Inflammatory and Metabolic Disease

Multiple Sclerosis

MS is a progressive inflammatory, demyelinating and neurodegenerative autoimmune disease of the CNS characterised pathologically by perivascular infiltrates of mononuclear inflammatory cells, demyelination, axonal loss and gliosis, with the formation of focal and diffuse lesions. These lesions mainly affect the optic nerves, brainstem, spinal cord and cerebellar and periventricular white matter, although cortical and subcortical grey matter damage is also prominent. This disease leads to chronic progressive and irreversible disability in most patients.

MS affects more than 2.3 million people worldwide; most often starts between 20 and 40 years of age; affects approximately two/three females per male; and is the leading cause of non-traumatic disability in young adults in Europe and North America. Half of all patients will need assistance with mobility within 20 years of diagnosis, and 50% of patients will eventually develop substantial cognitive deficits. As a consequence, MS is associated with a tremendous loss of health-related quality of life, work productivity and unemployment.

The global median prevalence of MS is 33 per 100,000 people, with a great variance between different countries. North America and Europe have the highest prevalence (>100 per 100,000), while and Asia and sub-Saharan Africa have the lowest. Although the precise cause of MS remains unknown and its pathogenesis is only partly understood, complex genetic traits as well as environmental and infectious factors, such as Epstein–Barr virus infection, vitamin D levels, smoking and latitude determine the susceptibility to develop the disease.

The clinical course of MS can follow different patterns over time, but is usually characterised by acute episodes of worsening (relapses, bouts), gradual progressive deterioration of neurological function or a combination of both these features (relapsing MS). Relapsing MS accounts for 85% of all MS. This clinical form typically presents as an acute clinically isolated syndrome (CIS) attributable to a monofocal or multifocal CNS demyelinating lesion. The presenting lesion usually affects the optic nerve (optic neuritis [ON]), spinal cord (acute transverse myelitis), brainstem (typically an internuclear ophthalmoparesis) and cerebellum (clumsiness and gait ataxia). Over the following years, patients usually experience episodes of acute worsening of neurological function, followed by variably complete recovery (RR course). Clinical and subclinical activity is frequent in this form. After several years of the RR course, more than 50% of untreated patients will develop progressive disability with or without occasional relapses, minor remissions and plateaus (SP course).

As long as the aetiology of MS remains unknown, causal therapy and effective prevention are not possible. Different disease-modifying treatments (DMTs) can alter the course of the disease, particularly in the RR form, by reducing the number and severity of relapses and the accumulation of lesions as seen on MRI, and by influencing the impact of the disease on disability. Patients with the SP form of MS, continuing relapses of activity and pronounced progression of disability may also benefit from immunomodulatory or immunosuppressive therapy.

Primary progressive multiple sclerosis (PPMS) forms comprise approximately 10% of MS cases. This form of MS begins as a progressive disease with occasional plateaus and relapses, and temporary minor improvements. Because patients with PPMS may have less inflammation than those with relapsing MS, they may be less likely to respond to immunomodulatory therapies.

With the availability of expensive DMTs that are thought to be particularly effective in the early phases of the disease, but can be associated with serious side effects, a prompt, accurate diagnosis of MS is more imperative than ever. MS diagnostic criteria are based on demonstration of dissemination in space (DIS) and dissemination in time (DIT) of lesions within the CNS, evidenced by clinical and paraclinical tests. Additionally, the diagnostic criteria require exclusion of alternative diagnoses that can mimic MS either clinically or radiologically. In formal terms, the diagnosis can be made on clinical presentation alone, but MRI should be done to support the clinical diagnosis and rule out other disorders. Furthermore, MRI findings can even replace some clinical criteria in a significant proportion of patients. A summary of the 2017 version of the McDonald criteria for patients with a CIS and PPMS is shown in Tables 58.1 and 58.2 .

Magnetic Resonance Imaging

MRI is the most sensitive imaging technique for detecting MS plaques throughout the brain and spinal cord. T ₂ /fluid-attenuated inversion recovery (FLAIR) images show areas of high signal intensity in the periventricular white matter in 98% of MS patients. This signal increase indicates oedema, inflammation, demyelination, reactive gliosis and/or axonal loss in proportions that differ from lesion to lesion.

MS lesions are generally round to ovoid in shape and range from a few millimetres to more than one centimetre in diameter. They are typically discrete and focal at the early stages of the disease, but become confluent as the disease progresses, particularly in the posterior hemispheric periventricular white matter ( Fig. 58.1 ). The total T ₂ lesion volume of the brain increases by approximately 5% to 10% each year in the relapsing forms of MS.

In general, MS lesions are centred on one or several medium-sized veins and tend to accumulate near the periventricular or outer surfaces of the brain and spinal cord. The lesions are usually round to oval but often show finger-like extensions in the periphery that follow the path of a small or medium-sized veins. Such ‘Dawson fingers’ can be readily appreciated on MRI as ovoid periventricular lesion, whose major axis is oriented perpendicular to the outer surface of the lateral ventricles ( Fig. 58.2 ). With the use of susceptibility weighted imaging (SWI)—a sequence that has shown high sensitivity for detecting iron-containing tissues and small veins, due to their paramagnetic properties—it has been demonstrated that a substantial proportion of white matter MS lesions show a central vein reflecting their perivenular topography ( Fig. 58.3 ). This finding seems to be less frequent in non-MS-related focal white matter brain lesions and, therefore, this central vein sign might discriminate MS from unspecific white matter lesions or from other diseases with similar brain MRI findings, such as NMOSD. Some MS lesions also show a characteristic hypointense rim (likely reflecting iron deposition within activated microglia and macrophagic cells) on SWI ( Fig. 58.4 ), which has been proposed as a marker of inflammatory activity in chronic non-enhancing MS lesions.

MS lesions tend to affect specific regions of the brain, including the periventricular white matter situated superolateral to the lateral angles of the ventricles, the calloso-septal interface along the inferior surface of the corpus callosum ( Fig. 58.5 ), and the juxtacortical white matter ( Fig. 58.6 ).

Cortical lesions are common in patients with MS, particularly in the progressive phases of the disease. However, presently available MRI techniques are not optimal for detecting these lesions, which are best visualised by 3D FLAIR sequences and newer MR techniques such as three-dimensional (3D) double inversion recovery (DIR) ( Fig. 58.7 ), phase-sensitive inversion recovery (PSIR), or magnetisation-prepared rapid acquisition with gradient echo (MPRAGE).

Posterior fossa lesions preferentially involve the floor of the fourth ventricle (and adjacent medial longitudinal fasciculus), the surface of the pons, the intrapontine trigeminal tract, and the middle and superior cerebellar peduncles ( Fig. 58.8 ). Predilection for these areas is a key feature that helps to identify differentiate MS lesions from focal areas of ischaemic demyelination and infarction that preferentially involve the central pontine white matter.

Approximately 10% to 20% of T ₂ hyperintensities are also visible on spin-echo T ₁ weighted images as areas of low signal intensity compared with normal-appearing grey matter. These so-called ‘T ₁ black holes’ have a different pathological substrate that depends, in part, on the lesion age. The hypointensity is present in up to 80% of recently formed lesions and probably represents marked oedema, with or without myelin destruction or axonal loss. In most cases these acute (or wet) ‘black holes’ become isointense within a few months as inflammatory activity abates, oedema resolves and reparative mechanisms like remyelination become effective. Less than 40% evolve into persisting or chronic black holes, which correlate pathologically with the most severe demyelination and axonal loss, indicating areas of irreversible tissue damage.

Chronic black holes are more frequent in patients with progressive disease than in those with RR disease ( Fig. 58.9 ), and more frequent in the supratentorial white matter as compared with the infratentorial white matter and are rarely found in the spinal cord and optic nerves.

Compared with patients with the more frequent relapsing forms of MS, patients with PPMS have smaller T ₂ lesion loads, smaller T ₂ lesions, slower rates of new lesion formation and, less often, gadolinium enhancement on brain MRI, despite their accumulating disability. The presence of extensive cortical damage, diffuse white matter tissue damage, and prevalent involvement of the spinal cord may partially explain this discrepancy between the MRI abnormalities and the severity of the clinical disease.

Focal or diffuse spinal cord signal abnormalities on T ₂ weighted MRI resembling those seen in the brain are detected in up to 90% of patients with a clinical diagnosis of MS and are frequently asymptomatic. Focal MS lesions involve the cervical region more often than the thoracic or lumbar regions, and in sagittal views they characteristically have a ‘cigar’ shape and rarely exceed two vertebral segments in length. On cross-section, they typically occupy the lateral and posterior white matter columns and do not spare the central grey matter. The lesions rarely affect exclusively the anterior columns or the central cord area, and seldom occupy more than half the cross-sectional area of the cord ( Fig. 58.10 ).

Enhancing MS lesions are seen less frequently in the spinal cord than in the brain (new enhancing lesions are four to ten times more common in brain than cord) but are commonly associated with new clinical symptoms and with concomitant enhancing brain lesions.

In some patients, mainly those with a progressive MS disease course, diffuse mild signal abnormalities, better identified on proton-density weighted and short tau inversion recovery (STIR) sequences, predominate along extensive segments of the spinal cord, and sometimes they are the only finding.

Acute ON is the earliest clinical symptom in about 20% of cases of MS and it occurs at some time during the course of the disease in 50% of patients. ON can usually be diagnosed on clinical grounds and MRI is not routinely required for supporting this diagnosis. However, optic nerve MRI can be useful in ruling out an alternative diagnosis, such as a compressive lesion, if the clinical presentation is atypical for demyelinating ON (absence of pain, severe visual loss, progression of visual loss or pain for more than 2 weeks and lack of recovery after 3 weeks).

The most sensitive MRI protocol for detecting acute inflammation of the optic nerve is a combination of axial/coronal fat-saturated T ₂ weighted, STIR or DIR, and contrast-enhanced fat-saturated T ₁ weighted sequences, which typically show swelling and increased signal intensity of the optic nerve with enhancement of the nerve itself ( Fig. 58.11 ).

These features that reflect demyelination and inflammation can be seen in up to 94% of patients with acute ON. The increased T ₂ signal may persist in the long term despite improvements in vision and is commonly associated with nerve thinning. T ₂ signal abnormalities may also be seen in MS patients without a history of ON and no visual symptoms. Alternatively, optical coherence tomography (OCT) and visual evoked potentials (VEP) may be used to detect (subclinical) involvement of the optic nerve.

Gadolinium-enhanced MRI is currently the reference standard to detect active inflammatory lesions in MS patients, identifying disease activity 5 to 10 times more frequently than clinical evaluation of relapses. The following facts apply:

• Contrast uptake is almost constant in recent new T ₂ lesions (relapsing forms).

• Enhancement correlates with an altered blood–brain barrier permeability (opening intercellular tight junctions) in the setting of acute perivascular inflammation with passive leakage of contrast from intravascular to interstitial space.

• Enhancement usually lasts from a few days to weeks (median duration 3.1 weeks; 55% <3 weeks).

• Rarely enhancing beyond 2 to 3 months, which should raise the concern for alternative diagnoses (vascular malformation, neoplasm, [neuro]sarcoidosis, etc.).

• Enhancement may be rapidly suppressed by steroid treatment.

• Enhancement pattern may evolve from nodular to ring over time.

• Incomplete (open) ring enhancement differentiates MS from tumours/abscess ( Fig. 58.12 ). This open ring pattern reflects the less inflammatory reaction of the cortical component of the MS lesion, with less blood–brain barrier disruption and as consequence no contrast uptake.

  

Although enhancing lesions also occur in clinically stable MS patients, their number is much greater when there is concomitant clinical activity. Contrast enhancement is a relatively good predictor of further enhancement and of subsequent accumulation of T ₂ lesions but shows no (or weak) correlation with the progression of disability and the development of brain atrophy.

A summary of MRI appearance of MS lesions is shown in Table 58.3 .

TABLE 58.3

Summary of Magnetic Resonance Imaging Appearance of Multiple Sclerosis Lesions

	Magnetic Resonance Imaging Characteristic of MS Lesions
Location	Supratentorial: juxtacortical (involvement U-fibres); periventricular, trigonum, temporal horns
	Corpus callosum (mainly inferior margin)
	Infratentorial: fourth ventricle, cerebellar peduncles, medulla oblongata, intra-axial segment of the trigeminal nerve and the pial and ventricular surface of the pons
	Cortical lesions (3D FLAIR, DIR, PSIR)
	Deep grey matter infrequent (more in the thalami)
Morphology	Sharp margins, oval/round, perivenular (Dawson fingers)
	Bilateral, slightly asymmetrical
	Later stages may converge
Signal intensity	T 1 : intermediate-low
	T 2 : hyperintense
	Black holes: signal intensity lower than the grey matter on T 1 spin-echo sequences
Enhancement	Nodular/homogeneous or ring-like (closed and open-ring)
	Frequent coexistence of enhancing/non-enhancing lesions
Optic neuritis	Hyperintense on fat-suppressed T 2 , STIR or DIR. Enhancement in acute phase
Spinal cord	Frequently cervical
	Short segment (less than two vertebral segments), less than half of the diameter of the spinal cord (cross-sectional area)
	Commonly peripheral in the spinal cord, most frequently lateral and dorsal white matter columns
	May enhance (and may present focal swelling)
	In progressive MS, diffuse subtle high signal (on T 2 /PD/STIR) and atrophy

3D FLAIR , Three-dimensional fluid-attenuated inversion recovery; DIR , double inversion recovery; MS , multiple sclerosis; PD, proton density; PSIR , phase-sensitive inversion recovery; STIR , short tau inversion recovery; PD, proton density.

Although MS is considered to be an autoimmune-driven inflammatory disease characterised by focal white matter demyelination, it is also apparent that neurodegenerative changes do occur from the earliest phases of the disease, which particularly—as the disease progresses—are partially independent of inflammatory demyelination . It is well accepted that neurodegenerative changes, irrespective of their aetiology, underlie the accumulation of permanent neurological disability that characterises MS.

Brain volume (a marker of brain atrophy) has emerged as the most robust MRI measure to assess the neurodegenerative component of the disease. The aetiology of CNS atrophy, which involves both white and grey matter, is multifactorial and likely reflects demyelination, Wallerian degeneration, axonal loss and glial contraction. Brain atrophy worsens with increasing disease duration, and progresses at a rate of 0.5% to 1.3% per year, although it may also occur early in the disease process (see Fig. 58.9 ). Whole-brain atrophy is a clinically relevant component of disease progression that correlates and predicts subsequent development of disability and cognitive impairment. However, grey matter atrophy is of particular relevance, because grey matter makes up more than half the total brain parenchyma, and tissue damage in grey matter is a large component of overall MS disease burden. Moreover, grey matter atrophy reflects disease subtype, and correlates disability and neuropsychological impairment to a greater extent than white matter atrophy or focal T ₂ lesion load, indicating that grey matter atrophy is a clinically relevant marker of disease progression and cognitive deterioration.

Spinal cord atrophy, mainly affecting the cervical segment, is a prominent MRI finding in MS, particularly in the progressive phases of the disease. This finding reflects the most destructive processes in MS, such as irreversible demyelination and loss of astroglia, neuronal cell bodies and axons. Cord atrophy has a strong impact on clinical disability, regardless of the brain MRI measures.

Several advanced MR quantitative techniques have been also used to measure the more destructive aspects of MS pathology and monitor the reparative mechanisms . These quantitative metrics, which include magnetisation transfer imaging, diffusion-tensor MRI, proton MR spectroscopy and functional MRI, could be used to better understand the natural history of MS and assess the effects of treatment . Although these advanced techniques provide valuable information about the degree and extension of tissue damage and in explaining patients’ clinical outcome, they still have not been validated regarding their actual contribution to patient management, especially in a longitudinal manner, and their use for monitoring of treatment effects is hampered by lack of standardisation. Therefore these techniques cannot be recommended for assessing and monitoring the neurodegenerative component of the disease and for monitoring the treatment response in clinical practice.

MR , Magnetic resonance; MRI , magnetic resonance imaging; MS , multiple sclerosis.

Summary Box: Multiple Sclerosis

• Multiple sclerosis affects more than 2.3 million people worldwide, most often starts between 20 and 40 years of age, affects approximately two/three females per male and is the leading cause of non-traumatic disability in young adults in Europe and North America.

• With the availability of disease-modifying treatments that are thought to be particularly effective in the early phases of the disease, accurate diagnosis of multiple sclerosis is more imperative than ever.

• MRI, which is highly sensitive for detecting multiple sclerosis lesions, has become the most important paraclinical tool for diagnosing and monitoring this disease.

• Multiple sclerosis lesions tend to affect specific regions of the central nervous system, such as the periventricular white matter, the calloso-septal interface, the juxtacortical white matter, the outer margin of the pons, the cerebellum and the dorsal and lateral columns of the spinal cord.

• Gadolinium-enhanced MRI is currently the reference standard to detect active inflammatory lesions in multiple sclerosis patients, identifying disease activity 5–10 times more frequently than clinical evaluation of relapses.

• Although MS is considered to be an autoimmune-driven inflammatory disease characterised by focal white matter demyelination, it is also apparent that neurodegenerative changes do occur from the earliest phases of the disease.

• Brain volume (a marker of brain atrophy) has emerged as the most robust MRI measure to assess the neurodegenerative component of the disease.

• Several advanced MR quantitative techniques can be used to measure the more destructive aspects of MS pathology and monitor the reparative mechanisms. However, these techniques have not been validated regarding their actual contribution to patient management and, therefore, cannot be recommended for assessing and for monitoring the treatment response in clinical practice.

Multiple Sclerosis Variants

Marburg Disease

MD (also termed malignant MS) is a rare, acute MS variant that occurs predominantly in young adults. This entity has a rapidly progressive course with frequent, severe relapses leading to death or severe disability within weeks to months after the onset of clinical signs, mainly from brainstem involvement, or mass effect with herniation. Because MD is often preceded by a febrile illness, this disease also may be considered a fulminant form of ADEM, if it has a monophasic course.

Pathologically, Marburg lesions are more destructive than those of typical MS or ADEM and are characterised by massive macrophage infiltration, demyelination (not restricted to the perivascular areas), hypertrophic astrocytes and severe axonal injury. Despite the destructive nature of these lesions, areas of remyelination are often observed. In MD, MRI typically shows multiple focal T ₂ lesions of varying size, which may coalesce to form large white matter plaques disseminated throughout the hemispheric white matter and brainstem ( Fig. 58.13 ). Perilesional oedema and enhancement are commonly seen.

Schilder Disease

SD is a rare acute or subacute disorder that can be defined as a specific clinical–radiological presentation of MS. It commonly affects children and young adults. The clinical spectrum of SD includes psychiatric predominance, acute intracranial hypertension, intermittent exacerbations and progressive deterioration. MRI shows large ring-enhancing lesions involving both hemispheres, sometimes symmetrically, and located preferentially in the parieto-occipital regions, with minimal mass effect and restricted diffusivity ( Fig. 58.14 ). Histopathologically, SD consistently shows well-demarcated demyelination and reactive gliosis with relative sparing of the axons. Microcystic changes and even frank cavitation can occur. The clinical and imaging findings usually show a dramatic response to steroids.

Baló Concentric Sclerosis

BCS is a rare condition, considered a variant of MS, with characteristic radiological and pathological features. Historically, BCS was considered an aggressive variant of MS that led to death in weeks to months of onset. However, with the widespread use of MRI, this MS variant is frequently identified in patients who have a complete or almost complete clinical recovery. The pathological hallmarks of the disease are large demyelinated lesions showing a peculiar pattern of alternating layers of preserved and destroyed myelin. These alternating bands can be better identified with T ₂ weighted sequences, which typically show thick concentric hyperintense bands corresponding to areas of demyelination and gliosis, alternating with thin isointense bands corresponding to normal myelinated white matter ( Fig. 58.15 ). This pattern also can be identified on T ₁ weighted images as alternating isointense (preserve myelin) and hypointense (demyelinated) concentric rings. These bands, which may eventually disappear over time, can appear as multiple concentric layers (onion skin lesion), as a mosaic, or as a ‘floral’ configuration. The centre of the lesion usually shows no layering because of massive demyelination (storm centre).

Contrast enhancement and decreased diffusivity are frequent in the outer rings (inflammatory edge) of the lesion ( Fig. 58.16 ). This Baló pattern can be isolated, multiple or mixed with typical MS-like lesions. Lesions occur predominantly in the cerebral white matter, although involvement of the brainstem, cerebellum and spinal cord has also been reported. A Baló-like pattern has been described in cocaine abusers, likely induced by an autoimmune reaction to levamisole, which is a common cocaine adulterant.

Pseudotumoural Lesions

MS can present as single or multiple focal brain lesions that may be clinically and radiographically indistinguishable from tumours. This situation is a diagnostic challenge and reasonably calls for biopsy despite clinical suspicion of demyelination. However, even the biopsy specimen may resemble a brain tumour because of the hypercellular nature of the lesions. On MRI, these pseudotumoural lesions usually present as large, single or multiple focal lesions located in the brain hemispheres. Clues that can help to differentiate these lesions from a brain tumour include a relatively minor mass effect or vasogenic oedema, and incomplete ring enhancement on T ₁ weighted gadolinium-enhanced images with the open border facing the cortical/subcortical grey matter (see Figs 58.12 and 58.14 ), sometimes associated with a rim of peripheral hypointensity on T ₂ weighted sequences. Nonetheless, the differential diagnosis between malignant gliomas and pseudotumoural demyelinating brain lesions may be impossible based solely on these conventional MRI features. Proton MR spectroscopy ( ¹ H-MRS) can provide useful additional information, although reports on the diagnostic value of this technique in the differential diagnosis with high-grade gliomas have yielded conflicting results. The ¹ H-MRS pattern of these lesions is characterised by the presence of lactate, macromolecules/lipids, and choline-containing compounds (Cho), with a marked decrease in N -acetylaspartate, a spectral pattern with similarities to the pattern typically described in high-grade gliomas. However, it has been described that an increase in glutamine/glutamate should suggest a pseudotumoural demyelinating lesion, while a high increase of myo -inositol and Cho should suggest a tumoural lesions. Dynamic susceptibility contrast (DSC) MR perfusion imaging has been also used to discriminate active tumefactive demyelinating lesions from high-grade gliomas based on the analysis of the relative cerebral blood volume (rCBV). This difference can be explained by important biological dissimilarities between these two types of lesions, with grade IV gliomas characterised by presence of neoangiogenesis and vascular endothelial proliferation leading to severe increase of rCBV, while tumefactive demyelinating lesions are characterised by intrinsically normal or inflamed vessels with only mild inflammatory angiogenesis, producing a normal or mild increased rCBV ( Fig. 58.17 ).

Neuromyelitis Optica Spectrum Disorders

Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder of the CNS with a predilection for the optic nerves and spinal cord. The discovery of aquaporin-4 (AQP4)-immunoglobulin G (IgG), an antibody against the astrocyte water channel in the CNS, clearly identified NMO as a disease separate from MS.

The high specificity of AQP4-IgG has permitted recognition of a wider spectrum of clinical and radiological features related to NMO. Other sites of CNS involvement not restricted to the optic nerves and spinal cord have been described in AQP4-IgG–seropositive patients such as the diencephalon, brainstem and brain hemispheric white matter. In this seropositive group, coexisting autoimmune disorders have also been recognised, and use of the term NMO spectrum disorder has been adopted.

The incidence of NMOSD is very low and represents less than 1.5% of individuals with demyelinating disorders, although there are important differences in its regional distribution worldwide.

Women are affected more often than men, and the median age at onset is late in the fourth decade, about 10 years later than typical MS. NMOSD appears to be a sporadic disease, although rare familial cases have been reported.

The core clinical characteristics of NMOSD are distinguished by the locations of the CNS lesions: optic nerves, spinal cord, area postrema, brainstem, diencephalon and cerebrum. Optic nerve involvement typically manifests as severe unilateral or bilateral ON. Complete acute spinal cord syndrome is a classic clinical manifestation of spinal cord lesions. Intractable nausea, hiccups and vomiting are related to area postrema involvement (dorsal area of the medulla oblongata). Patients with diencephalic involvement may have narcolepsy, anorexia, inappropriate diuresis, hypothermia and hypersomnia. In brainstem involvement, oculomotor dysfunctions, long tract signs and ataxia can be seen.

Approximately 85% of patients have a relapsing course with severe acute exacerbations and poor recovery, which leads to increasing neurological impairment and a high risk of respiratory failure and death due to cervical myelitis.

The clinical manifestations and prognoses are distinct in seropositive and seronegative NMOSD. AQP4-IgG–seropositive patients usually have more severe clinical attacks, worse outcome, more relapses (81% to 91%), higher female-to-male ratio, and more frequent coexisting autoimmune disorders compared with AQP4-IgG–seronegative patients.

Clinical features alone are insufficient to diagnose NMO; cerebrospinal fluid (CSF) analysis and MRI are usually required to confidently exclude other disorders. CSF pleocytosis (>50 leukocytes/mm ³ ) is often present, while oligoclonal bands are seen less frequently (20% to 40%) than in MS patients (80% to 90%). AQP4-IgG detection using the cell-based assay is reported to have a sensitivity of 76.7% and a specificity of 99.8% for NMO. Recent studies have demonstrated the presence of IgG antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) in AQP4-IgG-negative patients. However, MOG-IgG also has been found in association with other demyelinating disorders, including MS, ADEM, ON and longitudinally extensive transverse myelitis (LETM).

MOG-IgG–positive NMOSD patients usually have younger age of onset and are less frequently female than AQP4-IgG–positive patients and tend to have a monophasic course with a favourable outcome.

The International Panel for NMO diagnosis developed new diagnostic criteria that define the unifying term NMOSD, stratifying patients according to AQP4-IgG status as follows: (a) seropositive patients and (b) seronegative patients or those with unspecified serological status ( Table 58.4 ). In patients with AQP4-IgG, these new criteria require core clinical and MRI findings related to optic nerve, spinal cord, area postrema, brainstem, diencephalic or cerebral presentations. However, more stringent clinical and MRI criteria are required for the diagnosis of NMOSD without AQP4-IgG or when serological testing is unavailable.

ON is characterised on MRI as bilateral and longitudinally extensive optic nerve involvement, usually affecting more than half the length of the optic nerve and predominantly the posterior optic pathway including the intracranial segment of the optic nerves, the chiasm and optic tracts ( Fig. 58.18 ). During the acute and subacute phases, ON is usually identified as a thickened optic nerve with hyperintensity on T ₂ weighted images and enhancement on gadolinium-enhanced T ₁ weighted images. In chronic stages, atrophy of the optic nerves and variable hyperintensity on T ₂ weighted images are frequently observed.

On MRI, the cord lesions in NMOSD typically extend over three or more contiguous vertebral segments and, occasionally, the entire spinal cord (LETM) ( Fig. 58.19 ). The lesions are centrally located (preferential central grey matter involvement) and affect much of the cross-section on axial images. LETM lesions are the most specific radiological finding supporting the NMO diagnosis in adult patients and should prompt physicians to test for AQP4-Ab. Short transverse myelitis (STM) lesions, defined by extension to less than three vertebral segments on MRI, are far more common in MS than in NMOSD. However, it has been shown that STM is not uncommon in the first myelitis episode in AQP4-Ab-positive NMOSD. Subsequent myelitis episodes become longitudinally extensive in more than 90% of these patients. Certain MRI features, such as a central location of the spinal cord lesions and hypointensity on T ₁ weighted imaging, together with brain findings that are not consistent with MS, and an absence of oligoclonal bands in CSF, should raise the suspicion of NMO in patients showing an STM, and indicate testing for AQP4-Ab.

During the acute and subacute phase, the lesions are tumefactive and show contrast uptake. The presence of very hyperintense spotty lesions on T ₂ weighted images (‘bright spotty sign’) is a specific feature that helps differentiate NMO from MS, particularly in patients without longitudinally extensive spinal cord lesions, and likely reflects the highly destructive component of the inflammatory lesion (see Fig. 58.19C ). When the cervical spine is involved, extension into the dorsal brainstem, typically to the area postrema, is commonly observed (see Fig. 58.19 ).

Spinal cord lesions can progress to atrophy and necrosis and may lead to syrinx-like cavities on T ₁ weighted images.

NMO was long considered a disease without brain involvement, and a negative brain MRI at disease onset was considered a major supportive criterion for the diagnosis of NMO. However, various studies have shown that brain MRI abnormalities exist in a significant proportion (24% to 89%) of patients. These brain lesions, which are often asymptomatic, are commonly non-specific. They can be dot-like or patchy, less than 3 cm in diameter, and located in the deep white matter, brainstem, or cerebellum. Nonetheless, some brain MRI features appear to be quite characteristic and distinct from MS lesions. These abnormalities may parallel sites with high AQP4 expression adjacent to the ventricular system (circumventricular organs) at any level, such as the hypothalamus, periependymal areas surrounding the third and lateral ventricles, cerebral aqueduct, corpus callosum and dorsal brainstem adjacent to the fourth ventricle ( Fig. 58.20 ).

Involvement of the corpus callosum has been described in 18% of AQP4-seropositive NMO patients. The lesions typically involved its ependymal surface, with the involvement often affecting most of its length. In acute phases, oedematous and heterogeneous hyperintensity on T ₂ weighted images is usually observed, assuming a typical marbled or ‘arch bridge’ appearance (see Fig. 58.20A ).

In contrast to MS lesions, which are frequently centred by a small vein (central vein sign) and show a characteristic hypointense rim (likely reflecting iron deposition) on SWI, white matter lesions in patients with NMOSDs only infrequently demonstrate these features.

Lesions may also affect areas where AQP4 expression is not particularly high, such as the corticospinal tracts. These lesions, which can be unilateral or bilateral and may affect the posterior limb of the internal capsule and cerebral peduncle of the midbrain, are contiguous and often longitudinally extensive (see Fig. 58.20D ).

Other brain MRI findings described in NMO include extensive and confluent hemispheric white matter lesions and radial hemispheric lesions (sometimes corresponding to an extension of periventricular lesions), which are likely related to vasogenic oedema involving the white matter tracts. These lesions usually do not show mass effect or contrast enhancement, but a ‘cloud-like’ pattern of enhancement, defined as multiple patches of enhancing lesions with blurred margins ( Fig. 58.21 ), might be seen.

Some of the typical brain MRI findings may be specific to clinical presentations, such as intractable vomiting and hiccup (linear dorsal medullary lesions involving the area postrema and nucleus tractus solitarius) or a syndrome of inappropriate antidiuretic hormone secretion (hypothalamic and periaqueductal lesions).

As distinct from MS, ¹ H-MRS findings in NMOSD are normal in normal-appearing brain tissue (grey and white matter), with no N -acetylaspartate decreases or Cho increases. These normal findings occur both in patients with and without brain abnormalities on conventional MRI, indicating that brain tissue is not diffusely affected in NMOSD.

Brain lesions in MOG-IgG–positive NMOSD patients tend to compromise deep grey matter and infratentorial parenchyma, particularly the brainstem and cerebellar peduncles and adjacent to the fourth ventricle, with a poorly demarcated pattern and showing a distinct distribution compared with that in AQP4-IgG–positive patients. Compared with adults, children with MOG-IgG–positive status usually have more numerous and larger brain lesions, especially in the deep grey matter and brainstem. Spinal cord involvement is more likely to be described in lower segments of the spinal cord (conus and thoracolumbar spinal segment) in MOG-IgG–positive patients than in AQP4-IgG–positive patients. Distinct imaging patterns may also be seen in optic nerve involvement. Bilateral and preferable anterior optic nerve involvement is commonly described in MOG-IgG–positive patients. Perineural gadolinium enhancement on postcontrast T ₁ weighted images can be a distinctive imaging feature in these patients

Distinguishing NMOSD from MS is critical, particularly in the early stages, as the treatment and prognosis of these disorders differ. In fact, some evidence suggests that MS-modifying treatments such as interferon-β, natalizumab, and laquinimod exacerbate NMO. By contrast, several immunosuppressants (e.g. azathioprine, rituximab, mitoxantrone) seem to help in preventing NMO relapses.

A summary of radiological differences between NMOSD and MS is shown in Table 58.5 .

Acute Disseminated Encephalomyelitis

ADEM is a severe, immune-mediated inflammatory-demyelinating disorder of the CNS that predominantly affects the white matter of the brain and spinal cord, characterised clinically by new-onset polyfocal neurologic L symptoms, including encephalopathy, coupled with neuroimaging evidence of multifocal white matter inflammatory-demyelinating lesions. In the absence of specific biological markers, the diagnosis of ADEM is based on clinical and radiological features.

This disorder affects children more commonly than adults, with highest incidence in early childhood (median age at presentation is 5 to 8 years), and in contrast to MS, shows no sex preponderance. Incidence of ADEM has been reported to be between 0.3 and 0.6 per 100,000 per year. In most cases (50% to 75%), the clinical onset of the disease is preceded by prodromal symptoms (fever, malaise, headache, nausea and vomiting) related to viral (Mycoplasma pneumoniae) or bacterial infections, usually non-specific upper respiratory tract infections, which functions as a trigger to the inflammatory response. ADEM may also develop following a vaccination, especially against measles, mumps or rubella (postimmunisation encephalomyelitis). Less frequently, ADEM has been described in association with drug use, as a paraneoplastic disorder or in connection with rheumatic diseases.

One to three weeks after the onset of the prodromal phase, patients commonly present with non-specific multifocal symptoms, which develope subacutely over a period of days, frequently associated with encephalopathy (relatively uncommon in MS), defined as an alteration in consciousness (e.g., stupor, lethargy) or as a behavioural change unexplained by fever, systemic illness or postictal symptoms.

The clinical course of ADEM is typically rapidly progressive, with maximal deficits within 2 to 5 days. In the case of a prompt diagnosis and adequate therapeutic support, most children with ADEM have a favourable outcome with full recovery, despite the severity of the clinical presentation.

MRI is extremely important in establishing the diagnosis of ADEM. Unlike the lesions in MS, ADEM lesions are often patchy, and poorly margined ( Fig. 58.22 ). Lesions are usually large, but different sizes can be identified in the same patient (from a few millimetres to several centimetres). In large lesions with a tumefactive appearance, mass effect is typically mild or absent. Ovoid lesions (Dawson fingers) are much less frequent compared with MS.

There is usually asymmetrical involvement of the subcortical and central white matter and cortical grey–white junction of the cerebral hemispheres, cerebellum, brainstem and spinal cord ( Fig. 58.23 ). Lesions confined to the periventricular white matter and corpus callosum are less common than in MS. The grey matter of the thalamus and basal ganglia is often affected, particularly in children, and sometimes in a symmetrical pattern. However, the frequency of thalamic involvement in adult ADEM does not differ from that of adult MS. This can be explained by the fact that involvement of this structure is less common in adult ADEM than in childhood ADEM. Involvement of the cortical grey matter occurs in 30% of cases, and sometimes in the absence of any abnormality of the white matter.

Gadolinium enhancement is uncommon (14% to 30% of cases). Absence of contrast enhancement is especially frequent in cases with small lesions, whose blood–brain barrier integrity usually is rapidly restored in the acute phase of the disease. When present, contrast enhancement typically involves the vast majority of lesions simultaneously. The pattern of enhancement varies and can be complete or incomplete ring-shaped, nodular, gyral or spotty.

Most MRI lesions appear early in the course of the disease, supporting the clinical diagnosis of ADEM. Nonetheless, in some ADEM cases there may be a delay of more than 1 month between the onset of symptoms and the appearance of lesions on MRI, and even this examination may remain normal throughout the course of the illness. Therefore, a normal brain MRI scan obtained within the first days after the onset of neurological symptoms suggestive of ADEM does not exclude this diagnosis.

Opposite to what commonly occurs in MS, monophasic ADEM is not associated with the development of new lesions on sequential MRI performed more than 3 months after the disease onset. However, in around 50% of cases, new lesions and enlargement of existing lesions occur within the first 3 months. Complete resolution of MRI abnormalities within 6 months has been positively associated with a final diagnosis of ADEM, whereas incomplete resolution or persistence of lesions has been associated with a subsequent diagnosis of MS.

The spinal cord is affected in one-third of ADEM patients, predominantly the thoracic region. The cord lesions are typically large, extending over multiple segments (LETM), producing swelling of the cord, and showing variable enhancement. Lesions may be confined to the grey or white matter, or affect both ( Fig. 58.24 ).

In 2012, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) (Krupp et al. 2013) updated the consensus definitions for ADEM, which remains a diagnosis of exclusion. Beyond this, the new ADEM criteria require all of the following:

• First event of encephalopathy plus polyfocal neurological deficits.

• Presumed inflammatory demyelinating cause.

• Encephalopathy (alteration in consciousness or behaviour unexplained by fever, systemic illness, or postictal symptoms).

• Brain MRI abnormalities consistent with demyelination during the acute (3 months) phase.

• No new clinical and MRI findings emerge ≥3 months after initial event.

• Typical lesions on brain MRI:

  • Diffuse, poorly demarcated, large (>1 to 2 cm) lesions.

  • Involving predominantly cerebral white matter.

  • T ₁ hypointense lesions should not be observed.

  • Deep grey matter lesions (e.g. thalamus or basal ganglia) can be present, particularly in children.

ADEM typically follow a monophasic course, with an active phase lasting no more than 3 months, usually followed by clinical and MRI lesion improvement. Confirmation of this monophasic course, which is, per definition, not associated with the development of new T ₂ lesions more than 3 months after disease onset is retrospective and requires prolonged clinical and MRI follow-up. Therefore, it has been recommended to perform a reference brain MR 3 months after ADEM onset. Partial or complete resolution of the initial abnormalities in this reference scan is positively associated with a final diagnosis of ADEM, while the detection of new lesions on early follow-up scans (within 6 months) compared with the reference study indicates a possible relapsing demyelinating disease different from a monophasic ADEM.

This relapsing course may occur in 10% to 29% of patients initially diagnosed with ADEM after a follow-up of 24 months. Most of these patients will be classified as having MS or, less frequently, NMOSD, and only rarely a multiphasic form of ADEM. This multiphasic form, which accounts for less than 4% of ADEM cases, is defined as a new encephalopathic event consistent with ADEM, separated by at least 3 months after the initial illness but not followed by any further events. This second ADEM event can involve either new or re-emergence of prior neurological symptoms, signs and MRI findings.

Relapsing disease following ADEM that occurs beyond a second encephalopathic event is no longer consistent with multiphasic ADEM but rather indicates a chronic disorder, most often leading to the diagnosis of MS or NMO.

Acute Disseminated Encephalomyelitis Variants

Bickerstaff encephalitis.

Bickerstaff encephalitis (BE) is a rare acute syndrome considered a subgroup of ADEM or a subtype of anti-GQ1b IgG antibody syndrome (which also includes Miller Fisher syndrome [MFS]), where inflammation appears to be confined to the brainstem. The syndrome consists of localised encephalitis of the brainstem, commonly preceded by a febrile illness, and has a benign prognosis. Because of the clinical similarities between BE and MFS, some authors believe they are both within the same autoimmune disorder with a broad spectrum of symptoms, which include ataxia, ocular paresis and impaired reflexes (markedly reduced or absent in MFS, and variable in BE). However, in contrast to MFS (which is a peripheral nervous system [PNS] process), BE is a CNS disease. The MRI findings in BE, which are non-specific, include an extensive high signal intensity lesion on T ₂ weighted images affecting the midbrain and pons, and sometimes the thalamus and basal ganglia. The clinical outcome is good and parallels resolution of the MRI lesions ( Fig. 58.25 ). The pathogenesis of BE is uncertain; however, the absence of CSF oligoclonal bands and resolution of the clinical symptoms and MRI lesions suggest an inflammatory origin and make demyelination unlikely.

Acute haemorrhagic leukoencephalitis.

Acute haemorrhagic leukoencephalitis, or Hurst disease, is an uncommon condition that has been observed in patients of all ages. It is thought to be a hyperacute form, or the most severe variant of ADEM that typically follows influenza or upper respiratory infection. This usually fatal disease manifests clinically with abrupt onset of fever, neck stiffness, and hemiplegia, aphasia, brainstem dysfunction, seizures and a decreasing level of consciousness. At autopsy, the brain is congested and swollen, sometimes asymmetrically, and herniation is frequent. Multiple petechial haemorrhages are distributed diffusely throughout the brain. The perivascular lesions consist of ball-like or ring haemorrhages surrounding necrotic venules, sometimes with fibrinous exudates within the vessel wall or extending into adjacent tissue. Perivenous demyelinating lesions, identical to those occurring in ADEM, may also be present and are usually widespread with a pronounced neutrophilic infiltrate. CSF studies show pleocytosis with predominant polymorphonuclear cells in contrast to lymphocytic predominance in ADEM.

MRI shows extensive signal abnormalities affecting the periventricular and subcortical white matter and the cortical grey matter. T ₂ * weighted or susceptibility-weighted MR sequences show multiple haemorrhages in peripheral white matter of the cerebral hemispheres and deep grey matter ( Fig. 58.26 ). Lesions are larger and associated with greater mass effect and oedema than in ADEM and may be symmetrical. Contrast enhancement is variable. Survival depends on early aggressive therapeutic intervention, including combinations of corticosteroids, immunoglobulin, cyclophosphamide or plasma exchange.

Introduction

There are many different causes of CNS vasculitis and the diagnosis should always be suspected in patients who present with severe headache, focal or multifocal neurological dysfunction, altered cognition or consciousness, and non-specific MR or CT imaging findings. More often is the angiographic picture more convincing but the definitive diagnosis can only be made after confirmation by CNS biopsy. As the distribution of the CNS vasculitis can be segmented and focal, a positive biopsy is enough to confirm the diagnosis, while one single negative biopsy does not exclude vasculitis. Vasculitis has been reported to be responsible for 3% to 5% of strokes occurring in patients younger than 50 years of age. The CNS vasculitis can be divided into primary and secondary. There are no exact numbers of the incidence rate of either the primary or secondary vasculitides of the CNS. However, primary CNS vasculitis is relatively uncommon but has a generally worse prognosis.

Primary Angiitis of the Central Nervous System

Primary angiitis of the CNS (PACNS) is a rare and severe idiopathic disorder limited to the CNS that not only results in multifocal inflammation of predominantly small arteries but also can involve medium-sized leptomeningeal, cortical and subcortical arteries and veins. Its hallmark is a striking inflammatory alteration of the affected vessel wall. The mean age of onset is 50 years, and men are affected twice as common as women. The most frequent initial symptoms of PACNS are headaches and encephalopathy. Strokes or persistent neurological deficits occur in 40% of patients, and transient ischaemic attacks have been reported in 30% to 50% of patients but occur in less than 20% of patients at the onset of disease. Less commonly, seizures may also occur as the presenting symptom. MRI of the brain is abnormal in more than 90% of patients, but the patterns are not specific and seen predominantly in the subcortical white matter, followed by the deep grey and white matter, and the cerebral cortex ( Fig. 58.27 ). Other less common findings are infarcts ( Fig. 58.28 ), mass lesions and confluent white matter lesions which can be mistaken for MS, or cortical laminar necrosis. However, intracranial haemorrhages are infrequent ( Fig. 58.29 ). Parenchymal and leptomeningeal enhancement can be seen in up to 35% of patients. The CSF analysis is abnormal in 80% to 90% of the patients, with modest, non-specific elevations in total protein level or white blood cell count. Angiography has a low sensitivity and low specificity. Common findings are those seen in other forms of vasculitis, including single or multiple areas of segmental narrowing and dilatations along the course of a vessel, and vascular occlusions ( Fig. 58.30 ). New MRI techniques such as black-blood imaging or vessel wall imaging might demonstrate enhancement of the vessel wall with a dark vessel lumen ( Fig. 58.31 ).

The final diagnosis of PACNS is established by brain biopsy. The typical biopsy specimen reveals segmental inflammation of small arteries and arterioles, intimal proliferation and fibrosis, with sparing of the media, and in some cases multinucleate giant Langerhans cells. As PACNS is fatal if untreated, patients with biopsy-proven PACNS are treated with cyclophosphamide and prednisone.

The most frequent mimic of PACNS is a group of disorders known collectively as the reversible cerebral vasoconstriction syndrome (RCVS). This syndrome may occur spontaneously, but is usually associated with precipitating factors such as the use of vasoactive substances (ergotamine derivatives, amphetamines and nasal decongestants), contraceptives, recreational drugs (cannabis, ecstasy, LSD, cocaine, alcohol), late pregnancy or puerperium, sexual intercourse and catecholamine-producing tumours. Features that are suggestive of RVCS are acute thunderclap headache, with normal CSF analysis. Brain MRI is usually normal unless complicated by intracerebral (6%) or cortical subarachnoid haemorrhage (22%), cerebral infarct (4%) or posterior reversible encephalopathy syndrome (PRES) (9%). Cerebral angiography in RCVS typically demonstrates multifocal segmental cerebral artery vasoconstriction with no evidence of aneurysmal subarachnoid haemorrhage, which, by definition, substantially or completely reverses within approximately 3 months ( Fig. 58.32 ).

Secondary Central Nervous System Vasculitis

Secondary CNS vasculitis of the nervous system caused by an underlying disease is more commonly seen than PACNS and may involve either the CNS or the PNS or both. They can be further classified into a systemic disorder or infection with or without evidence of systemic vasculitis. One of those related to infection is the one caused by the varicella-zoster virus that might present with fever, headache, seizures or stroke-like symptoms due to encephalitis secondary to vasculitis in large or small vessels. MRI might demonstrate multiple areas of ischaemic and haemorrhagic infarcts of varying size, involving both the grey and white matter. Human immunodeficiency virus and herpes virus infections are other less common viral causes of secondary CNS vasculitis. Uncommonly, CNS vasculitis has been reported in association with some malignant conditions and drug abuse, including amphetamines and related sympathomimetic agents, cocaine and opioid drugs.