Benign MS

Relapsing–Remitting MS

Secondary Progressive

Primary Progressive

Ocular

Blurred vision, likely a manifestation of acute optic neuritis, is a very common initial symptoms of MS. This may have great variability in degree from gross total unilateral blindness to a subtle change in visual acuity. Vision changes may also be related to a poorly expressed diplopia secondary to an INO, one of the most common neuro-ophthalmologic manifestations of MS (Fig. 46-2). In the first instance, the differential diagnosis includes any process affecting the retina or cornea, and in the second, the diplopia may be related to a pseudo-INO, mimicking MS. This is typical of myasthenia gravis. Sometimes a true INO secondary to a stroke may occur in older hypertensive patients.

Figure 46-2 Multiple Sclerosis: Visual manifestations.

At times a subtle demyelinating lesion may be clinically uncovered by exposure to heat. For example, during a summer heat wave, or even just taking a shower, a patient may note relatively short-lived symptomatology, sometimes visual blurring or just a change in gait; this is known as Uhthoff syndrome. The symptoms are usually fleeting. These routinely disappear when the patient returns to more normal ambient temperatures.

The prognostic significance of an acute episode of optic neuritis (ON) has been the subject of numerous investigations. Today MRI provides an important means to put the ON event into a long term perspective. A recent ON study, with a median 6 years’ follow-up, demonstrated that slightly less than 50% of these patients had converted to clinically definite MS (CDMS). Most importantly, both the presence and the number of MRI-defined spinal cord lesions, and to a lesser extent gadolinium-enhancing lesions, as well as the number of infratentorial lesions at baseline were significant independent predictors of an even higher disability manifested as CDMS.

When temporally associated with a myelopathy, this clinical presentation is referred to as Devic syndrome, or neuromyelitis optica (NMO). This is a humorally mediated autoimmune demyelinating disorder that is immunologically distinct from MS. It is characterized by an autoantibody that recognizes aquaporin 4 (AQP4), a water channel expressed on astrocyte podocytes. NMO may sometimes have a poorer prognosis than MS although on occasion it is more acutely responsive to immunosuppression or chemotherapy. This Devic syndrome does not typically benefit from first-line long-term MS disease modifiers (Chapter 47).

Inner Ear or Cerebellum

A vague feeling of unsteadiness, dizziness, and sometimes a whirling vertigo with nausea are frequent symptoms of MS. Precise definition of exactly what patients mean by “dizzy” is essential. Frequently, patients are in fact reporting a sense of dysequilibrium likely representing cerebellar dysfunction and less commonly reflecting vestibular pathways. Such patients typically demonstrate a broad-based gait, various signs of dysmetria, a tremor not seen in patients with a primary vestibular lesion, and often vertical nystagmus (Fig. 46-3).

Figure 46-3 Multiple Sclerosis: Cerebellar and Brain Stem Manifestations.

The most common cause of true vertigo is either a primary vestibular neuronitis or the recurrent Ménière syndrome associated with hearing loss. These are both benign processes originating within the inner ear. However, one needs to always consider the possibility that the patient’s dizziness/vertigo has a primary CNS basis. One very important differential diagnostic clue to the latter is the finding of vertical nystagmus on the neurologic examination. This is not found when a peripheral mechanism for vertigo is present. The clinical demonstration of vertical nystagmus in a patient with vertigo requires an MRI to look for primary CNS disease.

Although spontaneous downbeat nystagmus is often the hallmark of another specific central nervous system lesion, namely an Arnold-Chiari malformation, this may also occur in MS patients reporting feelings of dizziness.

Myelopathies

Sensations of tingling, tightness, pins and needles, and electric shocks are common MS symptoms. Relatively early in the disease course, some of these patients report an electric shock–like sensation that usually radiates down the back or arms, occurring spontaneously when the patient bends his or her neck. This is known as Lhermitte’s sign (Fig. 46-4). This most commonly occurs with MS patients but often the patient does not report this per se. Rather the skilled examiner is trained to ask about such as it is pathognomonic and indicative of spinal posterior column dysfunction. Lhermitte’s sign can be reported with almost any form of spinal cord disease, including spondylosis with significant cervical spinal stenosis, a space-occupying lesion, vitamin B₁₂ (cobalamin) deficiency, or copper deficiency syndromes, especially in individuals who have had major gastrectomies or unusual diets, such as excess zinc that blocks copper absorption.

Figure 46-4 Multiple Sclerosis: Myelopathic Manifestations.

Other patients with MS frequently report a tight bandlike distribution of numbness. When circumferential or hemicircumferential, particularly in the midtrunk, the immediate concern is a possible transverse myelitis or primary spinal cord mass lesion. Sometimes patients describe a distribution suggestive of a polyneuropathy with bilateral symmetric numbness. On other occasions, numbness may occur acutely in the hand, compatible with mononeuropathy or stroke. Other myelopathies deserving consideration relate to tropical spastic paraparesis or AIDS.

Strokes and TIAs

Although MS is one of the most common neurologic disorders in young to middle-aged adults, stroke must always be considered. Carotid or vertebrobasilar dissection, paradoxical emboli, and CNS vasculitis are some of the more common stroke syndromes in younger adults. These may often mimic MS and require differential consideration in potential MS patients. Conversely, as technology has improved, the ability to recognize MS in an older population (aged >50 years) has become possible in cases that masquerade as microangiopathy secondary to atherosclerosis.

Clinical Vignette

A 58-year-old school teacher with a history of depression and sciatica noted the presence of left-sided weakness that progressed gradually over a year. She found it difficult to maneuver her left leg into a pair of pants and occasionally experienced buckling of the right leg when dressing. Her left-handed grasp of a pen was increasingly compromised and her handwriting was changing. Advancing fatigue was making it increasingly difficult for her to get through her work day. She began to experience difficulty driving due to stiffness and shaking of the right leg, and, eventually, she could not exit her car without lifting her right leg with her hands. This was associated with a band-like constriction sensation around her thorax and intermittent urinary incontinence that she attributed to child-bearing and age.

Neurologic examination demonstrated diminished fine coordinated movements of her dominant left hand, bilateral hand clumsiness, and right greater than left leg weakness, with increased tone distally in the lower extremities, and bilateral Babinski signs. Her gait was wide-based and she had a right foot drop. Sensory examination was normal except for mild symmetrically decreased vibration in the distal lower extremities.

MRI scan of the brain with and without contrast showed scattered focal areas of T2 and FLAIR hyperintensity in the periventricular white matter, some oriented perpendicularly to the ventricles. There was a single lesion in the anterior corpus callosum and one area of faint enhancement in the left cerebral peduncle. Diffusion-weighted imaging was normal. Thoracic spine MRI showed an enhancing lesion in the cord at T9. Visual evoked responses showed some delay on the right, and CSF analysis revealed four oligoclonal bands and negative Lyme testing.

In retrospect, the patient recalled a transient visual disturbance in the right eye at age 19 years that was construed as migraine. When questioned, she also recalled an occasional Lhermitte sign occurring as a young woman.

A wider diagnostic net needs to be cast in older patients who are considered to possibly have had a cryptogenic stroke who do not have underlying risk factors for stroke. As so well illustrated in this vignette, a careful history is once again the essence of neurologic diagnosis, especially knowledge of what are the best questions to ask. Diffusion-weighted imaging and MRI perfusion studies can be very helpful in distinguishing subacute ischemic lesions from demyelinating lesions.

Cerebral Mass Lesions

Gliomas, meningiomas, and even primary CNS lymphoma always require consideration in young patients with recent onset of focal neurologic dysfunction. Lymphomas particularly may mimic MS because of their periventricular distribution on MRI. Additionally, the relatively promising response of lymphoma to corticosteroids mimics that witnessed in some patients with MS. Similarly when patients present with cerebellar ataxia, cerebellar astrocytomas, hemangioblastomas, or other mass lesions must be excluded. When confronted with a patient with an evolving often asymmetric paraparesis, a mass lesion, particularly meningiomas, originating anywhere in the spinal axis, or even the parasagittal frontal cortex, require consideration.

Clinical Vignette

A 30-year-old woman, previously healthy, began to experience episodes of déjà vu and derealization. In her work as a bank teller, colleagues noted that she had distinct periodic slowness in her work and an occasional latency in responsiveness when dealing with customers. A friend suggested that she was suffering from anxiety, and she consulted a therapist who witnessed one of her spells. Suspecting a seizure disorder, the patient was referred to a neurologist, who found her to be diffusely hyperreflexic with a left Babinski sign, mildly increased tone in the lower extremities, and a jaw jerk. EEG demonstrated left temporal lobe slowing with sharp waves. MRI scan of the brain revealed a focal enhancing mass lesion in the left temporal lobe with modest edema and three tiny, non-enhancing white matter lesions located subcortically as well as in the periventricular regions. A glioblastoma multiforme was suspected; however, stereotactic biopsy showed demyelination with axonal sparing, sparse perivascular lymphocytic infiltration, and numerous periodic acid Schiff-positive macrophages.

The patient received a short course of IV methylprednisolone, and phenytoin therapy was initiated. Her episodes resolved and repeat MRI in 3 months showed near complete resolution of the mass-like region.

Occasionally an acute focal cerebral lesion may be the presenting sign of MS leading the clinician to suspect that the patient has a glioblastoma multiforme, the most malignant of brain tumors. Fortunately, stereotactic biopsy occasionally demonstrates a rare monofocal form of MS, monofocal acute inflammatory demyelination (MAID) (Fig. 46-5). This can mimic a primary brain tumor or abscess. It is a rare and unique demyelinating disorder that may herald, or be superimposed on, more typical MS or may be seemingly unassociated with MS. MAID usually affects the cerebral hemispheres, and its clinical and radiologic features suggest a brain tumor. In contrast, an acute myelitis or optic neuritis is a more common example of a monofocal demyelinating process. Patients with the “cerebral form” of demyelinating disease have symptoms atypical for MS, including an acute hemiplegia, hemisensory complaints, and visual field deficits. Less common symptoms include headaches, seizures, aphasia, an alteration in level of consciousness, and cognitive or psychiatric manifestations.

Figure 46-5 Brain MRI in Multiple Sclerosis.

Rarely, patients with a similar acute clinical presentation have multifocal CNS lesions, diagnosed as acute disseminated encephalomyelitis (ADEM) (Chapter 47). ADEM usually has widespread or multifocal MRI abnormalities.

Spinal Dural Arteriovenous Malformations

Patients with MS typically experience evanescent or waxing and waning symptomatology. However, there are two different forms of vascular anomalies that sometimes present with a relapsing–remitting temporal profile mimicking MS. Firstly a spinal dural arteriovenous fistula must also be an important part of the differential diagnosis. Although the physician typically suspects MS whenever a patient experiences intermittent myelopathic symptoms, very precise inspection of the MRI is essential in order to define the possibility of an epidural vascular lesion. Once diagnosed, surgical treatment or an embolization procedure is performed to obliterate the abnormal cord vasculature. Secondly the very rare pontine cavernous hemangiomas require consideration in the differential of intermittent brainstem symptoms, including diplopia, hemiparesthesias, and bilateral Babinski signs. Here the MRI is again essential in reaching this diagnosis. These patients have a focal pontine lesion identified and there is no evidence of a diffuse, multifocal set of demyelinating abnormalities characteristic of MS.

Peripheral Neuropathy

In patients with MS, the “numbness” per se is commonly a feeling of tightness or pressure rather than the more classic tingling sensation of a peripheral nerve disorder. Individuals with MS frequently complain of a poorly defined, and often variable, multifocal numbness. This is typically not confined to a single nerve root or peripheral nerve distribution; it may occur with both a chronic and acute temporal profile. When this is a slowly evolving process, entities such as vitamin B₁₂ deficiency, particularly when associated with a myelopathy manifested by Babinski signs, Lyme disease, HTLV-I, copper deficiency, or even the relatively unusual migrant sensory neuritis of Wartenberg, are part of the differential diagnosis. When both legs are involved in a relatively acute and symmetric fashion, with an evolving weakness, either the Guillain–Barré syndrome or a spinal mass lesion are common possibilities.

Neuromuscular Transmission Defects

Like MS, myasthenia gravis tends to occur in young women. It is characterized by combinations of intermittent visual difficulties, particularly diplopia often referred to by the patient as blurring, dysarthria, and fatigue, symptoms that also occur in MS. Lambert–Eaton myasthenic syndrome (LEMS), a presynaptic autoimmune, often paraneoplastic, disorder, also may cause intermittent weakness, bulbar signs, and fatigue (Chapter 70), mimicking the fatigue or nonspecific tiredness that are so commonly presenting signs of MS.

Myopathies

These disorders, often either mitochondrial myopathies or late-onset dystrophies of the oculopharyngeal type, present with an increased tendency to muscular fatigue. On neurologic examination, these patients frequently have both ptosis and limited extraocular muscle (EOM) function. However, as the EOM deficits are symmetric, most of these patients do not report any diplopia. Individuals with periodic paralysis have intermittent symptomatology; however, these events usually start in childhood and adolescence, are symmetric, are relatively short-lived, and rarely affect bulbar musculature.

Conversion Hysteria

All too often, patients eventually diagnosed with MS do not have any definitive findings on their initial neurologic examination. This often leads the initial and unsuspecting physician into a common and sad differential diagnostic error. One must take great care not to falsely apply diagnostic significance to various situational anxieties such as occupational stresses, marital discord, or financial worries as being emotional precipitants for ill-defined clinical presentations and suggest that the patient has a somatoform disorder (Chapter 26). Conversion hysteria must always be a diagnosis of exclusion. This relatively rare disorder frequently occurs in young adults, particularly women, within the setting of poorly articulated psychologic stress, sometimes related to sexual abuse such as incest.

These individuals invariably have normal examination results, although their subconscious attempts to demonstrate neurologic abnormalities often result in consistently inconsistent neurologic findings. These may often be a “give-way” weakness or very bizarre gait problems known as “astasia-abasia.” Repeat clinical neurologic evaluations, MRI, evoked potentials (EPs), and CSF examinations are all warranted. This allows one to always give the patient the benefit of doubt, repeatedly searching for clues to a much more common organic disease. Most importantly, there is no illness more likely to lead the physician to this clinical conundrum than MS.

Magnetic Resonance Imaging

The diagnosis of MS has become very well defined with MRI; a positive study provides the physician with a solid diagnostic base leading in most instances to an accurate MS diagnosis in upwards of 95% of patients. New lesions typically have uniform gadolinium enhancement, whereas a ringlike enhancement is compatible with reactivation of prior lesions. Acute-phase plaques appear as rounded areas of high-signal intensity on FLAIR and T2 sequences. Gadolinium enhancement on T1 sequences is secondary to inflammatory damage to the blood–brain barrier. Earlier-onset, but nonreactivated, lesions do not enhance at all. T2-weighted MRI has the highest degree of sensitivity and is particularly useful for demonstrating disease dissemination; however, this lacks somewhat in specificity. A primary value of T1-weighted gadolinium-enhanced imaging is that it provides an increased specificity by differentiating enhancing from nonenhancing lesions.

Classic MRI findings are typified by multiple well-demarcated ovoid plaques whose long axis are situated perpendicularly along callososeptal interfaces and demonstrate a perivenular extension within the corpus callosum (Dawson fingers). Furthermore, plaques have a propensity for the periventricular and subcortical white matter, middle cerebellar peduncle, pons, or medulla (see Fig. 46-5). Within the spinal cord per se, white matter lesions can involve any part of the many afferent or efferent tracts, particularly the dorsal columns. At times the lesion can be so large that it mimics an intramedullary tumor as characterized by a large expansile hyperintense upper cervical cord plaque as seen in Figure 46-6. MRI has unequivocally replaced CSF analysis, the oldest methodology, as well as various forms of evoked neurophysiologic potentials, as the primary diagnostic methodology.

Figure 46-6 Spinal Cord MRI in Multiple Sclerosis.

Increasingly powerful magnets and techniques, able to resolve variations from the norm, that sometimes mimic MS but may not be pathologic, sometimes complicate interpretation of abnormalities. “Unidentified bright objects (UBOs)” are the classic imitators seen in those who smoke, have hypertension, migraine headaches, or Lyme disease, or are present for indeterminate reasons. Similarly, Virchow-Robin spaces, dilated CSF-filled vascular areas, may give high T2 signal intensity. However, these can be distinguished from demyelinated plaques of MS because they are not present with proton density images.

MRI of the spinal cord may be particularly useful in substantiating a diagnosis (see Fig. 46-6). In clinically suspicious cases with normal or equivocal brain MRI, spinal cord lesions can be compelling, even without symptoms referable to the spinal cord. Spinal cord lesions, however, are sometimes not as easily identified because of the constraints of motion artifact. The increased availability of 3-Tesla magnets in the coming years will add further image refinement, particularly with primary spinal forms of MS.

There is a most interesting subset of patients who eventually prove to have MS but are first evaluated with symptoms that are seemingly nonspecific and definitely not classic for MS. They undergo MRI scanning primarily to assuage patient fears of a structural abnormality, such as a tumor or perhaps MS. In a serendipitous fashion, the study then uncovers unexpected white-matter demyelinating lesions compatible with MS. For the physician, these MR findings do not seem to collate with the patient’s presenting symptoms. However, these observations need to be taken seriously. Such results are extending our definition of the initial clinical picture of multiple sclerosis and are making the neurologic clinician even more alert to the relative subtleties of this disorder early in its course.

Clinical Vignettes

A 27-year-old woman with a history of depression since early adolescence experienced painful spasm in her neck after her psychiatrist increased her dose of Zyprexa. An MRI of her cervical spine revealed an abnormality in the left dorsolateral spinal cord at C7. It was a nonenhancing lesion, bright on T2 and FLAIR image. Her torticollis resolved following reduction of her Zyprexa dosage. Brain MRI showed two lesions within the corpus callosum. Visual evoked response was significantly delayed on the right eye compatible with a lesion between the retina and the optic chiasm.

A 34-year-old landscaper was struck by the trunk of a tree that was felled by a coworker, failing to heed a warning to stand clear. He lost consciousness and was taken to a local emergency room. He had awakened and was noted to be fully alert and oriented. CT of the spine showed a T3 compression fracture. The day after his injury, he developed a severe headache. Magnetic resonance angiography of the head and neck revealed no dissection or any other vascular abnormality. Although brain MRI revealed no hemorrhages, there were 11 periventricular lesions seen on T2 and FLAIR images. Some of these were oriented perpendicularly to the ventricles, the largest of which, in the right frontal lobe, showed some cystic changes with low attenuation on T1 images and mild enhancement. CSF analysis demonstrated six oligoclonal bands and the presence of myelin basic protein. None of these findings could be related to his long history of ADH.

These two vignettes emphasize how MRI can serendipitously demonstrate findings of MS in the absence of active clinical symptoms, raising the question, “How early is too early to offer immunomodulatory therapy?” There is no consensus on the approach to such patients. How to identify patients with a potentially benign course versus those at risk for significant future disease with later disability remains unknown. MRI will be a keystone as this treatment algorithm is eventually defined. With the increasing evidence of the efficacy of the various ABC drugs in lessening long-term deficits, if these medications are begun when the diagnosis of MS is well defined, there is an increased tendency to begin active therapy once the diagnosis is ensured in patients such as these.

Cerebrospinal Fluid

Lumbar puncture for CSF is becoming superfluous when the diagnosis is established by history, examination, and unequivocal and very supportive MRI images. MRI is also very useful in excluding other diagnoses, particularly Lyme disease, sarcoidosis, lymphoma, or multi-infarcts secondary to a primary CNS vasculitis. However, when there is no definite MRI confirmation or collation of an MS diagnosis, a CSF examination can still be a very useful diagnostic procedure. When indicated, this procedure is typically performed by neurologists and neuroradiologists.

The typical CSF profile of a patient with MS is summarized in Figure 46-7. The white blood cell count is typically normal, with less than 6 mononuclear cells/mm³ being present; however, occasionally one may see MS patients with up to 50 lymphocytes per cubic millimeter. This usually does not exceed 25 cells/mm³. Lymphocyte counts greater than 100/mm³ must arouse suspicion of other inflammatory or even neoplastic processes. Given the expectation of subtle, if any, pleocytosis, it is paramount to strive for an atraumatic tap. The number of cells present may correlate with enhancing MRI lesions and thus with disease activity. However, there is no apparent correlation between cell count and T2 lesion burden. The CSF glucose level is normal, appropriate to the generally benign cell counts.

Figure 46-7 Diagnostic Tests—Spinal Fluid.

The CSF total protein is normal in 60% of MS cases; rarely is it greater than 70 mg/dL. Healthy individuals may have a CSF banding pattern similar to that found within a concomitant serum immunoglobulin electrophoresis. In contrast, if CSF bands outnumber serum bands, an abnormal CNS immune response is suggested. Whenever a few well-defined B-cell clones migrate to the CNS, these cells begin to produce distinct populations of immunoglobulins that separate into the bands seen on electrophoresis. CSF IgG is relatively increased when compared with albumin and with the IgG present in the serum of the same subject. This is related to changes in the permeability of the blood–brain barrier and IgG synthesis by plasma cells within the abnormal CNS. In healthy patients, there is no discrete CSF banding; instead, a diffuse single band represents a mixture of polyclonal immunoglobulins that do not segregate into distinct groups. An in-situ CNS hyperimmune response may be associated with oligoclonal band production. However, this is not specific for MS as it may occur with other CNS inflammatory or infectious diseases.

Myelin basic protein is a molecularly large component of myelin that can be detected in a degraded form by CSF immunoassay. Although its presence is thought to correlate with active demyelination, this is a relatively nonspecific finding. When detected, the level seems to be related to the amount and rate of myelin destruction. Thus, a relatively inactive instance of “smoldering” MS is not typically associated with the presence of myelin basic protein. In contrast, other pathologic processes that rapidly destroy large amounts of myelin (e.g., stroke) also produce high levels of CSF myelin basic protein.

Evoked Potentials

Neurophysiologic studies provide a means to objectively analyze the integrity of neuronal pathways in both the central and peripheral nervous systems. Prior to the availability of MRI, EPs were a useful modality to identify subclinical CNS disease. Testing is relatively easy to perform and requires minimal patient cooperation, particularly when testing the visual and, less commonly, auditory pathways. Today the primary value of EP testing occurs when a patient presents with a myelopathy and one is attempting to define the presence of multiple areas of clinical involvement in space and time to establish a diagnosis of MS. As some patients either forget or previously had a prior subclinical optic neuritis, visual evoked responses (VERs) may still be quite useful in this one instance. However, brainstem and somatosensory EPs are no longer of major diagnostic value when considering a diagnosis of MS.

With VERs, a peripheral stimulus, typically a reversing high-contrast checkerboard pattern, provides a means to study the integrity of the visual system. The response latencies can yield objective data regarding the ability of the nervous system to transmit impulses efficiently from the optic nerve to the occipital cortex. If there is a unilateral absence or delay, one can conclude that there is slowing in conduction between the retina and the optic chiasm (Fig. 46-8). This is typical for a unilateral optic neuritis. It is particularly helpful as even if the patient totally regains his or her vision, the remyelination is not perfect; thus a marker is left for future reference. When bilateral changes are present with the potentials delayed, attenuated, or blocked because of a prior instance of CNS demyelination, one cannot precisely localize the lesion to the optic nerve as the lesion could be any place in the visual pathway.

Figure 46-8 Tests—Evoked Responses.

If a number of years later a patient develops a myelopathy, VER testing can provide an opportunity to define the previous presence of some damage to these pathways. The combination of an abnormal VER response and a myelopathy is almost unique for a diagnosis of MS.

Multiple Sclerosis Diagnostic Criteria

Although MRI provides a superb diagnostic testing modality, it always needs to be accompanied by an appropriate clinical setting to make an unequivocal diagnosis of MS. Clinicians utilize a set of consensus criteria that continually evolve as new technological advances become available. Clinical history and examination were the mainstays of diagnosis in 1965 when Schumacher et al. issued the first widely used criteria for MS; these required that five of six of the conditions shown in Box 46-1 be met before making a clinically definite diagnosis of multiple sclerosis.

MS diagnostic criteria were revised in 1983 as evoked response testing and neuroimaging began to allow the identification of lesions that were not clinically evident and gave credence to laboratory data supportive of MS. The latter included CSF findings of specific increased number of oligoclonal bands in the CSF in comparison to the serum, elevated IgG levels, and increased IgG index. Most recently in 2001, the McDonald criteria became the standard almost universally applied in clinical research as well as to justify disease-modifying therapies specific for MS treatment.

These preserved the traditional requirement of multiple attacks of disease separated in time and space. Additionally, these new criteria provided for consideration of MRI and CSF findings when only one objective MRI lesion is found, only a single clinical attack has occurred, or when disease progression is insidious. The McDonald Diagnostic Criteria were revised in 2005 to incorporate the growing role of MR imaging for making a diagnosis of multiple sclerosis as well as to foster early treatment without sacrificing sensitivity and specificity (Box 46-2).

The ability to make a diagnosis of MS as early and accurately as possible is critical to patient care and to producing the most meaningful clinical research. Once the diagnosis of MS can be confirmed, the issue of when to initiate therapy becomes paramount.

Immunomodulatory Therapy

Medical management of MS was once limited to palliative care. Although symptom treatment remains integral to MS care, immunomodulatory therapies are changing treatment. Pharmacologic interventions modify the course of MS through the reduction of relapse rate and MRI lesion burden, both of which are likely to affect disease progression.

Five drugs are approved by the USFDA for treatment of RRMS: interferon beta-1b, intramuscular interferon beta-1a, glatiramer acetate, subcutaneous interferon beta-1a, and natalizumab infusion. Subcutaneous interferon beta-1b (8 million U every other day) became available early in the 1990s, followed by intramuscular interferon beta-1a (30 µg once weekly) later in that same decade. An alternative form of subcutaneous interferon beta-1a used in Europe became available in the United States in 2002 and is injected three times per week (22–44 µg), delivering a greater weekly dose of interferon beta-1a. Flulike symptoms, the most prominent adverse effect, occur in approximately 60% of those who use interferons, but these effects are mitigated over time and can be treated effectively with NSAIDs.

Glatiramer acetate (20 mg subcutaneously daily) became available in the United States in 1996 and is an unrelated compound of polypeptides that may have fewer potential adverse effects and perhaps more than one mechanism of action on the aberrant immune response. Some of its benefit may be realized later in the course of treatment than with the interferons.

In 2004, natalizumab was approved for use in the United States and the European Union. It was temporarily withdrawn by the manufacturer in February 2005 due to the occurrence of two cases of progressive multifocal leukoencephalopathy (PML) in MS patients treated with a combination of interferon beta 1-a and natalizumab. PML is a rare, progressive, and universally fatal central nervous system infection primarily occurring in immunodeficient individuals, particularly those with HIV-AIDS or very rarely those taking long-term immunosuppressive medications, particularly corticosteroids. PML is caused by the unmasked virulence of the fairly ubiquitous papillomavirus, JC virus.

In 2006, natalizumab returned to the market with more stringent guidelines for administration and solely as monotherapy for relapsing forms of MS. To date, however, additional cases of PML continue to accrue at a low incidence even with natalizumab monotherapy. Although the risk of evolving PML remains the greatest deterrent for many patients and clinicians, cases of liver toxicity and a questionable association with melanoma have since come to light. Thus far, there have been no controlled trials to adequately assess the efficacy of natalizumab for secondary progressive multiple sclerosis (SPMS).

Each of these agents reduces relapse rates and decreases the MRI burden of lesions within the central nervous system. Differences in trial design make effective drug-to-drug comparisons very difficult. To date, the reduction in relapse rate over 2 years hovers around 30–35% each for interferon therapies and for glatiramer acetate, whereas natalizumab was shown to reduce relapse rate over 1 year by as much as 68% when compared to placebo. Preexisting factors may influence the choice of therapy in treatment-naive patients. For example, a history of depression, suicidal ideation, or both, which may be adverse effects of the interferon drugs, may make glatiramer acetate the drug of choice in certain individuals. Some patients may be more compliant with one medication than another, depending upon individual tolerances for site reactions, flu-like symptoms, frequency of treatment, and impact upon lifestyle. Patients who cannot achieve compliance with intramuscular or subcutaneous injection may be able to tolerate monthly infusion with natalizumab.

Mechanisms of Immunomodulatory Therapies

Interferons and glatiramer acetate alter the mechanism of antigen presentation in MS. A host of immune mechanisms are stimulated by the presentation of a candidate antigen, perhaps an intrinsic myelin protein or a viral antigen cross-reacting with a native myelin protein. Myelin reactive T cells become activated and cross the blood–brain barrier, where they can initiate inflammation of myelin-rich white matter. Interferons do not actually enter the CNS and hence exert their effects external to it. Although, like interferons, glatiramer acetate does not itself cross the blood–brain barrier, it does affect activity within the CNS by increasing the production of neurotropic factors in the brain.

Natalizumab is a humanized recombinant monoclonal antibody that exerts its effect upon activated T cells by binding to the alpha 4 subunit of integrins expressed on the T-cell surface. This disables the transport of activated T cells across the blood–brain barrier by blocking their binding to endothelial adhesion molecules, thus dramatically reducing the elaboration of abnormally proliferating white blood cell populations and associated cytokines present within the CNS of the MS patient.

Neutralizing Antibodies

Although the long-term safety of available first-line immunomodulating therapies is unclear, each type seems to be relatively well tolerated. However, the interferons, glatiramer acetate, and natalizumab are not naturally occurring human proteins and, as such, are prone to inducing antibodies in human recipients. The propensity for antibody production depends on the agent, dose, and route of administration. Substantial controversy exists as to the impact of these antibodies on long-term effectiveness of immunomodulatory medications.

Drug-induced antibodies simply bind to the molecules of the active agent and may have no significant function. Neutralizing antibodies are a subset of these binding antibodies that might interfere with drug activity by a steric hindrance of drug binding to its receptor or via remote effects on drug activity through binding at distant sites.

Some agents are more “foreign” than others and have a higher likelihood of inducing antibodies. Glycosylation renders substances more soluble in suspension; without it, aggregates that may be immunogenic are likely to form. This may account for the higher incidence of neutralizing antibodies with the use of interferon beta-1b (30–35%) compared with interferon beta-1a (15%). The latter is glycosylated, has no amino acid substitutions, and looks almost exactly like naturally occurring IFN-β. Higher doses of the drug, more frequent exposures, and delivery via subcutaneous injection may affect antibody induction. Natalizumab therapy is associated with antibody production that persists for greater than 6 months in 6% of patients. Natalizumab antibodies present beyond 6 months of monthly treatments appear to neutralize the drug and negate its benefits completely; therefore, antibody testing for natalizumab has become routine under a carefully administered monitoring program (TOUCH program) required for patients who are treated with natalizumab and their prescribing physicians. True hypersensitivity reactions to natalizumab have occurred in 2–9% of patients administered the drug, and these patients are more inclined than those without reactions to evolve persistent antibodies.

Treatment of More Severe Multiple Sclerosis

The protocol for treating recalcitrant MS is not formulaic. Only two agents are approved by the USFDA for rapidly progressive MS: mitoxantrone and interferon beta-1b. Mitoxantrone (12 mg/m² IV given every 3 months to a cumulative maximum dose of 144 mg) is a chemotherapeutic agent used to treat other immune-mediated disorders. Usually considered a treatment of last resort after multiple treatment failures, its categorization is due to its potential toxicities, the most worrisome of which is cardiac toxicity.

Two trials offered some evidence that interferon beta-1b favorably impacts secondary progressive disease with respect to various outcome measures (progression of disability scores, relapse rate reduction, MRI activity), not all of which were significant in both studies. High-dose interferon beta-1a has also been investigated in secondary progressive disease; two studies demonstrated efficacy compared with placebo. Although heterogeneity of study populations and outcome measures make these studies difficult to compare, they offer some rationale for choosing a new therapy in patients who have advanced from relapsing–remitting disease to a more aggressive RRMS or secondary progressive disease, regardless of previous treatments. Multi-interferon therapy and interferon plus glatiramer acetate are being investigated. Despite multiple investigations focused on other treatment strategies, their efficacies have remained largely anecdotal.

Azathioprine, Cyclosporine, and Cyclophosphamide

The equivocal benefits of azathioprine (2–3 mg/kg daily) in MS are realized in decreasing relapse rates and MRI lesion burden. Cyclosporine inhibits the production of lymphokines and seems to foster the expansion of certain populations of suppressor T cells. One cyclosporine and azathioprine comparison showed no differences between the two agents with respect to relapse frequency or expanded disability status scale, but therapy complications were more than twice as likely in the cyclosporine group as in the azathioprine group. Other studies of cyclosporine have been marred by high attrition in the treatment groups due to toxicities (renal failure, hypertension) that likely occur before any benefit is achieved. These observations have taken cyclosporine out of the usual arsenal of immunosuppressive therapy for the treatment of MS in many centers.

Cyclophosphamide is another immunosuppressive agent widely used to treat various neoplastic and autoimmune disorders. One study suggested some response based on expanded disability status scale scores to induction with booster infusions in patients younger than age 40 years. Toxicities include hemorrhagic cystitis, leukopenia, myocarditis, pulmonary interstitial fibrosis, malignancy, interstitial pulmonary fibrosis, and infertility. Mitoxantrone tends to be better tolerated, with fewer adverse effects, and has better evidence of efficacy in secondary progressive MS.

Methotrexate. Low-dose weekly oral methotrexate is not approved for use in MS but is used as an adjunct therapy in off-label use based on a limited number of studies in patients with MS and its efficacy in rheumatoid arthritis, another autoimmune disease. Methotrexate is a competitive inhibitor of dihydrofolate reductase and interferes with the production of reduced cofactors required for the synthesis of DNA and RNA. It seems to have both immunosuppressive and antiinflammatory effects and immunoregulatory action. Toxicities include pulmonary and liver fibrosis, cirrhosis, and bone marrow suppression.

Monthly Intravenous Methylprednisolone

In addition to its efficacy as acute therapy in relapses, cyclical infusions of 500–1000 mg IV glucocorticoids can be useful as a scheduled monthly or bimonthly treatment in patients whose frequent relapses signal a transition from RRMS to secondary progressive MS. This is generally a safe, well-tolerated approach for patients who have waning response to other conventional immunomodulators but are unwilling to undertake chemotherapeutic options.

Plasma Exchange

Plasmapheresis intervenes primarily at the level of humoral responses, thought to be less important in MS than cellular responses. There are no data supporting a significant treatment effect.

Intravenous Immunoglobulin

Limited data exist regarding IV immunoglobulin for MS. There are few long-term adverse effects but no evidence that it is more effective than other approved therapies for MS. Because MS is not a USFDA–approved indication for IV immunoglobulin, the expense of treatment is usually prohibitive.

Adjuvant Medical Problems and Treatments

Despite new therapies, for most people, MS eventually involves some adaptation in lifestyle. It may mean adopting a less frenetic pace with curtailed work hours, help with household management, less travel, napping, or avoidance of excessive heat. The demand for lifestyle modification can be one of the more frustrating aspects of MS.

Clinical Vignette

A 31-year-old ICU nurse had no explanation for her complaints of fatigue. She had long worked 36 hours per week in three 12-hour shifts with additional shifts in overtime, more often than not. She was not married, had no children, and had always made exercise a regular part of her routine. She was in the habit of running with her dog in the mornings and, while she used to find this invigorating and an energy booster for the coming day, she began to feel that she was really pushing herself to keep up with her usual activities on most days. By late morning, she would feel exhaustion setting in, even though she made it more of a point than ever to get plenty of sleep in her down time and began taking vitamin supplements.

She found herself cutting back on social activities, and her friends and colleagues saw the change and wondered whether she was depressed. Overall she had no history of mood disorder or any other perceived stressors, and had been happy with her life until she began to have significant physical and mental fatigue. From the neurologic perspective, she had no overt limb weakness, subjective sensory impairment, imbalance, visual difficulties, or pain. Similarly, there was nothing to suggest any underlying systemic disorder. However, the fatigue was taking over her life and she decided to seek further medical evaluation.

Her primary care physician found her thyroid function and B₁₂ levels normal; an ANA was positive with a speckled pattern. Consideration of an occult depression diagnosis led to a trial of an SSRI. However, she felt no better. Soon thereafter, she began to experience a vibrating sensation in her feet and a feeling of tightness in her upper thorax, as if she was wearing a bra that was too tight. She became convinced that either she was becoming a hypochondriac or her doctor was “missing something.” When she voiced this concern, her physician made referrals to a rheumatologist, an endocrinologist, and a neurologist. The endocrinologist felt that she had mild vitamin D deficiency and recommended some additional supplementation to her multivitamin, but was otherwise unconcerned. The rheumatologist felt there was no evidence for systemic lupus erythematosus or any connective tissue disorder, apart from possible fibromyalgia.

Her neurologist elicited a history of urinary frequency with relatively little urine volume with each void. On examination, she found diminished vibratory perception in the patient’s lower extremities up to the knees and diffuse hyperreflexia. A postvoid residual of 180 mL was measured by ultrasound. MRI revealed multifocal areas of chronic demyelination in the brain, cervical, and thoracic spinal cord.

Comment: This clinical scenario is not all that uncommon and emphasizes the importance of a careful neurologic evaluation in previously well-functioning young to middle-aged persons who begin to develop limitations in their abilities to perform their daily activities. One must be careful to not invoke the common diagnosis of chronic fatigue syndrome in such individuals until careful and often ongoing neurologic evaluations precisely exclude a diagnosis of MS.

Fatigue

Fatigue is often one of the most debilitating symptoms, particularly early on in MS. The primary “lassitude” of MS is an overwhelming sense of physical and mental exhaustion that has no identifiable cause but significantly interferes with normal activity. The majority of patients with MS rank it as their most disabling symptom affecting daily living. This eclipses bowel and bladder dysfunction, weakness, and balance problems. Although fatigue can be secondary to deconditioning, the advanced symptoms of MS that limit physical activity are not a prerequisite for fatigue. It has been associated with every stage of the disease, regardless of clinical subtype, and is often present in an apparently well-compensated individual who otherwise has little objective disability.

Persistent but ineffective neuronal firing of short-circuited neural pathways that do not affect movement in weak limbs, transmit cohesive visual impulses, or recruit the reflexes necessary to maintain balance may be a pathophysiologic correlate of primary MS fatigue. There is no specific link evident to provide objective measures of disease activity such as commonly used MS functional scales or MRI findings.

Additionally, some evidence exists of an association among MS-related fatigue, depression, and cognitive dysfunction. That this is true in patients without significant deficits and in patients who have not received a diagnosis suggests that the mental fatigue is not simply an epiphenomenon of a reactive depression. The fatigue of MS is likely a direct consequence of demyelination, inflammation, and axonal injury along shared neuronal networks that affect attention, depression, and cognitive dysfunction. Hypometabolism in the frontal cortex and basal ganglia resulting from this type of damage has been implicated in primary MS fatigue.

Sufficient rest is critical to managing fatigue in MS. Additionally some pharmacologic therapy is a useful adjunct to behavioral and lifestyle strategies. Despite the incomplete understanding of the pathophysiology of MS-related fatigue, clearly valuable pharmacotherapies mitigate a profoundly low energy level through modification of altered neurochemistry that results from damage to the CNS.

Wakefulness involves various arousal systems with complex circuits that project between the reticular activating system, limbic system, and frontal cortex. From the brainstem, monoamine-mediated pathways (dopamine, norepinephrine, serotonin, acetylcholine) ascend through the reticular activating system. Several useful agents operate along this pathway. The stimulant medications (methylphenidate, amphetamine salts, dextroamphetamine [Dexedrine], pemoline) affect this mesocorticolimbic system by enhancing global CNS activation but may produce undesirable side effects such as dependence through stimulation of central “reward mechanisms” (governed by the nucleus accumbens in the striatum), insomnia, appetite suppression, and peripheral autonomic effects, including tachycardia, dysrhythmia, and hypertension. Amantadine enhances dopamine release and seems to have some benefit in improving central attention and processing speed. Modafinil, used to treat narcolepsy, is also helpful in treating MS fatigue by increasing activity in the frontal cortex via activation of histaminergic neurons arising from the hypothalamus.

Pain

Multiple sclerosis is usually regarded as a disease of progressive neurologic dysfunction without significant pain. However, pain is a common problem deserving appropriate attention. Years of gait disturbance, abnormal forces on joints, repetitive motion injuries, wheelchair confinement, disuse, and painful muscle spasms are all typical sources of pain in MS. A regular exercise program is essential to prevent additional disability from deconditioning.

NSAIDs, gabapentin, pregabalin, and tricyclic antidepressants are often useful. For pain, narcotic medications are probably best avoided because they are likely to exacerbate fatigue and cognitive dysfunction. Aqua therapy is an excellent form of exercise that does not put undue stress on joints and provides buoyant support for weak limbs, allowing patients to maximize range of motion. Yoga is helpful for relaxation and flexibility maintenance. Shiatsu massage therapy may help to prevent contractures, but deep muscle massage may be overzealous and increase rather than mitigate pain. Acupuncture may disrupt aberrant pain pathways.

Bladder Dysfunction

Bladder symptoms, one of the most vexing problems commonly experienced, significantly influence quality of life in 50–80% of patients with MS. The degree of impairment usually parallels the degree of other neurologic deficits. Bladder hygiene is compromised by increased spasticity, loss of strength, and diminished mobility. Although bladder dysfunction rarely leads to life-threatening infection or secondary renal failure, the resultant recurrent or chronic urinary tract infections can potentiate other MS symptoms and are a common trigger for significant exacerbations.

On rare instances, an acute pyelonephritis may develop with a high fever; this may lead to a temporary exacerbation of the underlying neurologic deficits. In a way, this mimics the Uhthoff phenomena. This emphasizes the need to look for evidence of an underlying infection in anyone with MS who has an acute exacerbation; appropriate antibiotics will not only clear the infection but also lead to the resolution of the MS exacerbation.

Control of urination depends on the complex coordination of reflexive and volitional activities that rely on the integrity of complex pathways that traverse the subcortical white matter, spinal cord tracts, and reflex spinal cord centers. Lateral and posterior cervical spinal tracts are among the most common sites of demyelination in MS and are critical for all aspects of coordinating voluntary voiding.

Bladder dysfunction in MS is managed both pharmacologically and with adaptations in toileting. The most common pharmacologic agents diminish bladder contraction. Typically this is an antispasmodic anticholinergic, oxybutynin chloride. Dosage is usually initiated at 5 mg, the maximum being 20 mg daily. These are generally more effective than attempts to improve bladder emptying with cholinergic agents. Alpha-adrenergic agents increase bladder outlet resistance and sometimes help to treat urinary incontinence. Emptying the hyporeflexic or areflexic bladder is best accomplished by clean, intermittent self-catheterization.

Sexual Dysfunction

Unfortunately this continues to be a problem of “don’t ask, don’t tell” type. The presence of societal inhibitions have greatly disappeared about discussing this important part of the human condition in healthy individuals as well illustrated by the magazine covers at any supermarket checkout lane. However, this is a subject that most practitioners are woefully undertrained to adequately discuss so that the patient may receive appropriate guidance and therapy. Certainly this is a very important quality-of-life issue for the MS population. Neurologists must be cognizant of its frequent occurrence in MS and need to always ask the patient about whether they have concerns about their sexual abilities, particularly as influenced by their illness. If so, it is important to refer them to an appropriate urologic/endocrinologic sexual dysfunctions clinic for further care.

Pregnancy

Pregnancy in women with MS seems to have no long-term effects on MS progression. It may have some protective value, because the incidence of exacerbations is actually lower during pregnancy. In the 6 to 12 months after pregnancy, the exacerbation rate is higher than expected. The decision to bear children should probably take into account the pre-pregnancy tempo of disease and whether a woman with MS feels physically capable of keeping up with the rigorous demands of raising children. Family support and financial resources are also factors.

Heat

High ambient temperatures and high levels of humidity are often associated with MS worsening and possibly even exacerbations just as with febrile illnesses as noted above. During summer months, especially within temperate countries, patients are advised to avoid the stress of overexposure to high ambient temperatures, especially during heat waves. Where possible, air conditioning, ceiling fans, or avoidance of strenuous activities may lessen the chances for causing deterioration in the overall status of patients with MS.