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Objective: We studied a case series of peripheral nerve hyperexcitability (PNH) aiming to describe clinical characteristics, immunologic and cancer associations, antibodies against neuronal antigens (voltage-gated potassium channel antibodies [VGKC-Abs] and other), and muscle biopsy findings., Methods: Patients presenting with clinical and electrophysiologic signs of PNH were selected. We studied clinical and electrophysiologic features; a panel of non-neuronal organ-specific antibodies, immunofluorescence on rat nervous tissues, and radioimmunoprecipitation for VGKC-Abs; and muscle biopsies., Results: Thirty-eight patients were included. After the exclusion of 6 cases with axonopathy of known origin, patients were subdivided according to the presence of electrophysiologic findings of motor axonopathy and association with cancer: axonopathic-PNH (group A: 12 patients), isolated nonparaneoplastic PNH (group B: 16 patients), and isolated paraneoplastic PNH (3 with thymoma and myasthenia gravis, 1 with thyroid carcinoma). PNH clinical features were similar in groups A and B. We found an overall high prevalence of clinical autoimmunity (33% of group A and 63% of group B) and systemic non-neuronal autoantibodies (42% of group A and 75% of group B). However, VGKC-Abs were only positive in 2 patients of group B. Ten patients underwent muscle biopsy, which showed inflammatory changes in 2 cases and nonspecific myopathic features in 8., Conclusions: PNH is a heterogeneous disorder involving the peripheral nerves in patients with a high propensity for developing autoimmunity. Associated muscle diseases are frequent in the form of myositis, myasthenia gravis, or nonspecific myopathic pathologic findings. VGKC-Abs were uncommon in this series.

Objective: To characterize the clinicopathologic features of ataxic and painful forms of paraneoplastic neuropathy., Methods: Clinical, electrophysiologic, and histopathologic findings were assessed in 17 patients with paraneoplastic neuropathy., Results: Clinical features can be categorized into two groups: one group (13 patients) with predominantly deep sensory disturbance and a second group (4 patients) with predominantly superficial sensory disturbance. The former group showed severe sensory ataxia and predominantly large myelinated fiber loss in the sural nerve. The latter group showed marked pain, in particular, severe mechanical hyperalgesia, and predominantly small myelinated and unmyelinated fiber loss. Nerve conduction assessment indicated an axonal neuropathy pattern in both groups, while sensory action potentials were more markedly diminished in the sensory ataxic form. Anti-Hu antibodies were detected in half of the patients in both groups. Treatment for cancer was effective to improve or stabilize neuropathic symptoms in some cases from both groups. Immunotherapy was effective only for a short time., Conclusions: Paraneoplastic neuropathy can be characterized into two groups by the presence of sensory ataxia or severe spontaneous pain and severe mechanical hyperalgesia. Preferential small myelinated and unmyelinated fiber loss correlated to the cases of severe pain.

Objective: To assess use of whole-body 18F fluoro-2-deoxy-glucose (FDG)-PET and CT for diagnosing tumor in patients with antibody-positive paraneoplastic neurologic syndromes (PNS)., Methods: In order to directly compare CT and FDG-PET imaging in patients with various antineuronal antibodies, the authors performed in parallel CT scanning and FDG-PET in a series of 13 consecutive patients (9 women, 4 men, aged 59 +/- 14 years) with positive antineuronal antibodies (anti-Hu: 8, anti-Yo: 4, anti-Tr: 1) in whom the authors were searching for a tumor or tumor recurrence., Results: A new tumor or tumor recurrence was found in 10/13 patients (5 small cell lung cancer, 2 ovarian cancer, and 1 each neuroblastoma, Hodgkin's lymphoma, and lymph node metastasis of adenocarcinoma). All tumors except one with good clinical evidence for small cell lung cancer were confirmed histologically. For detection of tumor or tumor recurrence, CT was positive in 3/10 patients (sensitivity of 30%), and FDG-PET in 9/10 (sensitivity of 90%, difference between methods p < 0.01), but the combination of both methods showed a sensitivity of 100%., Conclusions: FDG-PET imaging is useful in tumor screening of patients with antineuronal antibodies, but should be complemented by CT scanning to increase sensitivity and accuracy of tumor diagnosis.

Objective: To determine whether serum Zic4 antibodies associate with paraneoplastic neurologic disorders (PND) and small-cell lung cancer (SCLC), and the association of these antibodies with other onconeuronal immunities associated with SCLC., Design/methods: The authors studied 498 patients (215 with PND and 283 without PND or without cancer). The presence of antibodies was tested with immunoblots of Zic4, HuD, and CRMP5 proteins. The tumor expression of these proteins was determined by immunohistochemistry., Results: Zic4 antibodies were identified in 61 patients. Ninety-two percent of patients with Zic4 antibodies had SCLC; detection of these antibodies segregated with the presence of PND (p = 0.031). Intrathecal synthesis of Zic4 antibodies was demonstrated in 5/7 patients with PND. None of 175 control patients without PND or cancer had Zic4 antibodies. Because of the robust association between Zic autoimmunity and SCLC, all patients were tested for other SCLC-related antibodies; concurrent Zic4, Hu, or CRMP5 antibodies occurred in the serum or CSF of 27% of SCLC patients with PND. Patients with isolated Zic4 antibodies were more likely to develop predominant cerebellar dysfunction than patients with several immunities (p < 0.001). Tumors of patients with and without onconeuronal antibodies coexpressed Zic, Hu, and CRMP5 proteins, indicating that the tumor expression of these antigens is necessary, but not sufficient, for immunologic activation., Conclusions: In patients with neurologic symptoms of unknown cause detection of Zic4 antibodies predicts a neoplasm, usually a SCLC, and suggests that the neurologic disorder is paraneoplastic. Detection of Zic4 antibodies often associates with anti-Hu or CRMP5 antibodies. Patients with isolated Zic4 antibodies are more likely to develop cerebellar dysfunction than those with concurrent immunities.