Multiple Sclerosis and Related Disorders



Multiple Sclerosis and Related Disorders


Sarah E. Conway

Maria K. Houtchens



MULTIPLE SCLEROSIS


Background



  • 1. Multiple sclerosis (MS) is the most common disabling neurologic condition of young adults in European and North American populations. It was first recognized as a disease entity in the latter part of the 19th century. The first description of “disseminated sclerosis” dates back to 1835 and is credited to French neurologist Cruveilhier. Jean Martin Charcot, at the Salpêtrière Hospital in Paris, France, described the ataxia and oculomotor abnormalities that are often observed in younger patients. The pathologic features at autopsy, described in the first few decades of the 20th century, are now well known.


  • 2. The cause of MS remains unknown but more recent data suggest that infection with Epstein-Barr virus (EBV) likely plays a role. However, over 95% of people in the United States have been exposed to EBV, and the prevalence of MS is 0.2%, so there are clearly other environmental and genetic factors at play. Other risk factors for MS include smoking, obesity, and low vitamin D. Historically, MS was defined as a T cell-mediated autoimmune central nervous system (CNS) disease triggered by unknown exogenous agents, in subjects with a specific genetic background. However, there is now increasing evidence that B cells play a role as well through various mechanisms including serving as antigen presenting cells that co-stimulate autoreactive T cells, and secreting proinflammatory cytokines.


  • 3. In most patients, MS is a chronic disease. In 85% of patients, it begins with a focal inflammatory lesion of the nervous system, developing over days and recovering after weeks to months. Further lesions develop and cause clinical relapses, usually at a rate of one or two every year without use of disease-modifying therapy (DMT). MRI data have shown us that lesions occur in the brain and spinal cord at a far more rapid pace, often 10 times as frequently as relapses that are clinically recognized. After a number of years, or even decades, some patients enter a slowly progressive phase of the illness, with increasing disability. Impairment of gait, reduced visual acuity, paresthesias and pain, loss of bladder control, and cognitive deficits dominate the clinical picture after the progressive phase has advanced further. Large registries of patients from France and Denmark found that reduction in life span because of MS is not common. Prior to the availability of DMT, studies found that more than 70% of patients were disabled and unable to work 10 years after diagnosis. More recent data suggest lower rates (40%) of unemployment and disability by 10 years.


  • 4. Other variants of MS occur. About 10% of patients have primary progressive MS (PPMS) (ie, no relapses are recognized and the patients steadily worsen from
    the onset). These patients most often present with slowly progressive gait impairment, leg weakness, and other nonspecific neurologic complaints. They also tend to be older and there is a higher proportion of males in this MS subtype. Another ˜10% have so-called benign MS, with few relapses and no disability although they have been known to have the disease for many decades. A small number of patients have acute and severe MS, with frequent and large lesions and poor recovery (Marburg variant, or malignant MS), and it is among this group that a fatal outcome is occasionally seen.


Epidemiology



  • 1. MS is the most common neurologic disease among young adults.


  • 2. Incidence is the highest from ages 20 to 40 years, but the disease can start in childhood or after age 60 years.


  • 3. In the United States alone, there are about 1,000,000 patients with MS and about 10,000 new cases are diagnosed yearly.


  • 4. Current estimates are that about 70% of patients with MS are female.


  • 5. There are zones of high and medium incidences, and there are places in the world where the disease is almost unknown.



    • a. Prevalence decreases with proximity to equator creating a so-called “North-South Gradient” of MS distribution.


    • b. High incidence includes all of Europe, North America, New Zealand, and southern Australia. In Minnesota and many of the northeastern states of the United States, one person of every 500 has MS (ie, a prevalence of 200/100,000). In general, MS is more than twice as common in the northern United States compared to the southern states.


    • c. Race plays an important role: U.S. residents who are of Japanese, Native American, or sub-Saharan African descent have a much lower incidence of MS than do people of Irish, British, or Scandinavian background under equal geographic circumstances.


    • d. Incidence of MS in African Americans is 25% of that of persons with Caucasian background. However, the disease tends to be more rapidly disabling and resistant to therapies in this patient population.


  • 6. If persons with ethnically and geographically low risk develop MS, the disease may be atypical in clinical manifestations and imaging findings.



Pathophysiology



  • 1. The pathologic hallmarks of MS are demyelination and predominantly perivenular inflammation. Severe or advanced disease causes axonal disruption and loss and cortical atrophy leading to a process of neurodegeneration.


  • 2. Historically, MS was considered a disease of cerebral white matter. Recent data provide evidence for gray matter involvement. Thalamic and cortical atrophy are significant predictors of cognitive impairment and disability in patients with MS. Cortical lesions are increasingly recognized with 7T MRI technology and are also correlated with cognitive impairment.


  • 3. The immunologic mechanism involves activation of autoreactive CD4+ cells in the peripheral immune system followed by their migration into the CNS via a disrupted blood-brain barrier (BBB). This is followed by reactivation of the cells by in situ myelin antigens, activation of B cells and macrophages, and secretion of proinflammatory cytokines and antibodies.



  • 4. The typical lesion of MS is a few millimeters to a centimeter in size. Viewed three dimensionally, a lesion is often ovoid or linear rather than circular. This is a feature of the MRI appearance. Activated T cells and macrophages are present. The cells express T helper 1 (TH1) cytokines such as interferon gamma (IFN-γ), tumor necrosis factor (TNF), and interleukin-2 (IL-2). Cytokines of the TH2 series such as IL-4, IL-10, and IL-13 are reduced. Many proinflammatory molecules, such as integrins and other adhesion molecules, are upregulated.



    • a. Microscopically, lesions show destruction, swelling, or fragmentation of myelin sheaths; proliferation of glial cells; variable axonal destruction (new and old plaques); and variable damage to neurons, but relative preservation of background structure, and cystic lesions are rare.


    • b. Early/acute lesions (days to weeks) show marked hypercellularity, macrophage infiltration, astrocytosis, perivenous inflammation with plasma cells and lymphocytes, and disintegration of myelin.


    • c. Active/nonacute lesions (weeks to months) show lipid-laden phagocytes with minimal inflammatory response at the center of lesions but prominent at the edges of lesions with increased numbers of macrophages, lymphocytes, and plasma cells.


    • d. Chronic inactive plaques (months to years) show prominent demyelination (almost complete loss of oligodendrocytes), extensive gliosis, and hypocellularity.


    • e. Remyelinating plaques may result from differentiation of precursor cells common to type II astrocytes and oligodendrocytes. They show uniform areas of aberrant and incomplete myelination (shadow plaques).


  • 5. Chronic lesions with poor recovery have the appearance on biopsy, at autopsy, or on MRI of an empty astroglial scar. The term multiple sclerosis refers to these late-stage discolored plaques or scars.


  • 6. Recent work has demonstrated the presence of meningeal lymphoid follicles and has linked the presence of these follicles to worsened disability progression and cortical demyelination and atrophy. Autopsy studies of progressive MS patients have found these lymphoid follicles in up to 40% of patients.


  • 7. Chronic oxidative injury may also occur and may be associated with neuronal mitochondrial damage.


Genetics



  • 1. Children of a parent with MS have a 1% to 5% chance of developing MS—an approximately 20-fold increase.


  • 2. A sibling of an affected person, including a nonidentical twin, has a 3% to 5% chance of having MS.


  • 3. An identical twin has a 30% chance of having MS if one includes asymptomatic twins with only MRI or spinal fluid findings.


  • 4. There are more than 200 polymorphisms associated with MS. The strongest associations are with the HLA-DRB1 locus.


  • 5. Genome-wide association studies have shown no convincing locus for an “MS gene.” It is likely that several genes contribute to susceptibility by increasing immune reactivity to common viruses or to antigenic components of myelin to which other persons are nonreactive.



Diagnosis



  • 1. Radiologically isolated syndrome (RIS): Describes patients with an absence of symptoms or exam findings who are incidentally found to have typical imaging
    for MS. Risk factors for conversion to MS in this patient population include younger age (<37 years), the presence of infratentorial or spinal cord lesions, and oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF).


  • 2. Clinically isolated syndrome (CIS), that is, optic neuritis (ON), transverse myelitis (TM), or a brainstem syndrome as the first ever episode of neurologic dysfunction. The patient does not meet criteria for MS diagnosis. Specific clinical syndrome depends on the location of lesion(s) within brain, spinal cord, or optic nerves. The attack typically progresses for several days, plateaus, and then improves over days, weeks, or rarely months. Improvement can be complete or partial.


  • 3. Most common presenting symptoms of MS include visual/oculomotor problems (49%), leg paresis/paresthesias (42%), and cerebellar ataxia (24%). Other symptoms may include progressive or abrupt cognitive changes, Lhermitte phenomenon (electrical painful paresthesias induced by neck flexion), Uhthoff phenomenon (worsening symptoms with increased body temperature), neuropathic pain, and fatigue.


  • 4. Clinically definite MS (CDMS): Patient meets revised McDonald criteria for MS diagnosis.



    • a. Revised McDonald criteria for diagnosis (2017) of relapsing-remitting MS (RRMS)



      • 1) Patients must present with a clinical symptom and meet criteria for dissemination in space and time. Other alternate diagnoses must also be excluded.


      • 2) Dissemination in space: MRI demonstrated involvement in at least two of four regions of the neuroaxis:



        • a) Periventricular


        • b) Juxtacortical or cortical


        • c) Infratentorial (brainstem/cerebellum)


        • d) Spinal cord


      • 3) Dissemination in time: Satisfied by either:



        • a) A single scan with enhancing and nonenhancing lesions.


        • b) An initial scan with presence of disease and a follow-up scan with new lesions


        • c) Presence of CSF-specific OCBs


        • d) New clinical relapse over time


    • b. Revised McDonald criteria for diagnosis (2017) of PPMS: One year of disease progression and two of the following three:



      • 1) Greater than or equal to one T2 lesion in an area typical of MS (periventricular, juxtacortical, infratentorial, or spinal cord)


      • 2) Greater than or equal to two T2 lesions in the spinal cord


      • 3) Presence of CSF-specific OCBs


  • 5. Over the course of the disease, each attack may leave some residual deficits. Accumulation of such deficits results in increasing disability. After several attacks of various types, a patient may present with common “fixed” problems:



    • a. Mild reduction in vision in one eye


    • b. Dysconjugate eye movements, with diplopia


    • c. Extensor plantar responses and inability to walk heel-and-toe


    • d. Reduced vibration sense in the legs


    • e. Urgency of bladder function


    • f. Cognitive impairment


  • 6. Common late-stage deficits include dementia, inability to stand or walk, slurred speech, ataxia, incontinence, and marked sensory loss in hands and legs.



Diagnostic Testing


Magnetic Resonance Imaging



  • 1. Although technically a diagnosis of MS can be made without MRI, it would be exceedingly rare for this to occur in the modern era. MS lesions are usually easily detected on conventional MRI and often are characteristic. Conventional MRI techniques are now widely accessible to community and academic neurologists. By scan:



    • a. Lesions are bright on T2-weighted and fluid-attenuation inversion recovery (FLAIR) images, indicating a higher than normal water content. These MRI sequences reflect the total burden of the disease (Figure 10-1A).


    • b. Lesions are usually isodense on T1-weighted images, indicating that the tissue itself is intact.


    • c. Lesions may be hypodense on T1-weighted images, indicating underlying axonal disruption (black holes) (Figure 10-1B).


    • d. Lesions may be present in many areas of the brain, but most typically, they are found adjacent to the lateral ventricles, oriented perpendicular to them, and in the corpus callosum (best seen on midline sagittal FLAIR images [Figure 10-2]), and in the cerebellar peduncles. MS plaques directly touch the ventricular wall following the location of the small venules. In contrast, small vascular lesions are usually seen several millimeters away from the ventricular wall.


    • e. Acute and subacute lesions (usually <4 weeks since formation) often show enhancement on T1 postgadolinium contrast sequences indicating inflammation, BBB disruption, and recent disease activity (Figure 10-3).



    • f. Size of cerebral lesions varies from 5 to 10 to 100 mm or greater.


    • g. Lesions are common in the spinal cord, especially the cervical cord opposite the C2 or C3 vertebrae. They typically involve less than two contiguous segments of the spinal cord and less than half of the transverse diameter of the cord.


  • 2. Most patients with MS have MRI findings that are characteristic of MS. Some may have atypical or nonspecific patterns of lesions. Only extremely rarely do patients with a typical clinical course suggestive of MS have a normal MRI. Such patients present great diagnostic difficulty, and repeated scans and other examinations may be required.


  • 3. Other research techniques are being explored. High field MRI (7T) may better define whether a lesion is perivenular, which may in turn enhance the ability to accurately diagnose MS. The “central vein sign” refers to a vein seen inside a white matter lesion on a susceptibility weighted MRI sequence and is an imaging biomarker of MS. It can be helpful in distinguishing MS from other neuroinflammatory diseases with a typical cut off of 40% or more of lesions being perivenular in MS.

















Other Tests



  • 1. Lumbar puncture is needed in some patients with MS but is not performed routinely in cases of diagnostic certainty. Characteristic findings in the CSF in MS are a modest number of lymphocytes (fewer than 50/mm3), total protein less than 0.8 g/L, elevated IgG synthesis levels (3.3 mg/d in 90% of patients), and high IgG index (0.7 or greater in 90% of patients). Myelin basic protein is normally <1 ng/mL, but increases in 80% of acute MS relapses. OCBs on electrophoresis is the most sensitive of the CSF tests, being present in 75% to 80% of patients with established MS, and in 50% to 60% of patients with CIS. OCBs may also be present in other infectious/autoimmune conditions such as Lyme disease, neurosarcoidosis, neurosyphilis, and human immunodeficiency virus (HIV).



  • 2. Evoked potentials testing—especially testing of visual evoked potentials—occasionally helps. It can establish evidence of prior damage to optic nerves in the absence of a clear clinical history by showing unilateral prolongation of P100 wave.


  • 3. Optic coherence tomography can identify retinal nerve fiber layer thinning suggestive of prior optic nerve damage and fellow non-affected eye thinning correlates moderately with brain atrophy.


  • 4. Translocator protein-Positron Emission Tomography (PET) of the brain can be used to detect microglial activation, which is more recently a target for therapeutic interventions.


Differential Diagnosis

Many other neurologic conditions may be confused with MS (Table 10-1). They fall into several categories:



  • 1. Relapsing diseases that may mimic MS clinically include other CNS inflammatory diseases such as lupus, sarcoidosis, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), or neuromyelitis optica spectrum disorder (NMOSD).


  • 2. Primary or secondary progressive disease clinically can mimic other degenerative processes such as hereditary ataxia, adrenoleukodystrophy, and motor neuron diseases such as amyotrophic lateral sclerosis.


  • 3. Diseases that look like MS by MRI findings, including other causes of “white spots”



    • a. Vascular disease: Small-vessel disease in hypertension, migraine, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)


    • b. Infections: Lyme disease, HIV, syphilis.


    • c. Granulomatous disease: Sarcoidosis, Behçet disease


    • d. Monosymptomatic demyelinating disease: TM and acute disseminated encephalomyelitis (ADEM)


    • e. Metabolic: vitamin B12 deficiency, leukodystrophies










Classification and Clinical Considerations



  • 1. Several MS classifications are used.



    • a. Based on disability accumulation: Benign MS (approximately 10% of all patients)—no or minimal neurologic disability after 10 to 15 years. Malignant MS (approximately 10% of all patients)—neurologic disability requiring ambulation assistance after ≤5 years.


    • b. Based on clinical course: RRMS. This subtype is the most common (85% of all patients fit into this disease category at diagnosis). It is characterized by relapses and remissions of neurologic disability over years to decades. Incomplete recovery from relapses often leads to disability accumulation. Secondary progressive MS (SPMS) follows RRMS in 10 to 25 years after the diagnosis historically in 60% to 80% of patients although early initiation of higher-efficacy DMT likely prevents progression to SPMS. SPMS is characterized by absence of relapses and progressive worsening of neurologic function involving the pyramidal system, cerebellar connections, dorsal columns,
      and cortical association fibers. Patients with progressive disease (PPMS and SPMS) most often present with unilateral leg weakness gradually evolving to a spastic paraparesis. Other symptoms that progressive patients frequently exhibit are ataxia, neuropathic pain symptoms, cognitive decline, and bowel and bladder symptoms. Ambulation assistance is often required. Careful history taking confirms absence of exacerbations of neurologic deficits. PPMS is more common in men in the fourth and fifth decades of life. It presents in a similar way to SPMS, but there are no preceding relapses. Prognosis is worse for this group of patients. A recent clinical trial demonstrated a modest benefit in PPMS patients treated with ocrelizumab (see section on Treatment).


  • 2. The combination of several epidemiologic, clinical, and imaging factors carry better prognosis for stable disease course. Favorable prognostic factors include:



    • a. Younger age of onset


    • b. Female sex


    • c. Monosymptomatic onset


    • d. Sensory symptoms or ON at onset


    • e. A few T2 or FLAIR lesions on first MRI


    • f. Long interval between first and second attacks


    • g. Low attack frequency in the first 2 years


    • h. Full recovery of function after the first attack


  • 3. There is no consistent evidence that anesthesia, surgical procedures, stress, or intercurrent illnesses worsen clinical outcome in MS patients. However, the aforementioned factors may temporarily aggravate preexisting neurologic deficit creating a “pseudo-exacerbation.” These are not considered true relapses, and it is important to screen patients for infections in the presence of transient or fluctuating neurologic worsening. Pregnancy is associated with lower relapse rates in the second and third trimesters, but an increase in relapse rates postpartum is sometimes observed, especially in patients who have not been appropriately treated with effective DMTs prior to pregnancy.


  • 4. Expanded Disability Status Scale (EDSS): Ordinal 0 to 10 scale; most widely accepted measure of disability in MS.



    • a. EDSS 0: No disability


    • b. EDSS 6: Needs unilateral ambulation assistance (cane)


    • c. EDSS 6.5: Need bilateral assistance with ambulation (walker)


    • d. EDSS 7: Most often reliant on wheelchair


    • e. EDSS 10: Death because of MS



Treatment


Treating Symptoms


Psychiatric Symptoms



  • 1. Depression: Over the course of a year, about 20% of MS patients have depression. Symptoms of irritability, altered sleep pattern, and low self-esteem occur. Women are twice as likely as men to become depressed. There is little correlation with disability; in fact, depression may be more common in the earlier stages, with less disability. There is a causative connection in that some of the frontal lobe and limbic connections may be damaged by MS lesions.



    • a. Selective serotonin reuptake inhibitors (SSRIs) are the mainstay of treatment of depression: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), or second-generation drugs such as bupropion (Wellbutrin), citalopram (Celexa), or escitalopram (Lexapro) (Table 10-2). Care should be taken that the dose is sufficient. Most SSRIs reduce libido. The involvement of a psychiatrist should be considered in difficult cases.


    • b. In addition to drug therapy, counseling or some other form of supportive psychotherapy is often beneficial. Ideal treatment is a combination of the two.


    • c. Tricyclic antidepressants are helpful but have many side effects, such as weight gain, dry mouth, and drowsiness. However, they may help insomnia or urinary urgency. Examples are amitriptyline, desipramine, or nortriptyline.


    • d. Selective serotonin and norepinephrine reuptake inhibitors (SNRIs) are useful in treatment of depression, such as venlafaxine (Effexor) and duloxetine (Cymbalta). Duloxetine is also helpful in treating pain in MS patients.


    • e. Fatigue can be a compounding issue and may be hard to distinguish from depression.


    • f. Depressed patients need to be followed, the success of treatment assessed, and risk of suicide should be considered at all times. In apathetic patients, thyroid deficiency, sleep apnea, and adverse effects of other medications should be considered.


  • 2. Other common disorders



    • a. Bipolar disorder: Lifetime prevalence is reported to be up to 8.4% in an MS population, according to some references. Psychiatric consultation is advisable because bipolar disease requires a separate set of long-term preventive drugs such as lithium carbonate, carbamazepine, or valproate.


    • b. Anxiety disorders: Prevalence is also increased. Can be treated with an SSRI, SNRI, or short courses of benzodiazepines if necessary. Psychological counseling can also be helpful.