Multiple sclerosis

MS is one of the most frequent CNS demyelinating diseases in young adults. The estimated prevalence of MS is more than two million people worldwide (Flachenecker and Stuke, 2008), and its world distribution is influenced by racial and ethnic differences (Rosati, 2001).

I. DEMYELINATING DISEASES OF THE CENTRAL NERVOUS SYSTEM

Disease Reference

Canine distemper encephalomyelitis (Appel, 1969; Beineke et al, 2009) Eosinophilic meningoencephalitis of dogs (Williams et al., 2008) Meningoencephalitis in greyhounds (Callanan et al., 2002) Feline polioencephalomyelitis (Vandevelde and Braund, 1979) Visna encephalomyelitis of sheep (Sigurdsson et al., 1957)

Dalmatian leukodystrophy (Bjerkas, 1977)

Caprine arthritis-encephalitis (Cork et al., 1974)

II. DEMYELINATING DISEASES OF THE PERIPHERAL NERVOUS SYSTEM

Disease Reference

Neuritis of the cauda equina in horses (Cummings et al., 1979) Chronic inflammatory demyelinating

Alaskan malamute polyneuropathy (Braund et al., 1997)

Chapter 1 - Introduction 7

Further, age and gender are important predisposing factors. The clinical onset varies between 20 and 40 years of age. It has been described that MS tends to affect women twice as often as men (Kurtzke, 1993), however, the importance of gender is under discussion since the year of birth seems to have a strong influence on the male:female ratio (Ebers, 2008). The reported estimated MS prevalence in Germany is 120.000 patients, mostly affecting women (71.0%) with an average presentation age of 44 years (Flachenecker and Stuke, 2008).

MS is defined as a chronic demyelinating disease of unknown etiology and possibly multifactorial causes. Genetic disorders (Compston and Coles, 2008), environmental factors (Kurtzke, 2005) and autoimmunity (Bernard and de Rosbo, 1991; Ota et al., 1990), as well as infectious causes have been suggested as demyelination initiators.

The HLA-DRB1 gene on chromosome 6, which codifies for a major histocompatibility complex type II antigen (MHC II), is the strongest genetic factor which influences MS susceptibility (Hauser and Oksenberg, 2006). Infectious agents related to MS, such as bacteria (Chlamydia pneumoniae; Sriram et al., 1999) and viruses (Epstein-Barr virus, herpes-simplex virus, varicella-zoster virus, human herpes virus 6, human corona virus and canine distemper virus) have been reported (Cepok et al., 2005b; Haahr and Hollsberg, 2006; Kurtzke, 1993; Panitch, 1994) but also questioned or excluded (Burgoon et al., 2009; Ebers, 2008; Kurtzke et al., 1988). Also retroviruses, such as the human T-cell leukemia virus (HTLV-1) and the MS-associated retroviral agent (MSRV) have been considered as possible etiologies for MS (Perron and Lang, 2009).

Sensory, motor, and cognitive impairments found in MS lead to a wide range of symptoms including depression, migraine, paraplegia and fatigue, as well as bladder and sexual dysfunctions (Pinkston et al., 2007). Symptoms may emerge suddenly and disappear completely depending on the MS form, but as the disease progresses, permanent neurological problems may appear (Figure 1-1). Some MS patients present the benign form of MS. These patients exhibit a low risk of disease progression and disability over time (Pittock and Rodriguez, 2008). Factors that induce less tissue damage during the inflammatory response in the CNS as well as different regulatory

8 Chapter 1 - Introduction

processes and repair mechanisms seem to be involved in the benign course (Rosche et al., 2003).

Figure 1-1. Symptoms onset and clinical course of multiple sclerosis (Lublin and Reingold, 1996; modified).

Multiple sclerosis has several forms that depend on the clinical onset, in which new symptoms occur discretely (relapsing forms) or emerge slowly (progressive forms). The symptoms onset of MS has been classified as benign, relapsing-remitting, primary progressive, secondary progressive and progressive-relapsing (Lublin and Reingold, 1996).

The most common clinical course of MS is the relapsing-remitting form (RRMS), observed in approximately 80-90% of the MS patients (Rosche et al., 2003). This disease form is characterized by sporadic neurological episodes (relapses) followed by periods of recovery (remissions) resulting in a wide spectrum of disabilities. Females

Chapter 1 - Introduction 9

are twice as often affected by RRMS as males (Trapp and Nave, 2008). The relapse rate varies among patients. On average, two episodes are reported per year and the remitting stage can last for months or years. The common late phase of neurological disability which follows RRMS in approximately 40% of patients is the secondary progressive MS form (SPMS), characterized by a continuous irreversible neurological decline unrelated to the relapses (Ramsaransing and De Keyser, 2006). The less common manifestation is primary progressive MS (PPMS), in which disability progresses continuously without remission (Trapp and Nave, 2008). Approximately, 10-20% of MS patients present the PPMS form. Gender does not appear to play a role for the incidence of this disease form. The SPMS and PPMS forms show a progressive clinical worsening (Bar-Or et al., 1999; Sospedra and Martin, 2005).

The pathologic features leading to permanent neurological disability in MS patients are demyelination and inflammation, as well as axonal damage and neurodegeneration (Trapp and Nave, 2008). Axonal degeneration occurs during acute inflammation (Trapp et al., 1998) and as a consequence of chronic demyelination (Bjartmar et al., 1999; Dutta et al., 2006; Ganter et al., 1999; Lovas et al., 2000).

The pathogenesis of demyelination in MS is not completely understood, however, the inflammatory response, consisting of blood-derived B-lymphocytes, T-lymphocytes and macrophages, has been characterized (Brück et al., 1996; Fraussen et al., 2009). As these immune cells enter the brain, the BBB is compromised and lesion areas become edematous. When the onset of neurological disability is rapid, axonal dysfunction probably results from nerve conduction blocks at the nodes of Ranvier (Lassmann et al., 2001; Trapp and Nave, 2008). Myelin sheaths and oligodendrocytes are destroyed by several mechanisms, associated with distinct pathological features (Brück et al., 2002; Love, 2006; Sospedra and Martin, 2005; Thompson et al., 1997). Accordingly, pathological changes in MS patients are subclassified into four groups (I to IV). Criteria such as plaque formation, apoptosis, and oligodendrocyte changes determine these patterns, stressing the heterogeneous nature of MS (Lucchinetti et al., 1996; Simon, 2005; Table 1-3).

10 Chapter 1 - Introduction

Table 1-3. The different patterns of CNS lesions in multiple sclerosis (Lucchinetti et al., 2000; modified).

Pattern Lesions

I Macrophage and T-cell mediated demyelination II Antibody and complement mediated demyelination III Distal oligodendrogliopathy and oligodendroglial apoptosis IV Primary oligodendroglial degeneration

Different pattern are based on the type of demyelination, oligodendrocytes destruction, and macrophage activation, as well as on the predominant inflammatory cell type and production of immunoglobulins. Pattern I involves macrophages and their associated products, such as tumor necrosis factor (TNF)-α, reactive oxygen intermediates (ROI) and proteinases that are responsible for collateral damage. Complement and myelin-specific antibodies contribute to pathological changes observed in pattern II.

Demyelination in pattern III might be induced by viruses, ischemic events or toxic substances, inducing apoptosis of oligodendrocytes. In pattern IV, myelin destruction is due to a metabolic defect, causing primary oligodendrocyte degeneration (Lassmann et al., 2001).