Autoimmune diseases of the brain, imaging and clinical review

Abstract

There is an extensive spectrum of autoimmune entities that can involve the central nervous system, which has expanded with the emergence of new imaging modalities and several clinicopathologic entities. Clinical presentation is usually non-specific, and imaging has a critical role in the workup of these diseases. Immune-mediated diseases of the brain are not common in daily practice for radiologists and, except for a few of them such as multiple sclerosis, there is a vague understanding about differentiating them from each other based on the radiological findings. In this review, we aim to provide a practical diagnostic approach based on the unique radiological findings for each disease. We hope our diagnostic approach will help radiologists expand their basic understanding of the discussed disease entities and narrow the differential diagnosis in specific clinical scenarios. An understanding of unique imaging features of these disorders, along with laboratory evaluation, may enable clinicians to decrease the need for tissue biopsy.

Introduction

Autoimmune brain diseases are a heterogeneous group of inflammatory disorders that cause brain damage through different pathways. Autoimmune brain damage may be secondary to well-known pathogenic autoantibodies against self-targets such as aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorder (NMOSD) and N-methyl D-aspartate receptors (NMDAr) in autoimmune encephalitis. On the other hand, multiple sclerosis (MS) is thought to be a T-cell-mediated immune disorder without known specific antibodies. Brain involvement can also be a presentation of well-recognized multisystemic autoimmune disorders such as sarcoidosis, systemic lupus erythematosus, and IgG4-related disease. In some diseases, such as acute demyelinating encephalomyelitis (ADEM) or acute hemorrhagic leukoencephalitis (AHLE), brain damage may be secondary to immune system over-activation, sometimes triggered by infections or vaccination, and in paraneoplastic syndromes, brain tissue may be involved due to secondary hormonal and immune-mediated processes without metastasis or malignant invasion. Clinical presentation varies widely, ranging from subtle symptoms to fulminant deterioration of consciousness. Clinical manifestation is determined by the location of brain tissue damage, extension of the lesions, and the type of neuronal cell affected. Early recognition of the underlying cause of the brain autoimmune disease is essential. While most diseases have overlapping and non-specific symptoms, besides lab data, imaging can help in differentiating and characterizing immune-mediated brain lesions in terms of signal change, topography, lesion length and width, gadolinium enhancement pattern, and evolution over time to narrow the broad differential diagnosis of these diseases.

Autoimmune disorders involving the brain are not common and, except for MS, differentiation between entities based on the radiological findings is a challenge for radiologists and usually the reports include a wide range of differential diagnoses. In this paper, we aim to provide a practical diagnostic approach based on the common radiological findings of the immune-mediated diseases involving the brain that can be used by most radiologists (Table 1). Our goal is to give a basic understanding to the readers about the distinguishing imaging findings and clinical presentations of immune-mediated diseases of the brain.

Demyelinating diseases

MS

MS is the prototypical inflammatory autoimmune disorder of the central nervous system (CNS) in young to middle-aged adults leading to long-term disability, with most patients presenting with periodic neurological relapses. ¹ The onset of MS usually occurs in young adulthood, between 20 and 40 years of age, and women are two to three times more frequently affected than men. ² North America and Europe have the highest prevalence (with 140 and 108 per 100,000, respectively), and Asia and sub-Saharan Africa countries have the lowest prevalence (2.2 and 2.1 per 100,000, respectively). ³

Common neurological manifestations of MS include optic neuritis, diplopia, sensory loss, limb weakness, gait ataxia, loss of bladder control, and cognitive dysfunction. ⁴ There are different clinical courses for MS, including clinically isolated syndrome (CIS), relapsing-remitting (RR) MS, progressive MS, and radiologically isolated syndrome (RIS). ⁵ CIS includes isolated events of symptomatic neurological disturbance lasting more than 24 h, without imaging findings to indicate demyelination of the CNS. ⁶ Progressive MS can be primary progressive, or secondary progressive (SP) after initial RR. ⁵ RIS refers to an entity in which white matter lesions fulfilling the criteria for MS occur in individuals without a history of a clinical demyelinating attack or alternative etiology. ⁷

The core diagnostic concept in MS is dissemination of demyelinating lesions in space (DIS) and time (DIT). Since the first introduction of McDonald criteria in 2001, it has been revised several times to increase sensitivity for earlier diagnosis and treatment of MS resulting in improved patient outcomes. ⁸ According to 2017 revised McDonald criteria, DIS is defined as the presence of at least one lesion in at least two out of four CNS areas including periventricular (lesions ≥3 mm) (Figure 1(b) and 1(c)), cortical, or juxtacortical (Figure 1(a)), infratentorial, and spinal cord.

Figure 1.

MS.

Axial T2-weighted images show well-circumscribed, ovoid juxtacortical (a) and deep white matter lesions (b) in a patient with MS. Enhancing periventricular lesions in axial post-Gd T1 weighted image (c) indicative of active demyelination. Axial T2 weighted (d), fluid-attenuated inversion recovery (e), and diffusion-weighted imaging (f) show periventricular ovoid lesion without mass effect, with peripheral restricted diffusion in tumefactive MS. Coronal post-Gd T1 weighted image (g) of the same patient shows incomplete rim enhancement. Axial T2-weighted image (h) shows concentric rings of T2 isointensity and hyperintensity related to alternating layers of myelinated and demyelinated brain tissue in Balo Concentric Sclerosis.

MS: Multiple sclerosis

On MRI, new T2 or Gd-enhancing lesions or simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions at any time fulfill DIT. ⁹ 3D FLAIR sequences have higher sensitivity compared with 2D FLAIR for detecting MS plaques. ¹⁰ Pathological studies have shown that MS lesions develop around small veins and venules. Central vein sign (CVS) is also seen in non-MS conditions, although with a lower percentage of association. ¹¹ Optimized susceptibility-weighted angiography (SWAN) and T2* protocols can detect CVS in more than 80% of MS lesions, ¹¹ but this feature is also seen in 45% of small-vessel disease lesions, ¹² 22% in migraine ¹³ and 32% in NMOSD. ¹⁴ While conventional MRI sequences are highly effective in detecting focal macroscopic brain tissue abnormalities, they may not correlate well with patients’ neurologic deficits.^15,16 Correlations between a patient’s clinical status and white matter (WM) lesion load remain modest; however, there is a stronger correlation between GM lesions, especially cortical lesions (CLs), and disease burden and brain atrophy. CLs are more difficult to visualize than WM lesions because of the lower myelin content in the cortex. Consequently, the change in myelin-related signal in CLs is smaller. CLs also generally exhibit less inflammation than WM lesions leading to limited alteration of T1 and T2 compared with WM. ¹⁷ Differential diagnoses of MS are summarized in Table 2.

Table 2.

Imaging differential diagnosis for MS

Entity	Distinguishing clinical feature	Distinguishing imaging feature	Important key to diagnosis
Migraines	Headache or aura predominates	Predominantly subcortical white matter lesions that are small, <3 mm, and do not enhance, few periventricular lesions [131]¥	Headache Lack of typical imaging features consistent with MS
Age-related small-vessel disease	Patient’s age Cardiovascular risk factors (HTN)	Small, <3 mm, non-enhancing lesions in periventricular and deep white matterSparing subcortical U-fibersSymmetrical caps lining the frontal horns of the lateral ventricles 132 Coexistent lacunar disease ± microhemorrhage	AgeLacunar disease and atypical white matter lesions for MSNo spinal cord lesions
NMOSD	Female to male ratio 9:1 in AQP4-Ab Bilateral ONCharacteristic clinical presentationHiccups, vomiting, and endocrine symptoms	Long segment optic nerve lesion ± optic chiasm involvement LETMBrain lesions in diencephalon, dorsal midbrain, or periependymal regionsCloud-like enhancementLess common brain atrophy and cortical lesions compared with MS 133	Serology, + AQP4-Ab and + MOG AbAtypical WM lesions for MS Long segment ON ± optic chiasm involvementLETM
ADEM	Acute presentationChildren > AdultPost viral infection, post vaccinationSpontaneous resolution and good outcome in most patients	Ovoid, (> 1-2 cm) lesions with blurred margins with bilateral asymmetric distribution 50% periventricular WM distribution of the lesions versus >90% distribution in MS 134 Gray matter disease predominates compared with MSSimultaneous enhancement 7 Lack of T1 black hole 135	History of prodromal virus infection or vaccinationNegative OCB in CSF
SLE	Clinical symptoms of a systemic disorder Early cognitive impairment 136	Normal neuroimaging in initial stages, then progressive confluent white matter lesionsMultiple ischemic lesions not restricted to any single vascular territoryIntra-parenchymal hematomas or micro hemorrhageLeptomeningeal enhancement	Presence of serologic autoantibodies/ inflammatory markers, ESRTissue or brain biopsyRestricted diffusion in DWIMicrohemorrhage in SWAN + OCB in MS
Susac syndrome	Encephalopathy, visual loss, deafness 41 ∞	“Snowball”, icicle and spoke lesions in the corpus callosumLeptomeningeal enhancement	AudiometryRetinal fluorescein angiographyCharacteristic brain imaging
Neuro- Behçet disease NBD	MS: female dominant, NBD: male dominantMS commonly presents with ON, sensory symptoms, cerebellar symptoms, ataxia, dysarthria while headache, and early cognitive changes common in NBDSpecial geographic distribution of NBD	Location of parenchymal lesions of NBD in the brain stem and pons and less common periventricular lesionsBrain stem atrophy in NBDLess spinal cord involvement in NBD	+ OCB in MSNeutrophils predominate CSF pleocytosis in NBD and lymphocyte predominate in MS 137 HLA typing and pathegy test
Hashimoto encephalopathy	Elevated antithyroid antibodiesClinical presentation different from MS	Normal MRI in 50% of casesNon-enhancing, non-specific WM lesions with no periventricular distribution	Clinical presentation and elevated antithyroid antibodiesImaging features not typical for MS
CADASIL	Chronic presentationHistory of stroke-like symptoms and cognitive declineFamily history of similar clinical syndrome	Confluent non-enhancing white matter changes involving the centrum semiovale/corona radiate, external capsule and anterior temporal lobesMicrohemorrhageLacunar infarcts and brain atrophy	Clinical presentationImaging findings Skin biopsy (genetic testing)

¥: The presence of at least three periventricular lesions has a strong value for conversion to MS. ¹³¹

∞: The complete triad is present in only 13% of patients at disease onset. ⁴¹

Note: NMOSD=neuromyelitis optica spectrum disorder, ADEM=Acute demyelinating encephalomyelitis, WM=white matter, ESR=erythrocyte sedimentation rate, CADASIL=Cerebral autosomal dominant arteriopathy with subacute infarct and leukoencephalopathy, OCB=Oligoclonal band, ON= optic neuritis, SLE= Systemic lupus erythematosus.

Table 1.

Diagnostic approach to the autoimmune diseases of the brain

Diagnostic approach to the autoimmune disease of the brain
I. Demyelinating diseases	MSAcute demyelinating encephalomyelitis (ADEM) Acute hemorrhagic leukoencephalitis (AHLE)Neuro myelitis optica spectrum disorder (NMOSD) and MOG-associated diseaseSusac syndrome (Demyelination mimic)
II. Predominantly parenchymal non- demyelinating diseases	Autoimmune encephalitis Hemophagocytic lymphohistiocytosisRasmussen’s encephalitisHypophysitis (lymphocytic and non-lymphocytic)Hashimoto meningoencephalitisSystemic lupus erythematosus (SLE)
III. Predominantly meningeal-involving diseases	SarcoidosisRheumatoid arthritisIgG4-related diseaseGranulomatosis with polyangiitis (wegner)
IV. Brain stem and posterior fossa	Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) Bickerstaff’s brainstem encephalitisParaneoplastic cerebellar degenerationBehçet disease

MS variants

Tumefactive demyelinating lesion (TDL) refers to a larger demyelinating lesion (>2 cm) which can mimic the appearance of a tumor. TDLs are commonly located in the cerebral hemispheric WM, especially the frontal and parietal lobes, but can be found elsewhere in the CNS including GM. TDLs typically have less mass effect than expected for brain tumors, and most often have a peripheral discontinuous enhancement (Figure 1(d), 1(e), 1(g)). ¹⁸ Other imaging features include peripheral restriction on diffusion-weighted images (DWI) (Figure 1(f)) and decreased relative cerebral blood volume in perfusion study. ¹⁹ Rare variants of MS include Balo’s concentric sclerosis (BCS), Marburg variant MS (MvMS), and Schilder’s disease. ¹⁸ BCS is characterized radiologically by T2 WI alternating isointense and hyperintense rings in T2 weighted images (Figure 1(h)). MvMS is a rare monophasic MS variant, distinguished by its relentlessly progressive clinical course with death within one year. On imaging, multiple confluent T2/FLAIR hyperintensities are present that are edematous and may enhance. Brain stem involvement is described in most cases and contributes to the mortality. ²⁰ Schilder’s disease is a very rare MS variant, primarily affecting children with atypical clinical presentation and CSF analysis for MS. There is no fever or recent infection/vaccination. On imaging, there are one or two bilateral symmetrical plaques involving centrum semiovale and with dimensions of at least 3 × 2 cm. ¹⁸

Acute demyelinating encephalomyelitis

ADEM is second only to MS as the most common idiopathic inflammatory demyelinating disease with a male to female ratio ranging from 1:0.8 to 2.3:1. ²¹ ADEM is probably post-infectious, including COVID-19, ²² or post-immunization encephalomyelitis, and is more common in children than in adults. ²³ Clinical manifestations include encephalopathy (unexplained by fever), polyfocal neurological signs and symptoms (e.g. ataxia, limb weakness, sensory changes, visual loss, cranial nerve impairment, or speech dysfunction), and seizure. ²⁴ Disease course varies from monophasic ADEM in >70% of patients, second episode in the same site of the brain in 10%, and multiple episodes in different sites in 10% of patients. ²⁵ The first demyelinating event might also represent the first manifestation of a chronic demyelinating relapsing disease, such as MS, NMOSD, or myelin oligodendrocyte glycoprotein associated disease (MOGAD). ²¹

Characteristic MRI features include bilateral but asymmetric, diffuse, large (>1–2 cm) FLAIR and T2-hyperintensities with indistinct borders that predominately involve the cerebral white matter of the brain (Figure 2(a-c)) and spine. Involvement of the basal ganglia and posterior fossa lesions is common. ²⁵ Various patterns of Gd enhancement (nodular, diffuse, a complete ring, or a partial ring) are seen in 30% of lesions. ²¹ Multifocal TDLs are seen in ADEM. ²⁶ Differential diagnosis of ADEM includes MS, viral encephalitis, collagen vascular diseases, Whipple disease, Behçet disease, and neurosarcoidosis. ²⁷

Figure 2.

Other demyelinating diseases.

Axial T2-weighted (a) and FLAIR (b) images demonstrate several cortical and deep white matter hyperintense lesions in a patient with ADEM. Axial post-Gd T1 weighted image (c) shows peripheral interrupted enhancement in the largest lesion in the right frontal lobe. Sagittal FLAIR (d) shows a typical “snowball” lesion (arrow) in the corpus callosum in a patient with Susac syndrome, which is not a true demyelination, but considered in the differential diagnosis of MS. Axial FLAIR (e) shows extensive confluent white matter hyperintensities, with faint peripheral enhancement in axial post-Gd T1 weighted image (f) in a patient with acute hemorrhagic leukoencephalopathy. Axial FLAIR (g) shows extensive and irregular periventricular hyperintense lesions along the ependymal lining. Axial post-Gd T1 weighted image (h) shows patchy enhancement with blurred margins, typical ‘cloud-like’ enhancement in NMOSD.

ADEM: acute demyelinating encephalomyelitis; MS: multiple sclerosis; NMOSD: neuromyelitis optica spectrum disorder

Acute hemorrhagic leukoencephalitis

AHLE or Hurst disease is a rare, hyper-acute variant of ADEM (nearly 2% of ADEM) with mostly fatal outcomes, in which the involved regions of the brain undergo hemorrhagic necrosis. Because of differences in pathology (increased neutrophils, small-vessel destruction with fibrin deposition, and hemorrhage), it has been discussed as a separate entity from ADEM. ²³ There is association with herpes simplex, influenza A, varicella-zoster, human herpesvirus 6, and Epstein-Barr virus infections, although the inciting infection is often not identified.^28–30 Progressive neurological deficits dominate the clinical picture. ³⁰

On imaging, there are multiple, confluent, large unilateral or bilateral hemorrhagic lesions of the cerebral WM, most commonly involving the frontal and parietal lobes (Figure 2(e-f)). The basal ganglia, thalami, brain stem, cerebellum, and spinal cord may be involved. Overall, the lesions are similar to those in ADEM except that the lesions are larger and hemorrhagic and have more associated edema and mass effect. ³¹ T2*sequence and susceptibility-weighted images are key sequences for the diagnosis. Major differential diagnoses are MvMS and acute necrotizing encephalopathy. Lack of fever, leukocytosis, and hemorrhagic foci in MRI differentiates MvMS from AHLE. ²⁰ Acute necrotizing encephalopathy is strikingly characterized by symmetric hemorrhagic necrosis of the thalami, midbrain, and pons. ³²

Neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated disease

Aquaporin-4 antibodies (AQP4-Ab) target the AQP4 water channels situated on astrocyte end foot processes and cause a primary astrocytopathy with secondary demyelination and the clinical phenotype of NMOSD. ³³ Myelin oligodendrocyte glycoprotein (MOG) is a molecule on the outer membrane of myelin sheaths and is expressed primarily within the brain, spinal cord, and optic nerves. It is a target for autoimmune antibodies and cell-mediated responses in demyelinating processes causing MOG-associated disease (MOGAD). ³⁴ Core clinical characteristics of both diseases include optic neuritis (ON), longitudinally extensive transverse myelitis (LETM), area postrema syndrome (intractable vomiting/hiccups), and acute brain stem syndrome due to periependymal brain stem lesions. ³⁵ Although there is clinical overlap, the underlying pathogenesis for each is unique, causing important phenotype differences. In NMOSD, more than 90% of patients are female and they are older patients compared with MOGAD. In NMOSD patients, acute myelitis is the most common neurological episode, and they show more severe neurological disability and relapses.^35–37 MOGAD has a milder degree of neurological disability with better prognosis with equal female to male ratio and ON is the most common presentation in adult patients with MOGAD. ³⁵

Brain MRI shows deep and subcortical WM lesions in nearly 50% of patients with NMOSD. ³⁴ These lesions are typically extensive with irregular and indistinct borders. Irregular periventricular lesions following the ependymal lining in a disseminated pattern, patchy enhancement with blurred margins, typical “cloud-like enhancement” (Figure 2(g) and 2(h)), and diencephalic lesions in bilateral hypothalamus are other MRI findings in NMOSD. ³⁸ Characteristic MRI features of ON in MOGAD include anterior optic pathway lesions with distinct optic nerve head swelling and injury of the retrobulbar nerve segment. Usually, the optic chiasm and the optic tract are spared. In turn, most NMOSD patients with ON have a posterior optic pathway and intracranial portion of the optic nerve and chiasm involved.^36,39 LETM involving ≥3 vertebral segments helps to differentiate NMOSD from lesions of MS. ⁴⁰ Involvement of the medullary conus is believed to be highly specific for MOGAD. ³⁴ Differentiation between NMOSD and MS is critically important because the treatment of each disease is distinct. For instance, disease-modifying drugs for MS, such as interferon-beta, may aggravate NMOSD. ³⁵

Susac syndrome (Sus) – Demyelination mimic

Sus is an autoimmune-mediated microangiopathy characterized by the clinical triad of retinal artery occlusion, subacute encephalopathy, and sensorineural hearing loss, although the complete triad is present in only 13% of patients at disease onset. ⁴¹ It is not a true demyelinating disease, but because of similar imaging findings to demyelinating disease, it is usually mistaken for MS. Sus typically presents in young women with a headache. ⁴²

On imaging, there are T2/FLAIR hyperintense (Figure 2(d)) and punched-out T1 hypointense lesions in the middle layer of the corpus callosum with sparing callososeptal interface, that is usually involved by MS. There are also T2/FLAIR multiple periventricular and deep white matter hyperintensities. Acute lesions show punctate enhancement. ⁴³ Leptomeningeal enhancement occurs frequently in Sus and could be helpful for diagnosis and in predicting clinical relapses. ⁴⁴ Major differential diagnoses are MS, ADEM, and vasculitis.

Predominantly parenchymal non-demyelinating diseases

Autoimmune encephalitis “N-methyl D-aspartate receptor (NMDAr)”

Autoimmune encephalitis refers to a family of disease processes that share overlapping clinical features and neuroimaging findings but are ultimately differentiated by the specific antibody subtypes driving the underlying immune-mediated attack on different CNS structures. ⁴⁵ Autoimmune encephalitis can be classified into two broad categories. The first group includes the classic paraneoplastic disorders associated with antibodies to intracellular antigens, such as anti-Hu. These antibodies are not directly pathogenic and involve cytotoxic T-cell responses targeting neurons. These disorders are strongly cancer associated with poor prognosis due to irreversible neuronal damage. The second group involves directly pathogenic autoantibodies to extracellular epitopes of ion channels and receptors such as the NMDA receptor, causing reversible effects on synaptic function in neurons with relatively little neuronal death, the cancer association is variable, and the prognosis tends to be much better. ⁴⁶ Anti-NMDAR encephalitis is the most frequent form of autoimmune encephalitis, classically seen in young women and children.^46,47

NMDAr encephalitis has a well-characterized progression of features characterized by an initial viral-like prodrome (fever, malaise, headaches, and anorexia), followed by psychiatric symptoms (anxiety, depression, schizophrenia, and psychosis), which progresses to include temporal lobe dysfunction (amnesia and seizures) and ultimately culminates in severe neurological deficits, including autonomic dysfunction, dystonia/dyskinesia, and profound encephalopathy. ⁴⁷ One unique feature of the NMDAr encephalitis subtype is that it is unlikely to have associated neuroimaging abnormalities on initial presentation (89%) or follow-up MRI of the brain (79%). ⁴⁸ Regardless of the etiology and antibody profile, there is a clear predilection in autoimmune encephalitis for antigens within the limbic system. ⁴⁹ In a minority of patients with positive MRI findings, variable sites of T2/FLAIR hyperintensities are seen, especially in medial temporal lobes (Figure 3(a)) with mild transient cortical enhancement without restricted diffusion or hemorrhage.^48,49 Other less frequent MRI findings include diffuse, poorly demarcated, large (>1–2 cm) lesions predominantly involving the cerebral WM, and deep GM abnormalities (thalamus or basal ganglia) (Figure 3(b)). ⁵⁰ In clinically suspicious cases with normal brain MRI, an FDG-PET CT scan is more sensitive for detection of temporal lobe abnormalities. ⁴⁷ Differential diagnosis includes other autoimmune diseases such as ADEM, MS, SLE, vasculitis, herpes encephalitis, underlying malignancy, nutritional deficiency (thiamin), and venous sinus thrombosis. ⁴⁶

Figure 3.

Predominantly parenchymal (non-demyelinating) involvement.

(a, b) Axial FLAIR images demonstrate hyperintensity in bilateral mesial temporal lobes and basal ganglia, in a patient presented with seizure, and subsequently, the presence of anti–N-Methyl-D-aspartate receptor autoantibodies was confirmed. Axial FLAIR (c) and GRE (d) images demonstrate extensive confluent white matter hyperintensities with central linear susceptibility changes due to hemorrhage in a patient diagnosed with hemophagocytic lymphohistiocytosis. Axial T2-weighted (e) image shows subcortical brain edema involving right insular and periinsular regions in acute phase of Rasmussen encephalitis. Axial T2-weighted (f) image from another patient with chronic Rasmussen encephalitis demonstrates right frontal lobe atrophy and loss of parenchymal high signal change. Sagittal post-Gd T1 weighted image (g) shows thickening and enhancement of pituitary stalk as well as enlarged enhancing pituitary gland in lymphocytic hypophysitis. Axial FLAIR (h) image demonstrates subcortical and white matter hyperintensities in the left frontal lobe in a patient with Hashimoto’s meningoencephalitis. Post-Gd T1 weighted image (i) shows faint marginal enhancement in the left frontal lesion (arrow).

Hemophagocytic lymphohistiocytosis (HLH)

HLH is a rare and life-threatening syndrome in which an uncontrolled and ineffective immune response leads to severe hyperinflammation ⁵¹ and nonmalignant diffuse infiltration of multiple organs, including CNS, by lymphocytes and histiocytes. ⁵² Primary HLH is due to genetic defects and exhibits autosomal recessive modes of inheritance leading to impaired function of natural killer cells and cytotoxic T cells. It mainly affects children, but it is also increasingly found in adolescents and adults. ⁵³ Secondary HLH occurs in the setting of an infection, an underlying rheumatologic disorder, or malignancy. ⁵⁴ Clinical presentations include unremitting fever, hepatosplenomegaly, cytopenia, hyperfibrinogenemia, elevated ferritin, triglycerides, and liver enzymes. Approximately 30% of patients show neurological manifestations including irritability, bulging fontanelle, seizures, alterations of the level of consciousness, and encephalopathy. ⁵⁵

MRI findings include extensive confluent T2/FLAIR hyperintense infiltrates in the cerebral (Figure 3(c) and 3(d)) and cerebellar white matter, diffuse leptomeningeal, and perivascular enhancement which corresponds to meningeal and perivascular infiltrations of histiocytes and lymphocytes, and a diffuse parenchymal volume loss. In several studies, symmetrical bilateral involvement of putamen is supportive of the CNS-HLH.^55,56

Rasmussen’s encephalitis (RE)

RE is a rare, progressive, and chronic encephalitis characterized by drug-resistant epilepsy, progressive hemiparesis, and mental impairment. It typically involves only one cerebral hemisphere, which becomes atrophic over time. ⁵⁷ Although a viral etiology was once proposed, no infectious pathogen has been linked to Rasmussen encephalitis. ⁵⁸ Favorable response to plasmapheresis and intravenous immunoglobulin (IVIG) supports an immune etiology, likely T-lymphocytes, in the pathogenesis of the disease, but the precise pathogenesis of RE remains unknown. The disorder affects mostly children or young adults. ⁵⁸ Clinical presentations can be subdivided into a prodromal stage with non-specific, low frequency seizure, and mild hemiplegia; an acute stage with frequent seizures, progressive hemiparesis; and finally, a residual stage with permanent and stable neurological deficits and continuing seizures. ⁵⁹

MRI shows initial swelling and high signal on T2/FLAIR in cortical or subcortical regions of the affected hemisphere (Figure 3(e)), and the insular and periinsular regions are the most affected cortical regions of signal change.^58,60 With time, severe atrophy and disappearance of abnormal signal in the affected parts of the brain develop (Figure 3(f)). ⁶⁰ Basal ganglia (caudate and putamen) atrophy is frequently seen in chronic stages. ⁶⁰

Differential diagnosis includes unilateral megalocephaly, cortical dysplasia, and Sturge-Weber syndrome. ⁵⁷

Hypophysitis (lymphocytic and non-lymphocytic)

Hypophysitis is a rare condition characterized by inflammation of the pituitary gland, usually resulting in hypopituitarism and pituitary enlargement. Pituitary inflammation can occur as a primary hypophysitis (most commonly lymphocytic, granulomatous, or xanthomatous disease) or as secondary hypophysitis (as a result of systemic diseases, immunotherapy, or alternative sella-based pathologies). ⁶¹ Lymphocytic hypophysitis (LH) is a rare disease of presumed autoimmune etiology, characterized by lymphocytic infiltration of the pituitary gland followed by fibrosis. LH is more likely to affect women, especially around pregnancy. ⁶² Recent recognition of IgG4-related disease (IgG4-RD) and the introduction of immune checkpoint inhibitors, as cancer therapies with endocrine adverse effects, has increased interest in inflammatory disorders affecting the pituitary gland.^61,63 By contrast with LH, IgG4-related hypophysitis generally presents at the seventh decade of life (mean age 62 years) and is associated with a 3·6:1 male predominance. Clinically, the patients usually present with headache, visual field defect, endocrine manifestations such as anterior pituitary hormone deficiencies, diabetes insipidus, and abnormal serum prolactin. ⁶⁴ The prevalence of anterior pituitary hormone deficiency in LH (31%) is less than IgG4-RD (63%). ⁶⁵

On imaging, there is intense and uniform enhancement of the symmetrically enlarged pituitary gland and thickened and non-tapering infundibulum (Figure 3(g)). Loss of the normal posterior pituitary gland and stalk T1 precontrast hyperintensity has also been observed. ⁶⁶ IgG4–RD hypophysitis is characteristically hypointense in T2 weighted images with similar homogenous enhancement. ⁶⁷ Differential diagnosis includes IgG4-RD, sarcoidosis, granulomatosis with polyangiitis, Langerhans cell histiocytosis, syphilis, and tuberculosis. ⁶⁷

Hashimoto meningoencephalitis (HE)

HE, also known as steroid-responsive encephalopathy, is associated with autoimmune thyroiditis and presents with encephalopathy and elevations in antithyroid antibodies without brain tumor, stroke, or infection of the CNS. ⁶⁸ Although it is a rare disorder with an estimated prevalence of 2/100,000, the fact that it is treatable makes it an important consideration in the approach to patients presenting with subacute encephalopathy. ⁶⁸ Patients are predominantly female and in their 5–6th decades of life, and the reported gender ratio of this disease is 4.1 in favor of women. ⁶⁹ HE presents with a wide variety of symptoms that include behavioral changes, confusion, cognitive decline, stroke-like episodes, amnestic syndrome, ataxia, seizures, myoclonus, and psychiatric manifestations. ⁷⁰

MRI is normal in approximately 50% of patients with HE. ⁷¹ In the remaining patients, the most common findings include non-specific T2-weighted and FLAIR image changes within the subcortical white matter (Figure 3(h–i)), generalized cerebral atrophy, bilateral hippocampal lesions, and dural enhancement. ⁷² Cerebellar T2 hyperintense lesions or atrophy are rarely seen. ⁷¹ Occipital lobes are relatively spared. HE brain lesions usually do not enhance following contrast administration. ⁷² Differential diagnosis includes infectious or autoimmune encephalitis, vasculitis, MS, and prion disease. ⁷⁰

Systemic lupus erythematosus

SLE is a chronic systemic inflammatory disease of autoimmune origin affecting 0.1% of the general population. ⁷³ Neuropsychiatric SLE (NPSLE) manifestations occur in up to 75% of patients during the disease course and are responsible for increased morbidity and mortality. ⁸⁷ The basic pathogenesis of NPSLE includes inflammation and ischemia. ⁷⁵ Vasculitis and antiphospholipid antibodies contribute to vasculopathy and thrombosis with subsequent multifocal small and large brain infarcts.^75,76 Lupus cerebritis is an example of autoimmune encephalitis in which precise antigens are less clearly established; ⁴⁶ however, some studies contribute NMDAr antibodies in the pathogenesis of lupus cerebritis. ⁷⁷ Secondary demyelination (rare 1.3%) is another suspected pathogenesis of NPSLE.^78,79 Clinically, NPSLE is heterogeneous and may vary from subtle signs, such as headache and mood disorders, to life-threatening conditions, such as stroke, myelopathy, and acute confusional state. ⁷³

On imaging, around 50% of NPSLE patients have no brain abnormalities on conventional MRI. Small subcortical and deep WM hyperintensities or confluent WM lesions (Figure 4(a), 4(d), 4(e)) are the most common types of small-vessel disease observed in SLE patients. These lesions are believed to represent either autoimmune cerebritis/myelitis or parenchymal edema and injury secondary to small-vessel vasculitis. ⁷³ Gd enhancement may be present in the subacute phase (Figure 4(b)). Subcortical white matter abnormalities may be secondary to recent episodes of hypertension or seizures, both common in SLE, with consequent disturbance of the blood-brain barrier.^79–81 Most commonly, these abnormalities are bilateral, symmetrical, and paramedian, involve the cortex and subcortical white matter, and are more prevalent in the posterior aspect of the brain (occipital, parietal lobes more than frontal lobes). ⁸² Another common finding in SLE is diffuse or regional brain atrophy. ⁷³ Hippocampal and corpus callosum atrophy are both associated with disease duration and long-term corticosteroid use.^77,83 Hippocampal atrophy is specifically associated with NMDAr antibodies. ⁷⁷ Up to 15% of NPSLE patients have large vessel infarcts with restricted diffusion in DWI (Figure 4(c)). ⁸⁴ Differential diagnosis includes arteriolosclerosis (“small-vessel disease”), MS, Susac syndrome, non-lupus antiphospholipid syndromes, Lyme disease, and other vasculitis such as primary angiitis of the CNS. ⁷⁵

Figure 4.

Predominantly parenchymal (non-demyelinating) involvement (continued).

(a) Axial FLAIR image shows scattered hyperintense foci in the subcortical area and bilateral basal ganglia with patchy areas of enhancement in axial post-Gd T1 weighted image (b) and a focus of restricted diffusion in the corpus callosum in DWI (c) (several other foci of restricted diffusion, not shown) representing acute cerebritis/vasculitis in SLE. Axial FLAIR images (d, e) from another patient with SLE show diffuse fulminant edema in bilateral centrum semiovale and cerebellar white matter.

DWI: diffusion-weighted images; SLE: systemic lupus erythematosus

Predominantly meningeal-based diseases

Sarcoidosis

Sarcoidosis is an autoimmune disorder of unknown etiology in which granulomatous inflammation develops in numerous organs. It has much higher prevalence among African-Americans, and females across all races and ethnic groups. ⁸⁵ Central nervous system involvement occurs in approximately 5% of sarcoidosis, Neurosarcoidosis (NS). ⁸⁶ Among patients with NS, cranial nerves (CN) are the most commonly involved nervous system structure (70%), followed by meningeal involvement (up to 40%), and brain parenchymal (10%) involvement.^85–87 Clinical presentation of NS depends on the area of involvement. CN palsy (most commonly CN II, VII, and VIII) is the commonest presentation.^87,88 Although CN VII has been reported as the most commonly involved CN clinically, the optic nerve and sheath have been reported to be the most commonly involved nerve radiologically. ⁸⁹ Meningeal involvement clinically presents with headache secondary to hydrocephalus or aseptic meningitis. ⁸⁷

Imaging findings include cranial nerve enhancement associated with thickening and enhancement of the basal leptomeninges (Figure 5(c and d)). Both diffuse and nodular patterns of enhancement have been observed. Signal intensity on T2 depends on the amount of fibrocollagenous material present. Longstanding dural lesions are relatively hypointense (Figure 5 (a and b)). ⁸⁵ Multifocal white matter changes or parenchymal involvement in NS have a predilection for the hypothalamus, brainstem, and pituitary gland. ⁹⁰ Adjacent leptomeningeal involvement is often seen with enhancing lesions and may represent the spread of leptomeningeal disease along the perivascular spaces. ⁹¹ Parenchymal lesions may be dark on T2-weighted MRI, similar to densely cellular metastatic or lymphomatous lesions. In addition, T2-hyperintense but non-contrast-enhancing parenchymal gray matter lesions have been reported in NS.^88,89 Longitudinally extensive myelitis with predominantly dorsal subpial ± meningeal enhancement was the most common imaging finding in spinal sarcoidosis. ⁹² Differential diagnosis of dural involvement includes calcified meningioma, lymphoma, dural metastases, granulomatosis with polyangiitis, IgG-4 related disease, Rosai-Dorfman disease, Erdheim-Chester disease, intracranial hypotension, and idiopathic pachymeningitis.

Figure 5.

Predominantly meningeal-involving diseases.

(a) Axial T2 weighted image reveals nodular T2 hypointense dural thickening and adjacent brain parenchymal edema in neurosarcoidosis. (b) Post-Gd T1 weighted image shows corresponding dural enhancement. (c) Axial FLAIR image in another patient with neurosarcoidosis shows leptomeningeal thickening, adjacent brain parenchymal edema and leptomeningeal enhancement in post-Gd T1 weighted image (d). (e) Coronal post-Gd T1 weighted image shows lepto and pachymeningeal enhancement in rheumatoid arthritis. (f) Coronal post-Gd T1 weighted image shows mostly leptomeningeal enhancement in IgG4-related disease. Granulomatosis with polyangiitis evidenced by hyperdense right tentorial thickening in non-contrast CT scan (g) and corresponding T2 hypointense right tentorial thickening in axial T2 weighted image (h). Axial and coronal post-Gd T1 weighted images (I, J) of the same patient show enhancement of bilateral tentorial leaflets.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune arthritis characterized by peripheral joint involvement and systemic inflammation. Its worldwide prevalence is about 0.5–1%, and middle-aged women are mainly affected. Serum levels of rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) IgG antibody can confirm the diagnosis of RA. ⁹³ Peripheral neuropathy and cervical spinal cord compression due to subluxation of cervical vertebrae are the most frequent neurological manifestations of RA. ⁹⁴ CNS involvement is quite unusual and occurs in longstanding seropositive RA. ⁹⁵ CNS involvement of RA can be broadly divided into two groups: rheumatoid meningitis and rheumatoid vasculitis. Clinical presentation of the former group includes aseptic meningitis, cranial neuropathy, hydrocephalus, headache, and sinus thrombosis. Rheumatoid vasculitis presents with seizure, confusion, and stroke.^93,94 On imaging, the most common MRI finding of CNS RA is meningeal enhancement (Figure 5(e)). ⁹⁶ MRI findings of RA vasculitis include multiple bilateral ischemic lesions often involving cortical and subcortical regions or focal cortical atrophy. ⁹⁷

IgG4-related disease

IgG4-RD is an autoimmune multisystem disease, mainly involving the pancreas, biliary tract, and kidneys, but all organs can be involved. It typically progresses over long periods of time and is slightly male dominant. It is usually responsive to steroid therapy.^66,98 The principal neurological manifestations result from orbital disease, pachymeningitis, pituitary gland, and stalk involvement, but cranial nerve and parenchymal brain involvement has also been reported. ⁶⁷ The neurological manifestations of IgG4-RD depend on the area of nervous system involvement, and frequently mimic malignancy, infection, and other inflammatory diseases. IgG4-related pachymeningitis presents with headache, adjacent CN palsy, and hydrocephalus. IgG4-related hypophysitis presents with panhypophysitis and diabetes insipidus.^66,67,99

On imaging, IgG4-related pachymeningitis typically induces a homogeneous hypertrophic and nodular pattern of meningeal thickening. Non-contrast MRI studies reveal these lesions to be hypointense or isointense relative to the brain parenchyma on T1-weighted and T2-weighted imaging. It should be considered in cases with unexplained hypertrophic or nodular pachymeningeal disease. ⁹⁹ Both CT and MRI imaging modalities show homogeneous enhancement on post-contrast studies (Figure 5(f)). ⁶⁷ Intralesional calcification and bone destruction are atypical. ⁹⁸ IgG4-related hypophysitis shows an enlarged pituitary gland or thickened stalk with hypointense T2 characteristics that enhance homogenously with gadolinium. ⁶⁷ Orbital involvement, ¹⁰⁰ peripheral neuropathy, and brain parenchymal involvement are other forms of IgG4-RD nervous system involvement.^67,101 Differential diagnosis of IgG4- related pachymeningitis and hypophysitis ⁶⁷ is similar to sarcoidosis and LH that was discussed earlier.

Granulomatosis with polyangiitis (GPA)

GPA is an autoimmune disorder characterized by necrotizing small-vessel vasculitis of unknown etiology. It is often associated with anti-neutrophil cytoplasmic antibodies (ANCAs). ¹⁰² GPA characteristically involves the upper and lower respiratory tract with lung nodules and alveolar hemorrhage and the kidneys with necrotizing glomerulonephritis. ¹⁰³ The nervous system is involved in 22% to 54% of cases. ¹⁰⁴ Peripheral neuropathies and CN palsies are the most common forms. CNS involvement is much less common and is estimated to occur in approximately 10% of patients. ¹⁰² Brain involvement can be broadly divided into meningeal and parenchymal involvement. In meningeal involvement, pachymeninges are affected more frequently than leptomeninges. ¹⁰⁵

Clinical manifestations of GPA pachymeningeal involvement vary depending on the location and extent of inflammation. Headache, neck stiffness, and CN palsies are the most common findings. ¹⁰⁶ GPA parenchymal involvement presents with ischemic stroke and intra-parenchymal hemorrhage secondary to vasculitis.^106,107

The hypertrophic pachymeninges is usually moderately to markedly hypointense (relative to the brain or spinal cord) on both TI- and T2-weighted images and shows avid enhancement (Figure 5(g-j)). ¹⁰⁸ GPA can also involve the pituitary gland. ¹¹⁷ Differential diagnosis of GPA hypertrophic pachymeningitis includes lymphoma, dural metastases, IgG-4 RD, Rosai-Dorfman disease, Erdheim-Chester disease, intracranial hypotension, and idiopathic pachymeningitis. ¹¹⁸

Brainstem and posterior fossa diseases

CLIPPERS

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid (CLIPPERS) is a brainstem predominant encephalomyelitis with biopsy findings consisting of prominent perivascular CD3+ T-cell lymphocytic inflammation. There is no sex preference, and the typical age of presentation is middle age. ¹¹¹ Clinically it presents with gait ataxia, diplopia, and other posterior fossa symptoms. Symptoms develop over weeks to months and abrupt progression is atypical for CLIPPERS. ¹¹² Robust clinical and radiological response to steroid and symptoms recurrence after steroid cessation is a rule for the diagnosis. ¹¹³

Brain MRI shows punctate, <3 mm, curvilinear T1 post-Gd enhancement centered in the pons and cerebellum (Figure 6(a–c)). Less commonly, extension of the lesions into the cerebral hemispheres and the spinal cord is seen. T2-FLAIR images may be relatively unrevealing, despite significant clinical disability. ¹¹³ A larger size of T2 hyperintensities compared with post-Gd T1, confluent large areas of enhancement, which are larger than punctate peppering, and poor clinical and radiological response to corticosteroid, are considered red flags for the diagnosis of CLIPPERS. ¹¹² Few cases have been reported with the development of lymphoma after the initial diagnosis of CLIPPERS.^114,115 Radiological differential diagnosis includes Neuro-Behçet disease, autoimmune encephalitis, sarcoidosis, MS, Bickerstaff’s Brainstem encephalitis, atypical infections (tuberculosis, Whipple’s, etc.), lymphoma, and vasculitis. ¹¹²

Figure 6.

Brain stem and posterior fossa.

(a, b, c) Axial T2 weighted, FLAIR, and post-Gd T1 weighted images reveal hyperintense foci in bilateral middle cerebellar peduncles and corresponding punctate foci of enhancement in CLIPPERS. (d) Axial FLAIR image reveals the acute phase of paraneoplastic cerebellitis with right cerebellar involvement. Axial FLAIR (e) shows a focal hyperintense lesion in the left cerebellar peduncle and patchy enhancement in post-Gd T1 weighted image (f) in Neuro-Behçet’s disease.

CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroid

Bickerstaff’s brainstem encephalitis (BBE)

BBE is a rare, immune-mediated disorder following a prodromal upper respiratory infection. It involves the brain stem and peripheral nervous system and is clinically characterized by a triad of ataxia, encephalopathy, and ophthalmoplegia. ¹¹⁶ The IgG anti-GQ1b antibody is frequently present in the acute phase serum of patients with BBE. ¹¹⁷ This condition has clinical features as seen in both Guillain-Barre ´syndrome and Miller Fischer syndrome. MRI changes are uncommon in practice, but abnormalities have been reported in as many as 30%, including T2 hyperintense lesions in the brainstem. ¹¹⁸ BBE is radiologically very similar to CLIPPERS but lesions of BBE are usually isolated to the brainstem, with no rostro caudal extension. The classic peppering noted in the latter has not been reported in BBE. ⁷²

Paraneoplastic cerebellar degeneration

Paraneoplastic cerebellar degeneration (PCD) is a collection of neurological disorders resulting from tumor-induced autoimmunity against cerebellar antigens. PCD is rare and occurs in <1% of patients with cancer. ¹¹⁹ There are nearly 30 different antibodies associated with this condition. ¹²⁰ PCD selectively affects the cerebellum and patients present with ataxia and gait instability. The most common subtypes of PCD are associated with anti-Yo and anti-Purkinje cell cytoplasmic antibodies that account for nearly 50% of cases. ¹¹⁹ Brain MRI is usually normal at the onset, or more rarely shows discrete meningeal enhancement around cerebellar folia. T2-hyperintense cerebellar WM, caudate nuclei, and cerebellar cortex have occasionally been reported in the acute phase. PCD shows mild to moderate cerebellar atrophy in the chronic phase (Figure 6(d)). ¹²¹

Behçet disease

Behçet’s syndrome is a systemic vasculitis with an unknown etiology affecting the small and large vessels of the venous (mainly) and arterial systems. ¹²² Genetic background (HLA-B51) ¹²³ and immune dysregulation triggered by infectious agents are suspected etiologies^124,125 The classical syndrome is characterized by recurrent oral aphthae, genital ulcers, variable skin lesions, arthritis, uveitis, and thrombophlebitis. ¹²⁴ Neurological involvement in Behçet disease, Neuro- Behçet disease(NBD) occurs in 10% of cases and is more frequent in men.^126,127 CNS is more affected than the PNS. ¹²⁸ CNS involvement is parenchymal in 80% of NBD that is basically meningoencephalitis, involving the brain stem and basal ganglia and, less commonly, the spinal cord and hemispheric lesions. Clinical onset is usually abrupt rather than having a mild progressive course. ¹²⁴ These patients present with headache, multiple CN involvement, cerebellar dysfunction, and tumor-like lesions. ¹²⁹ Non-parenchymal lesions are less common (13–23%) and occur as a secondary manifestation of vascular lesions such as dural sinus thrombosis, intracranial and extra-cranial aneurysm formation, and stroke. ¹²⁷

On imaging, parenchymal lesions are T2/FLAIR hyperintense lesions in the brain stem (Figure 6(e)), pons, the midbrain, and the diencephalon. Local mass effect and hyperintense DWI with restricted apparent diffusion coefficient due to cytotoxic edema is seen in the acute/subacute phase. ¹²⁴ Perfusion MRI reveals focal hypoperfusion. ¹³⁰ Post-Gd study shows heterogeneous enhancement during the acute phase of parenchymal NBD (Figure 6(f)). ¹²⁹ MRV and CTV demonstrate sinus thrombosis in non-parenchymal involvement. ¹²⁴ Chronic lesions are smaller in size, non-enhancing, and without restricted diffusion. Cerebral involvement does not give a specific pattern of presentation. NBD should be differentiated from MS, infectious processes such as TB, neurosarcoidosis, vasculitis, and CLIPPERS. ¹²⁴