In this chapter we review the inflammatory mechanisms involved in epileptogenesis, the caveats and limitations of the term autoimmune epilepsy, and two epileptic syndromes of autoimmune origin: epilepsy associated with GAD antibodies and Rasmussen encephalitis. The International League Against Epilepsy (ILAE) recently proposed the definition of acute symptomatic seizures secondary to autoimmune encephalitis for the seizures that occur in the setting of the active phase of immune-mediated encephalitis. In contrast, the term autoimmune epilepsy applies to chronic seizures considered to be secondary to autoimmune brain diseases. If promptly diagnosed and treated, patients with symptomatic seizures due to antibody-mediated encephalitis rarely evolve to develop epilepsy and, therefore, they do not fulfil criteria of autoimmune epilepsy. Scoring systems to predict autoimmune seizures are not very useful because they rely on the presence of additional neurological manifestations or diagnostic tests included in the definition of autoimmune encephalitis. Antibodies against neuronal surface antigens occur in a minority (<5%) of patients with isolated epilepsy; the significance of these antibodies is unclear as the spectrum of symptoms of these patients is not different from that of seronegative cases. In contrast, antibodies against GAD (an intracellular protein) occur in a small subset of patients with temporal lobe epilepsy that is usually refractory to anti-seizure medication.

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.

Autoimmune cerebellar ataxias include a heterogeneous group of disorders characterized by isolated or predominant cerebellar dysfunction caused by immune-mediated mechanisms. The best-characterized autoimmune ataxia is paraneoplastic cerebellar degeneration (PCD) that, depending on the type of cancer, associates with different paraneoplastic antibodies such as Yo antibodies in patients with breast or ovarian cancer, Tr (DNER) antibodies in patients with Hodgkin lymphoma, and SOX1 or voltage-gated calcium channel (VGCC) antibodies in patients with small-cell lung cancer (SCLC). Patients with PCD and SCLC can have concurrent symptoms of Lambert–Eaton myasthenic syndrome (LEMS). Non-paraneoplastic cerebellar ataxias usually associate with glutamic acid decarboxylase (GAD) or mGluR1 antibodies. Patients with autoimmune ataxia respond poorly to immunotherapy even when the associated antibodies are directed against neuronal surface antigens (VGCC, mGluR1). Cerebellar ataxia may occur in patients with dietary gluten sensitivity. The autoimmune pathogenesis of gluten ataxia is unclear. Acute cerebellar ataxia and acute cerebellitis are the most frequent causes of cerebellar dysfunction in children. Whereas the term acute cerebellar ataxia is used to define patients with normal MRI and a benign clinical course, the term acute cerebellitis implies a more severe disorder with MRI inflammatory changes. In these patients the long-term prognosis is less favourable.