Autoimmune Encephalitis

Introduction

Autoimmune encephalitis refers to a recently recognized group of immune-mediated disorders that involve the central nervous system (CNS). These conditions, which overlap in their clinical manifestations and imaging findings, are ultimately tied to specific antibodies ( Fig. 11.1 ). The clinical and imaging features depend on the particular CNS structure(s) targeted by the antibodies. In addition to limbic encephalitis, which may be the most common and best-known clinical presentation, involvement of the basal ganglia, cerebellum, brainstem, spinal cord, and even the peripheral nervous system has also been described.

Although recognition of autoimmune encephalitis is increasing, it still remains a diagnosis of exclusion. In the setting of atypical clinical features and an otherwise negative workup for other etiologies, the radiologist may be the first to suggest the diagnosis. Herein, we review the imaging findings associated with autoimmune encephalitis as well as some of the characteristic antibodies.

Autoimmune Encephalitis Subtypes: Overview

Broadly speaking, autoimmune encephalitides may be categorized into two groups based either on their association with a neoplastic process or the location of their target antigens ( Table 11.1 ).

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Group I antibodies target intracellular antigens and are often associated with underlying malignancies constituting the classic paraneoplastic disorders. These antibodies kill neuronal and cancer antigens via cytotoxic T-cell activation. They are more resistant to treatment and are associated with a poor prognosis and irreversible neuronal damage. Examples include Anti-Hu, anti-Yo, Anti-Ri (ANNA2), and anti-Ma.
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Group II antibodies, on the other hand, target cell surface antigens and are less often associated with an underlying malignancy. Although in many cases there is no clear etiology, they have been reported in association with an underlying autoimmune disorder or following an infection. Group II antibodies cause reversible effects through direct interactions by the antibodies on their target receptors (humoral immune response), causing functional disruption. These antibodies have a more favorable response to immunomodulatory therapies compared with group I antibodies. Examples include anti-NMDAR, anti-Caspr2, and anti-LG1.
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A third group comprises antibodies that target intracellular synaptic proteins (occasionally classified with group I antibodies), likely with contributions from both B- and T-cell mediated mechanisms. Examples include anti-GAD65 (glutamic acid decarboxylase) and stiff-person syndrome.

TABLE 11.1

Antibodies Associated With Autoimmune Encephalitis

	Group	Association With Malignancies	Clinical Findings	Imaging Findings
Anti-Hu (ANNA-1)	1	Small cell lung cancer	Encephalomyelitis, subacute sensory neuropathy, cerebellar degeneration	T2-FLAIR hyperintensity in limbic system, cerebellum, brainstem
Anti-Ma (Ma1/Ma2/Ma3)	1	Testicular cancer, small cell lung cancer, breast cancer	Brainstem dysfunction, ophthalmoplegia, limbic encephalitis uncommon	Variable T2 hyperintense signal in thalamus and brainstem
Anti-GAD (glutamic acid decarboxylase)	1	Type I diabetes	Stiff-person syndrome, limbic encephalitis	T2 hyperintensity in the limbic system
Anti-Yo (PCA-1)	1	Breast cancer, ovarian cancer	Cerebellitis (ataxia), vertigo, nystagmus	Cerebellar degeneration
Anti-CV2	1	Small cell lung cancer, thymoma	Choreiform movements	T2-FLAIR hyperintensity in the striatum; relative sparing of the medial temporal lobes
Anti-NMDAr	2		Viral prodrome, psychiatric symptoms; amnesia, seizures, and encephalopathy	Often normal; variable transient cortical T2 hyperintensity and enhancement
Anti-VGKC (voltage-gated potassium channel)	2		Epilepsy (early and intractable), limbic encephalitis	T2-FLAIR hyperintensity in medial temporal lobes progressing to mesial temporal sclerosis
Anti-GABA (2 subtypes—anti-GABA-A, anti-GABA-B)	2	Anti-GABA-B associated with small cell lung cancer	Similar to anti-VGKC but with better prognosis	Anti-GABA-A often shows extra-limbic abnormalities
Anti-GluR3 (glutamate receptor 3)	2		Rasmussen encephalitis, intractable epilepsy	Holohemispheric diffuse tissue loss and T2-FLAIR hyperintensity
Anti-GluR1 (glutamate receptor 1)	2	Lymphoma	Cerebellar ataxia	Cerebellar degeneration
Anti-AMPAr (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor)	2	Breast, lung, and thymic tumors	Subacute psychiatric symptoms	T2-FLAIR signal abnormality isolated to the hippocampi
Anti-LGI1 (leucine-rich, glioma-inactivated 1)	2		Epilepsy (early and intractable), limbic encephalitis	T2-FLAIR hyperintensity in medial temporal lobes progressing to mesial temporal sclerosis

FLAIR, Fluid-attenuated inversion recovery.

Imaging Findings

Magnetic resonance imaging (MRI) of the brain is helpful to exclude other pathologies such as primary or metastatic brain neoplasms as well as ischemic or hemorrhagic strokes. It is important to recognize that MRI alone is neither sensitive nor specific for the diagnosis of autoimmune encephalitis. However, in the appropriate clinical setting, it can help to suggest the diagnosis. Herein we present an overview of the imaging findings that can be observed in autoimmune encephalitis. Of note, the location of the imaging abnormality often correlates with the patient’s clinical symptoms but is not necessarily specific for a particular antibody (individual antibodies can be associated with a variety of encephalitic syndromes).

Limbic Encephalitis

First described by Corsellis et al., who identified inflammatory changes in the mesial temporal lobes of patients with lung cancer, limbic encephalitis has been reported across antibody profiles (both paraneoplastic and unrelated to cancer). Clinical manifestations may include short-term memory loss, seizures, and/or psychiatric symptoms. On MRI, there may be increased signal within the mesial temporal lobe(s) (amygdala and hippocampus) on fluid-attenuated inversion recovery (FLAIR)/T2-weighted sequences, which may initially be unilateral but then progress to involve both temporal lobes ( Fig. 11.2 ). Limbic structures outside of the temporal lobes, including the insula and cingulate gyrus (more common in paraneoplastic limbic encephalitis) ( Fig. 11.3 ), may be affected as well. These findings can be subtle initially and may be most conspicuous on FLAIR images. Associated swelling can be seen; it eventually subsides and may progress to atrophy over months to years.