DISEASE

Paraneoplastic syndromes and limbic encephalitis

Paraneoplastic syndromes of the nervous system and limbic encephalitis are a group of rare disorders where auto-antibodies can be used as diagnostic markers.

CLINIC: It can often be difficult to differentiate between symptoms that manifests as paraneoplastic neurological symptoms and autoimmune limbic encephalitis. We have therefore decided to describe these symptoms together. In many cases, the autoantibodies can be found in both symptoms where specific autoantibody can be related to a tumor in some patients and in another patient an underlying tumor may never be found

The term limbic encephalitis was originally described by Corsellis et al. (1968), and refers to a subacute onset of episodic memory loss, disorientation and anxiety, and is usually associated with seizures, hallucinations, sleep disturbances and histological evidence of inflammation in the medial temporal lobes. Signal changes in the medial temporal lobes or hippocampus is often found on MRI.

Paraneoplastic neurological symptoms Paraneoplastic neurological symptoms are immunologically mediated phenomena which arise secondary to malignancy. All parts of the central and peripheral nervous system can be involved and give sub-acute and chronic symptoms, such as encephalopathy, cerebellar degeneration and polyneuropathy. Small cell lung cancer (SCLC) is the most common underlying cause, followed by breast and ovarian tumors, but many different cancers may be associated with paraneoplastic syndromes. Symptom onset is usually sub-acute and precedes the cancer diagnosis in up to 70% of cases. The classical antibody markers of paraneoplastic syndrome was discovered in the 1990's when autoantibodies against "onco-neuronal" antigen was observed. These autoantibodies could bind to intracellular structures in fixed brain tissue using classical indirect immunofluerescens (IIF). The autoantibodies against intracellular structures are not pathogenic but the damage to the nervous system are considered to be caused by activated specific CD8 T cells. Classic examples of these antigens are Hu, Yo, Ri, Ma2, CV2/CRMP5 and Amphiphysin. At diagnosis, two independent methods should be used. Generally, treatment with immunotherapy is not effective for autoantibodies directed against intracellular antigens and focus of treatment should in most cases be to locate and remove the cancer. When the cancer can be treated or removed this will stop the production of the intracellular antigen and specific CD8 T cells will no longer be activated which will subside damage to the nervous system. Autoimmune encephalitis, limbic encephalitis, or "Autoimmune CNS channelopathies" During the 2000 decade further autoantibodies were discovered that were associated with several symptoms of the central and peripheral nervous system. These autoantibodies react with extracellular structures on the cell membrane and provide a symptom associated with encephalitis that are referred to as autoimmune encephalitis or limbic encephalitis. These autoantibodies are considered to be pathogenic, and in most occasions immunotherapy are effective. Immunotherapy should be started as early as possible in order not to get chronic injury caused by the pathogenic autoantibodies. Modern biotechnology has made it possible to test for autoantibodies in special in vitro cell systems. In these in vitro systems, laboratory strains of cells are transfected to express the specific antigens after which the cells are fixed for use in routine diagnostics where they can be used for the detection of the specific autoantibodies. Examples of extracellular antigens that has been associated with autoimmune encephalitis are the NMDA receptor, the glycine receptor, AMPA receptor 1 and 2, the GABA B receptor 1, voltage-dependent potassium channel (anti-VGKC) and related proteins LGI1 and CASPR2, GAD and voltage dependent calcium channel (anti-VGCC). There are many subsets of symptoms and autoantibodies with newly discovered specificity are continuously described in litterature. Due to the large number of antigens that available for diagnostic tests, Wieslab has divided the tests into different packages after the relevance for differential diagnosis but also for how the tests are performed in the laboratory. Other packages There are other packages that can be used for differential diagnosis for neurological symptoms such as Lambert-Eaton myasthenic syndrome which are caused by antibodies against the presynaptic voltage-dependent calcium channel (anti-VGCC). Small cell lung cancer is the most common underlying cause of the syndrome but may occur without underlying malignancy. This syndrome is described in more detail under the separate test package. The test package for autoantibodies at Myasthenia Gravis, Stiff person syndrome and packages for peripheral neuropathy are also described separately. Table. Example of autoantibodies associated with neurological symptoms and cancer. Figure. Algoritm for treatment of neurological symptoms related to autoantibodies.