Introduction
In 1868 Jean-Martin Charcot provided the first detailed anatomic illustrations of “la sclérose en plaques,” characteristic periventricular white matter lesions that are now appreciated as a pathologic hallmark of multiple sclerosis (MS), the most common autoimmune demyelinating disease of the central nervous system (CNS). Although MS is traditionally characterized by relapsing and progressive stages, the disease may be best understood as heterogeneous, with considerable overlap between stages. This is hypothesized as being due to a complex immune response whereby the adaptive immune system drives pathology in the early stages of the disease, then wanes and is overtaken by other disease processes mediated by the innate immune system, involving mitochondrial dysfunction, microglial activation, glutamate toxicity, and reduced compensatory ability, among other mechanisms, leading to gradual disability accumulation in older age. Treatment of MS remains a clinical challenge, being the most frequent cause of permanent disability in young adults, with annual healthcare costs totaling more than $10 billion in the United States.
Epidemiology
An estimated 727,000 people in the United States (309 people per 100,000) and 2.3 million people worldwide are affected by MS. The mean age of diagnosis is 31 years, though patients may present from the first to the seventh decades of life. MS affects females disproportionately, with an estimated female-to-male incidence ratio of 2.8:1, skewing further toward female predominance in more recent studies. Some have speculated that the changing social status of females during the past century contributed to increased rates of MS diagnosis, and several observations point to the important underlying role of hormones: (1) Increased female MS risk develops around age 11 years (near puberty onset); (2) earlier menarche correlates with earlier MS onset in multicenter case-control studies of pediatric MS; (3) females with MS may experience clinical worsening around the time of menopause. MS was historically thought to affect people of Northern European descent at higher rates, though recent studies have shown MS prevalence in Black Americans to be nearly as high as that in their White counterparts, with fewer people of Asian and Hispanic descent being affected.
MS is not typically considered to be a strongly genetic disorder; however, there is evidence of heritability, and genetic susceptibility is complex and multifactorial. Twin studies demonstrate a 25% concordance rate among monozygotic twins and a 5.4% concordance rate among dizygotic twins. A growing number of genes have been linked to MS risk, with recent genome-wide studies identifying over 100 alleles of significance with immune function that alter disease risk. Perhaps the best-studied genetic association is the link between MS and major histocompatibility complex class I and class II alleles, particularly HLA-DRB1. Recent work has characterized protective and risk alleles, although no combination can be used to definitively predict the development of MS, and genetic testing is not clinically available.
MS prevalence increases the farther one moves from the equator; this finding is hypothesized to be related to differences in genetic background, infection exposure, and vitamin D levels. In many countries with a high prevalence of MS (United States, Northern Europe, Russia, Canada, and New Zealand) there is a latitude gradient of MS risk; however, in regions with lower prevalence this relationship does not always hold. Classic MS migration studies have shown that individuals moving from low-to high-prevalence regions after age 15 maintain the low risk of the area from which they migrated, whereas individuals migrating before this age assume the risk of the region to which they move.
The relationship between MS risk and latitude led to the hypothesis of vitamin D functioning as a key mediator of MS susceptibility. Vitamin D is predominantly synthesized in the skin in response to ultraviolet light. Its receptors are expressed ubiquitously on immune cells and function to reduce immune activation of autoreactive T and B cells in MS. There is a relationship between low vitamin D levels and increased risk of MS, clinical relapse/progression, and new magnetic resonance imaging (MRI) activity, although evidence is mixed as to whether supplementation of vitamin D leads to significant differences in MS clinical outcomes. Nonetheless, vitamin D is an important developmental immunomodulator that is involved in immune system maturation and self-antigen recognition during critical developmental windows.
Cigarette smoke exposure (both direct inhalation and secondhand smoke) has been associated with an increased risk of MS. Smokers have a 50% higher chance of developing MS than nonsmokers, regardless of age at smoking start. Increasing cumulative pack-year exposure is associated with a higher overall risk of MS. Studies show that there may be a reduction in elevated MS risk among patients who quit smoking, by approximately 5 years later. Tobacco smoking has been shown to affect other aspects of the MS disease course as well: smokers have a higher risk of conversion from relapsing-remitting MS (RRMS) to secondary progressive MS (SPMS), and a higher risk of development of neutralizing antibodies to certain disease-modifying therapies (DMTs), making them less effective.
Obesity in childhood and adolescence has been associated with increased risk in both pediatric- and adult-onset MS, and abdominal obesity has been associated with worsened disability in people living with MS. Early exposure to shift work may also increase the risk of developing MS, possibly related to the negative effects of inadequate sleep in adolescence. Caffeine and alcohol are not believed to strongly affect disease risk.
Epstein-Barr virus (EBV) exposure has long been a hypothesized trigger for the development of MS, with many early studies demonstrating nearly 100% seropositivity in MS patients, and in pediatric-onset MS there is an unexpectedly high rate of asymptomatic EBV seropositivity. Mononucleosis in adolescence has been associated with increased subsequent risk of MS (relative risk: 2.3, 95% CI: 1.7–3.0). Recently a large cohort study showed a 32-fold increase in risk of MS after EBV seroconversion, a risk adjustment that is not seen after infection with any other virus (including cytomegalovirus, which is transmitted similarly). EBV infection is likely necessary, though not sufficient, for the development of MS; this is hypothesized to be due to “molecular mimicry” via amino acid sequence homology between virus proteins and myelin basic protein causing autoreactivity and infection of B cells, which may mediate chronic inflammation in MS.
Multiple Sclerosis Pathophysiology
The acute MS lesion is the pathophysiologic end result of a highly coordinated cascade of inflammatory activity. Active blood-brain barrier breakdown is mediated by the recruitment of perivascular inflammatory infiltrates comprised of myelin-reactive T cells, B cells, and macrophages. The pathologic hallmark of acute MS is focal white matter demyelination and relative sparing of axons with a variable associated perivascular inflammation or gliosis. Areas that are commonly affected in MS include the periventricular and juxtacortical white matter (regions with dense perivenular topography), although lesions may occur throughout the CNS, including the optic nerves, cerebellum, and spinal cord.
MS is commonly described as a disease of focal white matter demyelination; however, histologic studies have revealed a more complex pathology. Apart from lesions, it is well established that there is diffuse microglial inflammation of the normal-appearing white matter in MS even at disease onset. Axonal degeneration is present in MS lesions at all ages, frequently in regions of active or acute demyelination. Cortical gray matter demyelination is prevalent in MS, with subpial (type III) cortical demyelinating lesions considered to be a unique, specific feature of the disease. Cortical demyelination is frequently widespread on postmortem analysis of progressive MS patients, accrues with disease duration (though it is found in early disease stages), and has a correlation with cortical microglia and leptomeningeal inflammation on histology. The meninges are hypothesized immunologic regulatory sites for the inflammatory response in MS, and meningeal B-cell follicles (present in 40% of patients with progressive MS and also found in early MS stages) may function to organize and sustain chronic inflammation of progressive disease. Additional mechanisms drive chronic MS inflammation in parallel, including cytokine production, microglia and astrocyte activation, complement activation, glutamate excitotoxicity, iron accumulation, nitrous oxide production by macrophages, ion channel redistribution and dysfunction, and oxidative/mitochondrial injury, among other processes.
Multiple Sclerosis and Magnetic Resonance Imaging
MRI is used to confirm the presence of MS inflammatory lesions. Lesions are traditionally evaluated by T2-weighted fluid attenuation inversion recovery sequence (FLAIR), where they are visible as hyperintensities with distinct characteristics and spatial distribution. They are classically ovoid and oriented perpendicularly to the ventricles ( Fig. 21.1 ), giving the impression of finger-like projections on the sagittal T2-FLAIR sequence (known as “Dawson fingers”). MS lesions are commonly found in the periventricular white matter and corpus callosum, although they can be evident throughout the white matter. When the spinal cord is involved in MS, lesions usually span a single vertebral body, occupy a fraction of the cord on axial cross section, and lack associated cord edema. Acute lesions show active gadolinium contrast extravasation on T1 post-gadolinium MRI sequence due to active blood-brain barrier disruption. Contrast enhancement usually resolves by 30–40 days from onset and rarely persists until 8 weeks; if they are present for a longer duration, a diagnosis other than MS should be considered.
Making the Diagnosis of Multiple Sclerosis
RRMS typically presents in young adulthood (average age: 31 years) with exacerbations of neurologic symptoms lasting more than 24 hours in duration that may include weakness, numbness/paresthesias, optic neuritis, brain stem dysfunction (intranuclear ophthalmoplegia and nystagmus being common), impaired balance, L’hermitte sign, or transverse myelitis. Fatigue, cognitive dysfunction, and mood symptoms are underappreciated facets of MS presentation that often coincide with physical symptoms. MS attacks usually present over the course of days, plateau over the course of days to weeks, and recover over the course of weeks to months.
Studies of MS natural history that predate the treatment era cite high rates of SPMS transition among untreated patients, with as many as two-thirds of RRMS patients becoming progressive after ~15 years, though more recent data since the evolution of effective MS therapy have shown a lower risk of SPMS and longer disease duration prior to SPMS transition.
Secondary progressive transition is often contrasted with primary progressive MS (PPMS), which is rarer (10%–15% of patients) and is characterized by gradual disability accumulation from disease onset. Progressive MS (regardless of whether PPMS or SPMS) is often described in terms of worsening ambulatory dysfunction, though symptom progression may involve many symptoms that are attributable to RRMS, including fatigue, cognitive dysfunction, bowel/bladder dysfunction, mood/affective disturbances, sleep disturbances, sexual dysfunction, and spasticity. There is evidence to suggest that progressive MS may exist along a continuum rather than as a distinct transition point. Progressive disease (primary or secondary) begins around the same absolute age (41), and once progression begins, the rate of disability accrual is essentially identical, likely reflective of a common pathology at these stages. More recently, there has been effort to classify progressive MS by terminology that may better reflect the pathologic underpinnings of the progressive stage. Patients who have clinical relapses and/or MRI activity in the progressive MS stage (defined as active progressive MS), are viewed as a unique subpopulation of MS patients and may have better response to traditional MS DMTs compared to nonactive progressive MS patients. Treatment of nonactive progressive MS remains one of the major challenges in the field, as this stage is driven by processes that are not substantially affected by currently available therapies.
The McDonald criteria, most recently revised in 2017, are the standardized criteria used to diagnose MS. They outline requirements for dissemination in space and dissemination in time that can be met by a combination of clinical history and MRI. Dissemination in space requires that characteristic MRI lesions be present in at least two of four areas of the CNS (periventricular, cortical/juxtacortical, infratentorial, or spinal cord). Dissemination in time criteria can be met by the simultaneous presence of enhancing and nonenhancing lesions on contrasted MRI, by the development of new typical lesions on subsequent MRIs, or occasionally by the presence of oligoclonal bands in the cerebrospinal fluid (CSF) ( Table 21.1 ). Oligoclonal band testing is positive in 95% of patients with clinically definite MS and doubles the risk of progression to MS among patients with clinically isolated syndrome. Evoked potentials, optical coherence tomography, or prospective monitoring can provide additional evidence to support a diagnosis of MS but are not part of the formal diagnostic criteria.
| Relapsing-Remitting Multiple Sclerosis | ||
|---|---|---|
| Number of Lesions | Additional Data Needed for Diagnosis | |
| ≥2 clinical attacks | ≥2 | None |
| ≥2 clinical attacks | 1 |
|
| 1 clinical attack | ≥2 |
|
| 1 clinical attack | 1 |
|
| Primary Progressive Multiple Sclerosis | ||
| At least 1 year of disability progression without a history of clinical attacks |
| |
a Note that if lesions are all enhancing or all nonenhancing, this can also meet diagnostic criteria for clinically isolated syndrome until dissemination in time criteria are met.
For the diagnosis of PPMS, patients need to display a progressive worsening of symptoms over the course of 1 year with no history of clinical relapses. For diagnosis, patients also require at least two of the following: (1) at least one characteristic MRI brain lesion, (2) at least two MRI spinal cord lesions, (3) the presence of oligoclonal bands in the CSF (see Table 21.1 ).
Patients who have a single clinical attack corresponding to either a single lesion or multiple enhancing lesions without the presence of nonenhancing lesions are said to have Clinically Isolated Syndrome (CIS) (see Table 21.1 ). Clinicians assess clinical status and MRI lesion burden in CIS to determine whether to recommend treatment, but often treatment is initiated and justified based on approximately a 60%–75% rate of conversion to MS over 15 years. Risk factors for conversion from CIS to MS include increased number of initial MRI lesions, younger age at presentation, and the presence of CSF-specific oligoclonal bands.
Occasionally MS-typical lesions are incidentally found among patients obtaining an MRI for other reasons, such as headaches, trauma, etc., though they have never had symptoms of an MS clinical attack. These patients are said to have Radiologically Isolated Syndrome (RIS), which carries an approximate 30% risk of conversion to clinically definite MS at 5 years and ~50% at 10 years after the initial MRI. Risk factors for conversion to MS include the presence of CSF-specific oligoclonal bands and/or spinal cord lesions on initial MRI. Treatment is not routinely started in RIS stage, although in high-risk cases can be a consideration.
Nonspecific white matter lesions on MRI brain are one of the most common cause for MS misdiagnosis, as a differential diagnosis list includes normal variant (such as enlarged perivascular spaces), migraines, small-vessel ischemic changes (secondary to smoking, hypertension, or hyperlipidemia), infections, neoplasms, and leukodystrophies. MRI lesion features/topography along with history and physical exam help narrow the differential diagnosis list. One potentially helpful diagnostic imaging tool to evaluate nonspecific white matter lesions is T2* imaging for central veins which can be visualized in demyelinating disease at 3 T and 7 T MRI (‘central vein sign’). While not yet widely clinically available, the ultra-high-field 7 T MRI platform affords high sensitivity for detection of central veins to assess demyelinating etiology, with recent data suggesting that a >40% central vein sign cutoff distinguishes lesions typical of MS from non-MS cases.
The Differential Diagnosis of Multiple Sclerosis: Important Considerations Related to Clinical Presentation and Diagnostic Mimics
Multiple sclerosis can present with a wide variety of clinical symptoms depending on the location of inflammation, although typical MRI lesions can help to narrow the differential diagnosis. However, two common clinical presentations—optic neuritis and spinal cord myelitis—can occur in the absence of MRI brain lesions and have unique differential diagnoses to consider.
Optic Neuritis
Optic neuritis is the presenting attack in 15%–20% of MS patients, and ~40% of patients with first-time optic neuritis go on to be diagnosed with MS in the next 10 years. Symptoms typically include a subacute loss of vision associated with painful movements of the eye. Neuritis can be unilateral or bilateral but is more commonly unilateral in MS. Optic neuritis can sometimes be seen as T2 hyperintensity of the affected optic nerve on orbital MRIs (often with associated contrast enhancement) and often show signs of optic disc swelling on ophthalmologic evaluation. Ophthalmologic evaluation is highly recommended if a patient is suspected to have optic neuritis, as the symptoms overlap heavily with other disorders of the eye.
Optic neuritis is not specific to MS and is often seen in other neurodemyelinating disorders. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein antibody disorder (MOGAD) are two neuroinflammatory diseases that can present similarly to MS and should also be high on the differential when a patient presents with optic neuritis. Other considerations, such as infections, neoplasms, and ischemic changes, can be seen in Table 21.2 . In fact, optic neuritis has so many potential causes that clinical relapses of optic neuritis, per the 2017 McDonald criteria, are not sufficient to meet dissemination in space criteria.
| Optic Neuritis Specific | Transverse Myelitis Specific |
|---|---|
|
|
| Either | |
| |
Myelitis
The terms “myelitis” and “transverse myelitis” are often used synonymously to denote inflammation of the spinal cord, although the term “transverse myelitis” specifically refers to an inflammation that covers an entire transverse section of the cord. The myelitis that is encountered in MS is rarely transverse, as it tends to affect the spinal cord in an eccentric pattern, as can be seen by T2 hyperintense lesions on MRI. As with optic neuritis, NMO and MOGAD can cause myelitis similar to that seen in MS; particularly when myelitis involves the cervical spine, these diagnoses should be high on a differential. There are multiple causes of spinal cord lesions that should be considered when these abnormalities are seen on MRI (see Table 21.2 ).
Neuromyelitis Optica
Clinical Features
Neuromyelitis optica (also known as Devic disease) was first described by Dr. Eugene Devic in Paris in 1894. Due to NMO’s similar pattern of relapses of demyelination, specifically with episodes of optic neuritis and transverse myelitis, it was considered a variant of MS until the identification of the NMO-specific pathologic antibody Aquaporin-4 (AQP4) IgG in 2004. NMO affects mostly females, with a female-to-male ratio of ~9:1 and an average age of onset of 40 years. NMO is more common in East Asians (prevalence 3.5/100,000) and Blacks (prevalence 1.8–10/100,000) than in Whites (1/100,000).
AQP4-IgG targets the water channels in the endfeet of astrocytes, which activates the complement pathway and secondarily damages oligodendrocytes, causing demyelination. NMO relapses occur more frequently than MS relapses (annualized relapse rate of 0.82) and tend to be more severe with impaired recovery after attacks.
Although the formal diagnostic criteria for NMO are beyond the scope of this chapter, NMO, like MS, requires the presence of a clinical relapse with MRI changes and exclusion of alternative causes in order to make a diagnosis. Although most patients who are diagnosed with NMO have AQP4 antibodies, these are not required for diagnosis, with about 20%–30% being AQP4 negative. NMO lesions tend to be both larger and less well defined on MRI than in MS.
Eighty-five percent of patients with NMO present with either optic neuritis or transverse myelitis, which can make it difficult to distinguish NMO from MS. However, there are clinical, laboratory, and MRI characteristics that can help to differentiate these diagnoses ( Table 21.3 ). Optic neuritis in NMO is more likely to be bilateral, and both the vision loss and pain tend to be more severe. On MRI the optic nerve lesions tend to be longitudinally expansive and involve the posterior optic nerve or optic chiasm, in comparison to the short-segment lesions that are seen in MS. This is also seen in NMO transverse myelitis, which tends to be large (covering more than half of the transverse section of the spinal cord) and longitudinally extensive (covering at least three vertebral bodies) in comparison to the small, peripheral lesions that are associated with MS ( Fig. 21.2 ).
| MS | NMO | MOGAD | |
|---|---|---|---|
| Average age of onset | 20–40 | 30–50 | Bimodal:
|
| Female:male ratio | 2.8:1 | 9:1 | 1:1 |
| Clinical course at onset |
| Relapsing |
|
| Optic neuritis features |
|
|
|
| Transverse myelitis features |
|
|
|
| CSF oligoclonal bands | Persistently seen in 95% of patients with clinically definite MS | Transiently seen in <20% | Transiently seen in <20% |
| CSF white blood cells | Normal to mildly elevated | >50/µL in 13%–35% | >50/µL in 35% |
Disease Management and Prognosis
Treatment of acute NMO relapses should be initiated as soon as possible. Acute relapses of NMO are initially treated similarly to MS relapses, with high-dose intravenous steroids for 3–7 days. However, unlike in MS, plasma exchange (PLEX) can be considered a first-line therapy instead of or in conjunction with steroids, and it often has better outcomes than steroids alone. In cases in which steroids and/or PLEX have failed, intravenous immunoglobulin (IVIG) can be beneficial.
Until 2019 treatments for NMO were off-label and consisted of steroids, azathioprine, mycophenolate mofetil, methotrexate, and rituximab, along with other immunomodulators/immunosuppressors. However, since then, four treatments have been FDA approved for use in AQP4-positive NMO: eculizumab (a C5 complement inhibitor administered intravenously every 2 weeks after initial loading doses), inebilizumab (an anti-CD19 monoclonal antibody administered intravenously every 6 months after initial loading doses), satralizumab (an IL-6 receptor antagonist administered subcutaneously every 4 weeks after initial loading doses), and ravulizumab (a C5 complement inhibitor administered intravenously every 8 weeks after initial loading doses).
Living with NMO poses multiple challenges. Although most disability is accrued during relapses, with little to no progression occurring between attacks, recovery is often slow and incomplete, and many symptoms persist. Eighty-three percent of patients report pain as a very frequent symptom, and 30%–70% endorse cognitive changes. Prior to the recent development of FDA-approved drugs for NMO, by around 6 years of disease duration, 18% of patients had permanent bilateral visual disability, 34% had permanent motor disability, and 23% had become wheelchair dependent. Hope remains that with increasing use of newly developed drugs, the prognosis for people diagnosed with NMO will improve.
Myelin Oligodendrocyte Glycoprotein–Associated Disorders
Clinical Features
Myelin oligodendrocyte glycoprotein (MOG) is expressed on the outer surface of myelin only within the CNS, and as a result, MOGAD can present as a variety of demyelinating disorders. This is likely why many MOGAD patients were misdiagnosed as having MS or NMO prior to 2018, when cell-based assays for IgG1-MOG antibody became clinically available.
In contrast to MS and NMO, MOGAD does not have a gender predilection, occurring equally often in males and females. MOGAD can be diagnosed at any age but has a bimodal age distribution, occurring most often in children ages 1–10 years, followed by young adults ages 31–40 years. Presenting symptoms vary by age, with children more likely to present with acute disseminated encephalomyelitis (ADEM) and adults more likely to present with optic neuritis or transverse myelitis. Other epidemiologic data for MOGAD is limited due to the relative novelty of the diagnosis.
MOGAD, much like MS and NMO, presents with clinical attacks that are attributed to inflammatory demyelination; these attacks are often very similar to those in MS and NMO. With the exception of ADEM in children, the most common presentations of MOGAD are optic neuritis and transverse myelitis. As in NMO, in addition to the presence of MOG-specific antibodies, there are clinical, laboratory, and MRI factors that can help to differentiate MOGAD from these similar disorders (see Table 21.3 ).
White matter lesions in MOGAD tend to be less well defined than in MS, are not as frequently contrast enhancing, and are unique in that they tend to fully resolve with treatment. Optic neuritis in MOGAD is, as in NMO, more often bilateral and longitudinally extensive than in MS and on MRI is specifically associated with anterior optic nerve involvement and optic nerve sheath enhancement, features that are not typically seen in MS or NMO (although optic nerve sheath enhancement is not specific to MOGAD and can be seen in multiple other disorders, such as sarcoidosis, tuberculosis, and neoplasms). As in NMO, MOGAD more often presents with longitudinally extensive lesions in both the optic nerve and the spinal cord that are unlike those seen in MS (see Fig. 21.2 ).
Disease Management and Prognosis
As in MS and NMO, the first-line treatment of an acute relapse of MOGAD is high-dose intravenous steroids. However, unlike MS and NMO, MOGAD has a tendency to rebound after cessation of steroids, so a prolonged taper is recommended. For patients who do not respond to steroids, either PLEX or IVIG can be used.
As up to 50% of patients may have a monophasic course of MOGAD with a single clinical attack, maintenance therapy is not recommended until a relapsing course has been proven. There are no FDA-approved medications for the long-term management of relapsing MOGAD, but multiple immunomodulators/immunosuppressors have been used off label, including rituximab, azathioprine, mycophenolate mofetil, tocilizumab, and IVIG. Unfortunately, despite long-term treatment, some patients continue to have high relapse rates.
The long-term prognosis for MOGAD remains unclear. Most patients diagnosed with this disorder have good outcomes after attacks, but there are not yet good predictors for disease course or outcomes. Younger patients and those with fewer attacks tend to have better outcomes than older patients with more frequent attacks, but other demographic and disease factors have not been associated with disability accumulation. Many patients with positive MOG-IgG1 antibodies will become antibody negative over the course of their disease, but there remains equipoise about whether this has any impact on relapse risk. As with many of the diseases discussed in this chapter, more time is needed to better study these outcomes.
Management of Acute Exacerbations of Multiple Sclerosis
Acute MS exacerbations are treated with glucocorticoids, typically with a course of 3–5 days of intravenous methylprednisolone 1000–1250 mg daily without subsequent oral prednisone taper. A noninferior alternative regimen with equivalent bioavailability is oral prednisone 1250 mg daily for the same duration. Both formulations restore the blood-brain barrier as assessed by resolution of contrast enhancement on MRI. Glucocorticoids at the doses and durations that are used to treat MS flares have minimal side effects, though caution should be used in patients with recurrent infections, gastric reflux, or psychiatric history. Retreatment with steroids is commonly attempted for refractory flares, though patients who are experiencing more severe recurrent demyelinating events may benefit from plasmapheresis.
Multiple Sclerosis Maintenance Therapy
Management of MS has become increasingly complex, as there are now 26 FDA-approved DMTs for MS ( Table 21.4 ). MS medications can be broadly classified into three groups: (1) early injectable medications (beta-interferons and glatiramer acetate); (2) oral medications (sphingosine-1-phosphate modulators, fumarates, teriflunomide, and cladribine); and (3) infusion therapies/monocloncal antibodies (natalizumab, CD20-inhibitors, mitoxantrone, and alemtuzumab).
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
