2021 Mar 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.
Paraneoplastic encephalomyelitis (PEM) is a subtype of paraneoplastic neurological syndromes (PNS), a group of neurological manifestations associated with antibodies against intracellular and extracellular neuronal proteins that are invariably cancer-related, involving focal or multifocal inflammation of the brain or spinal cord or both.
The definite diagnosis of paraneoplastic neurological syndromes, per the 2004 definition, encompasses:
A classical syndrome (includes encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, and opsoclonus-myoclonus) and cancer develops within 5 years of diagnosis of the neurological disorder.
A non-classical neurological syndrome is one that resolves or significantly improves after cancer treatment, without immunotherapy.
A non-classical neurological syndrome with paraneoplastic antibodies and cancer develops within 5 years of the diagnosis of the neurological disorder.
Paraneoplastic encephalomyelitis typically involves B-cell activation, with the production of autoantibodies that identify immune marker disease subtypes. Originally thought to be totally separable from primary autoimmune disease, paraneoplastic antibody markers are now thought to be of three types:
- Autoantibodies targeting intracellular epitopes thought to cross-react between cancer and central nervous system proteins, glycoproteins, and complex carbohydrates. Associated diseases can include limbic encephalitis, encephalomyelitis, subacute cerebellar degeneration, opsoclonus myoclonus, optic neuritis, and rapidly progressive sensory polyneuropathy. These antibodies are not pathogenic in the classical sense. Patients do not usually respond to standard immunomodulatory therapies when these are the sole immune targets identified in the paraneoplastic process. Their function is just now being elucidated as providing targets for cytotoxic T cell infiltration into tumor and non-neoplastic cells with cross-reactive intracellular epitopes, the latter producing bystander destruction and paraneoplastic syndromes (for review, see). Understanding the mechanism of such intracellular antibody targeting against intracellular tumor antigens may eventually provide an effective cancer therapeutics method.
- Autoantibodies targeting intracellular epitopes at synaptic sites, producing potentially treatable conditions. Diseases like progressive encephalomyelitis with rigidity and myoclonus (PERM), stiff person syndrome, and cerebellar ataxia have been linked to such antibodies, and passive transfer of such intracellular epitope targeted antibodies from patients to naïve animal models can reproduce symptoms of the disease.
- Autoantibodies targeting extracellular epitopes that directly cause neurologic dysfunction. These autoantibodies were originally identified in non-paraneoplastic autoimmune disease, can be suppressed by antibody depleting or blocking therapies, and are often recognized as the first cancer evidence. Diseases produced by such antibodies include paraneoplastic myasthenia gravis, Lambert Eaton myasthenic syndrome, limbic encephalitis, encephalomyelitis, anti-myelin oligodendrocyte glycoprotein antibody-associated disease, and neuromyelitis optica spectrum disorder, among others. Recognizing the evolving concepts surrounding paraneoplastic and non-paraneoplastic autoimmune CNS disease has helped identify and treat these disorders.
There is overlap between traditional paraneoplastic disorders and extracellular epitope associated autoimmune encephalitides, a group of syndromes associated with autoantibodies against extracellular neuronal cell surface proteins, synaptic proteins, ion channels, or receptors, usually most common in the non-paraneoplastic disease. This is especially important in the era of cancer chemotherapy with checkpoint inhibitors. The incidence of immunological toxicity is much higher with these therapies than in traditional cancer chemotherapy, producing immune-related adverse events that may present as paraneoplastic neurologic syndromes. Recognizing which antibody targets are important in secondary immune disease production and which paraneoplastic antibodies are not amenable to immunomodulatory therapy is important for treatment decisions.