Книги по МРТ КТ на английском языке / MR Imaging in White Matter Diseases of the Brain and Spinal Cord - K Sartor Massimo Filippi Nicola De Stefano Vincent Dou

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CONTENTS

21.1.2.1Pathology 312

21.1.2.2Antibodies 314

21.1.2.3Cytokines 315

21.2General Diagnostics 316

21.2.1Serum 316

21.2.2Cerebrospinal Fluid 317

21.2.3Neuropsychiatric Testing 318

21.2.4 EEG and QEEG 318

21.3Imaging Diagnostics 318

21.3.1Computed Tomography 318

21.3.2 Digital Subtraction Angiography 319

21.3.3Single-Photon Emission Computed

21.4.4Diffusion-Weighted Imaging 325

21.4.5Perfusion-Weighted Imaging 325 References 325

Reports on the prevalence of SLE range from 1:2000 to 1:4000 and estimations of the female to male ratio vary from 5:1 to 10:1. Systemic lupus erythematosus is more common in people of Hispanic, African, or Asian descent. (Ainiala et al. 2001; Brey et al. 2002; Cervera et al. 2003). Genetic factors may contribute to the development of SLE as is suggested by the observed 25% concordance in identical twins (Giles and Isenberg 2001).

Systemic lupus erythematosus has a wide variety of possible presentations and for classification purposes a patient is considered to have SLE if at least 4 of the 11 criteria listed in Table 21.1 are positive. The mortality in SLE has decreased over the last couple of decades. In a literature-based study by Urowitz and Gladman (2000) published survival rates were collected from 1955 through 1999,showing an increase in 5-year survival from 50 to of 91%.A recent longitudinal study of 1000 patients over 10 years by (Cervera et al. 2003) found a survival rate of 92%; however, with this increase in survival due to better treatment options, these studies also revealed increased morbidity due to serious side effects of drugs such as steroids and cytostatic agents.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a relapsing and remitting course and symptoms based on multi-organ involvement. These symptoms are mainly caused by inflammation of connective tissues due to the presence of antibodies directed against various self-epitopes.

B. J. Emmer, MD, PhD; T. W. J. Huizinga, MD

Department of Radiology, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands M. A. van Buchem, MD, PhD

Professor and Head Neuroradiology, Department of Radiology, Leiden University Medical Center,Albinusdreef 2, Postbus 9600, 2300 RC Leiden, The Netherlands

Many SLE patients develop neurological or psychiatric symptoms during the course of the disease, with reported percentages as high as 75%. Brey et al. found a striking discrepancy between the percentage of SLE patients (28%) that met the accepted neurological criteria for the diagnosis of SLE based on current criteria by the American College of Rheumatology (Tan et al. 1982) and the percentage of SLE patients (80%) that met the more recently developed diagnostic criteria for neuropsychiatric (NP) syndromes associated with SLE using the neuropsychiatric SLE (NPSLE) case definitions (Brey et al. 2002; Table 21.2) In this context, diagnostic definitions for NPSLE as well as exclusion criteria have

been described. In patients with, for example, chorea, it is mandated that conditions such as Huntington disease and Wilson disease and medication associated with chorea be excluded (Huizinga et al. 2001;

The American College Of Rheumatology 1999).

Brey et al.also found a large contribution of NP manifestations to the overall SLE disease activity index (SLEDAI) and SLE damage index (SDI) suggesting that nervous system manifestations are an important source of both acute and chronic morbidity in SLE patients (Brey et al. 2002). The SLEDAI is a validated model of experienced clinicians’ global assessments of disease activity in lupus. It represents the consensus of a group of experts in the field of SLE research (Bombardier et al. 1992). The SDI records damage occurring in patients with SLE regardless of its cause (Gladman et al. 1996).

The NPSLE patients can be subdivided into primary and secondary NPSLE. In 40% of cases NPSLE is the consequence of secondary causes such as metabolic derangement based on SLE damage to organs other than the brain or due to side effects of drug treatment. These conditions are known as secondary NPSLE. In

the remaining 60% of cases the symptoms are ascribed to primary SLE involvement of the brain, which is referred to as primary NPSLE (Rood et al. 1999).

Primary NPSLE can be divided into focal and diffuse disease. The focal disease is strongly associated with the occurrence of thrombo-embolic events. Diffuse primary NPSLE is an elusive group of neurological, psychiatric, and cognitive symptoms (Bosma et al. 2002) comprising conditions such as aseptic meningitis, demyelination syndrome, seizures, cognitive dysfunction, headache, chorea, mood disturbances, myelopathy, cranial neuropathy, anxiety disorders, psychosis, and disorientation (Huizinga et al. 2001). Often no abnormalities are found on conventional neuro-imaging techniques in this group.

It is often unclear whether SLE patients with NP symptoms should be treated, and if so, what kind of treatment should be used. Diagnosing primary NPSLE is a dilemma since symptoms (Table 21.2) are non-specific and because a reliable diagnostic test is lacking. Despite the strict ACR case-definitions and the extensive research, primary NPSLE is still a diagnosis per exclusionem.

21.1.2.1 Pathology

Reports on histopathological findings in NPSLE are scarce. Bland vasculopathy of arterioles and capillaries is the most common finding and is associated with micro-infarction,most frequently observed in the cerebral cortex and brain stem. This vasculopathy is characterized by evidence of necrosis of the vessel wall, extravasations of fibrin and red blood cells, together with endothelial cell proliferation, hypertrophy, and the appearance of fibrin thrombi. Despite incidental perivascular cuffing of arterioles or venules,a true vasculitis, defined as nuclear debris and erythrocytes in the vessel wall,is not frequently demonstrated as a histological finding in NPSLE; however, very few studies are present from patients with acute symptomatology. So, the frequency of vessel involvement during acute symptoms in NPSLE is not exactly known. Rood et al. identified 65 case reports of patients with a histopathological description and acute symptoms in literature from 1966 to 1999 (Rood et al. 2001). In 20 cases there was infection, in 10 cases micro-infarcts and thromboembolic processes, and in 10 cases cerebral vasculitis. In conclusion, cerebral vasculitis is described in histopathological material obtained in patients with acute pathology. With regard to general histopathology studies, these series often describe patients with a history of NPSLE and thus the time course of the pathological changes with regard to symptomatology

is difficult to assess. In such studies the presence of vasculitis is relatively rare (Ellis and Verity 1979;

Hess 1997; Johnson and Richardson 1968; West 1994; Zvaifler and Bluestein 1982).

Although both inflammatory and thrombotic processes have been presumed to underlie the observed histological changes, the etiology of these findings is still unknown. Still, it is clear that complement, antibodies, thrombosis, and cytokines each have their part in the development of NPSLE.

Focal NPSLE can be explained by either a thrombotic event in a large vessel or by multiple events in small vessels. The first option is strongly associated with the presence of antiphospholipid antibodies (aPL). Antiphospholipid antibodies form a separate category within the group of auto-antibodies, and their presence may give rise to the development of thrombo-embolic disease, antiphospholipid syndrome (APS), cardiac lesions, fibromuscular dysplasia, vasculitis, and atherosclerosis. Antiphospholipid syndrome was first described in patients with SLE (secondary APS) but may occur in the absence of any other disorder (primary APS; Scolding and Joseph 2002). In the second option, vasculopathy of small vessels is the most likely cause. Thrombotic events, causing infarction with focal clinical signs, can be seen with conventional imaging techniques. On the other hand, when NP symptoms are due to events in small vessels, there often is a “clinico-radiologi- cal paradox”, i.e., a lack of abnormalities on conven-

tional MR images despite the presence of even severe symptoms.

It is much more difficult to incorporate the different observations in diffuse NPSLE into a single model.Vasculopathy is the most common abnormality at autopsy (Ellis and Verity 1979; Hess 1997; Johnson and

Richardson 1968; West 1994).This vasculopathy can be caused by the presence of autoantibodies and/or circulating cytokines activating the endothelial vessel walls in the brain. (Belmont et al. 1996; Carvalho et al. 1999; Clancy et al. 2001; Hess 1997; Renaudineau et al. 2002). This process may induce activation of inflammatory cells leading to adherence of neutrophils and platelets to the activated vascular wall,occlusion of small vessels,and release of toxic mediators (Belmont et al. 1996). These changes may lead to hypoperfusion (Chen et al. 2002a,b; Colamussi et al. 1995; Emmi et al. 1993; Huang et al. 2002; Kao et al. 1999a; Nossent et al. 1991; Waterloo et al. 2001) and increased permeability of the blood-brain barrier (BBB). Antineuronal antibodies may gain access to the brain through the breached BBB (Rood et al. 2001; Zvaifler and Bluestein 1982) or they may develop de novo beyond the BBB in brain tissue (Rekvig and Nossent 2003). The activity of antineuronal antibodies may give rise to hypometabolism, neuronal loss, demyelination, and eventually atrophy (Bosma et al.2000a,b; Brooks et al. 1997; Chinn et al. 1997; Griffey et al. 1990; Kao et al. 1999a,b; Otte et al. 1997; Sailer et al. 1997; Weiner et al. 2000b).

The mechanism of diffuse NPSLE probably also applies to cases with focal NPSLE without abnormalities on conventional imaging modalities. In these patients it is less likely that a thrombo-embolic process is the cause of the symptoms. In a large group of NPSLE patients markers indicating neuronal damage were markedly increased compared with SLE patients without NP symptoms (Trysberg et al. 2003). These findings agree with quantitative neuroimaging studies, showing loss of cerebral tissue in diffuse NPSLE (Bosma et al. 2000a,b). Furthermore, it has been shown in six patients that markers of neural damage normalize in CSF after treatment with cyclophosphamide (Trysberg et al. 2003).

21.1.2.2 Antibodies

Antibodies play a crucial role in the pathogenesis of SLE.A study by Arbuckle et al. describes the sequential development of autoantibodies years before SLE becomes clinically evident (Arbuckle et al. 2003). These authors suggest a model in which there are at

least three phases. The first phase includes the asymptomatic persons without SLE autoantibodies. In the second phase, defined as benign autoimmunity, there are laboratory changes without corresponding clinical manifestations. Antinuclear, anti-Ro (intracytoplasmatic), Anti-La (lymphocytotoxic antibodies), or aPl antibodies are most likely to be present during this phase. The third phase, defined as pathogenic autoimmunity, is characterized by the presence of the more ominous autoantibodies anti-double-stranded DNA (anti-dsDNA), anti-Sm (intranuclear RNA molecules), and anti-nuclear ribonucleoprotein antibodies.During this stage prominent signs and symptoms appear.

The best proof that antibodies mediate pathology is the transfer of maternal autoantibodies crossing the placenta, causing neonatal lupus erythematosus (NLE). Given the fact that clinical signs and symptoms, such as cognitive deterioration, are extremely difficult to assess in newborns, neuroimaging studies have been performed. Neuroimaging abnormalities, similar to those seen in adults with NPSLE, have indeed been found.These abnormalities often resolve spontaneously after the maternal antibodies gradually disappear from the infant circulation. A correlation with clinical signs has not been observed in NLE (Prendiville et al. 2003).

In NPSLE, associations have been observed between NP symptoms and the presence of aPl antibodies as well as with anti-ribosomal-P protein antibodies (Baraczka et al. 2002; Sabet et al. 1998; Sanna et al. 2003b; Teh et al. 1993; Weiner et al. 2000a); however, these finding have been refuted as often as they have been confirmed and a clear correlation with NP symptoms remains to be established (Hanly et al. 1993; Tzioufas et al. 2000). More recently, neuronal antibodies have been found in NPSLE patients that act against the N-methyl- D-aspartate (NMDA) receptor NR2 (Kotzin and Kozora 2001). Activation of this receptor is known to play an important role in memory and cognitive function (Scherzer et al. 1998).

In addition to anti-endothelial antibodies (Belmont et al. 1996; Carvalho et al. 1999; Renaudineau et al. 2002), anti-cardiolipin antibodies have been implicated in activation of endothelial cells (Hess 1997). Furthermore, aPLs have been found to be associated with epilepsy (Herranz et al. 1994) as well with other CNS manifestations of SLE and MRI abnormalities (Sanna et al. 2003b; Toubi et al. 1995; Whitelaw et al. 1999). IgG and IgA (aCL) have been found to be associated with deterioration of cognitive function in SLE patients (Hanly et al. 1999; Menon et al. 1999).