Autoantibody-­mediated encephalitis: Not just paraneoplastic, not just limbic, and not untreatable

Author and Disclosure Information

ABSTRACTAutoantibody-mediated encephalitis is a heterogeneous group of recently identified disorders, all caused by autoimmunity directed against components of the central nervous system. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with aggressive treatment.


  • Autoantibody-mediated encephalitis accounts for a portion of cases of unexplained status epilepticus, encephalitis, and acute-onset psychiatric symptoms.
  • Magnetic resonance imaging and cerebrospinal fluid analysis may be normal early in the disease course.
  • Patients can express more than one autoantibody and present with more than one neuronal syndrome.
  • Syndromes in which antibodies attack antigens on the surface of neurons are more likely to respond to immunotherapy than those involving intracellular antigens.
  • Anti-N-methyl-d-aspartate receptor encephalitis typically presents with psychosis, seizures, and movement disorders in young women and is often associated with an ovarian teratoma.
  • Limbic encephalitis, mediated by antibody to the voltage-gated potassium channel complex, is typically nonneoplastic and responds well to immunotherapy.



A 79-year-old woman with a history of breast cancer in remission and hypertension presented to a local emergency department because of subacute memory loss and compulsive shopping. Her serum sodium concentration was 127 mmol/L (reference range 132–148). Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were normal, and she was sent home.

Three days later, she experienced a generalized tonic-clonic seizure that evolved into status epilepticus. She was intubated and admitted to the intensive care unit. Cerebrospinal fluid analysis was normal, and infectious causes of encephalitis were ruled out. MRI showed increased signal in both hippocampi (Figure 1). Her seizures were refractory to treatment, and she was given pentobarbital to induce a coma.

Serum evaluation of neuronal antibodies revealed elevated titers of the voltage-gated potassium channel (VGKC) complex antibody, with subsequent subtyping confirming the leucine-rich glioma-inactivated protein 1 (LGI1) protein as the antigenic target.

She received a 5-day course of intravenous immunoglobulin and methylprednisolone, pentobarbital was withdrawn, and the seizures did not recur, but weeks later she remained comatose. Positron emission tomography (PET) of the brain revealed hypermetabolism in the medial and anterior aspects of both temporal lobes. She underwent five sessions of plasma exchange, after which she began to improve and follow commands. She was ultimately discharged to an acute rehabilitation facility after a 4-week hospital stay.

She received infusions of intravenous immunoglobulin twice a month for 6 months. At her last follow-up visit, she was seizure-free and neurologically intact except for mild inattention.


Figure 1. Left, axial fluid-attenuated inversion recovery magnetic resonance imaging shows increased signal in the hippocampus bilaterally (yellow arrows). Right, fluorodeoxyglucose positron-emission tomography shows hypermetabolism in the hippocampi (black arrows).

Although autoantibody-mediated encephalitic syndromes were first described more than 50 years ago,1,2 their autoimmune basis was not recognized until the early 1980s.3 In the past 10 years, a flood of novel clinical syndromes associated with neuronal autoantibodies has been described that may be markedly improved or even completely resolved with immunotherapy. In cases of unexplained seizure, encephalitis, or acute-onset psychiatric syndromes, suspecting these syndromes can lead to diagnosis, treatment, and a good outcome.

This review describes the key clinical autoantibody-mediated encephalitic syndromes, explains the better-characterized antibody associations, and discusses their diagnosis and treatment.


Autoantibody-mediated encephalitis is also known as autoimmune-mediated encephalitis, autoimmune-mediated limbic encephalitis, and autoimmune synaptic encephalitis.

How to categorize these syndromes is still in flux: they can be listed by the area of the brain affected, the antibody involved, or the name of the discoverer (eg, Morvan syndrome).

Autoantibodies identified in autoimmune encephalitis fall under two broad categories:

  • Those targeting intracellular (intranuclear or intracytoplasmic) antigens; the syndromes they cause are more likely to be paraneoplastic and less responsive to immunotherapy
  • Those targeting antigens on the neuronal surface: the syndromes they cause are less likely to be paraneoplastic and are more responsive to immunotherapy.4


Figure 2.

Below, we provide examples of neurologic syndromes of autoantibody-mediated encephalitis according to the region of the brain most affected, ie, the limbic system, the brainstem, or the cerebellum (Figure 2).


Memory loss, behavioral changes, seizures

Patients with limbic encephalitis (such as the patient described in the vignette above) present with symptoms attributed to dysfunction of mesial temporal lobe structures, most notably the hippocampus. Prominent symptoms include short-term memory loss, behavioral disturbances such as agitation and confusion, and psychiatric problems such as depression and psychosis. Recurrent seizures are a salient feature and, not uncommonly, progress to status epilepticus.

Antibodies are not all cancer-associated

Cerebrospinal fluid analysis can be normal or show abnormalities suggesting immune activation, eg, slight pleocytosis, elevated protein, increased immunoglobulin G synthesis, and oligoclonal banding.5

In many cases, an autoantibody is found in the blood or in the cerebrospinal fluid. Some patients may express more than one autoantibody, so the traditional view of “one antibody, one syndrome” is incorrect.

Although initially identified as a rare paraneoplastic disorder, limbic encephalitis sometimes occurs in the absence of malignancy.

Multiple antibodies have been linked to the syndrome (Table 1).6–9 The “classic” antibodies initially found in paraneoplastic forms are now generally viewed as nonpathogenic, in part because they are directed against intracellular antigens. Neuronal injury in paraneo­plastic limbic encephalitis is believed to be mediated by cytotoxic T lymphocytes, with neuronal autoantibodies being produced after the injury.4 Recently defined antibodies, such as those targeting the N-methyl-d-aspartate (NMDA) receptor6 and the LGI1 protein,7 are now understood to be common causes of limbic encephalitis.

Imaging usually shows limbic focal changes

Structural MRI or functional fluorodeoxyglucose (FDG)-PET imaging may show focal changes in limbic system structures, such as the mesial temporal lobes. It is now recognized that other cortical areas may be involved, and the term “limbic encephalitis” may give way to “cortical” or “focal encephalitis.”

In about 60% of patients, MRI shows hyperintense fluid-attenuated inversion recovery (FLAIR) or T2 signal changes in the mesial temporal lobes, likely reflecting inflammatory changes.4,10,11 On FDG-PET, hypermetabolism may be observed in the mesial temporal lobes early in the disease despite normal findings on MRI.12 Hypometabolism, either diffuse or localized to the mesial temporal lobes, eventually sets in, likely reflecting cytotoxic injury in the aftermath of prolonged inflammation or seizures.

Consider other causes

Before diagnosing limbic encephalitis, it is essential to evaluate for infectious meningoencephalitis, especially herpes simplex viral encephalitis. Thiamine deficiency (Wernicke encephalopathy), drug intoxication, prion disease, Hashimoto encephalopathy, tumor, and subclinical status epilepticus should also be considered. Some of these conditions are associated with the same neuronal autoantibodies detected in limbic encephalitis. Further complicating the picture, case reports have shown the presence of serum neuronal autoantibodies—VGKC complex13–15 and NMDA-receptor antibodies16,17—in confirmed cases of prion disease. In addition, adequately treated herpes simplex viral encephalitis can precipitate the production of NMDA-receptor antibodies and their characteristic syndrome.18–20


The brainstem—the midbrain, pons, and medulla—can be affected, either in isolation or more commonly as part of a more widespread autoantibody-mediated encephalitis. Symptoms and signs include eye movement abnormalities, ptosis, dysphagia, dysarthria, ataxia, facial palsy, vertigo, hearing impairment, reduced consciousness, and hypoventilation.21

Anti-Hu, anti-Ri, and anti-Ma2 antibodies are most commonly associated with brainstem encephalitis (Table 2). Anti-Ma2-associated encephalitis may improve after a combination of immunotherapy and tumor removal21; the others have a poor prognosis.

Neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders most commonly involve demyelination affecting the optic nerves and spinal cord, leading to unilateral or bilateral optic neuritis and transverse myelitis spanning three or more vertebral segments.22 The initial clinical manifestation may be an encephalitic pattern, affecting predominantly the brainstem in a restricted fashion,22 or the central nervous system in a more diffuse pattern, mimicking either acute disseminated encephalomyelitis or, in less severe cases, posterior reversible encephalopathy syndrome.23

Testing for antiaquaporin-4 antibody, also known as neuromyelitis optica immunoglobulin G, is the single most decisive laboratory test for diagnosing neuromyelitis optica spectrum disorders, so serum and cerebrospinal fluid evaluation for this autoantibody should be considered when caring for a patient whose clinical picture suggests brainstem encephalitis.22

Bickerstaff brainstem encephalitis

Bickerstaff brainstem encephalitis was first described more than half a century ago in patients with postinfectious ataxia, ophthalmoparesis, and altered consciousness. This rare disease was later found to be associated with antiganglioside GQ1b (anti-GQ1b) autoantibody. MRI is normal in about 90% of cases, so recognizing the clinical presentation and analyzing anti-GQ1b serum titers are critical to diagnosis.

Recovery is usually spontaneous and complete and can be hastened by immunotherapy, especially intravenous immunoglobulin.24

Other causes of brainstem encephalitis

The differential diagnosis of a presentation of brainstem encephalitis includes:

  • Infectious causes, the most common being Listeria species followed by enterovirus 71 and herpes simplex virus.25 Tuberculosis, brucellosis, and Whipple disease should also be considered.
  • Primary central nervous system inflammatory and demyelinating conditions, eg, multiple sclerosis and acute disseminated encephalomyelitis.
  • Systemic inflammatory conditions, eg, Beh­çet disease, systemic lupus erythematosus, and sarcoidosis.
  • Direct brainstem neoplastic involvement, as might occur in primary central nervous system lymphoma or leptomeningeal carcinomatosis.

Next Article:

Does allergic conjunctivitis always require prescription eyedrops?

Related Articles