Paraneoplastic Myeloneuropathies

Demographics, Antibody, and Oncologic Associations

Thirty-two patients had paraneoplastic myeloneuropathy as their initial presentation (table). Twenty were women (63%) and median age was 61 years (range 27–84 years). Chronic tobacco use was noted in 81% of patients (median 40 packs per year, n = 26). Underlying malignancy was detected in 25 patients. Small cell lung cancer (n = 11) and breast adenocarcinoma (n = 7) were the most common malignancies, with further details shown in figure 1. Neurologic symptoms manifested prior to cancer diagnosis in 22/25 patients and the remaining 3 cases had symptom onset within 3 years of cancer diagnosis.

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Figure 1 Cancer and Onconeural Antibody Associations

(A) Summary of onconeural antibodies and presence of cancer; 3 patients had unclassified neural specific antibodies. (B) Cancer association in 25 patients. Among 7 patients, no neoplasms were identified. ANNA1 = antineuronal nuclear antibody type 1 (anti-Hu); ANNA3 = antineuronal nuclear antibody type 3; CRMP5 = collapsin response mediator protein 5 (CV2); PCA1 = Purkinje cell cytoplasmic antibody type 1; KLHL11 = kelch-like protein 11.

Among 32 patients with paraneoplastic myeloneuropathy, 20 had antibody evaluations in the serum and 12 had both serum and CSF neural-specific antibody testing. Twenty-six had detectable onconeural antibodies: amphiphysin, n = 8 (serum only, n = 4; CSF and serum, n = 4; median serum titer 1:3,840; range 1:240–1:245,760 [normal < 1:120]; median CSF titer 1:64, range 1:4-1:960 [normal < 1:4]); ANNA1 (anti-Hu), n = 5 (serum only, n = 4; CSF and serum, n = 1, median serum titer 1:3,840, range 1:240–1:122,880; CSF titer 1:512); CRMP5, n = 6 (serum only, n = 3; CSF and serum, n = 3, median serum titer 1:3,840, range 1:240–1:491,520; median CSF titer 1:512, range 1:64–1:8,192); PCA1 (anti-Yo), n = 1 (serum titer 1:240; CSF titer 1:16); PCA2 (MAP1B), n = 2 (serum only, titers 1:240; 1:15,360); KLHL11, n = 1 (serum titer 1:240 and CSF titer 1:4); and combinations thereof: ANNA1/CRMP5, n = 1 (serum titer 1:960/1:240); ANNA1/amphiphysin, n = 1 (serum titer 1:61,440/1:30,720; CSF titer 1:4/1:1,024); ANNA3/CRMP5, n = 1 (ANNA3 serum titer 1:960, CRMP5 detected in both serum and CSF, serum titer 1:7,680 and CSF titer 1:1,024). Nineteen of these 26 patients were diagnosed with cancers. The remaining 7 patients had imaging findings suggestive of neoplasm, but pathologic confirmation was not available (figure 1). Among these, 1 patient had a breast mass, 4 had lung masses, and 2 had abdominal masses. Biopsy and histopathologic analysis in 2 of these 7 cases was nondiagnostic. In 3 patients, data regarding biopsy/histopathologic evaluation of the mass was not present in the patient records. In 2 patients, rapid neurologic deterioration and superimposed infection led to death prior to attempting biopsy. All 6 patients without characterized onconeural antibodies (unclassified neural specific antibodies, n = 3 [2 detected in serum, and 1 detected in both serum and CSF]) had pathologically confirmed cancer.

Clinical Characteristics

Patients frequently had a subacute presentation, defined as nadir of symptom severity occurring 1 to 3 months from onset (n = 23, 72%). Two patients (6%) presented acutely within 1 month and 7 (22%) presented with a more chronic decline. Most common clinical characteristics included neuropathic pain (n = 25, 78%), bladder dysfunction (n = 22, 69%), asymmetric paresthesias (n = 20, 63%), and unintentional weight loss of greater than 15 pounds (n = 20, 63%; median weight loss 20 pounds [range 15–75]). Neuropathic symptoms were non-length-dependent (n = 28, 88%) and radicular involvement was noted in 56% (n = 18) of patients. Patients commonly had cramping, spasms, or stiffness (n = 17, 53%), and in 2 patients with amphiphysin autoantibodies, simultaneous peripheral nerve hyperexcitability. Orthostatic intolerance defined by clinical history of syncope or lightheadedness and blood pressure changes upon standing was seen in 14 patients (44%) with supportive autonomic reflex testing in 4 patients. Gastrointestinal dysmotility at onset, defined as new, severe postprandial fullness or nausea, constipation, or diarrhea (n = 14, 44%) was also common; 1 patient had gastric motility studies, which demonstrated prolonged colonic and small bowel emptying.

Neurologic examination commonly demonstrated simultaneous hyporeflexia and hyperreflexia at different sites (n = 26, 81%). Hyporeflexia was usually present distally or in an asymmetric pattern. The majority of patients also had impaired vibration and proprioception (n = 22, 69%), Babinski response (n = 22, 68%), and asymmetric weakness (n = 21, 66%). Weakness was noted in both upper and lower limbs in 44% of patients (n = 14). Thirty-seven percent (n = 12) of patients had isolated lower limb involvement and 19% (n = 6) had isolated upper limb involvement.

Copper or vitamin B₁₂ deficiency related subacute combined degeneration was the primary diagnostic consideration at disease onset in 28 patients (88%) but was excluded by pertinent laboratory investigation. Among patients with CSF analysis (n = 28), the majority (23, 82%) had inflammatory changes (median CSF cell count 8 cells/mm³, range 0–74 cells/mm³ [lymphocytic predominant] and median CSF protein 73 mg/dL, range 31–188 mg/dL). Four patients did not have CSF collected; 2 had normal spine MRIs, but both were positive for amphiphysin autoantibodies and had breast or small-cell lung cancer, respectively.

MRI Characteristics of Patients With Paraneoplastic Myeloneuropathy

Several notable imaging findings were observed, and representative images are provided in figure 2. Imaging was not available for review in 1 patient. Spinal cord T2 hyperintensities were present in 19 patients (61%), and 14 (45%) were longitudinally extensive (≥3 vertebral segments) T2 lesions (table). Twelve patients (39%) did not demonstrate any spinal cord MRI abnormalities, despite myelopathic findings on examination. T2 hyperintensities were tract-specific in 12 of the 19 (63%) abnormal MRIs and dorsal columns (n = 6), lateral corticospinal tract (n = 5), or both dorsal column and corticospinal tracts (n = 1) (figure 2). Central gray matter abnormalities were also identified in 9 patients (29%). Half of the tract-specific lesions (n = 6, 50%) had bilaterally symmetric involvement of the spinal cord tracts. Approximately one-third of patients (n = 11, 35%) demonstrated active contrast extravasation. Ten patients (32%) demonstrated nerve root contrast enhancement, 8 limited to the lumbar roots (figure 2).

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Figure 2 MRI Spine Abnormalities in Paraneoplastic Myeloneuropathies

Cervical, thoracic, and lumbar spine MRI sagittal (A.a, B.a, C.a, D.a) and axial (A.b, B.b, C.b, D.b) sequences. (A.a, A.b) Collapsin response mediator protein 5 (CRMP5) (CV2) immunoglobulin G (IgG)–seropositive adult patient with asymmetric, longitudinally extensive T2-hyperintense lesion (white arrow) involving the right corticospinal tracts (blue arrow) with a concomitant axonal polyradiculoneuropathy. (B.a, B.b) Antineuronal nuclear antibody type 1 (anti-Hu) (ANNA1) and amphiphysin IgG–seropositive adult patient with longitudinally extensive T2-hyperintense lesion (white arrow) involving the right dorsal column (blue arrow) with a concomitant sensory neuronopathy. (C.a, C.b) ANNA1 IgG–seropositive adult patient with symmetric, bilateral, longitudinally extensive T2-hyperintense lesion (white arrow) involving the dorsal columns (blue arrows) and concomitant sensory predominant length dependent axonal polyneuropathy. (D.a, D.b) Adult patient with unclassified neural specific antibody with diffuse nerve roots enhancement on postgadolinium T1-weighted sagittal (white arrow) and axial (blue arrow) sequences.

Neuropathy Characteristics

Electrodiagnostic studies were performed in 31 patients, and all had electrophysiologic features suggestive of an axonal neuropathy. One patient additionally had some features of demyelination on nerve conduction studies, presumed secondary to axonal loss. One patient with clinically evident neuropathy did not undergo electrodiagnostic study. Clinical description of neuropathic pain radiating down one or more dermatomal distributions with proximal muscle weakness or evidence of denervation in the paraspinal muscles was considered indicative of radicular involvement. Polyradiculoneuropathy with evidence of nerve root and peripheral nerve involvement was the most common neuropathy phenotype (n = 16, 50%), closely followed by distal, asymmetric sensorimotor neuropathy (n = 10, 31%). Sensory ganglionopathy and symmetric length-dependent sensorimotor neuropathies were present in 2 and 4 patients, respectively.

Somatosensory evoked potentials performed in 2 patients demonstrated impairment in both central and peripheral proprioceptive pathways. Autonomic reflex testing was performed in 4 patients. Two patients had moderate to severe cardiovagal, adrenergic, and postganglionic sudomotor dysfunction. One had adrenergic and postganglionic sudomotor dysfunction and another had moderate to severe cardiovagal and adrenergic impairments with preserved postganglionic sudomotor function, suggesting a limited autonomic failure.

Management and Clinical Outcomes

Ten patients received only immunotherapy, 3 received only oncologic therapy, and 16 received both. First-line immunotherapies included 1 or more of the following: high-dose IV methylprednisolone (n = 19), IV immunoglobulin (n = 12), oral prednisone (n = 12), or plasmapheresis (n = 4). A subset of these patients received long-term immunosuppression: cyclophosphamide (n = 9), rituximab (n = 2), mycophenolate mofetil (n = 2), and azathioprine (n = 2). Three seropositive patients without pathologic diagnosis of neoplasm did not receive oncologic or immunologic therapy.

Median duration of follow-up was 24 months (range 5–133 months). Fifteen of 28 patients (53%) with long-term follow-up (>1 year follow-up) had favorable clinical outcomes with cancer treatment or immunotherapy at subsequent follow-up. Another 6 patients stabilized, whereas 7 continued to deteriorate despite therapy. At last known follow-up, 7 patients (22%) had died. Median follow-up for patients without identified malignancies was 11 months (range 10–20).

In patients receiving a combination of oncologic and immunologic therapy, outcomes were significantly favorable (median change in mRS before and after treatment) in comparison to those receiving either oncologic or immunologic therapy alone (−2 [range −3 to 0] vs 0 [range −1 to 2], p < 0.001). Furthermore, median mRS at posttreatment follow-up among the patients receiving combination therapy was significantly lower than patients receiving either oncologic or immunologic therapy alone (2 [range 1–4] vs 4 [range 2–6] p < 0.001).