Association between anti-Zic4 antibodies and sensory neuronopathy in small-cell lung cancer

Dear Editor:

In recent years, the identification of such biomarkers as neuronal antibodies has transformed the diagnosis of paraneoplastic neurological syndromes (PNS), enabling earlier detection.¹ The diagnostic criteria were updated in 2021, with the introduction of 3 levels of certainty ²; although these do not include pathognomonic neurological manifestations of cancer, they do establish high-risk clinical phenotypes.¹

One such example is sensory neuronopathy,³ one of the most frequent phenotypes, which is associated with significant diagnostic delays due to its clinical heterogeneity.⁴ Anti-Hu, anti-CV2, and anti-amphiphysin antibodies have been associated with this entity, facilitating clinical suspicion⁵; however, new correlations continue to emerge that may be useful when interpreted in the appropriate clinical context.^6,7 We present a case of sensory neuronopathy whose aetiology was established based on the presence of anti-Zic4 antibodies.

Our patient was a 63-year-old woman, an active smoker (10 cigarettes/day), with history of arterial hypertension and long-standing type III membranoproliferative glomerulonephritis. In February 2023, she was referred to the neurology department due to sensory hypoaesthesia of one year’s progression, initially affecting the distal lateral aspect of the right leg and presenting no correlation with a specific dermatome. Symptoms subsequently progressed distally, affecting the fingers and toes, and especially the third and fifth fingers of the left hand. The patient presented no symptoms of motor, thermal, autonomic, or sphincter dysfunction. The neurological examination revealed hypoaesthesia and hypoalgesia in both hands and feet (predominantly on the left side) and the lateral distal segment of the right leg, as well as moderately reduced vibration sensitivity in both legs, with absent Achilles tendon reflex bilaterally.

A neurophysiological study conducted in March 2023 revealed bilateral, distal axonal sensory polyneuropathy, of moderate intensity in the lower limbs and mild intensity in the upper limbs. Motor nerve conduction study results were normal. An aetiological study including glycosylated haemoglobin determination, serology studies (IgG and IgM for cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein-Barr virus, Treponema pallidum, Borrelia burgdorferi, HIV), vitamin analysis (B₁, B₆, B₁₂), and antibody determination (antiganglioside, anti-nodal/-paranodal, anti-MAG) yielded negative results. The autoimmunity study was positive for ANA (1/60), with a fine speckled pattern, also detecting elevated levels of IgM and rheumatoid factor. In the context of well-controlled, long-standing glomerulonephritis, these alterations were interpreted as immunological epiphenomena.

Onconeuronal antibody testing conducted at the reference laboratory using line blot immunofluorescence (EUROIMMUN®) revealed isolated reactivity for anti-Zic4 antibodies. No antibodies were detected against the remaining antigens included in the panel (Hu, Yo, Ri, CV2/CRMP5, Ma2, amphiphysin, SOX1). The sample was subsequently analysed at an external laboratory using indirect immunofluorescence for anti-Zic4 IgG antibodies, which confirmed strong reactivity (++++) at a titre of 1/3200. Results were confirmed independently at both centres.

In December 2023, the patient reported unintentional weight loss of 10 kg over 6 weeks. Before the aetiological study was completed, she visited the emergency department due to sudden respiratory difficulty. Chest radiography findings were compatible with superior vena cava syndrome, which was confirmed by chest CT. A bronchoscopy performed due to the presence of a right paratracheal conglomerate lymphadenopathy and an elongated tumour in the right upper lobe identified a stenotic endobronchial lesion, with an anatomical pathology diagnosis of lung neuroendocrine carcinoma stage T4N2M0.

The patient started treatment in January 2024, consisting of 6 cycles of chemotherapy with carboplatin plus etoposide, followed by chest radiotherapy for 7 weeks. Due to suspicion of paraneoplastic sensory neuronopathy, immunoglobulin treatment was proposed, but the patient postponed initiation until June 2024 due to the adverse effects of chemotherapy. Three cycles of immunoglobulins (400 mg/kg for 5 days) were administered starting in June, with an initially favourable response. However, due to clinical worsening, an additional cycle of immunoglobulins was administered in September; a follow-up chest CT scan confirmed cancer progression, with the appearance of new pseudonodular lesions in the right upper lobe. At present, the patient is awaiting assessment by the hospital tumour board. Fig. 1 provides a timeline of the patient’s progression.

Figure 1.

Timeline of the patient’s symptom progression and treatment.

Sensory neuronopathies are caused by damage to sensory neurons of the dorsal root ganglia. From a clinical viewpoint, they are characterised by multifocal, asymmetrical areas of hypoaesthesia and pain, associated with severe, disabling sensory ataxia.³ Despite the high sensitivity of the 2009 diagnostic criteria, delayed diagnosis and misdiagnosis for more prevalent conditions are frequent.⁴ Given that up to 20% of sensory neuronopathies of paraneoplastic origin, correct interpretation of biomarkers has significant diagnostic implications.⁵

Sensory neuronopathies associated with small-cell lung cancer are associated with anti-Hu and anti-CRMP5 antibodies,^8,9 while coexpression of anti-Zic4 antibodies is observed in up to 37% of cases.¹⁰ Although isolated anti-Zic4 antibody positivity has predominantly been described in cases of subacute cerebellar degeneration in the context of small-cell lung cancer,¹¹ recent identification in a patient with sensory neuronopathy and concomitant lymphoma suggests new associations.⁶ The involvement of the ZIC4 gene in neuronal development, including the peripheral nervous system, may provide a pathophysiological explanation for this yet poorly understood process.¹¹

The case presented here, a patient with sensory neuronopathy presenting anti-Zic4 antibody positivity and small-cell lung cancer, underscores the importance of testing for onconeuronal antibodies even in unlikely scenarios, to prevent diagnostic delays.

Patient consent

The patient gave written informed consent for the publication of her clinical case.

Ethical approval

This study did not require approval from any ethics committee since it is based on observational clinical data from a single patient. No interventions or experimental procedures were performed.

Funding

This case report received no funding.

Data availability

The data supporting the case presented here are available from the corresponding author upon reasonable request.

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This study did not use any materials from other sources.