Clinical Information

Neuropathy patients have variable sensory disturbance (loss or exaggerated sensation) with pain, weakness, and autonomic involvements such as sweat abnormalities, gastrointestinal dysfunction, and lightheadedness on standing. These symptoms are as a result of injury to the distal nerves, roots, ganglia or their gathering points (nerve plexus in the thighs and arms). Patients may have symmetric or asymmetric involvements of the extremities, trunk, and head including extraocular muscles. Subacute onsets and asymmetric involvements favor inflammatory or immune causes over inherited or metabolic forms. Depending on the specific inflammatory or immune mediated causes other parts of the nervous system may also be affected (brain, cerebellum, spinal cord).

In the evaluation of patients with immune mediated autoantibody neuropathies, nerve conduction studies and needle electromyography can help to classify the neuropathy as either: 1) primary axonal; 2) primary demyelinating; or 3) mixed axonal and demyelinating. This evaluation focuses on persons with primary axonal forms.

Well established neuronal autoantibodies responsible for axonal neuropathies include: antineuronal nuclear antibodies (ANNA1 and 3), Purkinje cytoplasmic antibody (PCA1 and 2), amphiphysin antibody, collapsin response mediator protein 5 (CRMP5) antibody, leucine-rich glioma inactivated 1 protein (LGI1) antibody, contactin-associated response protein 2 (CASPR2) antibody, and acetylcholine receptor (AChR) ganglionic neuronal antibody (Alpha-3). Other autoantibodies have preliminary evidence to support their association with neuropathy including: alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antibody (AMPAR), antiglial nuclear antibody (AGNA), antineuronal nuclear antibody, type 2 antibody (ANNA2), gamma-aminobutyric acid B receptor antibody (GABABR), glutamic acid decarboxylase 65 receptor antibody (GAD65), glial fibrillary acidic protein antibody (GFAP), N-methyl-D-aspartate receptor antibody (NMDAR), Purkinje cell cytoplasmic TR antibody (PCATR), dipeptidyl-peptidase-like protein-6 antibody (DPPX), and metabotropic glutamate receptor 1 (mGluR1).

A patient's humoral and cellular immune response leads to the neurological syndrome. This may be related to an underlying cancer or unidentified antigen trigger. If related to cancer it may be a new or recurrent malignancy, is usually limited in metastatic volume, and is often occult by standard imaging procedures. Autoantibodies specific for onconeural proteins found in the plasma membrane, cytoplasm, and nucleus of neurons, glia, or muscle are generated in this immune response and serve as serological markers of paraneoplastic autoimmunity. Cancers recognized in this context most commonly are small-cell lung carcinoma, thymoma, ovarian (or related Mullerian) carcinoma, breast carcinoma, and Hodgkin lymphoma. Pertinent childhood neoplasms recognized thus far include neuroblastoma, thymoma, Hodgkin lymphoma, and chondroblastoma.

This evaluation focuses on those antibodies with known associations with varied forms of peripheral axonal neuropathy. Seropositive patients usually present with subacute neurological symptoms of radiculopathy; plexopathy; or sensory, sensorimotor, or autonomic neuropathy, with or without a neuromuscular transmission disorder such as neuromuscular hyperexcitability. Other peripheral manifestation includes cranial neuropathies, especially loss of vision, hearing, smell, or taste. Commonly beyond the peripheral manifestation are encephalopathy, seizures, cerebellar ataxia, and myelopathy. Initial signs may be subtle, but a subacute multifocal and progressive syndrome usually evolves. Sensorimotor neuropathy and cerebellar ataxia are common presentations, but the clinical picture in some patients is dominated by striking gastrointestinal dysmotility, and limbic encephalopathy.

Cancer risk factors include past or family history of cancer, history of smoking, or social or environmental exposure to carcinogens.