Report

Myasthenia-like paraneoplastic syndrome with multiple cranial nerve tumor infiltration: A case report and literature review

Wen, Chunbei MMa,b; Yang, Jie MDa; Xu, Changyou MMa,b; Wei, Dongsheng MMa; Luo, Lijun MMa,*

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Medicine 102(20):p e33774, May 19, 2023. | DOI: 10.1097/MD.0000000000033774
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1. Introduction

Myasthenia gravis (MG) is a T cell-dependent, B cell-mediated, complement-involved autoimmune neuropathy characterized by acetylcholine receptor antibody at the neuromuscular junction or other components of the postsynaptic muscle endplate, leading to neuromuscular transmission disorders. MG manifests several typical features: Partial or systemic skeletal muscle weakness and easy fatigue; Aggravated symptoms following activities, and; Marked relief of symptoms after rest or application of cholinesterase inhibitors.[1] MG can be diagnosed based on the typical characteristics of fluctuating myasthenia and either an electrophysiological or serum antibody detection test.[2] A fast-acting acetylcholinesterase inhibitor administered intravenously can instantly reverse MG muscle weakness, but this type of diagnosis method is more subjective.

Approximately 10% to 15% of patients with MG have thymoma, and 40% of thymoma patients eventually develop MG.[3] When combined with thymoma, MG exists as a paraneoplastic syndrome (PNPS) of thymoma. The association between MG and thymoma has been widely documented in the literature,[4–6] its association with lung cancer has not been clearly described. Herein, we report a case of MG coexisting with lung adenocarcinoma.

2. Case presentation

A 55-year-old female patient was admitted to the hospital on May 11, 2022, due to “weakened chewing accompanied by dizziness and unsteady walking for nearly half a year”. Over the past 6 months, the patient gradually developed slurred speech, weakness in chewing, sporadic difficulty in swallowing, weakness in both lower limbs, and unsteady walking. Standing up from a sitting position made her dizziness more pronounced, which was likely caused by a shift in body position. The patient also had a dry nasal cavity that was prone to bleeding. In October 2011, the patient experienced right tinnitus, aural fullness, and hearing loss. She was diagnosed with “sudden deafness in the right ear” and received medical treatment. Subsequently, the hearing of the left ear gradually decreased, and no treatment was administered.

On March 11, 2022, because of an “obvious decline in hearing and vision and weakness of limbs for nearly 3 months”, she returned to the hospital for medical investigation. Biological tests indicated that the cerebrospinal fluid (CSF) was colorless and transparent. The total number of white blood cells in the CSF was 23 × 10^6/L (0–5 × 10^6/L). The amount of protein was 0.63 g/L (0.15–0.45 g/L). Sugar and chloride levels were normal, and no tumor cells were observed. Today, the left ear is almost completely deaf, and the right ear functions to a very low degree, partly reserved, making communication almost impossible. She had been suffering from a lung tumor for nearly 4 years, and pathological examination revealed lung adenocarcinoma (Fig. 1). Next-generation sequencing revealed an Epidermal Growth Factor Receptor missense mutation (NM_005228.3), c.2573T > G mutation (p. Leu 858Arg), and t790m. The patient was treated with osimertinib 160 mg qd for tumor-targeted therapy. No surgery was performed and there was no other medical history.

Figure 1.:
Right lung biopsy tissue (invasive lung adenocarcinoma) with predominantly acinar growth pattern.

Vital signs were stable with postural hypotension. The patient had slurred speech, dysarthria, and decreased visual acuity. She could normally frown and close her eyes but closed her lips loosely without an obvious decrease in facial pain sensation. The patient also had weakness in her cheeks and chewing problems. She was completely deaf on her left side and partially deaf on her right side. The patient’s gag reflex was sluggish. Her shoulder muscles were weak, and she could not extend her tongue past her lips, which was accompanied by atrophy and tremors. Limb proximal muscular strength was grade 4, and grade 5 distal muscular strength was present. The tendon reflexes of both upper and right lower extremities were +++, and her left lower extremity tendon reflexes were ++++. Both upper extremities passed the finger-nose test, and the heel-knee-shin test failed for both lower extremities. The pathological signs of the left lower extremity were suspiciously positive, Lasegue sign was (−), and meningeal irritation sign was (+).

Computed tomography of the lungs revealed thin-walled cavities in the lower lobe of the right lung and scattered solid nodules over the entire lung (Fig. 2). Magnetic resonance imaging scans of the brain, nasopharynx, cervical spine, and thoracic spinal cord revealed several lacunar cerebral infarctions, but no evident mass in the nasopharynx. There was an aberrant signal shadow in the right occipital lobe but no augmentation (Fig. 3). The results of the neostigmine test were negative. The following MG-related antibodies were absent: anti-acetylcholine receptor antibody, anti-muscle-specific tyrosine kinase autoantibody, anti-titin autoantibody, and anti-low-density lipoprotein receptor autoantibody. Anti-Hu, anti-Yo, anti-SOX1, and anti-voltage-gated calcium channel autoantibodies were negative for paraneoplastic antibodies.

Figure 2.:
Lung CT: (A and B) Partial solid nodules in the upper lobes of both lungs, (C and D) thin-walled cavity in the right lower lobe. CT = computerized tomography.
Figure 3.:
(A) Patchy long T2 and T2 Flair low signal shadows in the right occipital lobe, patchy edema around the posterior horn of the right lateral ventricle, no enhancement, (B) no cerebellar atrophy in the sagittal plane.

Electromyography (EMG) revealed that some of the muscles examined had compound muscle action potential (CMAP) amplitudes that were attenuated by low-frequency stimulation (3 Hz) (the left abductor pollicis brevis muscle was attenuated by 46.2%, the right orbicularis oculi muscle was attenuated by 11.6%, and the right frontalis muscle was attenuated by 11.4%). High-frequency stimulation (30 Hz) did not significantly enhance the CMAP amplitude of the tested muscle (left abductor pollicis brevis) (Fig. 4). Cerebrospinal fluid examination was repeated, and based on the pathological findings, scattered, mildly atypical epithelioid cells and poorly differentiated adenocarcinomas were considered (Fig. 5).

Figure 4.:
(A) The amplitude of the left abductor pollicis brevis muscle decreased by 46.2% after repeated stimulation at low-frequency (3Hz), (B) the amplitude decreased by 80.8% after repeated stimulation at high-frequency (30Hz).
Figure 5.:
A cerebrospinal fluid smear shows a small number of monocytes, lymphocytes, and scattered epithelioid cells with mild atypia, tending to be poorly differentiated adenocarcinoma.

The diagnoses were made as follows: Lung cancer with meningeal metastasis, multiple cranial nerve damage; Nervous system PNPS: secondary MG-like syndrome; Cerebellar and brainstem inflammation cannot be ruled out. Treatment should include supportive symptomatic care and immunotherapy in addition to treating the main tumor.[7] She was treated with neurotrophic (vitamin B group) therapy and advised to undergo hormone therapy, but the patient declined. After discharge, she received intrathecal chemotherapy with Pemetrexed in Xiehe, and tumor cells were again found in the CSF (Fig. 6). Subsequently, the patient stopped chemoradiotherapy and switched to cabozantinib on her own.

Figure 6.:
Cancer cells were again found in the cerebrospinal fluid, consistent with the lung adenocarcinoma phenotype.

One month later, family members complained that although the patient’s mental condition appeared to have marginally improved during chemotherapy, the patient’s proximal limb weakness, choking cough, and chewing difficulties persisted.

Informed consent was obtained from the patient for publication of the findings of this case report.

3. Discussion

PNPS can affect various organ systems, most notably the endocrine, neurological, dermatological, rheumatological, and blood systems. They are brought on by hormones, peptides, or cytokines secreted by tumors, or by immune cross-reactivity between malignant and normal tissues. Tumor neural antibodies can often be detected in the serum, but 30% of paraneoplastic nerve system syndrome (PNS) patients fail to detect related antibodies.[7] Common PNS, such as central nervous system syndrome (e.g., limbic encephalitis and paraneoplastic subacute cerebellar degeneration), neuromuscular junctions (e.g., Lambert-Eaton myasthenic syndrome [LEMS]), peripheral nervous system (e.g., autonomic neuropathy and subacute sensory neuropathy), and retinopathy are often prone to occur.[8]

A diagnosis of common PNS, such as LEMS and subacute cerebellar degeneration, was considered in this patient due to decreased muscle strength and ataxia, but this was not confirmed by related examinations. Re-frequency EMG revealed that CMAP waves were attenuated after low-frequency and high-frequency stimulation, which is consistent with the typical electrophysiological characteristics of MG.[9] Simultaneously, tumor cells were found in the CSF. Experts from multiple disciplines, including neurology, EMG, and oncology, have discussed this case. They ultimately agreed that cranial nerve injury caused by tumor infiltration could simultaneously involve the motor and sensory nerves. Owing to the influence of gravity, the latter group of cranial nerves is easily involved, and nerve injury is often asymmetric. There were pure sensory nerves II and VIII in this patient, mixed nerves V for the maxillary and mandibular branches, and X for cranial nerve injury. Multiple cranial nerve tumor infiltrations cannot be ruled out because MG syndrome is unable to fully explain the patient’s symptoms. In addition, the patient had instability in walking, Romberg sign was unstable with both eyes open and closed, and tendon reflexes were hyperactive. Although no abnormality was found on head Magnetic resonance imaging, brainstem and cerebellar inflammation due to tumor infiltration could not be excluded.

Taken together, our analysis and treatment provide new insights into our understanding of tumor-related MG-like neurological syndromes and the infiltration of cancer cells with neurological damage. In addition, brainstem and cerebellar inflammation caused by tumor infiltration cannot be completely excluded.

In small-cell lung cancer, PNPS is most frequently linked to lung cancer, with LEMS being the most prevalent PNS in the neuromuscular junction. When limiting the search time to 1990 to 2022, the search terms to “Lung Neoplasms” or “Adenocarcinoma of Lung” AND “myasthenia gravis” in Pubmed, most of the published cases are reports of other lung tumors complicated with MG,[10–21] but only 3 cases of lung adenocarcinoma[22–24] (Table 1). A thorough assessment of the literature led us to conclude that the causes of the coexistence of the 2 components have steadily become better understood over time, moving from an accidental phenomenon to an immunological problem to a paraneoplastic manifestation.

Table 1 - Reported cases of lung cancer with myasthenia gravis.
Age/sex Histology of cancer Clinical manifestations MG type Anti-nAchR antibody Electromyography Neostigmine or edrophonium test CSF Thymoma Order of occurrence Treatment Results Author's think Year Reference
For MG For LC For MG For LC
55 F Ad Muscle fatigue after chewing, slurred speech, and unsteady walking, with proximal limb weakness General + + MG developed 4 yr after lung cancer ChT Unchanged NA Need to start two treatments at the same time 2022 This case
71 M SCLC Ptosis, dysphagia, muscle fatigue after chewing General + ND + ND Synchronous Py, steroid, tacrolimus, IVIG ChT + RT IMPRV Stability Need to start two treatments at the same time 2018 [10]
60 M SCLC Ptosis, poor speech, weakness of limbs General + + + Lung cancer developed 11 mo after MG Py, steroid ChT IMPRV Stability Perhaps a paraneoplastic syndrome 2018 [11]
64 M NEC Ptosis, diplopia, weakness of limbs General + + Synchronous Py, steroid ChT + RT Worsen PR Perhaps a paraneoplastic syndrome 2015 [12]
38 M Ad Hemoptysis, chest pain, weakness of limbs General ND + ND ND Synchronous Death Perhaps a paraneoplastic syndrome 2014 [22]
69 F Ad Ptosis, weakness of limbs, dysphagia General + + ND ND + Synchronous Th SX Completely improve Stability Not sure if relevant 2012 [23]
56 M SCLC Ptosis, dysphonia, weakness of limbs General −, but Anti-Musk+ ND Lung cancer developed 8 mo after MG Py, steroid ChT Worsen Death Perhaps a paraneoplastic syndrome 2012 [13]
62 M NSCLC Ptosis, diplopia, weakness of limbs General + + ND ND Synchronous ND ND ND ND Perhaps a paraneoplastic syndrome 2011 [14]
65 M SCLC Ptosis, weakness of limbs, polypnea General + + + Synchronous Py, steroid, PE ChT IMPRV Death ND 2011 [15]
55 M NSCLC Ptosis, axial muscle weakness General + ND ND MG developed 2 years after surgery of lung cancer Py, steroid, PE ChT + RT + SX IMPRV ND May be related to some kind of autoimmunity 2010 [16]
77 M Sq Bulbar palsy General + + ND ND Lung cancer developed 6 yr after MG Py, steroid, Th SX IMPRV ND May be related to some kind of immune disorder 2006 [17]
46 M La, Ad Ptosis, diplopia Ocular + ND + ND Synchronous Steroid, AZA, Th RT + SX Death Perhaps a paraneoplastic syndrome 2000 [24]
56 M AC Ptosis, rhinolalia, facial weakness, weakness of limbs General + + ND ND Synchronous Steroid, AZA, Th SX IMPRV Survive Happenchance 1999 [18]
44 F Carcinoid Diplopia, dysarthria, dysphagia, diarrhea General ND + ND Synchronous Py, loperamide, Th SX ND ND Happenchance 1997 [19]
56 M SCLC Ptosis, weakness of limbs, polypnea General + + ND Lung cancer developed 18 mo after MG Anticholinesterase inhibitors ChT IMPRV Disappear Cause unknown 1995 [20]
49 M SCLC Ptosis, progressive generalized muscle weakness, dyspnea General + + ND ND Synchronous Edrophooium chloride ND IMPRV ND May be related to some kind of immune disorder 1994 [21]
AC = Atypical carcinoid, Ad = adenocarcinoma, anti-Musk = anti-muscle-specific tyrosine kinase autoantibody, AZA = azathioprine, CSF = cerebrospinal fluid, ChT = chemotherapy, F = female, IVIG = intravenous immunogloblin, IMPRV = improvement, La = large cell carcinoma, LC = lung cancer, M = male, MG = myasthenia gravis, NA = not available, ND = not described, NEC = poorly differentiated neuroendocrine carcinoma, NSCLC = non-small-cell lung cancer, Py = pyridostigmine, PE = plasma exchange, PR = partial response, RT = radiotherapy, Sq = squamous-cell carcinoma, SCLC = small-cell lung cancer, SX = surgery, Th = thymectomy.

In the case described by Wang et al,[25] a patient was admitted to the hospital with ptosis and diplopia as the main complaints. Physical examination revealed lung cancer. Neostigmine text, MG, and paraneoplastic antibodies were all negative. EMG was not performed considering LEMS based on the symptoms alone. This finding is similar to the clinical features of our patient. Mesolella et al[26] also reported a patient with laryngeal neuroendocrine carcinoma who did not undergo EMG examination and did not have paraneoplastic or MG-related antibodies. LEMS was diagnosed based on typical symptoms of proximal muscle weakness and autonomic dysfunction. As a result, we assume that the lack of prior reports on lung cancer and MG may be attributed to physicians propensity to make diagnoses; hence, the likelihood of diagnostic bias cannot be completely ruled out. Even in cases where MG syndrome has been identified, many people do not undergo CSF testing, which makes it difficult for doctors to properly comprehend the patient’s current condition. Furthermore, even in individuals with obvious imaging results and clinical symptoms, the positive diagnosis rate of CSF cytopathology is typically <50%, necessitating repeated testing.[27]

Successful cancer treatment does not always result in improvements in neurological function, and the mainstay of PNS treatment is immune-modulating drugs.[8] In patients with PNS, combination therapy targeting malignancy and immunomodulation may help improve functional status.[28] After discharge, the patient only received chemotherapy and targeted therapy for tumor metastasis and lacked immunotherapy for MG, so her symptoms did not improve dramatically.

Thus, clinicians should initiate antitumor therapy and immunotherapy simultaneously when tumor progression and MG-like syndrome are detected, which may improve the prognosis of patients. Our clinical reports and investigations may provide new insights for the near future. This is because MG will become an item on the list of PNS associated with lung tumors, along with LEMS and paraneoplastic cerebellar degeneration.

4. Conclusion

We report a case of a Chinese female patient with lung adenocarcinoma who may be associated with MG, although the reason for their coexistence remains unknown. More fundamental studies on PNPS are needed to clarify the probable link between the 2. CSF testing is critical for determining tumor progression and requires several examinations.


The authors thank the patient’s family members for their cooperation in providing the medical data necessary for this publication.

Author contributions

Investigation: Chunbei Wen, Changyou Xu, Dongsheng Wei.

Validation: Changyou Xu, Dongsheng Wei.

Writing – original draft: Chunbei Wen.

Writing – review & editing: Jie Yang, Lijun Luo.


compound muscle action potential
cerebrospinal fluid
Lambert-Eaton myasthenic syndrome
Myasthenia gravis
paraneoplastic syndrome
paraneoplastic nerve system syndrome


[1]. Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375:2570–81.
[2]. Gilhus NE, Tzartos S, Evoli A, et al. Myasthenia gravis. Nat Rev Dis Primers. 2019;5:30.
[3]. Toothaker TB, Rubin M. Paraneoplastic neurological syndromes: a review. Neurologist. 2009;15:21–33.
[4]. Basse C, Girard N. Thymic tumours and their special features. Eur Respir Rev. 2021;30:200394.
[5]. Ke J, Du X, Cui J, et al. LncRNA and mRNA expression associated with myasthenia gravis in patients with thymoma. Thorac Cancer. 2022;13:15–23.
[6]. Yasumizu Y, Ohkura N, Murata H, et al. Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma. Nat Commun. 2022;13:4230.
[7]. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85:838–54.
[8]. Shamji FM, Beauchamp G, Maziak DE, et al. Paraneoplastic syndromes in lung cancers: manifestations of ectopic endocrinological syndromes and neurologic syndromes. Thorac Surg Clin. 2021;31:519–37.
[9]. Katzberg HD, Abraham A. Electrodiagnostic assessment of neuromuscular junction disorders. Neurol Clin. 2021;39:1051–70.
[10]. Yamasaki M, Funaishi K, Saito N, et al. Acetylcholine receptor antibody-positive myasthenia gravis associated with small-cell lung cancer: a case report. Medicine (Baltim). 2018;97:e0541.
[11]. Jia R, Chen J, Ge R, et al. Coexistence of myasthenia gravis and Lambert-Eaton myasthenic syndrome in a small cell lung cancer patient: a case report. Medicine (Baltim). 2018;97:e10976.
[12]. Niimi K, Nagata E, Murata N, et al. Lung cancer associated with seronegative myasthenia gravis. Intern Med. 2015;54:1381–4.
[13]. Basta I, Nikolic A, Losen M, et al. MuSK myasthenia gravis and Lambert-Eaton myasthenic syndrome in the same patient. Clin Neurol Neurosurg. 2012;114:795–7.
[14]. Shaygannejad V, Ghasemi M, Rajaee Z. Myasthenia gravis as a presenting feature in a patient with lung cancer: a case report. J Res Med Sci. 2011;16:229–32.
[15]. Ohira M, Jeong D, Oh SJ. Seropositive myasthenia gravis associated with small-cell lung carcinoma. J Clin Neurol. 2011;7:43–6.
[16]. Peltier AC, Black BK, Raj SR, et al. Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer. Muscle Nerve. 2010;41:416–9.
[17]. Sakamaki Y, Yoon HE, Oda N. Non-small-cell lung cancer associated with non-thymomatous myasthenia gravis. Jpn J Thorac Cardiovasc Surg. 2006;54:207–11.
[18]. Burns TM, Juel VC, Sanders DB, et al. Neuroendocrine lung tumors and disorders of the neuromuscular junction. Neurology. 1999;52:1490–1.
[19]. Arruda WO, Rosa JF. A 44-year-old woman with diarrhoea and double vision. Lancet. 1997;349:1882.
[20]. Miyoshi R, Yamaji Y, Shima S, et al. [A case of small cell lung cancer that developed during therapy for myasthenia gravis]. Nihon Kyobu Shikkan Gakkai Zasshi. 1995;33:456–62.
[21]. Fujita J, Yamadori I, Yamaji Y, et al. Myasthenia gravis associated with small-cell carcinoma of the lung. Chest. 1994;105:624–5.
[22]. Eivaz-Mohammadi S, Gonzalez-Ibarra F, Hekmatjou H, et al. Myasthenia gravis-like syndrome presenting as a component of the paraneoplastic syndrome of lung adenocarcinoma in a nonsmoker. Case Rep Oncol Med. 2014;2014:703828.
[23]. Takizawa M, Oda M, Matsumoto I, et al. Myasthenia gravis complicated with lung cancer and middle mediastinal thymoma. Asian Cardiovasc Thorac Ann. 2012;20:486–8.
[24]. Leavitt JA. Myasthenia gravis with a paraneoplastic marker. J Neuroophthalmol. 2000;20:102–5.
[25]. Wang A, Zhang X, Yi J, et al. Successful treatment of advanced lung adenocarcinoma complicated with Lambert-Eaton myasthenic syndrome: a case report and literature review. Thorac Cancer. 2020;11:1334–8.
[26]. Mesolella M, Allosso S, Buono S, et al. Neuroendocrine carcinoma of the larynx with Lambert-Eaton myasthenic syndrome: a rare case report and literature review. J Int Med Res. 2021;49:3000605211014784.
[27]. Gao N, Xin T. [Advances in diagnosis and treatment of leptomeningeal metastasis of lung cancer]. Zhongguo Fei Ai Za Zhi. 2022;25:517–23.
[28]. Cheng YC, Chang A, Hsu WC. Anti-SOX1 antibody-positive paraneoplastic syndrome presenting with subacute cerebellar degeneration and lambert-eaton myasthenic syndrome: a case report. Acta Neurol Taiwan. 2021;30:74–7.

adenocarcinoma of lung; case report; myasthenia gravis; paraneoplastic syndromes; peripheral nervous system neoplasms

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