Clinical Features of Multiple Sclerosis
Multiple sclerosis (MS) is a demyelinating disease of the CNS that occurs more commonly in young women and is more prevalent further from the equator. In its most common clinical course, patients have multiple flares of symptoms at multiple time points, and recover from these attacks to varying degrees (relapsing-remitting MS). Later in the disease, patients with a relapsing-remitting course may enter a period of progressive decline, a scenario referred to as secondary progressive MS. Primary progressive MS is the least common clinical phenotype of MS, and is typically a spinal cord predominant illness with steady clinical decline from the time of onset rather than relapses and remissions. Even more rarely, the disease may present fulminantly with large tumor-like lesions (Marburg variant, tumefactive demyelination, or Balo’s concentric sclerosis).
Flares of MS present as focal neurologic deficits that emerge and evolve over hours to days and usually resolve completely or near completely in subsequent days to weeks. Deficits are referable to central nervous system sites (brain, brainstem, optic nerve, cerebellum, and/or spinal cord) and can include a region of paresthesias and/or weakness, diplopia (due to disruption of ocular-motor white matter tracts in the brainstem), vertigo (due to demyelination of the cranial nerve 8 entry zone or in the cerebellum), optic neuritis, transverse myelitis, ataxia, and/or trigeminal neuralgia. Trigeminal neuralgia occurs due to demyelination at the trigeminal entry zone in the pons (the nerve itself is peripheral; see “Trigeminal Neuralgia” in Chapter 13). Although MS is not a common cause of trigeminal neuralgia, unilateral or bilateral trigeminal neuralgia in a young patient should lead to consideration of and evaluation for MS.
Between flares of MS, the accumulation of subclinical lesions may cause cognitive symptoms, neuropsychiatric symptoms, and/or fatigue, but progression of focal neurologic deficits between attacks is uncommon in relapsing-remitting MS. On neurologic examination, patients often demonstrate upper motor neuron signs on examination (e.g., hyperreflexia, clonus, Babinski’s sign[s]) even outside of regions of new or prior clinical symptoms due to subclinical lesions that have caused CNS damage without having caused clinical flares.
Other classic symptoms and signs of MS include:
Uthoff’s phenomenon: recurrence or emergence of neurologic symptoms with heat (due to environmental temperature in the summer, hot bath, or exercise).
L’hermitte’s sign: electrical sensation down the spine with forward flexion of the neck. This can occur in any type of cervical myelopathy and is not specific to MS.
Internuclear ophthalmoplegia (INO) due to disruption of the medial longitudinal fasciculus (MLF) (see “Internuclear Ophthalmoplegia” in Chapter 11).
Afferent pupillary defect due to prior optic neuritis. An afferent pupillary defect may be present even in patients who have not had a clear clinical episode of optic neuritis (see “Impaired Pupillary Constriction Due to a Lesion of Cranial Nerve 2” in Chapter 10).
Neuroimaging in Multiple Sclerosis
Neuroimaging is critical in the diagnosis of MS. Lesions of MS have a characteristic morphology and distribution, and imaging characteristics can help to determine whether lesions are acute or chronic. The classic radiologic features of MS are small, ovoid T2/FLAIR hyperintensities that are perpendicularly oriented to the lateral ventricles and corpus callosum. Viewed on a sagittal image, the white matter lesions radiating outward perpendicular to the corpus callosum have been referred to as Dawson’s fingers (Fig. 21–1). Acute lesions may demonstrate enhancement with gadolinium, often in an open ring (as compared to the complete ring of contrast enhancement seen with tumor and abscess) (see Fig. 21–4). The damage caused by lesions over time can lead to T1 hypointensities at sites of prior demyelination (T1 black holes). Lesions in the brainstem, cerebellar white matter, and spinal cord are common. In the spinal cord, MS lesions are typically small and peripherally located (Fig. 21–2) (as compared to the longitudinally extensive lesions of neuromyelitis optica, see “Neuromyelitis Optica” below and Fig. 21–3).
MRI of brain lesions in multiple sclerosis. Axial (A) and sagittal (B) FLAIR MRI demonstrating periventricular hyperintensities oriented perpendicular to the ventricles (Dawson’s fingers).
MRI of spinal cord lesions in multiple sclerosis. Sagittal (A) and axial (B) T2-weighted MRI demonstrating a small, peripherally located T2 hyperintensity in the cervical spinal cord (compare to longitudinally extensive lesion in neuromyelitis optica in Fig. 21–3).
MRI of spinal cord lesion in neuromyelitis optica. Sagittal T2-weighted MRI demonstrating longitudinally extensive hyperintense lesion spanning more than three levels of the cervical spine in a patient with neuromyelitis optica.
MRI in acute disseminated encephalomyelitis (ADEM). A: Axial FLAIR image showing multiple large hyperintensities in the periventricular white matter. Note that the lesions in ADEM tend to be larger than those seen in MS (see Fig. 21–1). B: Axial postcontrast T1-weighted image demonstrating that the lesions in A exhibit incomplete (open) rings of enhancement.
Other causes of subcortical white matter lesions include chronic microvascular white matter changes, leukodystrophies (see Ch. 31), CNS vasculitis, demyelinating lesions in systemic autoimmune disease (e.g., Sjögren’s syndrome), and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy; see “Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukocencephalopathy (CADASIL) and Cerebral Autosomal Recessive Arteriopathy With Subcortical Infarcts and Leukocencephalopathy (CARASIL)” in Chapter 19). However, in most cases the clinical context in these entities is distinct from that of a patient with MS.
Previously, multiple clinical attacks “disseminated in space and time” were required for diagnosis of MS. Now, the ability of MRI to determine the presence of both acute (enhancing) and chronic (non-enhancing) evidence of demyelination on allows for the diagnosis of MS to be made at the time of an initial attack with accompanying MRI features demonstrating dissemination in space and time. According to the 2010 McDonald Criteria (Polman et al., 2011):
Dissemination in space is demonstrated clinically by history of two or more clinical demyelinating events affecting two different sites, or by MRI by demonstrating at least one lesion in two of the following four regions of the CNS: periventricular, juxtacortical, infratentorial, or spinal cord.
Dissemination in time requires two or more clinical attacks, a new lesion on MRI compared to a prior MRI, or can even be demonstrated on a single MRI if there are both enhancing (acute) and nonenhancing (nonacute) lesions.
Clinically Isolated Syndrome
When a patient presents with a first demyelinating event typical of MS (e.g., optic neuritis, transverse myelitis, or another focal symptom with suggestive imaging correlate), this is called a clinically isolated syndrome (CIS). Patients presenting with CIS will of course want to know whether they have MS, and if not, what the risk of developing the disease is in the future and whether that risk warrants initiating treatment. If a patient has normal brain imaging in the setting of a first attack of optic neuritis or transverse myelitis, the risk of future development of MS is two to three times lower than if there are characteristic lesions on MRI, but is still in the range of 10%–30% (depending on the presenting syndrome; see “Optic Neuritis” and “Transverse Myelitis” below).
If dissemination in space and time can be proven by MRI at the time of a first attack, then the diagnosis of MS can be made by McDonald Criteria (Polman et al., 2011). Some practitioners advocate treating all such patients with disease-modifying therapy. Other practitioners individualize treatments based on the clinical picture and apparent lesion burden on MRI, treating some patients who appear to have the highest risk, while following others closely clinically and with serial imaging studies. Based on evidence that vitamin D deficiency may be associated with an increased risk of the development of MS, many practitioners initiate vitamin D supplementation in patients with CIS.
If patients with CIS do not meet clinical-radiologic criteria for MS, some practitioners elect to look for ancillary evidence that could support increased risk for subsequent development of MS such as cerebrospinal fluid (CSF) oligoclonal bands or visual evoked potentials.
The presence of oligoclonal bands in the CSF that are not present in the serum indicates intrathecal IgG synthesis. CSF oligoclonal bands are present in the large majority of patients with MS, but are nonspecific and can be seen in CNS infections and other CNS inflammatory conditions. If oligoclonal bands are present in a patient with CIS, this does increase the risk of future development of MS, but not more so than MRI findings. Use of oligoclonal bands for diagnosis in MS has diminished with the advent of MRI criteria, but may be useful in cases of patients in whom the disease is suspected but clinical-radiologic criteria are not met. However, whether or not a patient with CIS and normal MRI who is found to have CSF oligoclonal bands should initiate treatment or just be followed with serial imaging is an individualized decision.
Visual evoked potentials (VEPs) examine a particular EEG of visual stimulation (P100) to evaluate conduction along the visual pathway. If the latency of P100 between the two eyes is significantly different, this suggests slowed conduction in one optic nerve, a sign of optic nerve dysfunction. In cases of possible MS, abnormal VEPs can suggest prior optic neuritis. The optic nerve can also be examined by optical coherence tomography to look for prior damage to the nerve.
Radiologically Isolated Syndrome
Occasionally, an MRI performed for another reason (e.g., headache) may demonstrate what appears to be a “textbook” appearance of MS, but the patient has had no clinical attacks and has a normal neurologic examination. This is called radiologically isolated syndrome (RIS). Such patients should be evaluated for other evidence of possible MS (e.g., spinal cord lesions on MRI, oligoclonal bands) and other causes of CNS white matter disease (e.g., systemic inflammatory disorders, cerebrovascular disease). However, this evaluation is commonly unremarkable. Even if ancillary laboratory or radiologic evidence suggestive of MS is discovered, it is unclear how this should be interpreted if the patient has no clinical history suggestive of demyelinating disease. Therefore, such patients are typically followed clinically and with serial imaging. About one third of patients with RIS will eventually develop MS and have presumably been discovered in the preclinical stage, while many appear never to develop any clinical features of the disease. As in patients with a clinically isolated syndrome, many practitioners initiate empiric vitamin D supplementation in patients with RIS.
Fulminant Demyelinating Disease
Rarely, fulminant demyelination can occur as a first attack of MS, in a patient with established MS, or as an isolated demyelinating phenomenon. Marburg variant MS, tumefactive demyelination, and Balo’s concentric sclerosis are names given to differing radiologic and pathologic appearances of these entities, which may be difficult to distinguish from tumor or other inflammatory condition of the CNS (e.g., CNS vasculitis, sarcoidosis, neuromyelitis optica). Biopsy is necessary for diagnosis. If steroids are ineffective in treating fulminant demyelination, patients may be treated with IVIg or plasma exchange. If these are ineffective, cyclophosphamide and/or rituximab may be considered.
Treatment of Multiple Sclerosis
Acute Treatment of Flares of Multiple Sclerosis
Acute attacks of demyelination are typically treated with a 3–5 day course of IV methyprednisolone. This treatment is utilized whether it is the first attack (clinically isolated syndrome) or if the attack occurs in a patient with known MS.
Long-term Treatment of Relapsing-Remitting MS
The goal of disease-modifying treatment for relapsing-remitting MS is to reduce the risk of flares and slow the progression of disability. The number of medications found to be effective toward these endpoints for relapsing-remitting MS continues to increase (Table 21–1). However, there are limited data to guide decision-making with respect to choices between agents or change from one therapy to another.
TABLE 21–1Commonly Used Treatments for Relapsing-Remitting Multiple Sclerosis. ||Download (.pdf) TABLE 21–1 Commonly Used Treatments for Relapsing-Remitting Multiple Sclerosis.
| ||Mode of Administration ||Side Effects/Toxicities ||Monitoring ||Mechanism |
|Interferon beta ||Subcutaneous or intramuscular injection || |
Injection site reaction
|Diverse immunomodulatory effects |
|Glatiramer acetate ||Subcutaneous injection || |
Injection site reaction
Flushing/anxiety with injection may occur
|None ||Multiple effects on T cells |
|Diethyl fumarate ||Oral (daily) || |
|CBC ||Diverse immunomodulatory effects |
|Fingolimod ||Oral (daily) || |
Increased risk of VZV infection
Cardiac monitoring with first dose
|Sphingosine receptor modulator → decreases migration of lymphocytes from lymph nodes |
|Teriflunomide ||Oral (daily) || |
Pregnancy category X
|LFTs ||Blocks pyrimidine synthesis → decreases division of inflammatory cells |
|Natalizumab (second-line agent) ||IV infusion (monthly) ||Increased risk of PML ||JC virus antibody every 6 months ||Monoclonal antibody against α4 integrin, decreases lymphocyte entry into CNS |
The agents in longest use for relapsing-remitting MS are the injectable treatments interferon beta and glatiramer acetate. Their long-term safety is well-established and the side effects are generally tolerable, so many practitioners use these as first-line agents. However, many practitioners now offer the option of an oral agent (teriflunomide, fingolimod, dimethyl fumarate) to patients with a new diagnosis of MS. Comparative efficacy is hard to gauge based on differing trial designs, but either injectables or oral agents are likely reasonable first-line options depending on a patient’s comorbidities. No therapy reduces the relapse rate to zero, so judging the success of therapy can be challenging since patients on any agent would still be expected to have relapses and development of new lesions on serial MRIs. If a patient is thought to have an unacceptable rate of relapse and/or significant increase in lesion burden on follow-up neuroimaging on one medication, change to another medication is often made.
Notable toxicities and adverse reactions of which to be aware include:
Bradycardia and macular edema with fingolimod. Baseline electrocardiogram (ECG) and cardiac monitoring are required with the first dose (due to risk of first-dose bradycardia). Baseline ophthalmologic examination and subsequent periodic ophthalmologic monitoring are also necessary.
Hepatotoxicity and teratogenicity of teriflunomide (pregnancy category X). Liver function monitoring is required, and women planning to conceive require elimination of teriflunomide with cholestyramine.
Progressive multifocal leukoencephalopathy (PML) with natalizumab (and less commonly with fingolimod and dimethyl fumarate). PML is an opportunistic CNS viral infection caused by the JC virus (see “Viral Focal Brain Lesions” in Ch. 20). The risk of developing PML with natalizumab treatment is related to three factors:
Whether the patient has antibodies to the JC virus
Whether the patient has received prior immunosuppressive therapy
Length of treatment with natalizumab beyond 2 years
Any patient being considered for natalizumab treatment must be screened for serum JC virus antibodies. In patients who are not found to have JC virus antibodies, the risk of developing PML is exceedingly low (about 1 in 10,000 [0.01%] even after 2 years of treatment), and this risk remains low even if the patient has received prior immunosuppressive therapy (~2.5 in 10,000 [0.025%]) (Fox and Rudick, 2012). In patients who are JC virus antibody positive, risk of PML after 2 years of treatment increases about 40-fold to approximately 40 per 10,000 (0.4%), and with prior immunosuppression such a patient’s risk would nearly triple beyond that to over 100 per 10,000 (1%) (Fox and Rudick, 2012). Given these risks, JC virus antibody–negative patients on natalizumab therapy must be screened for JC virus antibody every 6 months to evaluate for seroconversion. If PML develops during natalizumab treatment, natalizumab is discontinued, and plasma exchange is used to remove natalizumab.
MS therapies should be discontinued prior to conception in women seeking to become pregnant (though some practitioners continue glatiramer acetate during pregnancy).
Treatment of Progressive Multiple Sclerosis
Evidence is limited and inconclusive for the optimal treatment of both primary progressive MS and secondary progressive MS, so treatment is largely supportive. However, some practitioners treat patients with progressive MS with rituximab, methotrexate, steroids, cyclophosphamide, or mitoxantrone (mitoxantrone is rarely used due to cardiac toxicity).
Symptomatic Management in Multiple Sclerosis
In addition to trying to modify the disease course of MS, many symptoms of MS can be effectively treated: