22 Non-MS Inﬂ ammatory Diseases of the CNS: MR Features in Addition to the White Matter

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Non-MS Inﬂ ammatory Diseases of the CNS: MR Features in Addition to the White Matter 331

22 Non-MS Inﬂ ammatory Diseases of the CNS:

MR Features in Addition to the White Matter

Mario Mascalchi and Fabrizio Salvi

M. Mascalchi, MD

Professor, Sezione di Radiodiagnostica, Dipartimento di Fisiopatologia Clinica, Università di Firenze, Viale Morgagni, 85, 50134 Firenze, Italy

F. Salvi, MD

Sezione di Radiodiagnostica, Dipartimento di Fisiopatologia Clinica, Università di Firenze, Viale Morgagni, 85, 50134 Firenze, Italy

changes and, consequently, will not be addressed. In addition, the CNS damage associated with vasculitis due to the use of illicit drugs such as amphetamines will not be reviewed. On the other hand, the MR ﬁ nd- ings that can be observed besides the white matter damage in antiphospholipid antibody syndrome will be reviewed. Finally, after a brief account on post- infective angiitis, we shall review the wide spectrum of lesions beyond the white matter in sarcoidosis.

Conventional brain MR imaging is here considered the usual protocol that includes T1-weighted, proton density-weighted and T2-weighted (with and with- out inversion recovery RF pulse to attenuate the CSF signal) sequences, T1-weighted images after admin- istration of intravenous gadolinium chelates (at equi- librium) and MR angiography. In addition, the MR imaging ﬁ ndings in the optic nerve and spinal cord will refer to the usual techniques, namely T1-weighted and fat-suppressed T2-weighted images and contrast- enhanced, fat-suppressed T1-weighted sequences for the optic nerve, and T1-weighted, T2-weighted and contrast-enhanced, T1-weighted sequences for the spinal cord.

22.2.1 Systemic Vasculitides

22.2.1.1

Behçet’s Disease

Behçet’s disease (BD) is a systemic infl ammatory dis- ease of unknown aetiology that typically affects young adults in Japan, the Middle East and the Mediterranean area (Inaba 1989) along the ancient Silk Route. Since there is no specifi c laboratory or pathological feature, the diagnosis of BD rests entirely on clinical fi ndings and should satisfy the criteria fi xed in 1989 by an inter- national study group (Lancet). These include recurrent oral ulcerations, plus at least two of the following four features: recurrent genital ulcerations, uveitis, positive pathergy test, and one of the skin lesions among ery- thema nodosum, pseudofolliculitis and papulopustu-

CONTENTS

22.1 Introduction 331 22.2.1 Systemic Vasculitides 331 22.2.1.1 Behçet’s Disease 331 22.2.1.2 Sjögren Syndrome 334 22.2.1.3 Polyarteritis Nodosa 336

22.2.2 Antiphospholipid Antibody Syndrome 336 22.2.3 Post-infective Angiitis 338

22.2.4 Neurosarcoidosis 338 22.3 Conclusions 340 References 340

22.1 Introduction

Many non-multiple sclerosis (MS) inﬂ ammatory dis- eases of the central nervous system (CNS) can cause a multifocal white matter damage of the brain similar to that of MS. In many of them, however, the damage is not conﬁ ned to the white matter. Two of the latter con- ditions, namely systemic lupus erythematosus (SLE) and primary angiitis of the CNS, are dealt with in other chapters herein (Van Buchem: neuro-SLE; Okuda: pri- mary angiitis of the CNS). Herein, we shall review the conventional MR imaging features of the CNS (brain, optic nerve and spinal cord) lesions besides white matter in some of the systemic vasculitis–including Behçet’s disease, Sjögren syndrome and polyarteritis nodosa–which can help in the differential diagnoses of the white matter multifocal lesions (Miller et al.

1987). Other systemic angiitis including rheumatoid

arthritis (Bekkelund et al. 1995), giant cell arteri-

tis, and Wegener disease, albeit capable of producing

brain damage, usually do not determine white matter

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lar lesions. Neurological complications of BD occur in 10–49% of cases, usually after other manifestations of the disease (Inaba 1989).

Brain

The most common MRI ﬁ ndings in BD are focal white matter and grey matter lesions in the cerebral hemispheres and brainstem that can enhance after intravenous contrast administration, when examined in the acute phase (Kocer et al. 1999; Cellerini et al. 2003). A predilection was noted for the mesodien- cephalic junction, with a distribution pattern similar to that of the intra-axial veins, suggesting that in BD the vasculitis is predominantly perivenular (Kocer et al. 1999). In some instances, the mesodiencephalic lesion may present as a large pseudo-tumoral lesion that rapidly resolves after corticosteroids (Kermode

et al. 1989) (Fig. 22.1). In a minority of patients intra- parenchymal haemorrhagic lesions can be detected (Al Kawi 1991; Kocer et al. 1999), possibly reﬂ ect- ing a more necrotizing type of vasculitis, and these appear as hypointense areas due to deoxyhaemoglo- bin in the acute phase and due to haemosiderin in the chronic phase, when they are combined with overt atrophy (Fig. 22.2).

Thrombosis of the intracranial dural sinuses is another neurological presentation of BD and was emphasized as a common occurrence in one series (Wechsler et al. 1993). However, this was not con- ﬁ rmed in other series (Kocer et al. 1999; Cellerini et al. 2003). Interestingly, intracranial dural thrombo- sis generally affects younger individuals and does not occur in BD patients with multifocal brain lesions, and vice versa (Akman-Demir et al. 1999). The MRI features are similar to those in idiopathic intracra-

a b c

d e f

Fig. 22.1a–f. Behçet’s disease. Large pseudotumoral mesodiencephalic lesion in a 34 year-old-man. Axial T2-weighted images at clinical presentation (a, b) show a large hyperintense lesion in the right thalamo-capsular region and cerebral peduncle. Axial T1-weighted images (c, d) after intravenous administration of a gadolinium chelate demonstrate two small peripheral foci of contrast enhancement within the lesion (arrows a, b) and mild mass effect (b). Axial T2-weighted images obtained 3 months after corticosteroid therapy (e, f) show almost complete resolution of the signal change.

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Fig. 22.2a–d. Behçet’s disease. Multiple intra-parenchymal haemorrhages in a 40-year-old woman. Coronal T2*-weighted images (a–d) obtained 7 years after clinical onset of neurological symptoms in a patient with BD demonstrate multiple hypointense foci in the subcortical white matter (arrows in a, c and d) consistent with old haemorrhagic lesions and thinning of the cerebral peduncles (b)

a b

c d

Fig. 22.3a,b. Behçet’s disease. Optic nerve damage in a 37-year-old woman. Coronal STIR images show hyperintensity and slight swelling of the left optic nerve (arrows) extending from the intracranial (a) to the mid-orbital (b) portion. Reprinted from Salvi et al. 1999

a b

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nial venous thrombosis (Condor and Jarosz 2002) (Fig. 22.3) and include intra-parenchymal haem- orrhages with a lobar distribution, haemorrhagic infarcts in areas not corresponding to arterial terri- tories, and signal changes in the thrombosed sinuses that are different depending on the time elapsed between thrombosis and imaging, the MR sequence and the ﬁ eld strength of the magnet. Combination of MR imaging and MR angiography is always rec- ommended in the case of suspicion of dural sinus thrombosis, especially in the acute phase, when the thrombus may exhibit low signal in T2-weighted images due to deoxyhaemoglobin formation and hence be indistinguishable from the normal ﬂ ow- related signal void.

Optic Nerve

BD can affect the optic nerve and represent the ﬁ rst clin- ical evidence of the disease (Salvi et al. 1999). The MR imaging features are similar to those of MS and other secondary vasculitis affecting the optic nerve (Sklal et al.1996) and are better appreciated with fat-suppressed

T2-weighted images. They consist of increased signal intensity of one or both optic nerves (Fig. 22.4) and of contrast enhancement if the examination is performed in the acute phase (Kocer et al. 1999).

Spinal Cord

The spinal cord is involved in less than 20% of patients with BD and clinical signs of neurological involvement (Shakir et al. 1990). The cervical and thoracic segments can be affected, and MRI shows extensive lesions that exhibit contrast enhancement in the acute phase (Fig. 22.5) and almost completely resolve after steroid treatment (Mascalchi et al.

1998a; Kocer 1999).

22.2.1.2

Sjögren Syndrome

Primary Sjögren syndrome (SS) is most frequently a connective tissue disease (Laﬁ tte 2002), and its diagnosis rests on the clinical ﬁ ndings of xerosto- mia and xerophthalmia, positive lacrimal or minor

Fig. 22.4a–e. Behçet’s disease. Spinal cord damage in a 35-year-old woman. Sagittal T2-weighted image at presentation (a) shows an irregular, sharply deﬁ ned area of increased signal in the spinal cord from T6 to T8. Axial T2-weighted images (b, c) show increased signal of the left half of the cord at T7 (b) and of the entire cross- section of the cord except the posterior columns at T7–T8 (c). Sagittal T1-weighted image after intravenous administration of a gadolinium chelate (d) shows moderate patchy enhance- ment of the lesion. Sagittal T2-weighted image (e) 5 months after clinical onset and treatment with corticosteroids shows a normal spinal cord.

Reprinted from Mascalchi et al. 1998a a

d

g b

c d e

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salivary gland biopsy and high titres of antinuclear and anti-SSA (Ro) and anti-SSB (La) antibodies. Neu- rological complications can occur in up to one-third of patients with primary SS, sometimes representing the clinical onset of the disease. Although peripheral nervous system involvement predominates (Laﬁ tte et al. 2001), brain, optic nerve and spinal cord damage may be demonstrated by MRI.

Brain

Brain lesions in primary SS consist of nonspeciﬁ c, mul- tifocal white matter lesions that can be observed in patients with focal neurological deﬁ cit, psychiatric or

cognitive dysfunction alone, or in absence of any clini- cal sign or symptom of CNS dysfunction (Alexander et al. 1988; Pierrot et al.1993; Laﬁ tte 2002). No other brain lesion besides the multifocal white matter changes have so far been documented with MRI.

Optic Nerve

In primary SS, optic nerve involvement is dis- tinctly rare and usually symptomatic (Tesar et al.

1992; Kadota et al. 2002). In the only reported case (Kadota et al. 2002), the MRI features were indistin- guishable from those of other optic nerve vasculitis (Sklar et al. 1996)

a b

c

Fig. 22.5a–c. Behçet’s disease. Thrombosis of the right transverse sinus (subacute phase) in a 23-year-old woman. Axial T1-weighted (a) and coro- nal T2-weighted (b) images demonstrate abnormal hyperintensity in the right transverse sinus suggestive of endoluminal thrombus. The diagnosis is conﬁ rmed by phase-contrast MR angiography (axial view) (c), which shows lack of ﬂ ow in the right transverse and sigmoid sinuses

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Spinal Cord

Three variants can be recognized: (1) acute myeli- tis indistinguishable from acute transverse myelitis (Manabe et al. 2000; de Seze et al. 2001); (2) chronic myelitis similar to that observed in chronic MS (de Seze et al. 2001); and (3) tractopathy reﬂ ecting peripheral nervous involvement (Mori et al. 2001).

The latter is the consequence of sensory neuronopa- thy and consists of diffuse hyperintensity of the pos- terior columns in T2*-weighted images of the spinal cord, better appreciated in the cervical segment. Also, this MRI ﬁ nding is nonspeciﬁ c and can be observed in other diseases causing chronic deafferentation such as Friedreich’s ataxia (Mascalchi et al. 1994).

Interestingly, in many cases of primary SS the spinal cord damage is combined with optic nerve involvement (de Seze et al. 2001; Mochizuchi et al.

2000) featuring a neuromyelitis optica (Devic) syn- drome as in other systemic vasculitides such as SLE.

22.2.1.3

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a rare disease that affects middle-aged subjects and is characterised by focal, segmental necrotising vasculitis of small and medium- sized arteries. The nervous system is usually involved in the form of mononeuritis multiplex, but ischaemic or haemorrhagic strokes and subarachnoid haem- orrhages secondary to rupture of aneurysms, which more commonly involve the renal, hepatic and visceral

arteries, occur in 20–40% of patients, usually after the initial diagnosis is made (Reichhart et al. 2000)

Multifocal white matter lesions were observed in 18% of patients with PAN reviewed by Reichhart et al. (2000) (Fig. 22.6). No case of optic nerve or spinal cord damage has been reported so far.

Brain

Small infarcts in the deep cerebral hemisphere or brainstem related to thrombotic microangiopathy along penetrating arteries, rather than to vasculitis, are the most common MRI features besides white matter damage in PAN (Provenzale and Allen 1996; Reichhart et al. 2000).

Large infarcts and intra-parenchymal haemor- rhages are less common (Provenzale and Allen 1996; Reichhart et al. 2000; De Reuck 2003). On conventional MRI, infarcts show the usual appear- ance of well-deﬁ ned areas of increased signal in T2- weighted images, with a delay of several hours from the clinical onset (Fig. 22.6). Lesion contrast enhance- ment reﬂ ecting damage of the blood–brain barrier can be observed a few days after onset.

22.2.2 Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome (APS) is characterised by arterial or venous thrombosis and pregnant morbidity in the presence of anti-

a b c

Fig. 22.6a–c. Polyarteritis nodosa. Midbrain infarct in an 18-year-old-man. Axial T2-weighted image (a) demonstrates an irregu- lar but well-deﬁ ned focal area of hyperintensity in the left midbrain 5 days after stroke. Axial T1-weighted image after intra- venous administration of a gadolinium chelate (b) shows mild peripheral enhancement of the lesion. In axial proton density image (c), small hyperintense foci are visible in the peritrigonal white matter. The patient underwent catheter angiography, which enabled diagnosis of periarteritis nodosa by revealing a typical small aneurysm in the renal arteries

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cardiolipin antibodies and/or lupus anticoagulant.

Thrombocytopenia may be part of the syndrome (Harris 1986; Trent et al. 1997; Funauchi et al.

1997). APS can occur as either a primary disor- der or be secondary to a connective tissue dis- ease, most frequently SLE (Provenzale et al. 1996;

Sanna et al. 2003).

APS is considered among the immunomediated non-MS diseases of the CNS but is not a vasculitis.

In fact neuropathological examination indicates that the pathogenesis of the cerebral vasculopathy responsible for the cerebral white matter lesions is non-inﬂ ammatory and is associated with reactive endothelial hyperplasia and thrombosis of small arterioles (Westerman et al. 1992). The clinical and laboratory diagnostic criteria were deﬁ ned by an international committee (Wilson et al. 1999).

Recently, APS has emerged as an important cause of stroke in children and young adults, responsible for either arterial or venous thromboses (Takanashi et al. 1995; Kim et al. 2000; Heller et al. 2003). More- over, subclinical CNS involvement in the form of mul- tifocal cerebral white matter lesions mimicking MS is demonstrated by MRI in up to about 40% of patients with primary and secondary APS (Provenzale et al.

1996; Kim et al. 2000) (Fig. 22.7).

Brain

Large and small infarcts in children and young adults show the usual appearance on conventional MRI (Takanashi et al. 1995; Kim et al. 2000) (Fig. 22.8).

Also in the context of strokes in children, diffusion MR imaging has an established role for a more rapid detection of cerebral ischaemia (Gadian et al. 2000).

Haemorrhagic infarcts and intra-parenchymal haemorrhages are demonstrated by conventional MRI as areas exhibiting low signal intensity in T2- weighted images, due to the paramagnetic proper- ties of deoxyhaemoglobin in the acute phase, and high signal intensity in T1-weighted images, due to extracellular methaemoglobin in the subacute phase. Their identiﬁ cation should promote evalua- tion of the patency of the arterial or venous vessels with MR angiography, especially to rule out pos- sible concomitant dural sinus thrombosis (Kim et al. 2000).

Cortical atrophy was reported as an additional ﬁ nding in APS (Kim et al. 2000), but this is nonspe- ciﬁ c, representing a possible effect of chronic steroid therapy as in SLE.

Optic Nerve

The MRI features of optic neuropathy in APS that is nonspeciﬁ c resemble that in other form of “optic neuritis” (Besabs et al. 2001) (Fig. 22.7).

Spinal Cord

Spinal cord damage can be observed in patients with APS as primary clinical manifestation of the disease.

In some instances it shows the typical MRI features of spinal cord infarction (Hasegawa et al. 1993).

a b

Fig. 22.7a,b. Primary antiphospholipid syndrome. Cerebellar infarct in a 26-year-old woman. Sagittal T1-weighted (a) and coro- nal T2-weighted (b) images demonstrate a small focal area of signal change in the right cerebellar hemisphere in the territory of the right anterior cerebellar artery

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In other cases, the features are less distinctive and resemble those that can be observed in other sys- temic vasculitis.

22.2.3 Post-infective Angiitis

Although infective vasculitis can complicate the course of syphilis (meningovascular syphilis), tuber-

culosis (tuberculous meningitis), as well as fungal or bacterial (H. inﬂ uenzae, staphylococcal, pneumococ- cal) meningeal infections, these conditions generally do not determine multifocal white matter damage and, as such, they will not be reviewed here. On the other hand, several viral infections–namely, chicken- pox, measles, rubella and smallpox–can be followed by usually monophasic, multifocal white matter and grey matter damage (acute disseminated encephalo- myelitis) that is addressed elsewhere in this book.

A peculiar case of post-infection vasculitis is the syndrome of herpes zoster ophthalmicus with delayed contralateral hemiparesis (Eidelberg et al.

1986). This association is rare and based upon the usual temporal evolution (ﬁ rst herpes ophthalmicus, second headache and hemiplegia) and the demon- stration of viral particles in the smooth muscle cells of the media and varicella-zoster virus antigens in the media of the affected leptomeningeal vessels. Its pathogenesis is assumed to result from direct inva- sion of arterial walls via viral spread along the intra- cranial branches of the trigeminal nerve.

MR imaging demonstrates typical infarcted lesions with variable distribution in the anterior, middle and posterior cerebral arteries (Fig. 22.9).

22.2.4 Neurosarcoidosis

Sarcoidosis is a multisystem granulomatous disease, usually presenting with hilar adenopathy, pulmo- nary inﬁ ltration, and skin, eye and CNS involvement (Fig. 22.10). Very rarely, neurosarcoidosis may present

Fig. 22.8a,b. Primary antiphospholipid syndrome. White matter and optic nerve damage in an 8-year-old girl. Coronal proton density image (a) shows a focal white matter lesion in the left occipital lobe. Coronal STIR image (b) demonstrates hyperinten- sity of the left optic nerve in its posterior intraorbital portion

a b

Fig. 22.9 Midbrain infarct due to zoster angiitis in a 42-year- old man. Axial T2-weighted image obtained 6 months after right hemiparesis, which came 3 weeks after left zoster ophthalmicus, shows a focal area of signal change and mild thinning of the left cerebral peduncle

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Fig. 22.10a–e. Neurosarcoidosis. Hilar adenopathy, white matter and optic nerve damage and extra-axial mass in a 38-year- old woman. Chest X-ray at presentation (a) shows typical hilar adenopathy (arrows).

Coronal STIR image (b) demonstrates increased signal in the left optic nerve.

Axial proton-density-weighted images demonstrate a focal lesion near the roof of the left lateral ventricle (c) and a focal area of increased signal (arrow) adjacent to the right transverse sinus (d). The latter cor- responds to a small extra-axial enhanced mass (arrow) in an axial T1-weighted image obtained after intravenous admin- istration of a gadolinium chelate (e) a

b

c e

d

in the absence of systemic involvement, and in such cases it requires biopsy for the diagnosis (Seltzer et al. 1991; Cipri et al. 2000; Bode et al. 2001). Most of the CNS lesions in sarcoidosis are markedly sen- sitive to steroids (Lexa and Grossman 1994). How- ever, considering this phenomenon, an indirect clue of neurosarcoidosis can delay the correct diagnosis in patients presenting with other steroid-responsive lesions, in particular tumours including lymphoma and germ cell tumour (Mascalchi et al. 1998b).

Brain

Multifocal, cerebral white matter damage indistin- guishable from that seen in MS is common in neuro- sarcoidosis (Miller et al. 1988; Lexa and Grossman 1994) (Fig. 22.10). Although not speciﬁ c, a key fea- ture indicating sarcoidosis as the possible underlying substrate of the white matter lesions is diffuse focal leptomeningeal or dural enhancement better demon- strated by MRI after intravenous contrast administra- tion (Sherman and Sherry 1990; Khaw et al. 1991;

Seltzer et al. 1991). Additional features that should

raise suspicion of neurosarcoidosis include (Seltzer et al. 1991; Lexa & Grossman 1994): extra-axial contrast-enhancing masses mimicking meningioma (Fig. 22.10), intra-axial enhancing masses, periven- tricular enhancement, enlarged pituitary stalk, and enhancing nerve roots. All lesions, in particular their contrast enhancement, typically regress with steroid therapy (Lexa and Grossman 1994).

Optic Nerve

Optic nerve and chiasma are typical sites of CNS involvement in neurosarcoidosis (Bode et al. 2001;

Carmody et al. 1994). Enlargement of optic nerve and chiasma, associated with signal changes (Fig. 22.10) and contrast enhancement, is seen in the acute phase, and this regresses with steroid treatment. Atrophic optic nerve is observed in the chronic phase.

Spinal Cord

Spinal cord involvement in neurosarcoidosis is

extremely rare (Seltzer et al. 1991; Lexa and

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Grossman 1994). In the few available descriptions it was associated with extensive intramedullary lesions exhibiting contrast enhancement and was difﬁ cult to differentiate from an intramedullary neoplasm.

22.3 Conclusions

In addition to the multifocal white matter damage mimicking MS in secondary vasculitis and APS, the lesions include infarcts, haemorrhages, thrombosis of the intracranial dural sinuses and damage of the optic nerve and spinal cord of uncertain pathophysi- ology. It is noteworthy that the MRI features of these lesions are speciﬁ c, and, hence, the differential diag- nosis relies completely on the integration of clinical and laboratory ﬁ ndings.

The spectrum of lesions in neurosarcoidosis is wide, but coexistence of multifocal cerebral white matter lesions with meningeal enhancement or intra- axial or extra-axial contrast-enhancing masses should raise suspicions that this condition is present. How- ever, lacking systemic manifestations of the disease, diagnosis of neurosarcoidosis still requires biopsy.

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