Cases 1 and 2 were diagnosed with anti-CNTN1 AN at Kyushu University Hospital in 2017 and 2020, respectively. We also included a previously reported case (Case 3) presenting with subacute sensory ataxic neuropathy with thymoma (6), which was seropositive for CNTN1-IgG by further investigation.

CNTN1-IgG and NF155-IgG in sera from Cases 1 and 2 were evaluated by flow cytometric cell-based assay (CBA) as previously described (14, 15). Caspr1-IgG was screened by enzyme-linked immunosorbent assay (ELISA) using recombinant human Caspr1 protein (R&D Systems, Minneapolis, MN, USA) (16). In Case 3, serum CNTN1-IgG and NF155-IgG were measured at Kindai University by ELISA using commercially available recombinant human CNTN1 and NF155 proteins (Sino Biological, Beijing, China, and R&D Systems, Minneapolis, MN, USA, respectively) as a part of a comprehensive autoantibody evaluation. When positive, IgG subclass analysis was performed as for total IgG detection.

Serum neurofilament light chain (NfL) was measured in duplicate using a Simoa NF-light™ V2 advantage kit (Quanterix, Billerica, MA, USA) on a Simoa HD-X analyzer following the manufacturer’s instructions and standard procedures.

We performed a PubMed search using “neuropathy” and “thymoma” as keywords on 10th October 2024, which identified 65 articles. Then, we reviewed all suitable cases of demyelinating peripheral neuropathy with thymoma by a literature survey.

A 60-year-old man with a medical history of recurrent invasive thymoma was admitted to our hospital, with the chief complaint of limb weakness. The thymoma was incidentally found on a medical checkup at age 40 years. After thymectomy and postoperative radiation therapy, vitiligo vulgaris appeared on his face and hands. Fourteen and 17 years after the first resection, the thymoma relapsed in the anterior chest wall. Surgical treatments were performed and the histological subtype was type B3 thymoma according to the World Health Organization classification.

The patient presented with paresthesia of both feet spreading to all limbs less than two months before admission. He occasionally had pain similar to sore muscles on the lower back and left lower limb. Bilateral lower limb weakness progressively worsened, resulting in difficulty standing up without the support of the upper limbs. Just before admission, a medical checkup by chest computed tomography (CT) revealed the third recurrence of thymoma in the left intrapleural cavity. Neurological examination showed left-predominant paresthesia, diffuse hyporeflexia, and disturbance of deep sensation in the lower limbs ( Table 1 ). Manual muscle testing showed bilateral asymmetric weakness dominantly involving the distal part of left upper and lower limbs. Serum creatine kinase was within normal limits. Although a diagnostic workup found several autoantibodies against double-stranded deoxyribonucleic acid (dsDNA), acetylcholine receptor (AChR), and titin in his serum, no clinical evidence of systemic lupus erythematosus (SLE) or myasthenia gravis (MG) was observed. The Harvey–Masland test did not show any waning in the trapezius and abductor digiti minimi muscles. In addition, he was positive for CV2/collapsin response-mediator protein 5-IgG associated with mixed axonal and demyelinating neuropathy (17). Cerebrospinal fluid (CSF) findings showed albuminocytological dissociation (protein level 210 mg/dL and cell count 5/µL) and an IgG index of 0.66 (normal range: < 0.73). The initial differential diagnoses included paraneoplastic demyelinating neuropathy and multifocal chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, a nerve conduction study (NCS) revealed apparent conduction delay in all nerves examined and no rationale for multifocal distribution of demyelination was observed. Brain magnetic resonance imaging (MRI) detected no abnormal findings. Hypertrophy of cervical and lumbosacral nerve roots was not obvious on MR neurography ( Supplementary Figure 1 ).

Because of the acute deterioration of sensorimotor defects after admission, intravenous immunoglobulin (IVIg, 2 g/kg) was initially administered and slightly improved paresthesia in the left hand ( Figure 1A ). Three weeks later, the patient received the third thymectomy. Microscopic examination revealed a lobular proliferation of polygonal epithelioid cells and infiltration of fibro-adipose tissue in the chest wall, indicating the recurrence of type B3 thymoma ( Figures 2A, B ). Two weeks after thymectomy, the patient received two courses of intravenous methylprednisolone (IVMP, 1000 mg/day for 3 days), which did not affect his symptoms. Treatment was switched to IVIg, followed by maintenance dose IVIg (1 g/kg) once every 1–2 months for 4 years. Neurological symptoms and NCS findings gradually improved ( Figure 1A ). Even after the unexpected discontinuation of IVIg because of acute myocardial infarction, a further improvement in neurological symptoms was achieved with a total Inflammatory Neuropathy Cause and Treatment (INCAT) score of 5 (3 for arms and 2 for legs) at the last administration and 4 (2 for arms and legs) at the last follow-up. Incidentally, vitiligo vulgaris did not improve during treatment.

A 75-year-old man initially developed mild dysesthesia in four limbs. Concurrently, thymoma was incidentally found through the evaluation of emphysema. Although AChR-IgG was positive, the patient did not present with clinical or electrophysiological signs of MG. The patient had no other relevant medical or family history. Thymectomy was performed four months later, and the pathological classification was type AB thymoma, characterized by the proliferation of spindle cells admixed with mature lymphocytes, alternating with lymphocyte-rich areas composed of proliferating oval or polygonal epithelial cells ( Figures 2C–E ). After resection of the thymoma, limb dysesthesia and weakness deteriorated acutely resulting in requiring assistance when walking. Intense pruritus and lower limb pitting edema emerged. The patient was transferred to our department for further evaluation.

On admission, the patient presented with mild dysgeusia and dysphagia with no diurnal variation, symmetrical distal limb weakness, superficial and deep sensory disturbances, diffuse hyporeflexia, and ataxic gait with positive Romberg sign ( Table 1 ). Tremor was not conspicuous. CSF protein level and IgG index were 309 mg/dL and 0.57, respectively. NCS findings showed evident conduction delay in all nerves tested. Brain MRI was normal and brain N-isopropyl-p-[¹²³I] iodoamphetamine single-photon emission CT revealed no definite decreased perfusion. Cervical and lumbosacral MR neurography revealed slightly thickened nerve roots ( Supplementary Figure 1 ). On physical examination, skin lesions characterized by edematous erythema, blisters, and erosion affected the head, neck, and four limbs. Mucosal sites were intact. Skin biopsy findings and desmoglein 1 (DSG1)-IgG positivity were consistent with pemphigus foliaceus ( Supplementary Figure 2 ). Autoantibodies against DSG3 and bullous pemphigoid antigen 180 were not detected in the serum. The patient was diagnosed with nephrotic syndrome based on hypoalbuminemia (2.4 g/dL) and overt proteinuria (urine protein to creatinine ratio 5.3 g/gCr). His proteinuria selectivity index was 0.16, and urinary occult blood was negative. Hepatitis B virus serological status indicated past infection, which might have been a cause of secondary membranous nephropathy (MN). We did not measure autoantibodies targeting podocyte antigens including phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) (18, 19). The patient refused a renal biopsy.

The patient was treated with plasma exchanges followed by IVMP (1000 mg/day for 3 days) and oral glucocorticoids (prednisolone 50 mg/day), resulting in a gradual improvement of neurological findings as well as blisters and leg edema ( Figure 1B ). Three months after treatment initiation, the patient had no skin lesions and could walk without a cane over short distances. Urine protein and serum DSG1-IgG returned to negative six months later. NCS findings also showed remarkable improvement. Eighteen months after the initial treatment, oral glucocorticoids were tapered off, leading to the remission of neurological, skin, and renal symptoms. Fifteen months later, erythema reemerged on the head with an elevation of DSG1-IgG titers. Neurological and renal involvement remained in complete remission with an INCAT score of 0, and there was no evidence of thymoma recurrence. Considering the impact of systemic glucocorticoid administration on a patient with a history of pulmonary tuberculosis, pemphigus was treated with topical glucocorticoids at the last follow-up.

The clinical course of Case 3 was documented in detail by Nishijima et al. (6). Briefly, a 57-year-old man presented with a subacute onset of sensory neuropathy characterized by limb paresthesia, gait disturbance with sensory ataxia, autonomic symptoms, and very high CSF protein levels ( Table 1 ). Laboratory tests showed no positive autoantibodies such as anti-SS-A and anti-SS-B antibodies. NCS showed sensory conduction abnormalities and prolonged distal motor and F-wave latencies. Approximately three months after neurological onset, invasive thymoma was detected on chest CT. Although IVIg and thymectomy were not effective, daily oral glucocorticoids (prednisolone 30 mg/day) immediately improved his symptoms. The thymoma was pathologically classified as type B3. The patient achieved remission with slight distal paresthesia in the feet. Conduction delay on motor and sensory nerves returned to within normal limits.

Sera from Cases 1 and 2 were positive for CNTN1-IgG by CBA, whereas that of Case 3 was positive by ELISA. The IgG4 subclass of antibodies was predominantly elevated in all cases. Relevant immunoreactivity against CNTN1-IgG was found in the order of IgG1 > IgG2 in Cases 1 and 2. In Case 3, only weak reactivity for IgG1 was detected. Caspr1-IgG was not detected in sera from Cases 1 and 2, and was not tested for in Case 3. None of the three cases were positive for NF155-IgG.

In Case 1, initially suspected as paraneoplastic syndrome or multifocal CIDP, serum autoantibodies against paranodal proteins were not measured until maintenance IVIg was administered, demonstrating CNTN1-IgG positivity. The titer was decreased with the clinical improvement but was constantly positive ( Figure 1A ). The autoantibody status of Case 2 was evaluated before immunotherapy administration. Serum CNTN1-IgG returned to negative three months after treatment initiation, following an improvement in neurological findings ( Figure 1B ). Of note, Case 3 was seropositive for CNTN1-IgG when using a stock serum sample taken before immunotherapy administration. Follow-up measurements using serum from remission were negative for CNTN1-IgG.

sNfL levels of Cases 1 and 2 before immunotherapy were highly elevated (656 pg/mL and 1,170 pg/mL, respectively). At the end of the treatment when clinical remission was achieved, they were markedly decreased to 12.7 pg/mL and 19.5 pg/mL, respectively, which were within the normal ranges based on age-specific reference values (20).

Our literature survey identified ten cases of demyelinating peripheral neuropathy with thymoma (4–13). A summary of patients including Cases 1 and 2 is shown in Table 2 . Ten of eleven patients were male. The mean age at onset of peripheral neuropathy was 56.5 ± 10.6 years (standard deviation). Limb weakness and sensory ataxia were observed in 73% and 71% of patients, respectively. CSF protein levels were elevated in seven of nine patients with CSF data, and our three cases with CNTN1-IgG had levels > 200 mg/dL. Six patients had AChR-IgG including our Cases 1 and 2. Notably, Cases 1 and 2 did not develop symptoms related to MG. Apart from our cases, only two cases have been investigated for CNTN1-IgG positivity: one was positive (4) and the other was negative (9). On the pathological basis of thymoma, WHO classification was available for five patients: type B3 (n = 2) and type AB (n = 3). Immunotherapies were administered to nine patients and were effective for six. Three poor responders, one with Good’s syndrome and two with malignant thymoma, progressed to death. Another case of malignant thymoma with encephalopathy who did not receive immunotherapy or thymoma treatment resulted in death.