Neuroimmunology: Paraneoplastic and Other Autoimmune Syndromes—Peripheral Motor Sensory Unit

CRANIAL NERVES

Paraneoplastic autoimmune vision loss–associated optic neuritis, retinitis, and vitreous inflammation is syndromic with CRMP-5 IgG and SCLC. Although autoimmune retinopathy lacks inflammatory infiltrates, visual loss can be severe. This may be paraneoplastic, notably associated with SCLC and melanoma, or idiopathic. Antibodies to recoverin and other retinal proteins are identified; however, the visual-loss pathophysiology is poorly understood.

Multiple cranial neuropathies, including hearing loss, occur in a paraneoplastic context. Association with CRMP-5 IgG and SCLC is most frequent. Differentiating cranial nerve from brainstem pathology is difficult.

SPINAL CORD

Subacute onset myelopathy is associated with several different cancers and cancer-specific autoantibodies. Clinically, it is typically symmetric, with longitudinally extensive long-tract or gray matter–specific magnetic resonance imaging (MRI) changes. Motor involvement can be severe, especially the necrotizing variant having a distinct cord level.

“Stiff-man” syndrome (SMS), Moersch-Woltman syndrome, typically has severe, painful, and progressive muscle rigidity or stiffness prominently affecting the paraspinal musculature and/or leg muscles, sometimes unilaterally. High-serum GAD-65 autoantibody levels (usually >>>> 20 nmol/L) aids nonparaneoplastic SMS diagnosis. Ironically, SMS rarely occurs with thymoma in contrast to myasthenia gravis. Lower-titer GAD-65 may be seen with Hashimoto thyroiditis, pernicious anemia, and type 1 diabetes.

Amphiphysin antibody is a paraneoplastic stiff-person (SPS) marker associated breast or lung cancer. Atypical nonparaneoplastic stiff-person syndromes, particularly progressive encephalomyelitis rigidity and myoclonus (PERM), occur with antibodies to glycine receptors (GlyR). SPS variants are difficult to distinguish from other neuromuscular hyperexcitability, rigidity, or dystonia syndromes. Electrophysiologic testing is helpful. Concurrent involvement of multiple neuroaxis levels, and specific autoantibody profiles, that is, amphiphysin, identify paraneoplastic SMS patients.

MOTOR NEURON OR MOTOR NERVE SYNDROMES

These rarely occur in paraneoplastic contexts. Concurrent involvement of nonmotor neuroaxis regions and specific autoantibody profiles distinguish these motor neuronopathies from amyotrophic lateral sclerosis (ALS). However, ALS occasionally occurs coincident with neoplasms; no pathophysiologic relationship between the two is discernible. The clinical course is inexorably progressive, regardless of the neoplasm’s prognosis.

In contrast, paraneoplastic motor nerve syndromes may slow or remit with treatment of the underlying neoplasm. It is important to distinguish demyelinating inflammatory neuropathic syndromes, for example, multifocal motor neuropathy with conduction block, because these are immunotherapy responsive, particularly with intravenous immunoglobulin (IVIG).

Mononeuropathy, plexopathy, polyradiculopathy, and small-fiber neuropathy occur in isolation or multifocal presentations with cancer. Paraneoplastic autoimmunity rarely explains these syndromes; it is important for the clinician to look for those conditions such as metastatic disease, radiotherapy effects, anatomic deformities, and toxic medication metabolic disorders that are more typically responsible.

SENSORY NEUROPATHIES

Subacute sensory neuronopathy affecting the dorsal root and autonomic ganglia is a prototypic neurologic SCLC manifestation with ANNA-1 autoimmunity. It is distinguished clinically by affecting face, trunk, and extremities in contrast to a classic distal-predominant sensory peripheral neuropathy (PN). Associated large-fiber proprioceptive sensory deficits predispose to the sensory ataxia. Electromyography (EMG) demonstrates that peripheral sensory nerve action potentials (SNAPs) are absent.

Sensory neuropathy, distinguished from neuronopathy, is a painful and common paraneoplastic accompaniment. Concurrent motor involvement varies. Multiple autoantibodies occur, primarily related to the cancer. Many cancers are treated with peripheral neurotoxic chemotherapy. Furthermore, neuropathy patients often have multiple organ failures, making etiologic assignment problematic. EMG demonstrates low-amplitude SNAPs.

Myeloma and Waldenström macroglobulinemia are associated with monoclonal immunoglobulins. These entities have variable peripheral neuropathic presentations, sometimes severe, with distinct demyelinating features.

AUTONOMIC NERVOUS SYSTEM

Autonomic neuropathy or ganglionopathy usually occurs as a multifocal disorder associated with cancer, sometimes having multiple autoantibody markers. Orthostatic hypotension, anhidrosis, dry mouth, erectile dysfunction, impaired pupillary light response, fixed heart rate, and gastrointestinal dysmotility are variably present. Cancer-attributed symptoms, including cachexia, anorexia, early satiety, postprandial abdominal pain, and vomiting, may relate to gastroparesis or severe constipation.

Primary nonparaneoplastic autoimmune dysautonomias, associated with high titers for neuronal AchR antibodies, are often severe and disabling.

NEUROMUSCULAR JUNCTION

Lambert-Eaton myasthenic syndrome (LEMS) is a presynaptic peripheral cholinergic neuromuscular transmission disorder classically causing proximal limb weakness and sometimes bulbar and extraocular muscle dysfunction. Typically, weakness improves within seconds of voluntary muscle activation; symptoms often exceed physical examination findings. Electromyographic characteristics and seropositivity for neuronal calcium (Ca²⁺) channel autoantibodies distinguish presynaptic LEMS from postsynaptic myasthenia gravis. The P/Q-type Ca²⁺ channel antibody is specifically pathogenic, mediating presynaptic surface channel loss that distinguishes LEMS from most paraneoplastic disorders where neuronal, glial nuclear, or cytoplasmic antibodies are serologic markers but not clearly pathogenic.

SCLC occurs in 60% of LEMS patients; LEMS clinically affects 1% to 2% of SCLC patients, although the frequency of P/Q-type Ca²⁺ channel antibody is higher. Other antibodies, especially N-type calcium channel antibodies, frequently coexist. Limited dysautonomia is characteristic. Profound dysautonomia, especially if gastrointestinal motility is impaired, usually indicates an additional concurrent immune-mediated paraneoplastic mechanism often associated with ANNA-1, amphiphysin, or CRMP-5–IgG.

Myasthenia gravis (MG) is a postsynaptic disorder of peripheral cholinergic neuromuscular transmission. Fatigable ptosis, diplopia, and bulbar/extremity muscles weakness are characteristic. Antibodies directed at the extracellular muscle AChR domain are pathogenic in MG. Thymoma occurs in 10% to 15%. Here antibodies modulating (internalizing) the AChR, as well as antibodies directed against striated muscle, GAD-65, VGKC, CRMP-5, and neuronal AChR, are sometimes also identified. MG rarely occurs with other neoplasms.

Neuromuscular hyperexcitability disorders, including neuromyotonia, or cramp-fasciculation syndrome often occur as acquired idiopathic auto-immune and, rarely, paraneoplastic disorders. VGKC or contactin-associated protein 2 (CASPR2) antibodies are frequently identified.

MUSCLE

Cancer coexists in 15% of dermatomyositis patients, less frequently in polymyositis. It can usually be identified at time of myopathy diagnosis. Symptoms and signs are indistinguishable in paraneoplastic and nonparaneoplastic forms, although necrotic skin lesions, rapid onset, and older age provide clues to paraneoplastic dermatomyositis; no autoantibody markers are identified.

Acute necrotizing myopathy is rarely associated with a variety of cancers. Coincidental association with statin use is important to recognize. There are no antibody markers in paraneoplastic varieties, but antibodies to signal recognition particle (SRP) are reported in idiopathic autoimmune variants.

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