Demyelinating and Inflammatory Diseases

Main Text

Preamble

Once considered an “immune-privileged” site sequestered beyond the blood-brain barrier, we now know there is active and continuous immunologic surveillance in the CNS. A broad spectrum of noninfectious, inflammatory, autoimmune/autoantibody-mediated disorders can affect the CNS.

In this chapter, we begin our discussion of autoimmune CNS disorders with multiple sclerosis (MS). We follow with a discussion of postinfection and postvaccination inflammatory syndromes, such as acute disseminated encephalomyelitis (ADEM). We then discuss the integration of molecular diagnostics into the classification schema with a discussion of antibody-mediated demyelinating diseases, such as myelin-oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD) and aquaporin-4 (AQP4) antibody neuromyelitis optica spectrum disorder (NMOSD). We then turn our attention to less common inflammatory disorders, such as autoimmune encephalitis (AE), an autoantibody-mediated disease, and the rare diagnosis of acute hemorrhagic leukoencephalitis (AHLE).

This chapter concludes by discussing uncommon inflammatory-like disorders, such as Susac syndrome (SuS), CLIPPERS, neurosarcoidosis, and idiopathic inflammatory pseudotumors.

Multiple Sclerosis and Variants

Multiple Sclerosis

Etiology

While the precise pathogenesis of MS remains unknown, the generally accepted hypothesis is that myelin antigens are presented by macrophages, microglia, and astrocytes to T cells. This leads to the release of proinflammatory cytokines and an immune attack on myelin-oligodendrocyte complexes that results in the destruction of myelin, axons, and neurons.

Epstein-Barr virus (EBV) exposure, chemicals, smoking, diet, and geographic variability all contribute to MS risk. MS occurs less often in non-White compared with White patients. MS frequency also increases with increasing latitude and is most common in temperate climates.

Pathology

Location

Most MS plaques are supratentorial and are primarily (but not exclusively) located in the deep cerebral white matter, oriented perpendicular to the lateral ventricles (15-5). The majority occur at or near the callososeptal interface. Centripetal perivenular extension is common, causing the appearance of so-called Dawson fingers radiating outward from the lateral ventricles (15-8).

Other commonly affected areas include the subcortical U-fibers, brachium pontis, brainstem, and spinal cord (15-6). Gray matter (cortex and basal ganglia) lesions are seen in 10% of cases. Less than 10% occur in the posterior fossa (15-7).

Gross Pathology

Acute/subacute MS plaques are linear, round, or ovoid lesions with ill-defined margins. Chronic plaques have more defined borders with excavated, depressed centers.

Microscopic Features

Histopathologically, MS plaques typically demonstrate (1) relatively sharp borders (15-3), (2) macrophage infiltrates (both interstitial and perivascular), and (3) perivascular chronic inflammation (15-4). Acute lesions are often hypercellular with foamy macrophages and prominent perivascular T-cell lymphocytic cuffing (15-14).

MULTIPLE SCLEROSIS

Location

Size and Number

Chronic plaques range from chronic active to chronic silent lesions. Chronic active lesions have continuing inflammation around their outer borders. Chronic silent (“burned-out”) lesions are characterized by hypocellular regions, myelin loss, absence of active inflammation, and glial scarring.

Clinical Issues

Demographics

MS is the most frequent primary demyelinating pathology in the CNS. Onset typically occurs in young to middle-aged adults from 20-40 years of age. Up to 10% of all patients with MS become symptomatic in childhood.

The overall F:M ratio is 1.77:1.00. White patients of northern European descent living in temperate zones are the most commonly affected ethnic group. MS is significantly less common in Asian and African patients.

Presentation

MS presentation varies with heterogeneous neurologic manifestations, evolution, and disability. Intermittent neurologic disturbances followed by progressive accumulation of disabilities are typical.

Clinical MS Subtypes

Several major MS subtypes are recognized. From least to most severe, they are radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting MS (RR-MS), relapsing progressive MS (RP-MS), secondary-progressive MS (SP-MS), and primary-progressive MS (PP-MS).

Radiologically Isolated Syndrome

RIS is a new subtype described at the very mildest of the demyelinating disease spectrum. RIS refers to MR findings of T2/FLAIR lesions suggestive of MS in persons with no history of neurologic symptoms and with a normal neurologic examination.

By definition, patients with RIS have dissemination in space (DIS). When a clinical attack occurs in these patients, a diagnosis of MS can be made. Until that occurs, most experts agree that MS should not be diagnosed solely on the basis of MR findings.

Clinically Isolated Syndrome

The first attack of MS [most commonly optic neuritis (ON), transverse myelitis (TM), or a brainstem syndrome] is known as a clinically isolated syndrome. 1/2 of patients with ON eventually develop MS.

Disease progression to MS varies. Patients with MR-negative CIS have a 20% chance of developing MS. If patients with CIS have MR evidence for typical brain lesions, the chance of developing clinically definite MS is 60-80%. If imaging demonstrates old lesions in a different location, dissemination in time (DIS) is established, and the criteria for establishing MS are fulfilled (see below).

Relapsing-Remitting MS

The vast majority (~ 85%) of all MS patients experience relapses alternating with remission phases and are classified as having RR-MS. Attacks (“relapses” or “exacerbations”) are followed by periods of partial or complete recovery. New MR lesions often occur as part of a relapse but may also occur without symptoms.

Relapsing-Progressive MS

RP-MS is also known as SP-MS. In RP-MS, there is progressive worsening of neurologic function (accumulation of disability) over time. Almost 1/2 of RR-MS patients enter an RP-MS stage within 10 years. By 25 years following initial diagnosis, 90% of RR-MS cases become the RP-MS subtype.

Primary-Progressive MS

PP-MS is characterized by worsening neurologic function from the outset and lacks periods of remission. Approximately 5-10% of patients have PP-MS. Patients with PP-MS tend to have fewer brain lesions but more lesions in the spinal cord.

Diagnosis

The diagnosis of MS requires (1) elimination of more likely diagnoses and (2) demonstration of dissemination of CNS lesions in space and time. The 2017 revised McDonald diagnostic criteria incorporate clinical presentation (such as clinical presentation in a person with typical attack/CIS at onset) and additional data (e.g., MR evidence for DIS and DIT, characteristic CSF findings) to establish the diagnosis.

2017 REVISED MCDONALD CRITERIA FOR MULTIPLE SCLEROSIS DIAGNOSIS

Clinical Presentation

MR: Dissemination in Space

MR: Dissemination in Time

Imaging

General Features

Most MS plaques are small (5-10 mm), although large lesions can reach several centimeters. Plaques are usually multiple, although 30% of giant “tumefactive” plaques initially occur as solitary lesions and are relatively more common in children and young adults.

MULTIPLE SCLEROSIS: IMAGING

CT

MR

CT Findings

NECT is often normal early in the disease course, especially with mild cases. Solitary or multiple ill-defined white matter hypodensities may be present. Acute or subacute lesions may show mild to moderate punctate, patchy, or ring enhancement on CECT.

MR Findings

Over 95% of patients with clinically definite MS have positive findings on MR scans. Therefore, MR is the procedure of choice for both initial evaluation and treatment follow-up. The 2017 revised McDonald criteria for MS diagnosis allow MR to demonstrate DIS and DIT.

T1WI

Most MS plaques are hypo- or isointense on T1WI. A faint, poorly delineated peripheral rim of mild hyperintensity secondary to lipid peroxidation and macrophage infiltration often surrounds sharply delineated, hypointense “black holes.” This gives many subacute and chronic lesions a characteristic beveled or lesion-within-a-lesion appearance (15-11).

Chronic and severe cases typically show moderate volume loss and generalized atrophy. The corpus callosum becomes progressively thinner and is best delineated on sagittal T1WI.

T2/FLAIR

T2WI shows multiple hyperintense, linear, round, or ovoid lesions surrounding the medullary veins that radiate centripetally away from the lateral ventricles (15-8). Larger lesions often demonstrate a very hyperintense center surrounded by a slightly less hyperintense peripheral area and variable amounts of perilesional edema.

MS plaques often assume a distinct triangular shape with the base adjacent to the ventricle on sagittal FLAIR or T2WI images (15-5).

T1 C+

Punctate, nodular, linear, and rim patterns are seen during active demyelination (15-10). A prominent incomplete rim (“horseshoe”) of enhancement with the “open” nonenhancing segment facing the cortex can be present (15-9B), especially in large “tumefactive” lesions (15-12)(15-13).

Enhancement disappears within 6 months in > 90% of lesions. Steroid administration significantly reduces lesion enhancement and conspicuity and may render some lesions virtually invisible!

DWI and MRS

Although occasionally acute MS plaques can demonstrate restricted diffusion, such an appearance is atypical and should not be considered a reliable biomarker of plaque activity. MRS shows elevated myoinositol in acute lesions. “Tumefactive” MS shows nonspecific findings (elevated choline, decreased NAA, and high lactate).

Differential Diagnosis

Multifocal nonenhancing T2/FLAIR “white spots” are nonspecific imaging findings and have a broad differential diagnosis. It is helpful to suggest whether such lesions do or do not meet the revised 2017 McDonald criteria for multiple sclerosis.

Multifocal enhancing white matter lesions can be caused by ADEM, vasculitis, and Lyme disease. SuS (see later discussion) is often mistaken for MS on imaging studies, as both have multifocal T2/FLAIR white matter hyperintensities and both commonly affect young adult women. Lesions in SuS preferentially involve the middle of the corpus callosum, not the callososeptal interface (15-34).

“Tumefactive” MS can mimic abscess or neoplasm (glioblastoma or metastasis). “Tumefactive” demyelination often has an incomplete or horseshoe pattern of enhancement.

Multiple Sclerosis “Variants”

The relationship of atypical demyelinating disorders, such as Marburg disease (MD), Schilder disease (SD), Balo concentric sclerosis (BCS), and progressive solitary sclerosis (SS)as well as atypical idiopathic inflammatory demyelinating disorders (IIDDs), to the acute-onset MS spectrum remains uncertain.

Marburg Disease

MD is generally considered as an acute fulminant MS variant characterized by rapid, relentless progression and an exceptionally severe clinical course that usually leads to death within one year. Patients are typically young adults.

Marked lymphocytic infiltrates (15-14) with inflammatory changes in the perivenular spaces can lead to hyperacute, fulminant demyelination with a “centrifugal” pattern of contrast leakage from medullary veins on T1 C+ imaging (15-15). The presence of developmental venous anomalies (DVAs) seems to predispose to “tumefactive” demyelination centered around the “Medusa head”(15-16).

Imaging shows multifocal diffusely disseminated disease with focal and confluent white matter hyperintensities on T2/FLAIR. Strong patchy enhancement on T1 C+ is typical, and large, cavitating, incomplete, ring-enhancing, “tumefactive” lesions are common (15-17).

Schilder Disease

SD—a.k.a. myelinoclastic diffuse sclerosis—is a rare subacute or chronic demyelinating disorder characterized by one or more inflammatory demyelinating white matter plaques. SD is typically a disease of childhood and young adults. Median age at presentation is 18 years with a slight female predominance.

Although SD is considered to be a variant of MS, clinical features are atypical for MS, and the disease is usually monophasic with a low rate of recurrence. Signs of increased intracranial pressure, aphasia, and behavioral symptoms are typical. CSF is usually normal, and there is no history to suggest acute disseminated encephalomyelitis (ADEM) (i.e., no fever, infection, or preceding vaccination). Approximately 15% of cases progress to MS.

MR shows a hypointense lesion on T1WI that is hyperintense on T2/FLAIR. Rim enhancement—often the incomplete or open ring pattern—is seen during the acute inflammatory stage. The lesion rim usually restricts on DWI during the acute phase.

The differential diagnosis of SD can be difficult. “Tumefactive” MS can appear identical to SD on imaging studies. SD often mimics intracranial neoplasm or abscess both in clinical presentation and on imaging studies. Pyogenic abscess generally shows strong diffusion restriction in the lesion core. Perfusion MR may be helpful in distinguishing SD from metastasis and glioblastoma.

Balo Concentric Sclerosis

BCS is generally considered an atypical or variant form of MS and occurs as a discrete, concentrically layered white matter lesion. It is often described as having an onion ring or whorled appearance, caused by its peculiar pattern of alternating rims of demyelination and myelin preservation.

BCS is usually characterized by acute onset and rapid clinical deterioration. Peak presentation is between 20-50 years. The F:M ratio is ~ 2:1 and is most common in patients of east Asian origin.

Imaging studies reflect the distinctive gross pathology of BCS and vary with disease stage. Acute lesions have significant surrounding edema (15-18A). The actively demyelinating layers enhance on T1 C+ sequences. Other more typical MS-like plaques can also be present. Lesions in subacute/chronic BCS exhibit alternating bands of differing signal intensities on T2WI and resemble a “whirlpool” of concentric rings (15-18B).

Other Acquired CNS Demyelinating Syndromes

Preamble

The system of classification for CNS demyelinating syndromes has been strongly influenced by advances in the molecular diagnosis capabilities developed in the last decade or so. There is a trend towards defining demyelinating syndromes by the antibodies present rather than solely or even predominantly by the clinical and radiologic phenotype. Current clinical recommendations suggest testing for MOG and AQP4 antibodies in patients with acute CNS demyelination of suspected autoimmune origin. The debate continues on whether syndrome-based or biomarker-based criteria should prevail in these classification schemes. It behooves the radiologist to be aware of these important disease biomarkers and their relationship to such imaging-based clinical manifestations, such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), neuromyelitis optica spectrum disorder (NMOSD), and transverse myelitis (TM). There is significant overlap in imaging features between MOGAD, AQP4 NMOSD, and MS, but there are important clinical and imaging features that can help us potentially distinguish them. The following discussion will focus on the clinical (Table 15-1)and imaging features (Table 15-2)that may help distinguish these various clinical entities.

Acute Disseminated Encephalomyelitis

Terminology

ADEM is primarily a postinfection, postimmunization disorder that is also called parainfectious encephalomyelitis. Once considered a purely monophasic illness, recurrent and multiphasic forms (MDEM)of ADEM are now recognized. Approximately 50% of patients with a clinical and imaging diagnosis of ADEM will have anti-MOG antibodies.

Etiology

The immunohistopathologic features of ADEM mimic those of experimental allergic encephalitis, an induced autoimmune disease precipitated by myelin antibodies. Therefore, most investigators consider ADEM an immune-mediated CNS demyelinating disorder.

Pathology

Location

As the name implies, ADEM can involve both the brain and spinal cord. White matter lesions usually predominate, but basal ganglia involvement is seen in nearly 1/2 of all cases. Spinal cord lesions are found in 10-30% of cases. When the spinal cord is involved, it often manifests as longitudinally extensive TM (LETM) with lesions extending > 3 vertebral bodies in length. ON is seen in some patients with ADEM, especially those with MOG antibodies.

A rare ADEM variant, acute infantile bilateral striatal necrosis, occurs 1-2 weeks following a respiratory illness. Viral and streptococcal infections have been implicated and cause enlarged hyperintense basal ganglia, caudate nuclei, and internal/external capsules.

Size and Number

Lesion size varies from a few millimeters to several centimeters (“tumefactive” ADEM), and lesions have a punctate to flocculent configuration. Multiple lesions are more common than solitary lesions.

Gross Pathology

Small lesions are often inapparent on gross examination. Large “tumefactive” lesions cause a gray-pink white matter discoloration and often extend all the way to the cortex-white matter junction (15-19A). Mass effect is minimal compared with lesion size. Gross intralesional hemorrhage is rare and more characteristic of AHLE than ADEM.

Microscopic Features

“Sleeves” of pronounced perivenular demyelination with macrophage-predominant inflammatory infiltrates are typical. The outer margins of ADEM lesions are indistinct compared with the relatively well-delineated edges of MS plaques. Viral inclusion bodies are generally absent, unlike viral encephalitis.

ACUTE DISSEMINATED ENCEPHALOMYELITIS

Etiology and Pathology

Clinical Issues

Clinical Issues

Epidemiology and Demographics

ADEM is second only to MS as the most common acquired idiopathic inflammatory demyelinating disease. Unlike MS, there is no female predominance. ADEM occurs most commonly in spring and autumn.

ADEM can occur at any age but—perhaps because of the frequency of immunizations and antigen exposure—is more common in childhood with peak occurrence between 5-8 years of age. The overall estimated incidence is 0.8 per 100,000 persons annually. The incidence of childhood ADEM is estimated at 2-10 cases per million children per year.

Approximately 50% of patients with a clinical and imaging diagnosis of ADEM will have anti-MOG antibodies. Nearly all ADEM patients with MDEM and those with ON (ADEM-ON) will have anti-MOG antibodies.

Presentation

Symptoms typically occur a few days to a few weeks following antigenic challenge (e.g., infection or vaccination). The majority of children with ADEM have a nonspecific febrile illness preceding onset. Viral exanthema is usually absent.

Natural History

Disease course and outcome vary. Monophasic ADEM is the most common type. However, the disease sometimes follows an atypical course, waxing and waning over a period of several months.

Approximately 25% of patients initially diagnosed with ADEM experience a relapse. Recurrent ADEM is characterized by a second episode occurring within two years after the initial illness and involving the same anatomic area(s) as the original illness. Patients with persistently elevated anti-MOG antibodies on clinical follow-up are more likely to have recurrent demyelinating episodes.

MDEM is characterized by one or more subsequent events that involve a different anatomic area as demonstrated by a new lesion on MR or a new focal neurologic deficit. MDEM is usually associated with MOG antibodies.

More than 1/2 of all patients recover completely within one or two months after onset, whereas ~ 20% experience some residual functional impairment. Overall mortality in recent series is low.

ACUTE DISSEMINATED ENCEPHALOMYELITIS: IMAGING

Brain

Spinal Cord

Imaging

CT Findings

NECT is usually normal. CECT may show multifocal punctate or partial ring-enhancing lesions.

MR Findings

Multifocal hyperintensities on T2/FLAIR are the most common findings and vary from small round/ovoid foci to flocculent “cotton ball” lesions with very hyperintense centers surrounded by slightly less hyperintense areas with “fuzzy” margins (15-22A). Bilateral but asymmetric involvement is typical. Basal ganglia (15-20)and posterior fossa lesions are common.

Enhancement varies from minimal to striking. Punctate, linear, ring, and incomplete horseshoe patterns all occur (15-22B). Large “tumefactive” lesions with horseshoe-shaped enhancement resemble “tumefactive” MS. Leptomeningeal/pial enhancement is often seen, especially in MOGAD (15-21). Cranial nerve enhancement is relatively common. Acute lesions may show restriction on DWI. ON is uncommon at initial presentation but frequently accompanies MDEM (15-23). Involvement of the spine is seen with regular frequency, especially in those ADEM patients with associated MOGAD. Long-segment myelitis is most common (15-24).

Differential Diagnosis

The major differential diagnosis of ADEM is MS. “Tumefactive” lesions—including those with incomplete ring enhancement—occur in both disorders. ADEM is more common in children and often has a history of viral infection or immunization. MS more commonly involves the callososeptal interface and typically has a relapsing-remitting course, whereas most cases of ADEM are monophasic. Spinal lesions, when present, tend to be short segment in MS, whereas, in ADEM, they are more likely to be long segment (> 3 vertebral segments).

NMOSD may be difficult to distinguish from recurrent ADEM. AQP4-positive NMOSD is more likely to involve the area postrema and is more likely to exhibit ependymal and leptomeningeal enhancement. NMOSD is much more common in adults, whereas ADEM is much more common in children.

Although very rare, treatment-associated demyelinating diseases with TNF-α inhibitors, such as etanercept, can mimic ADEM and NMOSD on imaging studies (15-25). Demyelination associated with anti-TNF agents typically develops from one week to 12 months after treatment initiation.

Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica (NMO)is an autoimmune inflammatory demyelinating disease of the CNS. The diagnostic criteria for NMO have recently been broadened and the disease renamed NMOSD.

Etiology

The most common form of NMOSD is an autoimmune-mediated water channelopathy characterized by the presence of autoantibodies to AQP4. AQP4 is located in the foot processes of astrocytes and is the most abundant water channel in the CNS. It is especially highly expressed in the circumventricular organs surrounding the third and fourth ventricles.

A specific biomarker of the disease, AQP4-IgG, is 90% specific and 70-75% sensitive for NMOSD. NMOSD can be AQP4-IgG seropositive or seronegative (less common). Most seronegative NMOSD is positive for MOG antibodies.

Pathology

Location

In classic NMOSD, one or both optic nerves are involved together with the spinal cord (15-26). The cervical cord is most commonly affected. Lesions usually surround the central canal and classically extend over three or more consecutive segments (15-26B).

Brain lesions may occur anywhere (15-27) but frequently cluster around the periependymal surfaces of the ventricles, corpus callosum, cerebral aqueduct, area postrema, and dorsal brainstem (15-28).

Optic nerve lesions are often bilateral, long in extent, and favor the posterior optic nerves and chiasm (15-26A).

Microscopic Features

It is the immunohistochemistry of AQP4-IgG that is diagnostic. AQP4-IgG binds to the abluminal face of microvessels at sites of immune complex deposition. The active demyelination in NMOSD is characterized by astrocytic injury, vessel hyalinization, and eosinophilic infiltration, findings not typically present in either MS or ADEM.

Clinical Issues

Epidemiology and Demographics

NMOSD is a worldwide disease and does not exhibit the characteristic geographic gradient of MS. Patients with NMOSD are, on average, 10 years older than patients with MS. Mean age at initial diagnosis is ~ 40 years. Pediatric-onset NMOSD does occur and represents 3-5% of cases. The F:M ratio for AQP4-positive NMOSD is ~ 3:1.

Between 10-25% of NMOSD patients are seronegative for AQP4. MOG antibodies are found in 15-40% of seronegative NMO. Seronegative NMO is equally distributed among the sexes.

Presentation and Natural History

In adults, NMOSD is classically characterized by severe uni- or bilateral ON and LETM. Involvement of other CNS regions (either by clinical presentation or MR findings) is now recognized as part of the NMOSD spectrum (see box below).

AQP4-seropositive NMOSD patients usually have more severe clinical disease and worse outcome than individuals who are seronegative. The vast majority of cases (85-90%) are relapsing, although monophasic illness may occur.

Almost 30% of NMOSD patients are initially misdiagnosed with MS. Some patients also develop clinical features of anti-N-methyl, D-aspartate receptor (NMDAr) encephalitis.

2015 REVISED NEUROMYELITIS OPTIC SPECTRUM DISORDER DIAGNOSTIC CRITERIA: AQP4-IgG POSITIVITY

AQP4-IgG positivity + 1 core clinical characteristic

2015 NEUROMYELITIS OPTICA SPECTRUM DISORDER CRITERIA: AQP4-IgG NEGATIVITY

If AQP4-IgG negative

Treatment Options

Accurate diagnosis is essential because some drugs used for MS can worsen NMOSD. Recent studies suggest that the therapeutic options in NMO should be immunosuppressive rather than immunomodulatory drugs. Plasma exchange can be used in severe cases.

Imaging

MR imaging has become an essential tool for NMOSD diagnosis, particularly for recognition of AQP4-IgG seronegative patients. Radiologists may be the first to recognize the disease.

The most common MR findings are (1) bilateral, longitudinally extensive optic nerve hyperintensity &/or enhancement consistent with acute ON (15-26)and (2) hyperintense, enhancing LETM (three or more contiguous vertebral segments). So-called short TM occurs in ~ 15% of patients.

The presence of brain lesions varies. Between 30-60% of NMOSD patients have nonspecific T2/FLAIR hyperintensities in the cerebral white matter, so this finding does not exclude the diagnosis per se. However, if lesions are found in areas where AQP4 is highly expressed (e.g., undersurface of the corpus callosum, dorsal brainstem, and periependymal surfaces around the third ventricle) or so-called pencil-thin ependymal enhancement is present, NMOSD should be considered.

Differential Diagnosis

While there are numerous differential diagnoses, the major differential diagnosis of NMOSD is MS in adults and ADEM (usually with MOG antibodies) in children. Bilateral, long-segment optic nerve involvement and LETM are more characteristic of NMOSD. The brain is typically more involved in MS. The presence of a cortical or juxtacortical U-fiber lesion is much more characteristic of MS than NMOSD. AQP4-IgG is almost always negative in MS.

Approximately 15-40% of AQP4-IgG seronegative patients have antibodies to MOG. MOGAD targets oligodendrocytes, not astrocytes, and most commonly presents with ADEM imaging features in children and NMOSD imaging features in adults.

ADEM can have LETM that is identical to NMOSD. “Tumefactive” lesions and gray matter involvement are also more suggestive of ADEM.

Primary CNS vasculitis is often multifocal, frequently “blooms” on T2* SWI, and causes cortical/subcortical and basal ganglia infarcts.

SuS is characterized classically by bilateral sensorineural hearing loss, branch retinal artery occlusions, and subacute encephalopathy. It involves the middle layers of the corpus callosum, not the periependymal surfaces.

Other Autoimmune Disorders

Preamble

In this section, we consider other autoimmune CNS disorders, such as autoimmune encephalitis (AE) and AHLE. SuS—often mistaken for MS—is also considered here.

Autoimmune Encephalitis

AE is a family of closely related disease processes in which an antibody-mediated attack causes a localized CNS inflammatory response. The prevalence and incidence of AE has been underestimated in the past but may be nearly equal to infectious encephalitis.

AEs share overlapping clinical features and imaging findings and are differentiated by specific antibody subtypes. Most—but not all—are characterized by limbic dysfunction and varying involvement of the temporal lobes and neocortex.

In addition to paraneoplastic and non-tumor-associated disorders, the AEs are further subdivided according to the cellular location of their neuronal antigens.

Group I antibodies target intracellular antigens, whereas group II antibodies target cell surface antigens. Group I antibodies are more closely associated with underlying malignancy, although anti-glutamic acid decarboxylase (GAD)disease targets intracellular antigens but is most commonly associated with nonneoplastic conditions, such as type 1 diabetes mellitus.

Terminology

The AEs are differentiated by—and named according to—specific antibody subtypes that cause immune-mediated attacks on the CNS.

AE can be paraneoplastic or nonparaneoplastic. Paraneoplastic-associated disorders, such as anti-Hu and anti-Ma encephalitis, are discussed in Chapter 31. Nonneoplastic AE is discussed here. Because of its unique imaging findings, AQP4 and NMOSD are discussed separately in this section.

Etiology

The major antigens responsible for inciting AE are an ever-expanding group of antibodies that is shown in the box below.

Antibodies against cell surface antigens, such as leucine-rich glioma inactivated 1 (LGI1), are among the most common autoantibodies in patients with nonneoplastic autoimmune-mediated CNS disease.

Another common group of autoimmune disorders are those with ion channel antigens. These include the most common AE, N-methyl, D-aspartate receptor (NMDAR or NMDAr)and γ-aminobutyric acid receptor (GABAr)encephalitis, which has a higher association with malignancies, such as small cell lung cancer, than other group II autoantibodies.

Less common subtypes include anti-glutamate receptor 3 (GluR3)autoantibodies (associated with Rasmussen encephalitis) and voltage-gated calcium channel (VGCC)encephalitis.

NONNEOPLASTIC AUTOIMMUNE ENCEPHALITIS

Group I

• Intracellular antigens

• Often associated with underlying malignancy

• Examples

 Anti-Hu (75% due to small cell lung cancer)

 Anti-Ma (~ 50% due to testicular germ cell tumors)

 Anti-Ri (breast, small cell lung), anti-Yo (ovarian, breast)

 Anti-GAD (usually not associated with malignancy)

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