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Vasculitis and Other Inflammatory Disorders

Imaging Findings
  • Esther Sánchez AliagaEmail author
Living reference work entry

Abstract

The spectrum of inflammatory and immunologically mediated vessel diseases (IIMVD) englobes a heterogeneous group of rare disorders in which inflammation affecting the vessel wall or the perivascular space, of both arteries and veins, is the result of an immune response precipitated, in the majority of the cases, by an unknown element. Primary and secondary vasculitis, Susac syndrome, CLIPPERS, neurosarcoidosis, and immunoglobulin G4-related disease, included in this category, frequently manifest with very similar clinical and laboratory features. Clinical neuroradiology, with imaging findings incorporated in several of the diagnostic criteria, plays a pivotal role for establishing the diagnosis, serves as guidance for additional examinations during the diagnosis work-up, and enables monitoring disease evolution and treatment. Radiological evaluation using brain MRI is the rule, but, in many cases, diagnosis requires the combination of diverse radiological techniques, mainly those ones allowing assessment of brain vessels such as CT Angiography (CTA), MR Angiography (MRA), or Digital Subtraction Angiography (DSA), or those that can add valuable information to exclude other diagnosis like spinal MRI or CT and MRI of other organs. Nevertheless diagnosis of these disorders is for both clinicians and radiologist difficult and requires a multidisciplinary approach with extensive clinical, radiological, and laboratory evaluation and frequently tissue biopsy.

Keywords

Inflammatory and immunologically mediated vessel diseases IIMVD Vasculitis Susac CLIPPERS Neurosarcoidosis IgG4-related disease MRI 

Inflammatory and Immunologically Mediated Vessel Diseases

Definition and Highlights

Inflammatory and immunologically mediated vessel diseases (IIMVD) include a wide spectrum of entities in which inflammation affecting the vessel wall or the perivascular space, of both arteries and veins, is the result of an immune response. The triggering element precipitating this immune response, factors that determine location, type, and size of vessel involved and precise pathogenesis, is, in the majority of the cases, unclear. In primary and secondary vasculitis, the main pathological feature is the presence of inflammation and fibrinoid necrosis in the vessel wall, Susac syndrome is considered to be an endotheliopathy, CLIPPERS pathology reports perivascular infiltration, neurosarcoidosis (NS) is characterized by the presence of granulomas but vasculitis can also occur, and tissue biopsy in immunoglobulin G4-related disease (IgG4-RD) shows consistently presence of obstructive phlebitis. They represent a group of relatively rare diseases, difficult to diagnose and to distinguish from each other, due to the wide overlap in their clinical presentation and radiological features, the nonspecific laboratory findings at initial general blood and CSF analysis, and the absence of specific biomarkers. Clinical presentation accompanied by a detailed medical and family history and physical examination are essential elements to establish the clinical suspicion of an IIMVD. The diagnostic work-up includes laboratory analysis and neuroimaging, commonly brain MRI, frequently combined with other imaging modalities, CT Angiography (CTA), MR Angiography (MRA), Digital Subtraction Angiography (DSA), Ultrasound (US), as well as Positron Emission Tomography (PET) commonly co-registered with CT (PET-CT). Definitive diagnosis frequently requires tissue biopsy and exclusion of other diagnosis, most commonly lymphoma, lymphomatoid granulomatosis, disseminated malignancy, autoimmune-demyelinating idiopathic disorders, histiocytosis, and other noninflammatory vasculopathies.

Clinical and radiological findings, imaging and diagnostic strategies, and treatment when no specific clinical disorder is suspected will be covered in the first part of this chapter. Pathology, pathophysiology, and demographics as well as clinical and radiological findings of particular disorders included in this chapter will be covered throughout its different sections.

Clinical Findings

IIMVD may appear with similar clinical presentation compared with other entities consisting of headaches, encephalopathy, focal or multifocal neurological deficits that will depend on the affected cerebral of spinal cord structures, cognitive deficits, and psychiatric features. Particular clinical presentations that are considered to be suggestive of IIMVD are summarized on Table 1. Routine laboratory blood and CSF analysis are generally normal or may show signs of inflammation. Clinical course is not specific and range from acute to subacute, progressive chronic, or relapsing remitting.
Table 1

Clinical presentation suggestive of inflammatory and immunologically mediated vessel diseases

1. Multifocal symptoms accompanied by headache, psychiatric symptoms, and signs of a systemic inflammatory, rheumatologic, connective tissue disorders, or sicca symptoms (vasculitis)

2. Stroke in young patients without classical vascular risk factors

3. Focal neurological symptoms associated with visual disturbances and/or hearing loss (Susac)

4. Neurological symptoms in patients known with systemic vasculitis

5. Subacute onset of ataxia and dysarthria (CLIPPERS)

6. Cranial nerve neuropathy, specially facial, optic, or multinerve (NS, IgG4-RD)

NS neurosarcoidosis, IgG4-RD immunoglobulin G4-related disease

Systemic features such as fever, malaise, night sweat, arthralgia, presence of skin abnormalities, and symptoms related to dysfunction of other organs should be searched, as their presence will help narrowing the differential diagnosis.

Imaging Strategy and Recommended Protocol

Although CT may be used in the emergency setting in patients presenting with acute neurological deficits, initial radiological examination when an IIMVD is suspected is commonly a brain MRI. MRI protocol should allow recognition of features that support the diagnosis of IIMVD, serve as guidance for further investigations when IIMVD is suspected, and exclude other diagnosis, including noninflammatory vessel disease, nonvascular inflammatory autoimmune disease, and other pathology such as tumors, infections of metabolic disorders, which can present with similar clinical symptoms. If a specific disease is suspected, dedicated MRI protocols design for demonstrating specific MRI features should be performed and will be discussed on the different sections of this chapter. The initial clinical findings are commonly nonspecific and do not support a specific diagnosis, and in this situation it is essential to perform an adequate MR imaging protocol, as shown below (Standard IIMVD protocol). Inclusion of contrast-enhanced T1-weighted sequences and at least one angiographic sequence is highly recommended.

Recommended Brain MRI Protocol (Standard IIMVD Protocol)

Mandatory Sequences

  • Axial unenhanced T1-weighted

  • Axial T2-weighted

  • Axial FLAIR or 3D FLAIR (preferably)

  • Axial diffusion-weighted (DWI)

  • Susceptibility-weighted (SWI) or gradient-echo (GRE)sequences

  • Axial contrast-enhanced T1-weighted (preferably with fat suppression) or 3D contrast-enhanced T1-weighted

  • MR angiography (MRA): Time of flight (TOF)

Optional Sequences*

  • High-resolution vessel wall imaging sequences

  • Advanced MRI: Perfusion Imaging, Diffusion Tensor Imaging (DTI)

* Should be adapted to the suspected pathology (will be discussed throughout the different sections included in this chapter) and may be performed at initial MRI or a later stage during diagnostic work-up for more detailed characterization of findings.

T1-weighted sequences enable the identification of areas containing subacute blood products, cortical laminar necrosis, and focal parenchymal lesions. In addition, the sequences will be used for comparison with contrast-enhanced T1-weighted sequences. T2-weighted images serve for the detection of infarcts, hypoxic-ischemic and gliotic or demyelinating changes in the brain parenchyma. Compared to T2-weighted, FLAIR sequences are superior to depict parenchymal lesions bordering the cerebral spinal fluid (CSF) and those located in the subarachnoidal spaces. DWI allows detection of acute infarcts and differentiation between acute and old lesions, and SWI or GRE sequences are useful for demonstrating the presence of macro- or microbleeds. Dural, epidural, or leptomeningeal enhancement and/or parenchymal enhancing lesions can be identified on contrast-enhanced T1-weighted series (preferably with fat saturation technique). When large vessels are involved, postcontrast series may show vessel wall thickening and enhancement. MRA-TOF sequences may provide luminal information, such as arterial stenosis, occlusion, and dilatation, but has a limited resolution in the evaluation of most of the intracerebral vessels, and therefore, if small vessel vasculitis such as Susac or CLIPPERS are initially suspected, this sequence can be spared. If a vasculitis is consider to be the most probable diagnosis, contrast-enhanced high-resolution intracranial MR vessel wall imaging, preferably at 3T field strength, will improve visualization of vessel wall thickening and enhancement. MR perfusion (dynamic susceptibility contrast or arterial spin labeling techniques) may allow detection of parenchymal perfusion defects, and DTI may add valuable information about axonal integrity.

Spinal imaging is usually not performed for initial radiological evaluation, unless presence of spinal cord symptoms, but may be performed during diagnostic work-up to narrow the differential diagnosis.

Recommended Spinal MRI Protocol

Mandatory Sequences

  • Sagittal T1-weighted*

  • Sagittal PD or STIR/T2-weighted

  • Axial T2-weighted (at the level of the findings)

  • Sagittal and axial contrast-enhanced T1-weighted (at the level of the findings)

*To avoid excessive scan time spinal MRI may be performed after post contrast brain series if brain and spine are schedule on one session.

Radiological evaluation requires often the combination of several imaging modalities, including ultrasound (US), DSA, or CTA, if a vasculitis is suspected; PET or PET-CT in search for a favorable location for biopsy, and CT or MRI of other organs to support systemic disease.

Imaging Findings

There are no pathognomonic MRI findings for IIMVD, although MRI may show certain patters on T2-weighted and contrast-enhanced T1-weighted sequences, especially when combined, which may point towards the diagnosis of an IIMVD (Table 2). Some of these patterns are nonspecific and some might be very characteristic for a specific disorder.
Table 2

MRI patterns in inflammatory and immunologically mediated vessel diseases and differential diagnosis (right column)

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Axial FLAIR images show multiple focal lesions in the subcortical white matter and corpus callosum (A, arrow) as well as bilaterally in the posterior limb of the internal capsule (B, arrow). Notice the linear hyperintense areas in the subarachnoid space (A, arrowhead) highly suggestive of leptomeningeal of subarachnoid disease, considered a major red flag for MS

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Axial FLAIR image demonstrates multiple old watershed infarcts, bilaterally distributed (A), combined with a recent right paramedian brainstem infarction in a patient known with a Wegener granulomatous sinusitis, suggesting the diagnosis of vasculitis

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Axial T2 images show the presence of a focal T2 lesion in the left mesencephalon (A) associated with a large mass-like lesion in the right hemisphere (B). Contrast-enhanced T1-weighted images show multiple areas of enhancement right temporal lobe, in the left mesencephalon (C), and at the margins of the mass-like lesions (D), with an enhancement pattern very unusual for a tumor or an abscess. Due to the mass effect, the patient underwent decompression surgery and biopsy was performed demonstrating the presence of a vasculitis

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Axial T2 image reveals a T2 hypointense dural mass (A) in the anterior cranial fossa showing homogenous and intense enhancement on contrast-enhanced T1-weighted images (B) in a patient with neurosarcoidosis

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Leptomeningeal nodular enhancement (arrows in A), and along the facial nerve (A) and linear and homogeneous in both frontal lobes (arrow in B) in a patient with neurosarcoidosis

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Contrast-enhanced T1-weighted sequences in a patient with miliary enhancement pattern in the brainstem and cerebellum in a patient with CLIPPERS (A). Perivascular enhancement in a patient with neurosarcoidosis (B)

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Axial contrast-enhanced fat saturation T1-weighted images showing a multifocal patchy enhancement pattern in a patient with the final diagnosis of PACNS

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Sagittal T2 images showing a longitudinal extensive myelitis (A) in a patient with sarcoidosis. Other possible finding in patients with sarcoidosis is the presence of leptomeningeal enhancement (B), in this case with a nodular pattern

T2-weighted of FLAIR patterns include:
  1. 1.

    Multiple focal T2 lesions that might resemble MS, usually with presence of associated findings that are unusual for MS (red flags), or that might resemble noninflammatory small vessel disease

     
  2. 2.

    Presence of multiple ischemic lesions in different stages and in different vascular territories frequently associated with focal, confluent, or diffuse T2 hyperintense lesions

     
  3. 3.

    Mass-like lesion without the classical appearance of a high grade tumor, metastasis, or abscess

     
Contrast-enhanced T1-weighted patterns include:
  1. 1.

    Meningeal enhancement, including presence of dural enhancement, epidural masses, or leptomeningeal enhancement (homogenous or nodular)

     
  2. 2.

    Perivascular or miliary enhancement

     
  3. 3.

    Patchy parenchymal, frequently multifocal, enhancement

     
Spinal cord findings on T2-weighted and contrast enhanced T1-weighted include:
  1. 1.

    Focal or extensive myelitis (with or without enhancement)

     
  2. 2.

    Meningeal enhancement including presence of dural enhancement, epidural masses, or leptomeningeal enhancement (homogenous or nodular)

     
Additional relevant features that may suggest a specific disorder are:
  1. 1.

    Presence of associated micro-/macrohemorrhages or venous sinus thrombosis (Behçet, PACNS).

     
  2. 2.

    Presence of lesions in structures often visible on brain MRI such as the orbit and the parotid gland (NS, IgG4-RD), paranasal sinuses (Wegener), lacrimal glands (Sjögren, IgG4-RD), pituitary stalk (IgG4-RD), or mediastinal lymph nodes (NS) when spinal MRI is performed.

     
  3. 3.

    Location of the most prominent findings. An infratentorial location is more commonly seen in CLIPPERS or Behçet.

     
  4. 4.

    Combination with demographic, especially age may help. Differential diagnosis in children and adolescents includes polyarteritis nodosa (PAN), Kawasaki, and postinfectious vasculitis.

     

Diagnostic Strategy

Given the difficulty in diagnosing IIMVD, a multidisciplinary approach is necessary. In presence of neurological symptoms suspect of an IIVMD, a detailed anamnesis, medical history, physical examination followed by general blood and CSF investigations, and neuroimaging, usually MRI, are mandatory. Results will guide further radiological studies (Table 3), laboratory analysis, and management of the patients, yet biopsy may be often necessary to achieve a final diagnosis.
Table 3

Summary of diagnostic work-up

Radiological Report and Checklist

Radiological report should contained a detailed description of imaging findings relevant for a particular clinical question and always be accompanied by the radiological interpretation of them in the patient clinical setting. Recommended structure of the radiological report is as follows:
  • MRI technique: Anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal).

  • MRI findings: Systematic and comprehensive description of all the relevant imaging findings related to the clinical problem:
    • Presence of MRI T2/contrast enhanced T1-weighted patterns suggestive of an IIMVD. Describe size, morphology and location of the findings. Particularly describe:
      • Characteristic findings common to all group of IIVMD

      • Features that are more suggestive of a particular entity (see proposed radiological report for the different diseases included in this chapter)

      • Additional features (nasosinusal cavity, orbit, lacrimal, or parotid glands)

      • Nonclassical findings for IIVMD

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant.

  • MRI conclusion: Based on the combination of demographic characteristics, clinical picture findings and MRI findings, the most probable category of disease (IIMVD) and if possible a particular disorder within this category should be mentioned together with most common differential diagnosis. Relevant findings that do not support the clinical suspicion should be described as well. Finally, recommended additional investigations should be included in the conclusion.

Treatment Monitoring

IIMVD are associated with significant morbidity and mortality rates. Although some deficits might be not reversible, in most cases early and aggressive treatment can rapidly control the symptoms and improve the outcome. Treatment includes in the majority of the cases the use of steroids and/or immunosuppressive therapy, and MRI is one of the tools that can monitor the response of the inflammatory component to these treatments. Treatment should be continued until sustained resolution occurs, as assessed by means of MRI. Absence of response or worsening should always alert for an alternative diagnosis. Recurrent of inflammation can occur when lowering treatment doses and constitutes an indication for imaging. As these groups of diseases may relapse, prolonged immunosuppressive treatment may be necessary and treatment-related complications may occur. In this setting, if a patient presents with new neurological symptoms, focus will not only be the detection of new disease-related findings but also the early detection of therapy-related complications such us opportunistic infections, being progressive multifocal leukoencephalopathy (PML) (Fig. 1), and fungal infections some of the most severe.
Fig. 1

Patient with a 15-year history of sarcoidosis and prolonged immunosuppressive treatment presenting with new motor weakness in the left hand. T2-weighted image (a) shows a lesion sharply defined towards the cortex, without expansive effect. DWI (b) demonstrates a characteristic ring of high signal intensity bordering the lesion consistent radiologically with PML; polymerase chain reaction (PCR) demonstrated JC virus in CSF

Standard monitoring protocols or monitoring biomarkers are not available for this category of disorders.

As treatment and monitoring are very similar within the different entities included in this groups, this section will not be discuss further in the different sections.

Primary and Secondary Vasculitis

Definition and Highlights

Vasculitis represent a group of diseases defined by the presence of inflammation and necrosis of blood vessel wall, involving arteries and veins. Its pathogenesis is unclear, the role of immune response vascular damage varies with the disease, and a triggering factor is in the majority of the cases still unknown. Vasculitis can involve large, medium-sized, small, and variable-sized vessels of both the peripheral and central nervous systems, leading to stenosis or occlusion, microaneurysm formation, or rupture of the vessels, resulting in various types of neurological dysfunction and imaging findings secondary to focal or multifocal infarction, diffuse ischemia, or hemorrhage. Cerebral vasculitis can occur as a disorder restricted to the CNS or in the context of a systemic inflammatory process, systemic autoimmune disorder, connective tissue disease, infections, neoplasia, drug abuse, or radiation therapy. Diagnosis is complex and includes extensive clinical and paraclinical examinations and often requires biopsy. Treatment includes the use of steroids and/or immunosuppressive therapy.

Classification

Vasculitis can be classified according to its cause, location, and size of affected vessel or neuropathological findings. The classification from the 2012 Revised International Chapel Hill Consensus Conference on Nomenclature of Systemic Vasculitides (Table 4) is the most widely used (Jennette et al. 2013).
Table 4

Classification of vasculitis according to the 2012 Revised International Chapel Hill Consensus Conference on Nomenclature of Systemic Vasculitides

Type of vasculitis

Disease entities

Large-vessel vasculitis

Takayasu arteritis

Giant cell arteritis (GCA)

Medium-sized vessel vasculitis

Polyarteritis nodosa (PAN)

Kawasaki disease

Small-vessel vasculitis

IgA vasculitis

Microscopic polyangiitis

Granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis

Variable-sized vessel vasculitis

Behçet disease

Cogan syndrome

Single-organ vasculitis

Primary angiitis of the CNS (PACNS)

Vasculitis associated with systemic disease

Systemic lupus erythematosus (SLE)

Sjögren

Rheumatoid arthritis (RA)

Antiphospholipid antibody (APLA) syndrome

Scleroderma

Vasculitis associated with probable etiology

Infection-induced vasculitis

Acute septic meningitis

Mycobacterium tuberculosis

Neurosyphilis

Viral (HIV-related, varicella-zoster vasculopathy)

Fungal (mucormycosis, aspergillosis)

Parasitic (cysticercosis)

Malignancy-induced vasculitis

Drug-induced vasculitis

Radiation-induced vasculitis

HIV human immunodeficiency virus, IgA immunoglobulin A

This classification includes primary isolated CNS vasculitis, primary systemic vasculitis with CNS involvement, and secondary vasculitis as complication of classically nonvasculitic systemic disorders. Large vessel vasculitis affects the aorta and its main branches, and the vertebral, basilar, external carotid, internal carotid, A1 segment of anterior cerebral (ACA), M1 segment of medial cerebral (ACM), and P1 segment of the posterior cerebral (PCA) arteries. Medium-vessel vasculitis involves cerebral arteries distal to the bifurcation of the MCA, as well as the anterior and posterior communicating arteries. Small-vessel vasculitis affects arterioles, venules, and capillaries (Wengenroth et al. 2013).

Basic Epidemiology and Demographics

CNS vasculitis is rare. Their incidence and demographics varies significantly among types of vasculitis and in many cases is not clearly documented. The majority of the CNS vasculitis affects with equal frequency men and women, although there is a clear female preference in SLE and Sjögren, whereas Behçet has been more commonly described in males. CNS vasculitis tends to affect more often adults. In general CNS vasculitis occurs in Takayasu and SLE at a younger age than PACNS, PAN, or GCA. Kawasaki vasculitis, IgA vasculitis, and vasculitis related to infection (acute septic meningitis and Varicella Zoster) tend to affect children.

Pathophysiology and Pathology

The pathogenesis of vasculitis remains poorly understood and varies between types. Three main mechanisms of vascular injury have been described (Bougea and Spantideas 2017):
  1. 1.

    Cell-mediated inflammation mediated by cytotoxic CD8+ T cells

     
  2. 2.

    Immune complex (IC)-mediated inflammation or in situ formation of immune complex within the vessel wall

     
  3. 3.

    Antineutrophil cytoplasmic antibody (ANCA)-mediated inflammation

     

The triggering element initiating and driving this inflammatory response is unknown. Inflammation of the wall vessel with obstruction of the vessel lumen, increased coagulation, and alterations in vasomotor tone causing hypoxia and/or ischemia lead to the clinical manifestations.

The pathological hallmark in vasculitis is an inflammatory infiltrate within the vessel wall, associated with destructive mural changes (fibrinoid necrosis) (Fig. 2). Histological changes allow classification of vasculitis according to the presence or absence of granulomas, antineutrophil cytoplasmic antibodies (ANCA), immune complex deposits in the vessel wall, and/or the size of the vessel implicated, while clinical history and systemic associated disease are necessary for final classification.
Fig. 2

Brain biopsy pathology showing the classical findings of vasculitis on hematoxylin-eosin with presence of arteriolar wall fibroid necrosis (a) and thrombosis (b)

Clinical Findings

Diagnosis is challenging since almost any clinical picture can occur. The CNS may be affected by vasculitis with variable frequency depending on the disease and, although some entities may manifest with some particular features (Tables 7 and 8), the neurological presentation may be quite similar among different types of vasculitis. Damage results from focal, multifocal, or diffuse vascular injury affecting any part of the CNS and leading to signs of symptoms of dysfunction including cognitive deterioration, psychiatric symptoms, focal deficits, transient ischemic attacks, stroke, and headaches. Particular clinical scenarios suggestive of CNS vasculitis are summarized in Table 1. Presence of general systemic features such as fever, night sweats, or more specific disease-related systemic features are helpful in narrowing the differential diagnosis. An alternative clinical setting in which the patient is already known with a systemic inflammatory disorder, connective tissue disease, infection, or malignancy is possible. In those cases, if neurological symptoms are present, examinations will aim to demonstrate that a CNS vasculitis is the cause of them.

The clinical course is commonly acute (headaches, seizures, and stroke-like events) or subacute (encephalopathy, progressive cognitive changes), but chronic progressive presentations and spontaneous relapses and remissions have been described.

Laboratory findings related to an acute inflammatory response are common. Once a vasculitis is suspected, extensive blood and CSF analysis are mandatory for further characterization.

Imaging Features

CT and MRI may show similar findings in CNS vasculitis, but MRI has a higher sensitivity in revealing parenchymal changes. On imaging, diverse diseases coursing with CNS vasculitis shared common parenchymal findings, such as focal or diffuse hypoxic-ischemic changes, combination of new and old infarcts with sometimes coexistence of micro- or macrohemorrhages, and leptomeningeal or parenchymal enhancement (Fig. 3). Findings related with vessel wall inflammation that can be demonstrated with US, CTA, MRI/MRA, or DSA (Fig. 4) can also be presented. Focal or more commonly multifocal stenosis with areas or localized dilatation and sometimes occlusions are typical findings in vasculitis. Circumferential thickening and enhancement of vessel wall may be demonstrated on contrast enhanced T1-weighted sequences or when using MR intracranial vessel wall imaging (IVWI) techniques. Common imaging findings on CT/CTA, MRI/MRA, and DSA are summarized on Table 5.
Fig. 3

The combination of focal white matter hyperintensities on T2-weighted image (a), increased signal intensity in the subarachnoid spaces on FLAIR image (b) together with presence of foci with restricted diffusion related to acute infarction (c) are suggestive of CNS vasculitis

Fig. 4

Angiography (a) illustrates the classical “string of beads” appearance of vasculitis in a patient with PACNS. T1-weighted fat saturation image (b) shows thickening and concentric enhancement of the wall of the basilar artery in a patient known with Wegener sinusitis supporting the diagnosis of vasculitis

Table 5

Parenchymal and vascular imaging findings in vasculitis

 

Parenchymal findings

Vascular findings

CT

CTA

Uni/multifocal ischemic lesions (new/old combined; multiple vascular territories)

Diffuse or focal hypoxic-ischemic changes

Macrohemorrhage, SAB

Atrophy in chronic stages

Indication CTA: large vessel vasculitis

Acute phase: arterial concentric wall thickening with mural enhancement and low-attenuation ring on delayed images

Chronic phase: arterial wall is slightly thickened with high attenuation ring or calcifications

Arterial stenosis, occlusions and dilatation, aneurysm

MRI

MRA

Uni/multifocal ischemic lesions (new/old combined; multiple vascular territories)

Diffuse or focal hypoxic-ischemic changes

Leptomeningeal enhancement with or without associated parenchymal enhancement

Microhemorrhages, occasionally macrohemorrhages and SAB

Atrophy in chronic stages

Indication MRA: large- and medium- sized vessel vasculitis

Increased vessel thickness in large vessel vasculitis with wall edema

Vessel wall enhancement

MRA: uni/multifocal stenosis and focal dilatation; occlusions

IVWI: circumferential arterial wall thickening and enhancement

DSA

Cerebral perfusion deficits

Indication: any vasculitis

Multifocal luminal irregularities and stenosis

Sometimes occlusions and aneurysm

May be normal in small-sized vasculitis

Limitation: no information about vessel wall

CT computed tomography, CTA computed tomography angiography, MRI magnetic resonance imaging, MRA magnetic resonance arteriography, DSA digital subtraction angiography, SAB subarachnoid blood, IVWI intracranial vessel wall imaging

Some particular radiological findings that may be present in the different types of vasculitis like presence of venous thrombosis or pachymeningitis are highlighted in Tables 7 and 8.

Imaging Strategy and Recommended Protocol

The purpose of imaging is the assessment of parenchymal and vascular, both luminal and vessel wall, changes that support the diagnosis of a vasculitis and the exclusion of vasculitis mimickers. Although CT may be used in the emergency setting in patients presenting with acute neurological deficits, MRI, including MRA, is the most commonly used neuroimaging modality when a vasculitis is suspected. US and CTA have been shown useful for the evaluation of vessel lumen changes and vessel wall pathology, especially in large vessel vasculitis. Since both CTA and MRA have a limited resolution, DSA is still performed, especially when medium-sized and small vessel vasculitis are suspected. In contrast with DSA where vessel wall changes are not evaluable, thickening and multifocal homogeneous, smooth, intense, and concentric enhancement of the vessel wall can be demonstrated with MRI when using intracranial vessel wall imaging (IVWI) sequences (Mandell et al. 2012).

Recommended dedicated MRI protocol in vasculitis is similar to the one recommended for IIVMD but should include high resolution vessel well imaging if available.

Recommended Brain MRI Protocol (Vasculitis)

  • Axial unenhanced T1-weighted

  • Axial T2-weighted

  • Axial FLAIR or 3D FLAIR (preferably)

  • Axial diffusion-weighted (DWI)

  • Susceptibility-weighted (SWI) or gradient-echo (GRE)sequences

  • Axial contrast-enhanced T1-weighted (preferably with fat suppression) or 3D contrast-enhanced T1-weighted

  • MRA–TOF*

  • High-resolution MR vessel wall imaging sequences*

* Due to the technical limited resolution will not add value to the examination and can be spared if a small vessel vasculitis is suspected

Radiological evaluation almost always includes de combination of several imaging modalities which varies depending on patient condition, type of vasculitis suspected, available MRI technology, and radiological expertise. The most commonly used combinations are MRI/MRA followed by DSA, as well as CTA followed by DSA in cases of large vessel vasculitis.

US has a role in detecting hypoechoic edematous wall swelling (halo sign) in the temporal artery in patients with GCA. FDG-PET or PET-CT is very sensitive in detecting large vessel inflammation and in identifying a favorable location for biopsy.

Diagnostic criteria are available for several vasculitis and often require pathological confirmation, nonetheless radiological findings may support the diagnosis if biopsy is not feasible.

Primary Angiitis of the CNS (PACNS)

PACNS is an uncommon single-organ vasculitis, representing less than 2% of vasculitis cases involving the CNS. Although described in children and elderly, it usually manifests at the fifth decade affecting equally frequent men and women. The pathogenesis is unknown. Typically involves small- to medium-sized vessel (both arteries and veins) mainly those in a leptomeningeal or subcortical location, with a focal and segmental distribution. In most cases the underlying histopathology is granulomatous. Clinical presentation is nonspecific, most commonly patients present with subacute clinical manifestations of CNS dysfunction, frequently including headache and cognitive impairment. Focal symptoms appear later in the disease. Intracranial hemorrhage, spinal syndrome, and constitutional symptoms (fever, weight loss) are infrequent, and there is lack of generalized inflammation. Laboratory test is nonspecific.

MRI is highly sensitive (>90%) however not specific (Hajj-Ali and Calabrese 2014). Cortical and subcortical infarctions, parenchymal and leptomeningeal enhancement, intracranial hemorrhage, tumor-like lesions, and increased signal intensity on T2-weighted sequences are often seen (Fig. 5).
Fig. 5

FLAIR images show multifocal ill-defined hyperintense lesions located in the brainstem (a) and in both cerebral hemispheres (b, c). Contrast-enhanced T1 weighted images demonstrate patchy and punctate enhancement at the level of the FLAIR lesions. DSA was normal. Final diagnosis was PACNS

DSA may occasionally show alternating segments of stenosis with normal and dilated intervening segments and arterial occlusions. Findings are usually bilateral and are nonspecific and possibly present in other nonvasculitic diseases (vasospasm, CNS infection, reversible cerebral vasoconstriction syndrome-RCVS, and atherosclerosis). Leptomeningeal or parenchymal biopsy remains the standard of reference for the diagnosis of PACNS, but DSA supports the diagnosis when biopsy is not undertaken or results are negative. Exclusion of other vasculitis and nonvasculitis disorders is also mandatory for establishing the diagnosis of PACNS (Salvarani et al. 2012).

Reversible cerebral vasoconstriction syndrome (RCVS) is the most common mimicker from PACNS and its differentiation is important because prognosis and treatment requirements differ. In the absence of validated diagnostic criteria (Calabrese et al. 2007), several clinical, laboratory, and imaging characteristics may be useful to distinguish RVCS from PACNS (Table 6).
Table 6

Differential features between primary angiitis of the central nervous system (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS)

 

PACNS

RCVS

Clinical data

  

Age

Gender

Trigger

Headache

40–60 years

Slightly more frequent in male

Absent

Insidious

20–40 years

Primarily women

Frequently identifieda

Acute and severe (thunderclap)

Cognitive impairment

Frequent

Unusual

Onset

Usually gradual and progressive

Acute, rapid development

Course

Progressive with frequent appearance of infarcts

Monophasic self-limited within 1–3 months

Cerebral spinal fluid

Abnormal (increased protein and mild pleocytosis)

Normal or minimal protein increased

Magnetic resonance imaging

Abnormal >90%

Normal (>70%) unless complicated by stroke, PRES, or hemorrhage

Angiography

May be normal

Single or multiple abnormalities

Multiple diffuse areas of stenosis and dilatation that must reverse in 6–12 weeks

Cerebral nervous system or leptomeningeal biopsy

Vasculitis

Normal

Treatment

Glucocorticoids

Immunosuppressives

Calcium-channel blockers

Glucocorticoids

Table modified from Rovira et al. (2016)

PRES posterior reversible encephalopathy syndrome

aSympathomimetic or vasoactive drugs, peripartum, eclampsia, strenuous activity, bathing in hot or cold water

Large, Medium-, Small-, and Variable-Sized Vasculitis

CNS involvement occurs with variable frequency in vasculitis, and although most of CNS vasculitis share many clinical and radiological findings, some of them also may manifest with characteristic systemic or neurological features that are useful for establishing the diagnosis. Table 7 includes detailed information about histopathology and demographics and highlights some of the most relevant clinical and radiological features of large-, medium-sized vessel, small-sized vasculitis, and variable sized vasculitis. Diagnostic criteria for the various vasculitis are available in many instances.
Table 7

Clinical and radiological features in large vessel, medium-sized vessel, small vessel vasculitis, and variable-sized vasculitis

 

Clinical features

Radiological features

Takayasu (Fig. 6)

PA: granulomatous

<50 years

F = M

Aorta and major branches involved

Arm claudication and decreased or absent peripheral pulses

Up to 1/3 of patients present with TIA, stroke or hypertensive encephalopathy

Increased thickness and dilatation of the aorta and common carotid arteries along with calcifications with areas of stenosis

In chronic phase complete vascular occlusion

Cerebral hypoperfusion

Giant cell arteritis

PA: granulomatous

>50–55 years

F > M

Temporal artery commonly involved

Retinal ischemia, optic neuropathy, diplopia, unilateral headache, facial pain, jaw claudication

Association with polymyalgia rheumatic

Increased ESR and CRP values

4% stroke or TIA

Frequent involvement of temporal artery

Mural thickening and enhancement of the temporal artery wall

US: hypoechoic arterial wall (halo sign)

Diagnosis requires biopsy in many cases

PAN

PA: necrotizing granulomatous

50–60 years

F = M

Skin and renal involvement (70%). Gastro-intestinal symptoms (45%)

PNS involvement 40%: peripheral neuropathy

CNS involvement 10–20%: diffuse encephalopathy with cognitive decline stroke-like symptoms and seizures

Spinal cord symptoms due to involvement of spinal arteries

Intracerebral or subarachnoid hemorrhage multiple aneurysma of small and medium-sized arteries

In late stage stenosis and ischemia

Spinal cord involvement

Kawasaki

PA: necrotizing

Infants and children

F = M

Coronary vasculitis 50%

Acute febrile vasculitis, seizures, facial palsy

CNS involvement 30%

Subdural effusions

Lesions with reversible T2 hyperintensity in the splenium corpus callosum

PRES

IgA vasculitis

(Henoch-Schonlein purpura)

IgA immunocomplex disease

Most common vasculitis in children between 4 and 7 years

Purpura, arthralgia/arthritis, abdominal pain, glomerulonephritis

CNS manifestation rare: Hyperintensive or uremic encephalopathy

Rare

Findings related with hyperintensive or uremic encephalopathy

Focal ischemia or hemorrhage described but rare

Microscopic polyangiitis

PA: necrotizing

ANCA present

Glomerulonephritis, skin manifestations

Mononeuritis multiplex

CNS involvement is common (37–72%)

Peripheral neuropathy common

Hemorrhage, nonhemorrhagic cerebral infarction

Pachymeningitis

Variable degrees of small vessel disease with involvement of white and gray matter

Granulomatosis with polyangiitis (Wegener)

PA: necrotizing

ANCA present

Sinusitis, otitis, lung disease

CNS late involved up to 35%. Stroke is rare. Basal cranial nerve involvement

Usually antiproteinase 3 can be measured in serum

Cerebral lesions due to invasion by granulomas from sinonasal cavity or

Necrotizing vasculitis in setting of acute sinusitis/otitis/lung disease

Leptomeningeal enhancement

Associated pathology mastoid/sinuses (granulomas)

Eosinophilic granulomatosis with polyangiitis

(Churg Strauss)

PA: necrotizing

ANCA present

Lung, skin, peripheral nerves involved

Asthma, hypereosinophilia, and necrotizing vasculitis

Confusion, seizures, coma, cranial nerve palsy

Optic neuropathy common

Nonspecific vascular findings

Behçet disease (Fig. 7)

M > F

Turkey

Recurrent orogenital ulcers, ocular inflammatory disease, and cutaneous manifestations

CNS involvement 5–30%

Parenchymal form 80%:

 Large brainstem lesions, extending basal ganglia: T2 hyperintense and enhancing

 Meningoencephalitis, cranial nerve palsy: leptomeningeal enhancement

Vascular form 20%:

 Sinus thrombosis, arterial occlusions, and aneurysm

In chronic forms: predominant infratentorial atrophy

Cogan syndrome

Nonsyphilitic interstitial keratitis and audiovestibular dysfunction

CNS involvement 30%: headache, psychosis, coma, convulsion neuropathy, stroke

Vasculitis 12%

Hemorrhage, pachymeningitis, nonhemorrhagic cerebral meningoencephalitis, cranial neuropathy

Venous sinus thrombosis

Enhancement membranous labyrinth

PA pathology, F female, M male, TIA transitory ischemic attack, US ultrasound, ESR erythrocyte sedimentation rate, CRP C-reactive protein, CNS central nervous system, PNS peripheral nervous system, PRES posterior reversible encephalopathy syndrome, IgA immunoglobulin A, ANCA anti-neutrophil cytoplasm antibody

Fig. 6

CTA illustrates findings in a large vessel vasculitis (Takayasu), with presence of thickening and subtle enhancement of the internal carotid artery at its origin (a) and thickening and wall edema more distally (b)

Fig. 7

Contrast enhanced T1-weighted image reveals an enhancing mass (a) with extensive perifocal edema (b) located in the diencephalon in a Turkish male very suggestive of a Behçet disease. Follow up MRI shows residual subacute hemorrhage (c) and evident decrease in mass size and edema (d)

Vasculitis Associated with Systemic Disease

Systemic inflammatory autoimmune disease may manifest with CNS vasculitis. Involvement of CNS is very variable and related with vasculitis but also with nonvasculitic vasculopathy. In the majority of the cases, the presence or systemic inflammatory disease with presence of extracranial manifestation are the clue for the diagnosis. Table 8 highlights the main clinical and radiological features of the vasculitis included in this group.
Table 8

Clinical and radiological features of vasculitis associated with systemic disease and vasculitis associated with probable etiology

 

Clinical features

Radiological features

SLE

F ≫ M

Second to fourth decade

Skin, joints, lungs, and kidneys may be affected

CNS involvement 20–75%, less than 10% due to vasculitis, rest is noninflammatory vasculitis

Small vessel vasculitis

20–40% associated antiphospholipid antibody (additional risk of neuropsychiatric events)

Psychosis, stroke, seizures, movement disorders, headache, and neurocognitive dysfunction

Nonspecific small, punctate, focal lesions in the subcortical and periventricular white matter (present in the majority of NPSLE patients, but not specific). May mimic MS

Sometimes more severe findings, such as diffuse brain atrophy (43%), cerebral edema, cerebral infarcts, and intracranial hemorrhage

Angiography: stenosis or occlusion internal carotid artery

Spinal cord involvement 1–3% (longitudinal extensive myelitis)

Sjögren

F > M

Middle age

Xerophthalmia, xerosmia (lymphocytic infiltration salivary and lachrymal glands)

Two forms: primary or secondary (associated with SLE, RA, scleroderma, etc.)

CNS involvement 25–20%, usually later than sicca manifestations

Trigeminal neuropathy, recurrent aseptic meningoencephalopathy, unifocal or multifocal parenchymatous lesions

Possible presentation with optic neuritis and myelitis associated with AQP4 antibodies

Extensive white matter and gray matter lesions

Microbleeds

Angiography: multiple arterial stenosis

Spinal cord: longitudinal extensive myelitis

Antiphospholipid antibody syndrome (APS)

Arterial and venous thrombosis, miscarriage, and APLAs

Two forms: primary (no predisponent conditions) and secondary (SLE, HIV…)

APS is strongly associated with recurrent transient ischemic attacks, and strokes in young adults, secondary to arterial or venous thrombosis and thrombocytopenia

White-matter abnormalities suggesting small-vessel disease, including acute infarcts and microhemorrhages

Rheumatoid arthritis

Primary involvement joint

CNS involvement is rare (more often in long standing active RA)

Vasculitis-like symptoms including stroke, seizures, meningitis, intracranial hypertension

Pachymeningitis and dural nodules

CNS vasculitis is rare

Scleroderma (progressive systemic sclerosis)

Skin and the connective tissue affected

Widespread microvasculopathy and diffuse tissue fibrosis

Seizures, headache, cognitive impairment depression, and anxiety

Nonspecific and common with other types of vasculitis, including infarction in medium-sized artery territories

Cavernomas, calcifications, localized brain atrophy, and white-matter hyperintensities

 

Clinical/radiological features

in vasculitis associated with probable etiology

Acute septic meningitis

May cause vasculitis and infarcts in 5–15% adults and up to 30% in neonates with bacterial meningitis

Tuberculosis meningitis

Most common cause of chronic meningitis

Secondary to rupture of tuberculoma in the subarachnoid space specially basal cisterns and Silvian fissure infecting traversing vessels

Ischemic infarction up to 40%

Induce vasculitis in small and medium sized arteries often lenticulostriate or posterior cerebral branches or thalamoperforating

Neurosyphilis

Vasculitis results from direct spirochete invasion of vascular endothelial cells

Manifest with stroke, middle cerebral artery more common than basilar artery

Varicella Zoster

Spectrum of vasculitis includes infarction of the brain and spinal cord, aneurysm formation, SAB and cerebral hemorrhage, middle or anterior cerebral artery dissection

Angiography: stenosis, thrombosis, beading along proximal branches of the anterior and middle cerebral arteries

In children presenting with unilateral basal ganglia infarction, Varicella Zoster virus must be included in the differential diagnosis, rarely is bilateral

HIV related

Both medium arteries and veins may be affected with development of aneurysm, vessel occlusion, embolic disease, and venous thrombosis. Fusiform aneurysms may occur

Fungal vasculitis

Important in the setting of leukopenia, sepsis, and immunosuppression. Vasculitis may be acute, subacute or late complication

Cerebral infarction results from direct vascular injury, from microabscesses or contiguous extension along sites of infection

Cysticercosis

Vasculitis occurs in around 50% of patients with subarachnoid cysticercosis. Middle and posterior cerebral arteries are the most affected. Multivessel involvement is frequent

Malignant induced

Hodgkin lymphoma and hematological malignancies may be related with vasculitis

Drug-induced

Antibiotic, chemotherapy, cocaine, heroin may cause vasculitis, usually medium-sized vessels, resulting in stroke and hemorrhage

Radiation-induced

Large vessel vasculitis. Injuries evolve slowly to produce ischemia years or decades after irradiation

SLE systemic lupus erythematosus, F female, M male, NPSLE neuropsychiatric systemic lupus erythematosus, CNS central nervous system, MS multiple sclerosis, RA rheumatoid arthritis, AQP4 aquaporin 4, APS antiphospholipid antibody syndrome, APLA antiphospholipid antibody, HIV human immunodeficiency virus

Vasculitis Associated with Probable Etiology

This section includes vasculitis associated with a variety of infections, malignancies, drug, and radiation vasculitis. Table 8 highlights the main clinical and radiological features of the vasculitis included in this group.

Radiological Report and Checklist

Recommended structure of the radiological report includes description of characteristic radiological findings related to vasculitis (checklist):
  • MRI technique: Anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal)

  • MRI findings: Systematic and comprehensive description of all the relevant imaging findings related to a possible vasculitis. If present describe intensity pattern, define extension, location and morphology of findings
    • Absence or presence of parenchymal findings:
      • Uni/multifocal ischemic lesions (new/old combined in multiple vascular territories)

      • Diffuse or focal hypoxic-ischemic changes

      • Leptomeningeal enhancement with or without associated parenchymal enhancement

      • Microhemorrhages, macrohemorrhages, or SAB

    • Absence of presence of vascular findings:
      • Increased vessel thickness in large vessel vasculitis with wall edema.

      • Vessel wall enhancement

      • MRA TOF: uni/multifocal stenosis and focal dilatation; occlusions

      • IVWI: circumferential thickening and enhancement

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant

  • MRI Conclusion: The radiological impression supporting or excluding the diagnosis should be mentioned in the conclusion. Relevant findings that do not support the clinical suspicion and point towards other disease category as well as advice on additional investigations should be part of the conclusion.

Susac Syndrome

Retinocochleocerebral vasculopathy; SICRET syndrome (small infarction of cochlear, retinal and encephalic tissue syndrome); RED-M (microangiopathy with retinopathy, encephalopathy, and deafness).

Definition and Clinical Highlights

Susac Syndrome (SS) is a rare disease characterized by the clinical triad of encephalopathy, including focal or multifocal neurological manifestations, psychiatric features and headache, hearing loss and branch retinal arterial occlusions (BRAOs) that affect mostly middle-aged women. The clinical triad is considered to be pathognomonic; however, only a minority of the patients present with the complete triad at disease onset. From unknown etiology, it is most likely an autoimmune-mediated endotheliopathy that affects the microvasculature (precapillary arterioles) of the brain, retina, and inner ear leading to ischemia. MRI, retinal fluorescein angiography, and audiometry are important to establish the diagnosis. Differential diagnosis with other neurological, ophthalmological, and otological entities is challenging. Although some damage may be irreversible, early diagnosis allowing early and aggressive therapy with administration of immunosuppressive is crucial for clinical improvement or recovery.

Basic Epidemiology and Demographics

SS is an infrequent disease and very limited epidemiological data are available. The true incidence is unknown being the number of reported SS in the literature slightly above 300.

SS affects women 3–4 times more frequently than men and the first symptoms usually manifest between 20 and 40 years of age. Only 13% of the patients present initially with a complete triad of symptoms with a reported mean delay of 5–7 months between the first symptoms and the developing of a complete clinical triad. In some series, men present with the complete triad of symptoms more often than women, suggesting that although more prevalent in females is probably more severe in males (Greco et al. 2014).

Pathophysiology and Pathology

SS is probably an immune-mediated endotheliopathy leading to the damage and inflammation-related occlusion of the microvasculature (precapillary arterioles) of the brain, retina, and inner ear. SS pathophysiology is still unclear. Antiphospholipid and/or antiendothelial cell antibodies may play a role in endothelial cell injury in SS, but other entities such as idiopathic vasospasm, hypercoagulable phenomena, and viral infection also might play a role (Greco et al. 2014). Some reports have linked SS with pregnancy and hormonal therapy.

Brain biopsy material shows perivascular inflammation of small vessels and microinfarcts. Arteriolar wall proliferation, lymphocytic infiltration, and basal lamina thickening are present, but in contrast with vasculitis, absence of necrosis in the vessel walls is the rule. Capillary occlusion has also been reported involving the leptomeninges, retina, apical turns of the cochlea, and semicircular canals.

Clinical Features

The classical clinical presentation consists of encephalopathy, visual disturbances, and sensorineural hearing loss (Susac et al. 2007). Headaches, including migraine-like and oppressive headaches, most likely related with damage to leptomeningeal vessel, are a very frequent symptom in SS and may occur up to 6 months before the onset of other symptoms. A variety of additional neurological acute deficits or subacute findings may develop, including cognitive dysfunction and psychiatric symptoms. MRI brain is the modality of choice for demonstrating brain involvement (Fig. 8).
Fig. 8

Typical features of Susac syndrome with presence of centrally located hyperintense lesions in the center of the corpus callosum (snowballs) on sagittal FLAIR image (a) associated with BRAO (b) and Gass plaques (c) on ophthalmologic examinations

Visual disturbances, most commonly, scotoma and photopsia, are secondary to branch retinal artery occlusions (BRAOs), which may be extensive or subtle, unilateral, or bilateral and should be documented by fluorescein angiography (FLA) or funduscopy. Other retinal ophthalmological findings are briefly summarized on Table 9.
Table 9

Summary of clinical and paraclinical findings in Susac syndrome

Encephalopathy

MRI findings

Headaches:

 Migraine-like or oppressive

Neurological deficits:

 Motor and sensible deficits

 Aphasia, dysarthria

 Gait and bladder disturbances

Cognitive dysfunction:

 Memory loss

 Confusion

 Dementia

Psychiatric symptoms:

 Paranoia

 Personality and behavioral changes

T2/Flair lesions central in the corpus callosum (snowball) (100%)

T1 hypointense round or linear holes (spikes) in the corpus callosum

White matter lesions periventricular, subcortical and in corona radiata

T2 lesions in the deep gray matter (70%)

Perivascular and leptomeningeal enhancement (30%)

Old or recent lacunar infarcts

Corpus callosum and brain atrophy (in chronic stages)

Spinal leptomeningeal enhancement

Diffusion tensor imaging (DTI): mean fractional anisotropy reduction in the genu of the corpus callosum

Visual disturbances

Ophthalmological examination

Scotoma, blurred vision, photopsia

 Uni or bilateral

 Small to extensive deficits

Funduscopy and fluorescein angiography: branch retinal arterial occlusions, Gass plaques (plaque-like, chronic accumulations of serous material that has extravasated through the loosened “tight junctions” between endothelial cells), arterial wall hyperfluorescence near the site of obstruction

Optical coherence tomography (OCT): sectorial damage of the inner retinal layers from the retinal nerve fiber layer through to the outer plexiform layer

Spectral domain OCT (SD-OCT): reliably detect highly disease-specific retinal pathologies

Hearing loss

Otological examination

Sensorineural hearing loss

 Bilateral and asymmetric

 Low-medium frequencies

Tinnitus

Peripheral vertigo

Audiogram: Pure-tone or speech for diagnosis of hearing loss

Caloric testing of the vestibular organ, nystagmography, and/or vestibular evoked myogenic potentials for diagnosis of peripheral vertigo

Laboratory

Cerebral spinal fluid: Lymphocytic pleocytosis and elevated protein levels. Oligoclonal bands and elevated immunoglobulin G index are rarely found

No serological biomarkers

Sensorineural hearing loss, caused by occlusion of the apical cochlear arterioles and those of the semicircular canals, typically affects low or middle frequencies and tends to be bilateral and asymmetric. Presentation can be sudden and hearing loss may be mild and insidious or may be fluctuating and suggestive of Meniere’s syndrome. Hearing loss should be objectified by audiogram. Table 9 shows other otological findings that may be present in SS.

Laboratory test is not specific and there are no serological biomarkers. Nevertheless serum and CSF are necessary to exclude differential diagnosis.

Imaging Features

In SS involvement of the corpus callosum is the rule. The most characteristic MRI abnormality is the presence of T2/FLAIR hyperintense roundish lesions (snowballs) in the central portion of the corpus callosum best recognizable on sagittal T2-weighted or FLAIR images (Susac et al. 2003) and sometimes involving its entire thickness. These snowballs result in residual holes, especially in the splenium of the corpus callosum. Linear defects of the corpus callosum (spokes) or wedge-shaped lesions extending from the roof of the corpus callosum are also commonly seen. Focal T2 lesions in the white matter (periventricular, subcortical, and centrum semiovale) are very frequent and involvement of the gray matter is a common finding (above 70%). MRI may show multiple microinfarcts and lacunes in different stages, some of them with diffusion restriction and contrast enhancement. Leptomeningeal enhancement can be seen in up to 30% of the cases, while parenchymal enhancement has been described in 30–70% of cases. Atrophy of the corpus callosum and mean fractional anisotropy reduction in the genu of the corpus callosum have been documented. Enhancement of nerve roots in the cauda equine has been documented in patients with SS presenting with cauda syndrome. Figure 9 illustrates radiological findings in SS.
Fig. 9

Set of axial FLAIR images showing multiple hyperintense lesions throughout both hemispheres and in the corpus callosum (a, b, c, d). Contrast-enhanced T1-weighted images show multiple foci of enhancement (e, f, g). Notice snowballs appearance of the lesions on sagittal FLAIR image (h) which in association with hearing loss and visual disturbances are characteristic for Susac syndrome. (Courtesy of Alex Rovira)

Differential diagnosis includes a wide range of pathologies including most commonly MS. Most important differential features are compiled on Table 10. Other entities to consider in the differential diagnosis in SS include acute disseminated encephalomyelitis (ADEM), vasculitis of the CNS, and infectious encephalitis. To prevent misdiagnosis and delayed treatment, criteria for definitive, probable, and possible diagnosis of SS have been proposed by the European Consortium of Susac syndrome (Kleffner et al. 2016). From a radiological perspective, it is important to underline that the presence of typical findings on cranial MRI, hyperintense, multifocal, round small lesions, at least one of them in the corpus callosum (“snowball”) on T2-weighted sequences are included in the diagnostic criteria and are mandatory to establish the diagnosis of definite Susac syndrome.
Table 10

Differential features between Susac syndrome and multiple sclerosis (MS)

 

Susac

MS

Corpus callosum

Central or entire thickness

Callososeptal interface

More frequently genu and body

Deep gray matter

Common

Uncommon

Lacunes

Frequent

Absent

Leptomeningeal enhancement

Common

Rare

Parenchymal enhancement

Common, focal

Focal or ring like

Spine:

  

Spinal cord lesions

Leptomeningeal enhancement

Absent

Present

Frequent

Absent

Imaging Strategy

MRI is the modality of choice when a SS is suspected though CT may be performed in emergency setting in patients presenting with acute symptoms. Sagittal FLAIR images, essential for the recognition of lesions centrally located in the corpus callosum, T2-weighted sequences, for demonstration of gray matter involvement, and DWI, for assessment of acute ischemia, should be included in the MRI scan protocol. Additional spinal imaging is required if patients present with spinal cord or cauda syndrome as well as if the differential diagnosis with MS or other disorders is unclear.

Recommended Brain MRI Protocol (Susac)

Mandatory Sequences

  • Axial unenhanced T1-weighted

  • Axial T2-weighted

  • Sagittal FLAIR or 3D FLAIR

  • Axial diffusion-weighted (DWI)

  • Axial contrast-enhanced T1-weighted or 3D contrast-enhanced T1-weighted

Optional Sequences

  • DTI

If spinal imaging is indicated, MRI protocol should include sagittal T2-weighted or T2/PD-weighted or STIR, and contrast-enhanced T1-weighted sequences.

DSA is not indicated since the arterioles involved are too small to be visualized on angiograms.

Radiological Report and Checklist

Recommended structure of the radiological report includes description of characteristic radiological findings related to Susac (checklist) and it is as follows:
  • MRI technique: anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal)

  • MRI findings: Presence of absence of following findings should be mentioned to support or exclude the diagnosis of SS. If present, describe signal intensity pattern, define extension, location, and morphology
    • Relevant findings relate to SS:
      • Lesion in the central corpus callosum

      • White matter lesions periventricular, subcortical, corona radiata

      • Lesions in the central gray matter

      • Acute infarcts

      • Old lacunes

      • Leptomeningeal or parenchymal enhancement

      • Spine: spinal leptomeningeal enhancement

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant.

  • MRI conclusion: A final conclusion should always be included in the report. Level of suspicion of the findings being related to SS, differential diagnosis, and/or additionally investigations when necessary should be mentioned.

CLIPPERS

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.

Definition and Clinical Highlights

CLIPPERS is a recently described relapsing-remitting inflammatory CNS disorder of unknown etiology predominantly affecting the brainstem and cerebellum with or without involvement of supratentorial structures such as basal ganglia, thalamus, corpus callosum, cerebral white, and spinal cord. Clinically is characterized by subacute onset of symptoms related to brainstem, cranial nerve, and cerebellar involvement and radiologically, on MRI, by the presence of punctate and curvilinear gadolinium enhancement “peppering” the pons (Pittock et al. 2010). There are no serum or CSF biomarkers. Diagnosis is difficult and includes extensive investigations to rule out other diseases, including lymphoma, vasculitis, and other immunological disorders. It is a treatable disorder characterized by clinical and radiological response to corticosteroids. Whether CLIPPERS represents a separate new disease or a syndrome with various etiologies is still unclear.

Epidemiology and Demographics

Epidemiological data are scarce, to date only a few cases of CLIPPERS have been described in the literature. Available data show that the usual age of onset of symptoms is in midlife, with a wide range from 16 to 86 years, and there is no clear gender predilection.

Pathological Features and Pathophysiology

Although the pathophysiology of CLIPPERS remains unknown, the pathological features, CSF findings, and the clinical-radiological responds to steroids suggest an autoimmune-mediated or other inflammatory pathogenesis (Dudesek et al. 2014). Its predilection for brainstem involvement remains unclear.

Pathology of biopsy specimens from CLIPPERS patients shows a perivascular (from both small arteries and veins) infiltration compose of predominantly of CD3+ and CD4-positive T cells, histiocytes, and activated microglia accompanied frequently by parenchymal diffuse infiltration most commonly in the white matter and occasionally in the gray matter and leptomeninges. Monoclonal or atypical lymphocyte population or characteristic histological features of vasculitis and/or granulomas are absent (Simon et al. 2012). Although no specific, the histopathological findings on biopsy may add final support to the diagnosis but most importantly may exclude alternative diagnosis.

Clinical Features

In CLIPPERS the onset of symptoms tends to be subacute and the clinical course is relapsing-remitting. The most common clinical presentation is a subacute onset of ataxia and dysarthria. In fact, ataxia and dysarthria are so typical that their absence should be considered nonclassic for CLIPPERS (Dudesek et al. 2014). A wide range of other symptoms related with brainstem, cranial nerve, and cerebellar involvement may occur and present in various combination or more rarely in isolation. Other features related to long tract affections and/or spinal cord syndrome, pseudobulbar symptoms, cognitive dysfunction headaches, and fatigue have been described (Table 11).
Table 11

Common and generally absent features in CLIPPERS

Common features

Generally absent features

Brainstem-, cranial nerve-, and/or cerebellar dysfunctions

 Ataxia

 Dysarthria

 Dysarthria

 Diplopia/oculomotor

 Nystagmus

 Altered sensation or tingling of the face

 Vertigo

Long tract affections and/or spinal cord syndrome

 Paraparesis

 Spasticity, long tract motor signs

 Altered sensation/sensory loss of extremities

Cognitive dysfunction

 Cognitive deficits

 Dysexecutive syndrome

 Psychomotor slowing

Possible additional features

 Pseudobulbar

Symptoms/signs

 Quantitative consciousness

 Fever, night sweating, weight loss

 Lymphadenopathy

 Arthritis

 Uveitis

 Oral and/or genital ulcers; pathergy

 Sicca syndrome (keratoconjunctivitis sicca, xerophthalmia)

 Meningism

 Altered symptoms of hypothalamic dysfunction (polydipsia/polyuria)

Cerebral spinal fluid

 Marked pleocytosis (>100/μl) or malignant cells

Table modified from Dudesek et al. (2014)

Clinical improvement of resolution when treated with steroids is one of the hallmarks from this entity. Lack of improvement or worsening should be considered an alert feature that points against CLIPPERS. Symptoms may relapse when withdrawing steroid treatment.

Blood and CSF investigations are nonspecific. Mild pleocytosis, mildly elevated protein, and/or CSF oligoclonal bands may be present. Laboratory tests aim to rule out evidence of specific inflammatory, demyelinating, infectious, neoplastic, paraneoplastic, or vasculitic disorders.

Imaging Features

MRI features are incorporated in the definition of CLIPPERS. The signature finding is the presence of multiple punctuate or curvilinear enhancement peppering the pons with or without involvement of the cerebellar peduncles and cerebellum (Fig. 10). The enhancement may extend into the cerebral hemispheres (thalamus, internal capsule, corpus callosum, basal ganglia, white matter) and spinal cord. These punctuate enhancement lesions are typically small (<3 mm), bilateral, and symmetrical distributed and do not show associated vasogenic edema or mass effect. Characteristically lesion load and size decrease as the distance from the pons increases (Pittock et al. 2010). On T2-weighted sequences lesions present as small focal or confluent lesions with mild to moderate hyperintensity and the extension is restricted to the area of enhancement. When spinal cord lesions are present, they tend to follow the same pattern as brainstem lesions. Lesions typically rapidly diminished and resolved after treatment with steroids (Fig. 11). In chronic stages, pontocerebellar and spinal cord atrophy may be observed. Findings that differ from those described above should be considered as nonclassic for CLIPPERS and an alternative diagnosis should be investigated. Differential diagnosis is large, most frequently includes vasculitis, CNS lymphoma, intravascular lymphoma, lymphomatoid granulomatosis, neurosarcoidosis, Sjögrem, and CNS demyelinating disease (Simon et al. 2012). Brain biopsy should be considered prior to treatment. Classic and nonclassic radiological findings are summarized on Table 12.
Fig. 10

Classical findings in CLIPPERS. Set of T2 images show the presence of multiple, small, partially confluent, T2 mild hyperintense lesions centered at the level of the brainstem (a, b) extending into the middle cerebellar peduncles (a) and the deep white matter (c). Set of contrast enhanced T1-weighted (fat saturation) images show punctuate enhancement peppering the brainstem (e, f) and extending into cerebellar hemispheres (e, f) as well as thalami, basal ganglia and deep white matter (g, h). Notice that the T2 lesions do not exceed the extension of the enhancement and absence of mass effect or vasogenic edema

Fig. 11

Right set of images show the typical findings on CLIPPERS on contrast enhanced T1- weighted images (a, b) and T2 weighted images (c, d). Left set of images demonstrate complete resolution of enhancement (e, f) and T2 findings (g, h) after treatment with steroids

Table 12

Classic and nonclassic findings in CLIPPERS

 

Classic

Nonclassica

Location

Brainstem and cerebellum

May extend throughout brain and spine

Cortical, leptomeningeal, dural, hypothalamic-pituitary

Enhancement

Punctate/nodular enhancement <3 mm

Peppering brainstem

Lesion burden tends to be lower further away from the pons

Ring enhancement/internal necrosis

Larger asymmetric lesions

Other than classic pattern

T2 signal intensity

Mild to moderate hyperintense

Extension limited to the area of enhancement

Strong hyperintensity

Extension larger than the area of enhancementb

Spinal cord

Similar T2 and enhancement pattern to brain lesions

Other than classic pattern

Secondary features

Absence of vasogenic edema

Absence of mass effect

Absence or restricted diffusion

Vasogenic edema

Mass effect

Restricted diffusion

Response to steroids

Rapid response

Resolution

No rapid resolution

Worsening of findings

Change in the predominant enhancement pattern

aConsider another diagnosis

bUsually in combination with asymmetric larger enhancing lesions

Imaging Strategy and Recommended Protocol

Brain MRI findings are essential part for the diagnosis of CLIPPERS. T2-weighted and contrast-enhanced T1-weighted, preferably with fat suppression techniques, are imperative to depict CLIPPERS’s signature findings, but MRI protocol should be also suitable to asses other possible mimickers. Imaging of the spinal cord might help in the differential diagnosis.

Recommended Brain MRI Protocol (CLIPPERS)

Mandatory Sequences

  • Axial unenhanced T1-weighted

  • Axial PD/T2-weighted

  • Axial FLAIR or 3D FLAIR (preferably)

  • Axial diffusion-weighted (DWI)

  • Axial contrast-enhanced T1-weighted (preferably with fat suppression) or 3D contrast-enhanced T1-weighted

Optional Sequences

  • Spinal cord sagittal PD or STIR/T2 and contrast-enhanced T-weighted

Radiological Report and Checklist

Recommended structure of the radiological report includes description of characteristic radiological findings related to CLIPPERS (checklist) and it is as follows:
  • MRI technique: Anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal)

  • MRI findings: Systematic and comprehensive description of all the relevant imaging findings related to possible CLIPPERS. If present describe intensity pattern, define extension, location, and morphology of findings
    • Absence or presence of classic MRI features:
      • Small mild T2 hyperintense lesions bilateral and symmetric in the brainstem; lesion burden decreases further away from pons

      • Small enhancing foci peppering the brainstem

      • Concordance extension between T2 lesions and enhancement

    • Any nonclassic finding should be mentioned in the report:
      • Cortical, leptomeningeal, dural, hypothalamic-pituitary involvement

      • Ring enhancement or internal necrosis

      • Larger asymmetric lesions; extension larger than the area of enhancement

      • Lesions markedly T2 hyperintense

      • Vasogenic edema

      • Mass effect

      • Restricted diffusion

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant.

  • MRI conclusion: A final conclusion should always be included in the report. Define if the radiological findings support the diagnosis of CLIPPERS. If any nonclassic findings are present, alternative diagnosis fitting with those findings should be mentioned.

Since response to corticoids is one of the features that defines CLIPPERS, follow-up MRI is mandatory. MRI protocol should include same sequences, contrast dosis, and timing for an optimal comparison. Radiological report should specifically describe if lesions decreased, resolved, increased, or changed in MRI pattern. Nonclassic response should suggest an alternative diagnosis.

Neurosarcoidosis (NS)

Definition and Clinical Highlights

Sarcoidosis is a rare, multisystem granulomatous disease of unknown origin characterized pathologically by the presence of noncaseating granulomas. The respiratory and lymphatic systems are affected most frequently. When CNS is involved, neurosarcoidosis (NS), cranial neuropathy, commonly facial and optic, is the most frequently reported manifestation, but many other combination of neurological symptoms can be present depending on the site and extent of involvement. Manifestations may be monophasic, relapsing, or chronic and the onset varies from acute to a slow, progressive, or chronic evolution. MRI is the most sensitive tool, in detecting and localizing lesions. Nevertheless diagnosis requires histology and therefore one imaging goal consists in finding suitable lesions for biopsy. Despite no cure, treatment is based on use of corticosteroid and immunosuppressive therapy. Treatment monitoring will focus on detection of activity or complications related with the treatment.

Epidemiology and Demographics

Subclinical CNS involvement is seen in up to 25% of patients in autopsy series, whereas clinically recognizable involvement is estimated in 5–15% of patients with sarcoidosis and usually occurs within the first 2 years of illness. In up to 70% of the cases with neurosarcoidosis, neurological symptoms are the first manifestation of sarcoidosis.

NS can occur at any age and race, but it usually manifests before the age of 40 and affects, like systemic sarcoidosis, more common to African-American (Spiegel et al. 2012). NS appears to be more common in women than in men in most, but not all, series.

Pathological Features and Pathophysiology

Histopathologically sarcoidosis is characterized by the presence of noncaseating granuloma. Several etiologies have been suggested including a common environmental exposure, infectious agent, and/or abnormal immune response probably related with genetic predisposition. Granulomatous inflammation in sarcoidosis is predominantly a T-helper 1 immune response mediated by a complex network of lymphocytes, macrophages, and cytokines (Gerke and Hunninghake 2008). Involvement of the brain parenchyma is probably the result of the extension of granulomatous exudates along subarachnoidal and Virchow-Robin spaces secondary to an initial granulomatous inflammatory meningitis.

Clinical Features

Manifestation of NS are variable and depending on the site and extent of involvement, may be monophasic, relapsing, or chronic and the onset varies from acute explosive to slow progressive. Cranial neuropathy is the most frequent manifestation of NS being the facial and the optic nerve those most commonly involved. Aseptic meningitis, acute or chronic, hydrocephalous, areabsortive or obstructive, endocrinological manifestations, symptoms of space-occupying mass, seizures, encephalopathy, psychiatric disorders, a wide variety of spinal cord syndromes, peripheral and small fiber neuropathy (Hoitsma et al. 2010) may occur (Table 13).
Table 13

Summary of clinical manifestations in neurosarcoidosis

Clinical manifestations

Features

Cranial neuropathy

Facial nerve and optic nerve most common

Acute of chronic meningitis

Most frequently in the basal leptomeninges (manifest with cranial nerve palsies)

May lead to hydrocephalous

Hypothalamic dysfunction

Due to subependymal granulomatous infiltration in the third ventricle, hypothalamus, and pituitary gland

Intracranial masses

Granulomas may mimic clinical features of space occupying mass

Encephalopathy

Dementia, psychosis, seizures, stroke-like episodes due to vasculitis, neuroendocrine disturbances, leptomeningeal infiltration, mass lesions

Seizures

Related to leptomeningeal infiltration with cortical irritation, parenchymal masses, and metabolic alterations

Spinal cord

Myeloradicular symptoms

Extradural, intradural extramedullary and intramedullary possible involvement

Peripheral neuropathy

Multiple mononeuropathies, polyradiculopathy, Guillain–Barre syndrome, and symmetric distal polyneuropathy

Small fiber neuropathy

Relatively frequent, difficult to asses

Scenarios in which NS should be suspected and neuroimaging is indicated include (Ibitoye et al. 2017):
  1. 1.

    Patient known with sarcoidosis that develop a neurological problem

     
  2. 2.
    Patient not known with sarcoidosis presenting with syndromes highly suggestive of NS
    • Uveoparotid syndrome

    • Cranial oligoneuropathy (for example, a bilateral facial neuropathy)

    • Lesions of the cervical or thoracic spine

    • Cauda equine syndrome

    • Pituitary and/or hypothalamic involvement

     
  3. 3.

    Patients with neuro-inflammatory disease in whom common mimics have been excluded

     

Laboratory findings are nonspecific yet CSF increased angiotensin-converting enzyme liter, and CD4:CD8 ratio and soluble interleukin-2 receptor may be helpful for the differential diagnosis with sarcoidosis mimickers.

Imaging Findings

The most common radiological finding in NS is meningeal involvement. Presence of epidural masses, typically T2-hypotense, most commonly but not exclusively located in the supratentorial space, and basal meningitis are typical features in NS (Fig. 12). Enlargement and enhancement or cranial nerves and perivascular enhancement are common findings. Spinal involvement may occur (Fig. 13). Radiological features are summarized on Table 14.
Fig. 12

Nodular basal leptomeningeal enhancement (a) extending in the medulla oblongata (b) in a patient with systemic sarcoidosis. Neurosarcoidosis may also manifest as dural/epidural T2 hypointense masses, as shown on images c and d. Notice the hypointense T2 signal intensity (c) and the homogenous and strongly enhancement on contrast enhanced T1-weighted image (d) in a patient presenting with bilateral cranial nerve palsy

Fig. 13

Spinal manifestations of neurosarcoidosis. Image a corresponds to a patient with systemic sarcoidosis and presenting with a clinical picture suggestive of a transverse myelitis. Sagittal T2-weighted image shows the presence of a longitudinal extensive myelitis. Image b corresponds to a patient presenting with paraplegia. Sagittal T2-weighted image shows a dural mass at high thoracic level. Notice hypointense T2 signal highly suggestive of sarcoidosis

Table 14

MRI imaging findings, sequences of choice for detection and differential diagnosis in neurosarcoidosis

 

MRI sequence

MRI features

Differential diagnosis

Dural/epidural

C T1 and T2

Dural thickening

Epidural masses

Hypointense T2

Meningiomas, dural metastasis, lymphoma

Wegener, IHP, rheumatoid nodulosis

Leptomeningeal

C T1

Nodular enhancement

Suprasellar and frontobasal

TBC, malignancy, infectious, vasculitis, Wegener

Cranial nerves

C T1

Enlargement CN II, CN VII

Enhancement CN II, CN VII

Optic neuritis, Lyme disease

Perivascular

C T1

Focal enhancement specially basal ganglia

TBC, malignancy, Wegener, infectious, vasculitis

Parenchyma

FLAIR and T2

Focal/peripheral nodule enhancement

Focal white matter lesions

Small vessel disease

Multiple sclerosis

Metastasis

Ventricles

C T1 and FLAIR

Hydrocephalus

Subependymal enhancement due to granulomatous infiltrate

Any obstructive lesion, subependymal metastasis, ventriculitis

Spine

T2 and C T1

Meningeal enhancement or dural mass

Longitudinal extensive myelitis

Infection, malignancies

Neuromyelitis optica, vascular malformations

C T1 contrast-enhanced T1-weighted, IHP idiopathic hypertrophic pachymeningitis, TBC tuberculosis, CN cranial nerve

Orbital findings (thickening and enhancement of the optic nerve), temporal bone findings (thickening and enhancement of the facial nerve), hypothalamic enhancement, abnormalities in the pituitary gland, or parotid swelling are features sometimes recognizable on MRI examination thought frequently only partially scanned.

Imaging Strategy and Recommended Protocol

MRI of the brain is the imaging modality of choice when NS is suspected and contrast-enhanced T1-weighted sequences are mandatory for lesion identification. Spinal cord should be imaged in patients presenting with spinal cord syndrome or if spinal imaging might help with the differential diagnosis. If optic nerve symptoms are the most prominent feature, imaging the orbit is indicated.

Recommended Brain MRI Protocol (Sarcoidosis)

Mandatory Sequences

  • Axial unenhanced T1-weighted

  • Axial T2-weighted

  • Axial FLAIR or 3D FLAIR

  • Axial diffusion-weighted (DWI)

  • Axial contrast-enhanced T1-weighted (preferably with fat suppression) or 3D contrast-enhanced T1-weighted

Optional Sequences

  • Orbital imaging including T1-weighted, STIR or T2 with fat suppression, and contrast-enhanced T1-weighted images with fat suppression

  • Imaging spine including T2-weighted, unenhanced T1-weighted and contrast contrast-enhanced T1-weighted, with or without fat suppression

Thoracic imaging using high resolution CT and PET studies may be necessary for establishing the diagnosis and identifying lesions suitable for biopsy.

The diagnosis is based on three criteria: a compatible clinical and/or radiological picture, histological evidence of noncaseating granulomas, and exclusion of other diseases that may produce a similar histological or clinical picture, including tuberculosis, malignancies, vasculitis, or MS (Table 14).

Radiological Report and Checklist

Recommended structure of the radiological report includes description of characteristic radiological findings related to neurosarcoidosis (checklist) and it is as follows:
  • MRI technique: Anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal)

  • MRI findings: Systematic and comprehensive description of all the relevant imaging findings related to a possible NS. If present, describe signal intensity pattern, define extension, location and morphology
    • Presence or absence of following findings should be mentioned
      • Dural and epidural involvement; hypointense on T2-weighted

      • Leptomeningeal enhancement; basal cisterns

      • Cranial nerves: Optic or facial nerve enlargement and/or enhancement. Check rest of cranial nerves

      • Perivascular enhancement

      • Presence of parenchymal lesions: T2 hyperintense lesions and nodular enhancing lesions

      • Hydrocephalous (subependymal enhancement)

      • Associated finding: Pituitary gland and hypothalamus, orbit, temporal bone and parotid gland

      • Myelitis (longitudinal extensive) and spinal meningeal enhancement.

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant.

  • MRI conclusion: A final conclusion should always be included in the report. Define if the radiological findings support the diagnosis of neurosarcoidosis. In patients not known with sarcoidosis include differential diagnosis and recommendation for additional investigations. In patients known with systemic sarcoidosis, any new brain lesions should be categorized as related to sarcoidosis or to treatment complication.

Immunoglobulin G4-Related Disease

Definition and Clinical Highlights

Immunoglobulin G4-related disease (IgG4-RD) is a recently described multiorgan, immune-mediated, fibro-inflammatory disease of unknown etiology. Histology shows a very characteristic triad of infiltration of IgG4-bearing plasmocytes, storiform fibrosis, and obliterative phlebitis, and it is accompanied by high IgG4 levels in serum. The main clinical feature is the enlargement of the affected organ. Although the more common affected organs are the pancreas (autoimmune pancreatitis), salivary and lacrimal glands (sclerosing sialadenitis/dacryoadenitis), biliary tree (sclerosing cholangitis), retroperitoneum, kidneys, thyroid gland, lungs and aorta, any organ might be affected. Neurological manifestations are uncommon and when present involvement of the meninges (hypertrophic pachymeningitis) and the hypophysis (hypophysitis) are the most frequent findings. Parenchymal brain involvement and changes secondary to associated vasogenic edema, although rare, have been described. Diagnosis requires exclusion of other etiologies and frequently biopsy. It is a treatable condition that responds to glucocorticoids.

Epidemiology and Demographics

Epidemiological data are scarce. Involvement of the nervous system has been reported as rare in all the published series with pachymeningitis as the most common manifestation. It appears to have a male predominance (Baptista et al. 2017) affecting middle-age and elderly subjects.

Pathological Features and Pathophysiology

Pathophysiology is unclear, but studies suggest that IgG4 is probably not the pathogenic factor and that CD4 plays an important role in the developing of this disease.

Three key histopathology features are present in IgG4-RD, lymphoplasmacytic infiltration, obliterative phlebitis, and storiform fibrosis. Obliterative phlebitis consists of partial or complete obliteration of medium-sized veins and commonly appears as an inflammatory nodule next to a patent artery. Presence of obliterative arteritis may occur with absence of vessel wall necrosis as a differential feature with vasculitis (Kamisawa et al. 2015).

Clinical Features

The most frequent neurological manifestations of IgG4-RD are secondary to either hypertrophic pachymeningitis, with headache, cranial nerve palsies (Lu et al. 2014), and less common vision disturbances and motor weakness, or to hypophysitis with hypopituitarism, diabetes insipida or both (Bando et al. 2013). More frequently visual disturbances are secondary to dacryoadenitis or inflammatory eye disease with presence of painless eyelid swelling (unilateral or bilateral), ocular movement restrictions, exophthalmos, ptosis, anopsia, or hemianopsia.

Imaging Features

On MRI hypertrofic pachymeningitis may manifest as focal or diffuse thickening of the pachymeninges, typically hypointense on T2-weighted sequences and enhancing, and result in compression of surrounding structures, specially cranial nerves. Involvement of the spinal nerve roots by paravertebral masses may occur and appear usually hypointense on T2-weighted sequences and show enhancement on contrast-enhanced T1-weighted images. Absence of normal T1 hyperintensity in the posterior pituitary may be identified in patients presenting with diabetes insipida.

When visual disturbances are present, orbital findings with enlargement or lacrimal glands, extraocular muscles or perineural enhancement, scleritis or uveitis may be visible on brain MRI (Fig. 14).
Fig. 14

Orbital manifestations in a patient with IgG4-RD presenting with exophthalmos and visual disturbances. Notice the bilateral enlargement of the lacrimal glands (a, arrows) associated with enlargement of the extraocular muscles (b) and the subtle enhancement around the optic nerves (b, d)

These imaging findings are not specific and many other etiologies including sarcoidosis, histiocytosis, infections, and malignancies may appear with similar radiological findings.

Diagnosis requires presence of IgG4 in serum and histological confirmation.

Imaging Strategy and Recommended Protocol

MRI is superior to CT for the evaluation of meningeal, skull base, and sellar region involvement. MRI protocol should include T2-weighted sequences, since lesions tend to show hypointense signal, and contrast-enhanced T1-weighted sequences.

Recommended Brain MRI Protocol (IgG4-RD)

Mandatory Sequences*

  • Axial unenhanced T1-weighted

  • Axial T2-weighted

  • Axial or coronal contrast-enhanced T1-weighted (eventually with fat suppression) or 3D contrast-enhanced T1-weighted

Optional Sequences

  • Imaging pituitary gland**: Sagittal T1-weighted with fat suppression, coronal T1-weighted and T2-weighted, and sagittal and coronal contrast-enhanced T1-weighted

  • Imaging orbita*** including T1-weighted, T2-weighted, and contrast-enhanced T1-weighted fat suppression (axial and coronal).

* In pachymeningeal presentation; ** mandatory in hypophysitis presentation; *** mandatory in orbital presentation

FDG PET-CT and gallium SPECT/CT have been described as potentially useful tools for diagnosis and monitoring of this disease.

Radiological Report and Checklist

Recommended structure of the radiological report includes description of characteristic radiological findings related to IgG4-RD (checklist) and it is as follows:
  • MRI technique: Anatomical area covered (brain, spinal cord), field strength, type of sequences performed (specific imaging protocol), type and dose of contrast agent used. Degree of assessment (optimal, suboptimal)

  • MRI findings: Systematic and comprehensive description of all the relevant imaging findings related to a possible IgG4-RD. If present describe intensity pattern, define extension, location, and morphology of findings
    • Absence or presence of MRI features related to hypertrophic pachymeningitis
      • Focal or diffuse T2 hypointense, enhancing thickening of the pachymeninges

      • Focal meningeal masses

      • Compression of structure, especially cranial nerves

    • Absence or presence of MRI features related to hypophysitis
      • Enlargement of the pituitary stalk

      • Enlargement of the anterior pituitary (usually T2 hypointense and enhancing)

      • Signal intensity of the posterior pituitary

    • Evaluate the presence of enlargement of the lachrymal gland or any other abnormality in the orbit

    • Any incidental or unexpected finding should be clearly described and interpreted as either clinically relevant or nonsignificant

  • MRI conclusion: A final conclusion should always be included in the report. Define if the radiological findings support the diagnosis of IgG4-RD. In de novo patients’ alternative diagnosis according to the clinical history should be included.

Clinical/Sample Case: Inflammatory and Immunologically Mediated Vessel Diseases

Patient history: 60-year-old male presented at emergency department with subacute onset of headache, dizziness, paresthesias on legs, progressive ataxia, and cerebellar dysarthria. His family and clinical history were unremarkable. CT performed at the emergency department showed a hypodense area in the cerebellum. Routine laboratory evaluation was normal.

Purpose of MRI: Rule out tumoral or inflammatory pathology of the CNS.

Imaging technique: A standard IIMVD was performed including MRA-TOF.
Fig. 15

Findings on initial brain MRI

Findings (figure 15): Area of low intensity in the superior vermis on T1-weighted image. Subtle areas of multifocal brain hyperintensities on T2-weighted and FLAIR sequences (cerebellum and left frontal lobe) and in the subarachnoid spaces (left parietal region). Contrast-enhanced T1-weighted sequence showed multiple areas of enhancement with variable patterns, punctiform, probably perivascular in the corona radiata and linear leptomeningeal in the superior vermis and left parietal region. Lesions did not show restriction on DWI. MRA- TOF did not show any abnormalities.

Interpretation: Multifocal hyperintense T2 lesions in the supra- and infratentorial compartment combined with an enhancement pattern predominantly perivascular and leptomeningeal were considered suggestive of inflammatory vessel disease, possible vasculitis or sarcoidosis. Differential diagnosis included lymphoma or other malignancies, and infectious process. CSF analysis was recommended.
Fig. 16

Second brain MRI performed due to clinical deterioration

Clinical course: CSF analysis showed reactive-inflammatory findings and no evidence of lymphoma. Extensive serological and microbiological analysis was required. Due to clinical deterioration with the development of a new right hemiparesis and aphasia, a new MRI was performed (Fig. 16).

Imaging technique: Vasculitis protocol. Additional MR venography (MRV) was performed.

Findings: New area with subtle T1 hyperintensity in left fronto-parietal region, related to subacute blood products, with extensive edema, located adjacent to the area of abnormal subarachnoid signal intensity visible on previous scan, was identified. Postcontrast T1-weighted images showed increase of leptomeningeal enhancement. No abnormal vessel wall enhancement or areas with restricted diffusion were identified. MR venography showed patency of dural venous sinuses.

Interpretation: Increase of abnormalities specially leptomeningeal enhancement with new subacute hemorrhagic lesion in left fronto-parietal region. No venous thrombosis was identified. Findings are suggestive of inflammatory vessel disease, possible vasculitis. Hemorrhagic lesions were considered not typical for sarcoidosis. DSA was recommended.

Diagnosis: Biopsy instead of DSA was performed. Pathology showed findings consisting with vasculitis. Results of extensive serological and microbiological analysis resulted negative, and no evidence of systemic disease was found allowing the final diagnosis of PACNS.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Radiology & Nuclear MedicineVU University Medical CentreAmsterdamThe Netherlands

Section editors and affiliations

  • Alex Rovira
    • 1
  1. 1.Department of RadiologyHospital Universitari Vall d’HebronBarcelonaSpain

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