Decoding Multiple Antibody Positivity: Lessons from Paraneoplastic Sensory Ataxia

Abstract

Paraneoplastic neurologic syndromes are cancer-associated, immune-mediated neurologic manifestations that may involve any part of the nervous system. They usually present with characteristic neurologic features and should be considered in high-risk phenotypes such as limbic encephalitis, encephalomyelitis, rapidly progressive cerebellar syndrome, opsoclonus–myoclonus, sensory neuronopathy, enteric neuropathy, and Lambert–Eaton myasthenic syndrome. The diagnosis is made by antibody positivity in the serum or cerebrospinal fluid, in the presence of an appropriate clinical phenotype. Findings on antibody testing by immunoblot should always be verified by immunofluorescence. We report a rare case of sensory neuronopathy with triple paraneoplastic antibody positivity (anti-Hu, anti-collapsing response-mediator protein 5, and anti-amphiphysin) on immunoblot but only anti-Hu positivity on immunofluorescence. The presence of lower facial dyskinesias should raise the possibility of an immune-mediated neurologic syndrome in the appropriate clinical context.

Introduction

Paraneoplastic neurologic syndromes (PNS) are cancer-associated, immune-mediated neurologic manifestations that may involve any part of the nervous system.[1] They have an association with cancer, but may predate the cancer diagnosis in 60% cases.[1] PNS usually present with characteristic neurologic features and should be considered in high-risk phenotypes such as limbic encephalitis, encephalomyelitis, rapidly progressive cerebellar syndrome, opsoclonus–myoclonus, sensory neuronopathy (SNN), enteric neuropathy, and Lambert–Eaton myasthenic syndrome.[1] The diagnosis is made by antibody positivity in the serum or cerebrospinal fluid (CSF), in the presence of an appropriate clinical phenotype.[1] We report a rare case of sensory neuronopathy with triple paraneoplastic antibody positivity (anti-Hu, anti-collapsing response-mediator protein 5, and anti-amphiphysin) on immunoblot but only anti-Hu antibody positivity on immunofluorescence for confirmation of immunoblot findings.

Case Summary

A 54-year-old gentleman presented with burning pain and paresthesia of his hands and feet for the past 2 years. Six months after symptom onset, he developed slippage of footwear without awareness and imbalance while walking at night. Subsequently, he started requiring the support of a person to walk in the past year, along with developing a high-steppage gait. He was unable to reach for objects precisely. He developed involuntary movements of all four limbs (right > left) and face at rest. His severe imbalance led to wheelchair-bound status for the past 3 months. He had undocumented weight loss over the past 3 months, accompanied by anorexia. He had no radicular pain, band-like sensation, bladder or bowel involvement, or fasciculations. He denied fever, joint pains, cough, or oro-genital ulceration. He was a chronic smoker and had been smoking four or five cigarettes/day for the past 30 years. There was no other relevant personal, past, or family history.

Examination revealed generalized wasting with pseudoathetoid movements in both hands and legs (right > left), along with perioral dyskinesias [Video 1]. He had hypotonia of all limbs. Power was normal. Deep tendon reflexes were absent. Loss of joint position and vibration sense up to the elbow and knee was noted. There was also loss of pain and temperature sensations distal to the ankle and wrist bilaterally. A provisional diagnosis of sensory ataxia was considered.

Blood investigations (hemogram, renal and liver function tests, viral markers, thyroid profile) were normal. Tests for antinuclear antibody, extractable nuclear antigen, tumor markers, serum and urine electrophoresis with immunofixation, light chain assay, and angiotensin converting enzyme were non-revealing. Toxicological screen in both blood and urine and serum autoimmune profile testing (anti-N-methyl d-aspartate receptor [anti-NMDAR], anti-contactin associated protein 2, anti-leucine-rich glioma inactivated 1, anti-gamma amino butyric acid B, anti-α-amino-3-hydrooxy-5-methyl-4-isoxazalepropionic acid receptor 1 and 2) were non contributory. Magnetic resonance imaging (MRI) of the brain and spine were normal. Nerve conduction studies (NCS) revealed sensory–motor nerve involvement in axonal pattern (sensory nerve actional potentials were nonrecordable in bilateral median, ulnar, radial, sural, and superficial peroneal nerves; motor NCS revealed amplitude drop and F wave prolongation in the right peroneal nerve). CSF examination showed no cells, protein- 60 mg/dl, and sugar- 73 mg/dl (corresponding blood sugar- 130 mg/dl). Infective workup in CSF was negative. CSF cytology for malignant cells was negative. Serum paraneoplastic antibody panel (anti-Hu, Ri, Yo, CRMP-5, PNMA-2, amphiphysin, SOX-1, Tr, GAD 65, Zic4, titin, and recoverin) was strongly positive (3+) for anti-Hu, anti-CRMP-5, and anti-amphiphysin antibodies (tested by immunoblot assay for qualitative determination in 1:100 dilution along with tissue immunofluorescence). However, confirmatory testing by immunofluorescence revealed positivity for anti-Hu antibody alone [Figure 1]. Whole body positron emission tomography (PET) scan was normal. A diagnosis of paraneoplastic SNN was made. He was treated with pulse methylprednisolone (1000 mg intravenously for 5 days) followed by plasma exchange (five cycles, 250 ml/kg body weight). He improved symptomatically [Supplementary Video 1] and was further treated with rituximab (1000 mg), two doses given 2 weeks apart. He was able to walk with the support of a person at the last follow-up, 3 months after initial treatment. We plan to repeat PET scans every 6 months to look for the appearance of a malignancy.

Figure 1.

(a) Immunoblot testing for antineuronal antibodies reveals multiple positive bands (anti-Hu+++, anti-amphiphysin+++, and anti-CV2+++), though the intensity is highest for anti-Hu. (b) Indirect immunofluorescence demonstrates only anti-Hu positivity, with cerebellar Purkinje neurons showing nuclear fluorescence. Note absence of fluorescence characteristic of amphiphysin or CV2 in GL and ML, respectively, confirming their absence. GL: granular layer, ML: molecular layer

Discussion

SNNs result from involvement of sensory neurons in the dorsal root ganglia.[1,2] They can occasionally have additional motor impairment due to the involvement of adjacent motor nerve roots. A diagnosis of SNN should be considered in a patient with sensory ataxia if the SNN score [Table 1] is above 6.5. The common causes for SNNs include Sjogren’s syndrome, platinum-based chemotherapeutic drugs, and PNS.[2,3] A paraneoplastic origin should be especially considered in the presence of an inflammatory CSF picture or associated motor deficit.[1,2] The most common paraneoplastic antibodies associated with SNNs are anti-Hu and anti-CRMP5.[2] Our patient had probable SNN (SNN score of 12.7), inflammatory CSF findings, and positivity for anti-Hu antibody.

Table 1.

Diagnostic criteria for SNN[2]

	Yes/no	Points (if yes)
A. Possible SNN – score >6.5
a) Ataxia in the lower or upper limbs at onset or full development	Yes	3.1
b) Asymmetrical distribution of sensory loss at onset or full development	Yes	1.7
c) Sensory loss not restricted to the lower limbs at full development	Yes	2.0
d) At least one SNAP absent or three SNAP <30% of the lower limit of normal in the upper limbs, not explained by entrapment neuropathy	Yes	2.8
e) Less than two nerves with abnormal motor nerve conduction studies in the lower limbs	Yes	3.1
B. Probable SNN if possible, SNN AND two of the following:
The initial workup does not show biological perturbations or NCS/EMG findings excluding SNN
The patient has one of the following disorders: onconeural antibodies or a cancer within 5 years, cisplatin treatment, Sjogren’s syndrome
MRI showing high signal in the posterior column of the spinal cord
C. Definite SNN if DRG degeneration is pathologically demonstrated (although DRG biopsy is not recommended)

DRG: Dorsal root ganglia, EMG: Electromyography, MRI: Magnetic resonance imaging, NCS: Nerve conduction studies, SNN: Sensory neuronopathies, SNAP: Sensory Nerve Action Potential

The presence of lower facial dyskinesias in our patient was quite striking. Among autoimmune disorders, perioral dyskinesias are usually reported with anti-NMDAR encephalitis, and anti-Ri- and anti-CRMP5-positive PNS have been described to have jaw dystonia and chorea, respectively.[4] The presence of abnormal facial movements might, therefore, signify the presence of an immune-mediated neurologic syndrome, in the appropriate clinical setting.

The presence of dual paraneoplastic antibody positivity is not uncommon. However, to the best of our knowledge, triple-antibody positivity has only been reported once previously in a 78-year-old man who tested positive for anti-Hu, anti-Purkinje cell cytoplasmic antibody, and anti-CRMP5 antibodies and was found to have a small cell lung carcinoma (SCLC).[5] Such multiple antibody positivity is likely to be the result of a multifaceted immune response to numerous co-immunogenic onconeural proteins existing within individual tumors.[5] This might also be responsible for multifocal neurologic involvement and impairment, as was seen in our patient as well.

The diagnosis of PNS requires exclusion of other possible etiologies that can present similarly. These usually include autoimmune, infectious, toxic–metabolic, and neurodegenerative disorders.[1] Thereafter, PNS-CARE score [Table 2] should be calculated, which provides diagnostic certainty. Higher scores are associated with increased likelihood of the clinical presentation being paraneoplastic. All differential diagnoses were ruled out in our patient by relevant testing, and his PNS-CARE score was 7 (probable PNS).

Table 2.

PNS-CARE score[1]

	Points
Clinical level
High-risk phenotype	3
Intermediate-risk phenotype	2
Defined phenotype epidemiologically not associated with cancer	0
Laboratory level
High-risk antibody (>70% cancer association)	3
Intermediate-risk antibody (30%–70%)	2
Lower-risk antibody (<30% or negative)	0
Cancer
Found, consistent with phenotype and (if present) antibody or not consistent, but antigen expression demonstrated	4
Not found (or not consistent), but follow-up <2 years	1
Not found and follow-up ≥2 years	0
Diagnostic level
Definite: ≥8
Probable: 6–7
Possible: 4–5
Non-PNS: ≤3

PNS: Paraneoplastic neurologic syndromes

The common malignancies associated with SNN include SCLC, bronchial cancer, breast cancer, Hodgkin’s lymphoma, ovarian cancer, bladder cancer, prostate cancer, and neuroendocrine tumors.[6] The cancer association of anti-Hu is 85% and the most common associated cancers are lung cancer (SCLC more often than non-small cell), neuroendocrine tumors and neuroblastoma. Our patient was a chronic smoker with SNN and had anti-Hu antibody positivity. Thus, it is likely that SCLC may be uncovered on future testing. Since paraneoplastic antibodies are not pathogenic and mostly serve as biomarkers and multiple antibodies predict the cancer,[5] they can help in dedicated screening in addition to whole body screening (e.g., computed tomography of the chest to look for SCLC in our patient).

Our patient was triple paraneoplastic antibody positive on immunoblot. However, he showed isolated positivity for anti-Hu antibody on immunofluorescence, underscoring the need to confirm immunoblot results with immunofluorescence testing.

Conclusion

To conclude, SNN is a neurologic syndrome with typical clinical and electrophysiologic features, and may be a PNS. Multiple antibody positivity likely results from a multipronged immunogenic response to numerous onconeural antigens present within individual tumors. The presence of lower facial dyskinesias should raise the possibility of an immune-mediated neurologic syndrome, in the appropriate clinical context.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.