Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the CNS characterized by demyelination of neurons in the brain and spinal cord white matter. Patients with MS disease, which is characterized by the inflammation, demyelination, and scarring (sclerosis) of nerve tissues, initially experience intermittent and eventually chronic neurological dysfunction. Focal damages to the myelin and axons lead to disruption or blocking of nerve signals within the brain and spinal cord, causing a range of debilitating symptoms. MS is the most common cause of neurological disability in young adults, affecting over two million people worldwide. MS usually arises between 15 and 50 years old, with an average onset of 34. Despite ongoing research, the cause of MS is unknown, and its pathophysiology remains poorly understood. Disease-modifying drugs or symptomatic therapies are the current treatment options to help with the management of symptoms and slowing the progression of the disease and relieving specific symptoms. For health practitioners, it is important to comprehensively understand the condition of their patients with MS, especially when they want to perform an invasive procedure. Understanding how to manage, treat, and care for MS patients will allow practitioners to avoid inflicting harm on patients.
Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS) and is characterized by the inflammation, demyelination, and scarring (sclerosis: Greek for scarring) of nerve tissues.1 , 2 , 3 Myelin acts as a protective sheath over the nerve tissue. Focal lymphocytic infiltration damages the myelin and axons, which leads to disruption or blocking of nerve signals within the brain and spinal cord, causing a range of debilitating symptoms.1
MS is the most common cause of neurological disability in young adults, affecting over 23,000 people in Australia and more than two million people worldwide.4 Most people are diagnosed between the ages of 20 and 40, and roughly three times as many women have MS as men.5
While the earliest descriptions of MS date back to the 14th century, it was French neurologist Jean-Martin Charcot in 1868 who provided the earliest insight into the pathology of MS.6 , 7 At a time when many diseases were generalized and grouped as “nervous disorders,” Charcot described MS as “la sclerose en plaques” and established the Charcot Triad, a set of diagnostic criteria (nystagmus, intention tremor, and scanning speech) to aid in the differentiation between MS and similar diseases of the nervous system.6 , 8 , 9 Through postmortem analysis, Charcot classified the various forms of MS and linked the clinical features of MS with pathological changes in the CNS.6 Charcot was also the first person to diagnose MS on a living patient.10
Since then, research has been focused on achieving a deeper understanding of the mechanisms and processes of MS and on advancing imaging techniques such as MRI.8 Despite ongoing research on MS, the cause of MS is unknown, and its pathophysiology remains poorly understood.4 Currently, there is no cure for MS.3 One leading hypothesis is a combination of genetic disposition in addition to environmental or viral factors.5 Current treatment options such as disease-modifying drugs or symptomatic therapies help to manage symptoms and slow the progression of the disease or relieve specific symptoms.5 This chapter aims to discuss multiple sclerosis, and ultimately, the oral complications and management of a patient with MS receiving dental treatment.
MS is an autoimmune inflammatory disease of the CNS. It is characterized by demyelination of neurons in the brain and spinal cord white matter, resulting in initially intermittent and eventually chronic neurological dysfunction.11 , 12 MS usually arises between 15 and 50 years, with an average age of onset being 34.13
The pathogenesis of MS is complex and involves a range of processes that produce the final sclerotic plaque. MS is initiated by inflammation, followed by demyelination and remyelination. As the disease progresses, astrocytosis and oligodendrocyte depletion occur and toward the final stages, neuronal and axonal loss result.1 Mature oligodendrocytes are responsible for the synthesis of myelin, a fatty substance that envelopes the axons of neurons within the CNS and is vital to the rapid conduction of nerve signals. Without this myelin sheath, signals are reduced and can even cease, accounting for the neurological dysfunction that is characteristic of MS. Initially in MS, there is transient inflammation, which reduces neuronal conduction and therefore causes episodic dysfunction.1 However, as the disease evolves, chronic neurodegeneration occurs through the formation of sclerotic plaques in the brain and spinal cord white matter, and this is associated with persistent dysfunction and disability.1 Thus, the complex pathogenesis of MS accounts for the evolution of symptoms experienced, from episodic to eventually chronic dysfunction (Fig. 3.1).
While the etiology of MS is not completely understood, it is evident that it is multifactorial involving both genetic and environmental factors.12 Environmental factors such as Epstein-Barr virus, cigarette smoking, and reduced vitamin D levels can interact with and trigger genes in individuals with complex risk profiles, causing an autoimmune response to self-antigens.11 , 12 , 14
Four forms of MS exist: relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and progressive relapsing MS (PRMS).14 RRMS is the most common type and affects 90% of patients.15 It involves periods of acute neurological disturbances (relapse) that last days to weeks, followed by partial or full recovery.13 , 16 About 50% of cases of RRMS progress to SPMS within ten years, which is characterized by worsening of the condition due to neuroaxonal loss without inflammation, independent of relapses.1 , 12 , 13 , 17 The median age of onset for RRMS and SPMS is 30 years old.12 PPMS affects 10% of patients, with the median age of onset being 40.12 , 15 PPMS is characterized by a gradual progression of disability, without discrete relapses, usually due to spinal motor involvement. PRMS involves a steady progression of the disease with relapses, with or without recovery.13
In order to diagnose MS, clinical, radiographical, and laboratory testing evidences (including cerebrospinal fluid analysis and evoked potentials) are utilized. Clinical evidence in terms of the range and severity of symptoms can vary widely among patients and can overlap with other CNS conditions including cognitive impairment, unilateral painful loss of vision, tremor, vertigo, bladder dysfunction, sensory loss, and weakness.1 Radiographical evidence through magnetic resonance imaging (MRI) aids diagnosis and monitoring of MS. It enables the detection of abnormalities in the white matter of the CNS, thereby indicating the distribution of lesions and aiding the monitoring of new plaques over time.1 Therefore, the necessity of careful investigations with a complete medical history and physical examination is critical to the correct diagnosis of MS.
While no cure exists for MS, a range of therapies can be used. Medications used include first-line therapies, which stop or slow progression of the disease, while second-line therapies reduce symptoms. Rehabilitation therapies may also be harnessed alongside first- and second-line therapies to improve symptoms.13 , 14 , 15
Hence, as a multifactorial disease, MS has a complex pathogenesis and requires a range of investigations in order to appropriately diagnose and manage the disease. Furthermore, the disease itself has a range of oral and facial manifestations, and many of the medications used in treatment have oral implications, posing an array of considerations for the dental treatment of patients with MS.13 , 14 , 15
The most ubiquitous demyelinating disease of the CNS that leads to permanent disability is MS.18 It has a diverse prevalence throughout the world, and is most commonly seen in developed countries.
The highest prevalence of MS was found to be in North America (140/100,000 population) and Europe (108/100,000), while the lowest prevalence in East Asia (2.2/100,000 population) and sub-Saharan Africa (2.1/100,000 population).19 According to the Multiple Sclerosis International Federation, the global median prevalence of the disease has elevated from 2008 to 2013, that is, 30/100,000 to 33/100,000 population, respectively.19 There are 12,000 new diagnoses of MS per year in the United States alone.20
Furthermore, the mean age onset of the disease varied from 29 to 33 years old, and the onset was younger in females.21 A study carried out by Duquette and colleagues have shown that the onset of MS under the age of 10 was 0.3%. They emphasized that childhood MS was more common in females (75.2%).21
In addition, the mortality of individuals with the disease was significantly higher than that of the general population when matched for age, gender, race, and ethnicity.21 The life expectancy of the MS patients was 6 to 14 years lower than that of the healthy population.19 Also, mortality rates were higher in Caucasian and then subsequently African American, Hispanics, American Indians, and Asian. Caucasian populations had approximately ten times higher mortality rates than Asian populations.19
Moreover, due to the increase in the incidence of the MS in women, the MS ratio between male and female has been altered over the past thirty years.19 From the data obtained by European Database for Multiple Sclerosis system, it is noted that from 1960 to 2005, the gender ratio adjusted for the year of MS onset has increased to 2.45 from 1.60 (p = 0.017).19 The Canadian Collaborative Project on Genetic Susceptibility to MS analyzed the sex ratio (female to male) of MS by year of birth among 27,073 patients born from 1931 to 1980. The ratio was 1.90 for cases born from 1931 to 1935, and increased gradually to 3.21 for those born from 1976 to 1980.20
There is a significant association between MS and dental caries. Due to muscle weakness and spasticity and medications, individuals with MS may encounter challenges to maintain basics of oral self-care. MS patients have 2.24 more carious teeth than the general population.20 , 22 , 23
The primary cause of damage in MS is thought to be autoimmune inflammation associated with demyelination and phagocytosis in the CNS (Fig. 3.2).24 Although many studies have suggested that genetic, environmental, and infectious agents may be among the factors influencing the development of MS, the specific elements that start the cause of inflammation are unknown.24 Demyelination in MS is activated by myelin-reactive T cells in the periphery, which then express adhesion molecules. This allows their entry through the blood–brain barrier (BBB).14
Dysregulation of the BBB is one of the earliest cerebrovascular abnormalities seen in MS, as well as the transendothelial migration of activated leukocytes.25 Breakdown of the BBB allows the immune cells to move across, attacking the myelin around the nerves.26 Although the breakdown of BBB is incompletely understood, it suggests involving indirect chemokine/cytokine-dependent leukocyte-mediated injury and direct effects of cytokines/chemokines on the adhesion between the endothelial cells on BBB.25 During normal immune surveillance, chemokines are responsible for initiating intracellular signaling and guiding the movement of leukocytes through the peripheral tissues.26 However, during MS chemokines on endothelial cells of BBB are altered, promoting entrance of immune cells.26
CD4 T-cells are considered central to initiating the CNS inflammation and are the most used cell type to adoptively transfer encephalomyelitis and most commonly used in experimental model to study the human inflammatory demyelinating disease (experimental autoimmune encephalomyelitis: EAE).27 However, the array of adaptive immune components (CD8 T-cells and antibody) and innate immune components (microglia/macrophages) reflects the actual extent and specificity of the tissue injuries.27
The primary progression of MS is initiated by the innate immune system influencing the effector function of T and B cells.14 Initiation of the innate immune system involves activation of specific receptors, mainly toll-like receptors (TLRs) in an antigen nonspecific manner through microbial products.14 TLR-activated dendritic cells (DCs) become semi-mature and produce inhibitory cytokines such as IL-10 or TGF-beta by inducing regulatory T-cells.14 As maturation of dendritic cells continues, the CD4 T-cells start to differentiate into Th1, Th2, or Th17 phenotypes.14
The adaptive response is initiated by the interaction between antigen-presenting cells (APC) and T lymphocytes (T-cells).14 APC includes B cells, microglia, dendritic cells, and macrophages, which can activate several types of T-cells such as CD4 and CD8. CD4 T-cell, exposed to specific interleukins, polarizes to effector T-cells (Th1, Th2, or Th17).14 These effector T-cells secrete specific cytokines. Th1 and Th17 secrete proinflammatory cytokines promoting inflammation, while Th2 produce IL-17, IL-21, IL-22, and IL-26.14 CD8 cells kill cells, leaving axons exposed and promote vascular permeability, transect axons, activate oligodendrocyte death in the event of MS lesions, and show regulatory function in the progression of MS.14
The neurobiology of MS comprises a complex array of factors, with one of the main components being genetic. The genetic component is suggested by the high incidence of cases in certain ethnic populations and familial aggregation of cases.28
The disease is more prevalent in northern European ethnic groups as opposed to Asian or African ethnic groups, irrespective of location. The risk of developing MS increases with a family history of the disease.29 In European populations, the risk of MS is 0.2%, which increases to 2 to 4% in siblings of MS patients and 30% in monozygotic twins. When studies were done of step-siblings, half-siblings, and adoptees, it was demonstrated that the familial risk was due to genetics and not due to lifestyle conditions.28
In the last five years due to the advent of genome-wide studies, the genetic risk factors for MS have increased from 1 to up to 50 various factors.30 The first genetic risk factor, found in 1970, was the human leukocyte antigen (HLA) region. The HLA region is involved in almost all diseases which are immune related, including MS.31 HLAs are also known as major histocompatibility complex (MHC) proteins, which are found on the surface of antigen-presenting cells. Each person has a unique set of HLAs, except for identical twins that have the same antigens. The HLAs have a role in cell-to-cell contact during antigen presentation in immune reactions.31 In MS, the HLA region on chromosome 6p21 has an increased degree of polymorphism, and through DNA-based typing, it was discovered that it was the DRB1*1501 allele.32 In European population, the frequency of the allele is 3 to 20%. The frequency of the allele has a positive correlation with population risk of MS. Each copy of the allele increases the risk of MS by threefold, making it the strongest genetic indication of MS.32
In terms of disease activity, course and severity, and age of onset, MS is considered as a heterogenous disease in a clinical point of view. Studies have shown that there could be genetic implications in these clinical aspects; however, the extent of these implications is relatively unknown.32 Furthermore, genetic risks that are currently known account for 25% of sibling recurrence risk yet the remaining portion of the risk is unexplained.30 Although genome-wide research has increased knowledge of the genetic component significantly, the underlying function and clinical mechanisms are yet to be studied.
The identification of MS involves a physician’s diagnosis of the condition using their clinical judgment. The diagnosis does not use just one test or is not based on just one clinical feature. It must satisfy certain criteria that have been formalized as the most recent McDonald criteria. According to these criteria, neurologic lesions should show dissemination in space and in time to exclude alternate diagnosis.11 Initially, these criteria were based on clinical evidence but now these have been updated with the help of MRI and laboratory tests.11 The diagnosis involves:
A spinal tap and testing for oligoclonal bands (OCBs) using cerebrospinal fluid (CSF).33
Signs and symptoms of MS usually involve motor, sensory, visual, and autonomic systems (Fig. 3.3) due to the presence of multifocal lesions in the CNS.1 These vary in an individual depending on the location of the lesion and occur as sudden episodes or as part of a steady progression.34