In this chapter we review the CNS syndromes mediated by autoimmune or inflammatory mechanisms in patients with cancer. Paraneoplastic neurological syndromes (PNS) are considered to be immune-mediated disorders against proteins expressed by the tumour and nervous system. The autoimmune hypothesis is supported by the presence in serum and CSF of antibodies against neural proteins that are also expressed in the tumour. Less frequently the tumour does not express neuronal proteins but predisposes to immune dysregulation and autoimmune mechanisms. Novel cancer therapies that enhance anti-tumour immune responses frequently cause inflammatory CNS disorders. Immune checkpoint inhibitors have been associated with a wide range of immune-related adverse effects, including an increased incidence of PNS. Another type of cancer therapy is based on the use of T cells genetically engineered to express chimeric antigen receptors (CARs) that recognize molecules present on the surface of tumour cells. CAR T cell therapy can cause severe, potentially lethal, encephalopathy syndromes mediated by massive release of cytokines instead of autoimmune mechanisms. Post-transplant autoimmune encephalitis are rare disorders that mostly occur after allogeneic haematopoietic stem cell transplantation. They are related to graft versus host disease and, sometimes, they associate with antibodies against neuronal surface antigens.

About 20 years ago the group of diseases currently known as ‘autoimmune encephalitis’ or ‘antibody-mediated encephalitis’ was unknown and the entire field of ‘autoimmune neurology’ non-existent. Since then, 18 autoimmune encephalitis and the corresponding syndromes have been described, including 16 in which the antigens are expressed on the cell surface of neurons and two on the surface of glial cells. The characterization of these autoimmune encephalitis was facilitated by the cumulative knowledge provided by research on autoimmune disorders of the neuromuscular junction (myasthenia gravis and Lambert–Eaton myasthenic syndrome) and the paraneoplastic neurological syndromes. Up to 12.6 per 100,000 persons are affected by encephalitis annually. Of these, it has been estimated that 20–30% are caused by autoimmune mechanisms. In children the most frequent types of autoimmune encephalitis are acute disseminated encephalomyelitis (ADEM), anti-MOG, and anti-NMDAR encephalitis. In young adults, particularly women, anti-NMDAR encephalitis, and in late adulthood, anti-LGI1 encephalitis, are the most prevalent autoimmune encephalitis. The most frequently used classifications combine information related to three features: mechanisms of disease (cytotoxic T cell or antibody-mediated mechanisms), type of antigen (intracellular vs cell surface), and presence or absence of a tumour. The detection of a neoplasm frequently serves to categorize the autoimmune encephalitis as paraneoplastic.

Antibodies against neural intracellular antigens have been classified in three groups: (1) markers of paraneoplastic neurological syndromes (onconeural antibodies) and therefore the presence of an underlying cancer; (2) markers of non-paraneoplastic neurological syndromes; and (3) markers of autoimmune retinopathies. All antibodies against neural intracellular proteins recognize linear epitopes, are detected by immunoblot, and are considered non-pathogenic. An exception is the amphiphysin antibodies that can potentially reach the antigen that is briefly exposed to the extracellular space during the process of synaptic vesicle recycling. The most common onconeural antibodies are Hu (markers of paraneoplastic neurological syndromes associated with small-cell lung cancer), Yo (paraneoplastic cerebellar degeneration and breast and ovarian cancer), and Ma2 (limbic and brainstem encephalitis with testicular seminomas). The two most common antibodies present in non-paraneoplastic CNS syndromes are glutamic acid decarboxylase (GAD) and glial fibrillary acidic protein (GFAP) antibodies. GAD antibodies are biomarkers of stiff-person syndrome and also occur in some patients with cerebellar ataxia or drug-resistant temporal lobe epilepsy. GFAP antibodies associate with meningoencephalitis and a broad spectrum of symptoms without a clear specific syndrome. Unlike the other antibodies against intracellular antigens that are usually detectable in serum and CSF, GFAP antibodies are predominantly detected in CSF.

Limbic encephalitis is characterized by the subacute onset, usually <3 months, of memory and cognitive deficits, behavioural changes, and seizures. The most typical deficit is impairment of short-term memory. Brain MRI shows FLAIR and T2 signal abnormalities involving bilaterally, less frequently unilaterally, the hippocampus and amygdala. Limbic encephalitis was initially considered a paraneoplastic syndrome, but after the discovery of several immunological subtypes we now know that >60% of cases are non-paraneoplastic and usually associated to LGI1 antibodies. Paraneoplastic limbic encephalitis mainly associates with small-cell lung cancer and Hu or GABAbR antibodies, testicular seminoma and Ma2 antibodies, Hodgkin disease and mGluR5 antibodies, and thymoma and AMPAR antibodies. Limbic encephalitis may be triggered by treatment of cancer with immune checkpoint inhibitors. The response to immunotherapy and outcome vary according to the type of antibody and presence or absence of an underlying tumour. In patients with antibodies against intracellular antigens (onconeural, AK5), immunotherapy is usually ineffective. In contrast, most patients with LGI1 antibodies show substantial improvement after treatment with steroids and immunotherapy. Patients with cancer and GABAbR or AMPAR antibodies respond better to treatment than those with the same type of cancer and onconeural antibodies, and worse than those of patients with LGI antibodies.

The diagnosis of autoimmune encephalitis should be considered in patients with rapid progression (<3 months) of short-term memory loss, decreased or altered level of consciousness, lethargy, personality change, or psychiatric manifestations in association with at least one of the following criteria: new-onset seizures or focal CNS symptoms, CSF pleocytosis, or MRI features suggestive of brain inflammation. Many alternative causes of encephalitis can be excluded after a careful clinical history and evaluation of the CSF, brain MRI, and routine blood tests. Some types of encephalitis can be suspected before receiving the results of neural antibodies, according to the clinical presentation (for instance, faciobrachial dystonic seizures in anti-LGI encephalitis, or psychotic manifestation in anti-NMDAR encephalitis) or brain MRI features (temporal lobe involvement in limbic encephalitis). Antibody testing may show false positive and negative results, particularly when only serum is examined, results are not confirmed with additional laboratory studies, or the test is used indiscriminately without selection of patients.

This chapter focuses on the syndromes that are associated with antibodies that target proteins of the inhibitory synapses. Two antibodies are directed against intracellular presynaptic proteins, including glutamic acid decarboxylase (GAD), a key enzyme in the synthesis of GABA, and amphiphysin, which is involved in the presynaptic reuptake of neurotransmitters. Both antibodies are associated with stiff-person syndrome (SPS), which results in rigidity in proximal muscles of legs, abdomen, and lower back, impaired gait, muscles spasms, exaggerated startle responses to acoustic or tactile stimuli, and anxiety and task-specific phobias. Three antibodies are directed against cell surface receptors, including GABAaR and GABAbR, and the glycine receptor (GlyR). Encephalitis with prominent seizures is the common presentation of patients with antibodies against GABAaR or GABAbR, whereas antibodies against GlyR associate with an SPS variant named progressive encephalomyelitis with rigidity and myoclonus (PERM). In addition, this chapter includes the antibodies against dipeptidyl-peptidase-like protein 6 (DPPX), an auxiliary subunit of the Kv4.2 potassium channels that is not restricted to inhibitory synapses, but patients with this disorder frequently show CNS hyperexcitability and sometimes clinical features similar to PERM.

In this chapter we review the CNS syndromes mediated by autoimmune or inflammatory mechanisms in patients with cancer. Paraneoplastic neurological syndromes (PNS) are considered to be immune-mediated disorders against proteins expressed by the tumour and nervous system. The autoimmune hypothesis is supported by the presence in serum and CSF of antibodies against neural proteins that are also expressed in the tumour. Less frequently the tumour does not express neuronal proteins but predisposes to immune dysregulation and autoimmune mechanisms. Novel cancer therapies that enhance anti-tumour immune responses frequently cause inflammatory CNS disorders. Immune checkpoint inhibitors have been associated with a wide range of immune-related adverse effects, including an increased incidence of PNS. Another type of cancer therapy is based on the use of T cells genetically engineered to express chimeric antigen receptors (CARs) that recognize molecules present on the surface of tumour cells. CAR T cell therapy can cause severe, potentially lethal, encephalopathy syndromes mediated by massive release of cytokines instead of autoimmune mechanisms. Post-transplant autoimmune encephalitis are rare disorders that mostly occur after allogeneic haematopoietic stem cell transplantation. They are related to graft versus host disease and, sometimes, they associate with antibodies against neuronal surface antigens.