Multiple Sclerosis Case File
Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD
CASE 24
A 24-year-old law student was studying late at night for an examination. As he looked at his textbook, he realized that his left arm and left leg were numb. He dismissed the complaint, recalling that 6 or 7 months ago he had similar symptoms. He rose from his desk and noticed that he had poor balance. He realized that his vision was blurred and remembered that he also had some blurred vision approximately 1 to 2 years earlier that had resolved. He had not seen a physician for any of these previous symptoms. He went to bed and decided that he would seek medical consultation the next day.
▶ What is the most likely diagnosis?
▶ What is the next diagnostic step?
▶ What is the next step in therapy?
ANSWERS TO CASE 24:
Multiple Sclerosis
Summary: A 24-year-old man developed multiple neurologic symptoms and, in retrospect, recognized that he had had multiple symptoms over the past 1 to 2 years.
- Most likely diagnosis: Multiple sclerosis (MS).
- Next diagnostic step: See a physician and undergo a careful neurologic assessment. Blood studies, lumbar puncture, brain imaging, and visual-evoked responses can be indicated.
- Next step in therapy: Probably intravenous corticosteroids followed by an immune modulatory therapy directed at improving disease course.
ANALYSIS
Objectives
- Understand the differential diagnosis of MS.
- Describe how to evaluate for MS.
- Understand the prognosis of MS.
- Describe when and how to treat MS.
Considerations
This is a case of a young man who notes symptoms suggestive of a hemisensory deficit, visual disturbance, and imbalance. Although the patient has not undergone a medical evaluation, his symptoms suggest involvement of at least two sites of the central nervous system (CNS), the spinal cord or brain contralateral to the side of numbness, and possibly his optic nerve affecting vision. The case presentation is also significant for similar symptoms in the past that resolved without treatment. In a young, presumably healthy person with acute onset of symptoms localized to the CNS that are separated by time (current and past symptoms) and space (different areas of the nervous system), MS is the diagnosis until proven otherwise.
APPROACH TO:
Multiple Sclerosis
DEFINITIONS
MULTIPLE SCLEROSIS (MS): MS is a chronic immune-mediated inflammatory disease, usually beginning in young adults and characterized by relapsing, remitting, or progressive neurologic deficits due to demyelinating lesions in the brain or spinal cord.
INTERNUCLEAR OPHTHALMOPLEGIA: A syndrome of diplopia and nystagmus caused by a lesion in the medial longitudinal fasciculus (MLF). The ipsilateral eye cannot adduct because the communication from the contralateral abducens nerve to the oculomotor nerve is disrupted, resulting in diplopia with horizontal gaze to the opposite side. The contralateral eye will also have nystagmus in
horizontal gaze.
CLINICAL APPROACH
Epidemiology
MS is the most common cause of neurologic disability in young adults, affecting over 1 million individuals worldwide. There are between 250,000 and 500,000 patients with MS in the United States. MS is more common in northern climates in Europe and the United States, with a prevalence of approximately 1 per 1000 people in these areas. It is more common in women than men by a ratio of 2:1, with a peak incidence of 24 years. Symptoms usually begin between the ages of 20 and 40.
Research studies reveal that the risk of MS is increased in individuals born or living in temperate zones, but people born or migrating to low-risk areas (ie, nontemperate zones) prior to 15 years have decreased risk. This suggests that exposure to some factor prior to age 15 is important in the genesis of MS. Migration, ethnic, and twin studies suggest that MS is related to genetic as well as environmental factors. If one member of an identical twin pair has MS, there is a 30% chance the other twin will have MS (vs a 2.6% risk for other siblings).
Pathophysiology
MS is restricted to the CNS and spares the peripheral nervous system from injury. The pathologic hallmark of MS is focal demyelination within the brain and spinal cord. In MS, discrete areas of damaged myelin, termed plaques, are embedded within normal-appearing tissue. Within each plaque, damaged myelin is associated with inflammatory infiltrates of lymphocytes and macrophages, astrogliosis, and oligodendrocyte injury. It is not known whether the immune response observed in MS plaques is a primary process or secondarily caused by other etiologies, such as infectious, toxic, or metabolic injury. The resulting demyelination and subsequent degeneration of axons account for the disability of patients with MS.
DIAGNOSIS
The criteria for diagnosing MS are constantly changing, in part because of increasingly sophisticated brain imaging and immunologic investigations. According to the 2010 McDonald criteria, a definitive diagnosis can be made if the patient has two or more attacks (“dissemination in time”) with objective evidence of two or more lesions (“dissemination in space”).
Clinical Features
The onset of MS symptoms usually occurs over several days and is seldom sudden. Acute optic neuritis is the presenting symptom in 20% of patients and affects 50% of all patients at some point. The optic disc may appear normal if the inflammation is retrobulbar, but disc edema is seen in the one-third of patients with anterior optic neuritis. Patients typically complain of blurring and loss of vision with eye pain. The eye pain may precede other symptoms and usually worsens with eye movement.
The brainstem is commonly involved in MS. Patients may have double vision, internuclear ophthalmoplegia, facial weakness, facial myokymia, vertigo, dysphagia, and dysarthria. Trigeminal neuralgia is characterized by very brief, severe, lancinating maxillary or mandibular pains, and occurs in 1% of MS patients. Trigeminal neuralgia can be due to causes other than MS, but when these symptoms occur in a young adult, MS should be highly suspected.
Fifty percent of MS patients have cerebellar signs sometime during the course of their illness. These patients can have limb tremor, ataxia, scanning speech (ie, cerebellar dysarthria), and titubation of the head or trunk. Charcot triad, consisting of intention tremor, dysarthria, and nystagmus, is a well-recognized syndrome in MS but occurs rarely.
Weakness affects up to 89% of MS patients and is typically due to a lesion involving the corticospinal tract. Spasticity can be present even without weakness and can lead to gait impairment. Patients can also have sensory symptoms, such as tingling, pins and needle sensations, numbness, or a sensation of a band around the torso. About 87% of MS patients will have sensory complaints sometime during their illness, and over 50% of patients will complain of pain/unpleasant sensations at some point. A partial transverse myelitis is seen in many patients and may result in motor, sensory, bowel, and/or bladder symptoms.
Patients with MS may complain of sensations of electricity running down their spine, sometimes extending into the limbs (Lhermitte sign). This symptom is often aggravated by flexing the cervical spine (bending the head forward) and should raise suspicion of MS or other compromise of the upper cervical spinal cord. MS patients can experience sudden and transient neurologic deterioration if their body temperature is elevated (Uhthoff phenomenon). This can occur with fever, increased physical exertion, or taking a hot bath.
Many MS patients have bladder dysfunction. Overactive bladder is present in two-thirds of patients, but some may have underactive bladder symptoms. Acute urinary retention may occur with transverse myelitis. Bowel dysfunction is less common but still prevalent, especially constipation; however, incontinence may occur with severe transverse myelitis. Sexual dysfunction is also prevalent among both male and female patients.
Cognitive impairment in processing, executive dysfunction, and visual memory is seen in 40% to 70% of patients. This is associated with both white matter involvement and diffuse brain atrophy over time. Depression affects 30% to 45% of patients, but it is unclear if this is due to the disease process or if it is a comorbid disorder. MS patients also have a high incidence of migraine-type headache.
Diagnostic Studies
Although the diagnosis of MS relies on recognition of the clinical pattern of disease, several studies are useful in confirming the diagnosis. On magnetic resonance imaging (MRI), typical MS lesions are bright lesions on T2-weighted sequences, especially in the periventricular, juxtacortical, and infratentorial regions (Figure 24–1). These lesions are usually linear or ovoid and at right angles to the ventricular surface, which give the classic “Dawson fingers” appearance on sagittal views. Hyperintense lesions are also commonly seen in the spinal cord. T1-weighted images may show “black holes” of old, burned-out plaques. Newer techniques of brain imaging, such as fluid-attenuated inversion recovery (FLAIR), provide increased sensitivity and specificity for MS white matter lesions. FLAIR images detect two to three times the number of lesions observed on T2-weighed images.
Analysis of cerebrospinal fluid (CSF) also helps in diagnosing MS. In cases where the MRI is normal or shows a pattern that is consistent with other disease processes, such as microvascular ischemia or infection, CSF analysis is indicated. Oligoclonal bands occur in more than 95% of patients with MS, but these are not diagnostic since they can occur in other CNS conditions such as systemic lupus erythematosus, neurosarcoidosis, subacute sclerosing panencephalitis (SSPE), subarachnoid hemorrhage, syphilis, and CNS lymphoma. Elevated immunoglobulin G (IgG) index is also seen in many MS patients but is less sensitive than oligoclonal bands. Increased CSF white cells can be seen in MS, but CSF leukocyte counts greater than 50 mm3 of CSF are rare in MS and should prompt the physician to consider other diagnoses.
Electrophysiologic studies of the visual pathways and spinal cord dorsal columns are sometimes useful in documenting involvement of these pathways when imaging studies or physical findings do not support the clinical impression. Visual-evoked potentials, in which a patient views repeated reversal of light and dark checkerboard stimuli while a computer averages scalp electrode potentials, are useful in evaluating patients for MS. Prolongation of the P100 wave reflects compromise of the pathway between the optic nerve and the brain.
Optical coherence tomography is a noninvasive ophthalmic imaging study performed in the clinic. Retinal nerve fiber layer (RNFL) thinning occurs due to retinal axon loss. While it is more pronounced in patients with a history of optic neuritis, RNFL thinning has been detected early in the disease process of patients without visual complaints.
The differential diagnosis of MS is broad. Many different conditions can mimic MS because of primary or secondary demyelination of CNS pathways. However, the clinical history, physical examination, and diagnostic studies are fundamental in distinguishing these conditions from MS. To rule out other conditions, consider sending screening laboratory studies such as vitamin B12 level, treponemal antibody testing, Borrelia burgdorferi serology, antiphospholipid antibodies, and inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], antinuclear antibody [ANA]).
CLINICAL COURSE
There are different clinical patterns or types of MS:
- Relapsing-remitting MS is the most common form of MS, accounting for 80% to 90% of cases. It is characterized by sudden onset (over hours or days) of neurologic symptoms that usually last several weeks and then resolve, often leaving few or no deficits. The frequencies of these relapses are highly variable but average about one in every 2 years. Some degree of disability is usually present over time. Between attacks, fatigue and sensitivity to heat is common.
- Secondary progressive MS is seen in most but not all patients with an initial relapsing-remitting course. Patients will develop neurologic decline that is not related to the discrete attacks in addition to incomplete recovery from attacks. MS can continue to worsen for many years and then level off with moderate to severe permanent disability.
- Primary progressive MS is slowly progressive without any clearing of symptoms or relapses and accounts for 10% to 20% of cases. Diagnosis requires 1 year of clinical progression and two of the following: one or more MRI lesions in the brain, two or more MRI lesions in the spinal cord, and CSF with oligoclonal bands and/or elevated IgG index.
- Progressive-relapsing MS is seen in 5% of patients, with progression at the onset but with subsequent acute relapses as well.
- Clinically isolated syndrome is characterized by the first demyelinating event that is suggestive of MS. It places the patient at risk for further relapses. Common presentations include optic neuritis, internuclear ophthalmoplegia, sixth nerve palsy, cerebellar symptoms, and partial transverse myelitis. Some patients will go on to develop relapsing-remitting MS and suffer from multiple attacks, whereas others will have no further evidence of demyelinating disease. It is difficult to predict whether a given individual will develop MS following symptom onset, but risk is increased if there are any lesions on MRI or oligoclonal bands in the CSF. After 20 years, 82% of clinically isolated syndrome (CIS) patients with an abnormal MRI progressed to MS, compared to only 21% of those with a normal MRI.
- Radiologically isolated syndrome, or preclinical MS, is the evidence of demyelinating disease on imaging in patients with no history of a clinical attack. Patients typically underwent imaging for an unrelated issue. One in three will experience an attack within 5 years.
TREATMENT
Treatment of patients with MS needs to be individualized for each specific patient and tailored to his or her problems and needs. The treatment should be focused on both the disease and the associated symptoms.
Acute Management
For acute flares, the standard treatment is intravenous steroids for about 5 days. Steroids have not been shown to decrease the risk of future attacks or change the natural history of the disease. The goal is to hasten recovery from the acute attack.
Maintenance Therapy
Immunomodulating agents or disease-modifying therapies can be used to modify the course of MS and thus are used on a chronic, ongoing basis. These agents can impact the relapse rate, slow progression of disability, and prevent the accumulation or burden of MRI lesions. Since axonal damage leading to irreversible neurologic disability is already present at the onset of the disease, immunomodulatory therapy should start as soon as possible.
The interferon medications are injectable therapies that may work by altering T cells and sealing the blood-brain barrier against their entry into the CNS. Glatiramer acetate is another injectable therapy. The molecule mimics myelin basic protein and interferes with antigen presentation. It is the only immunomodulator for MS that is pregnancy class B and thus is the treatment of choice in a pregnant patient. Natalizumab is an IV infusion therapy that prevents migration of activated T cells across the blood-brain barrier. It can decrease disease exacerbations and enhancing lesions, but its use is limited by the risk of JC virus reactivation, which can lead to progressive multifocal leukoencephalopathy. Mitoxantrone is an antineoplastic intravenous therapy that is used as a second-line treatment due to its cardiotoxicity and myelosuppressive effect.
In recent years, the most significant breakthrough in MS therapy has been the development of oral therapies. While the older therapies have more long-term surveillance data, the newer agents are attractive not only for their effectiveness but also for their convenience. Fingolimod was the first approved oral agent in 2010. It is a sphingosine analog that inhibits lymphocytes from leaving the lymph node. Side effects include bradycardia, so the first dose must be given in a monitored setting. Teriflunomide is another oral therapy that acts as a pyrimidine synthesis inhibitor to decrease T-cell and B-cell proliferation and activation. It is pregnancy class X, and men must use birth control as well because levels can be detected in the semen. It can remain in the circulation for up to 2 years if accelerated clearance protocols (ie, activated charcoal or cholestyramine) are not used. Dimethyl fumarate promotes anti-inflammatory and cytoprotective activities mediated by activation of the Nrf2 antioxidant response pathway. It is given in twice-daily oral doses, and patients frequently complain of flushing and gastrointestinal (GI) upset.
Another immunomodulatory treatment option is alemtuzumab, a humanized monoclonal antibody that binds CD52 on T cells and B cells to cause cellular and complement-mediated lysis. It is administered via IV infusion in two doses separated by 1 year. It is FDA approved for relapsing patients who have failed at least two other disease modifying agents. There is an increased risk of thyroid diseases, autoimmune disorders, and idiopathic thrombocytopenia. Ocreluzimab is a CD20 B cell monoclonal antibody which has been shown beneficial in patients with PPMS compared to placebo. It is the first therapy receiving FDA approval for this subset of MS patients.
Symptomatic Therapy
Symptomatic therapy for MS can include physical and emotional rest, physical therapy, amantadine or modafinil for fatigue, anticholinergic medication for bladder dysfunction, baclofen or tizanidine for spasticity, selective serotonin reuptake inhibitors (SSRIs) for mood disorders, and clonazepam or valproic acid for cerebellar tremor. Dalfampridine is a prescription medication that blocks potassium channels to enhance conduction in damaged nerves. It has been shown to improve walking in MS patients, and patients report improved fatigue as well.
CASE CORRELATION
- See also Case 23 (Optic Neuritis) and Case 22 (Subacute Combined Degeneration of the Spinal Cord)
COMPREHENSION QUESTIONS
24.1 A 28-year-old man is noted to have double vision and leg weakness. A suspicion of MS is entertained. Which of the following findings would be consistent with the diagnosis?
A. Oligoclonal bands in CSF
B. Onset of symptoms was preceded by a febrile illness
C. Abnormal peripheral nerve conduction by electromyography (EMG)/nerve conduction velocity (NCV) studies
D. Meningeal enhancement on contrast MRI of the brain
24.2 A 33-year-old man is noted to have recurrent episodic weakness. He is diagnosed with MS. Which of the following findings is consistent with the diagnosis?
A. The diagnosis of MS is based on clinical lesions separated by time and space.
B. Oligoclonal bands in the CSF are specific for MS.
C. Steroids are effective in improving the course of disease.
D. This is a genetic disorder well characterized on chromosome 11.
24.3 The same patient in Question 24.2 is noted to another episode of acute weakness. What is the best treatment option?
A. Fingolimod
B. Corticosteroid therapy
C. Dalfampridine
D. Interferon
ANSWERS
24.1 A. Oligoclonal bands are present in the CSF of over 95% of MS patients but are not specific to the disease. Onset of symptoms following a viral illness would raise concern for an acute post-infectious demyelinating syndrome. The acute post-infectious demyelinating syndromes can be differentiated from MS by their single phase, whereas MS requires evidence of disease occurring over time. An abnormal nerve conduction study is more consistent with a peripheral demyelinating process as opposed to the central demyelinated process that occurs in MS. While an MS patient could also have a peripheral neuropathy, it is not part of the MS disease process. Meningeal enhancement is not seen with MS.
24.2 A. Clinical exacerbations separated by time and space are the hallmark of the diagnosis of MS. Steroids are used in acute exacerbations only and not for long-term disease-modifying therapy. MS is not due to a specific genetic defect.
24.3 B. Steroids remain the standard of care for acute MS exacerbations, despite the development of many new immunomodulatory medications. Fingolimod and interferon are used for long-term maintenance therapy. Dalfampridine provides symptomatic relief but does not treat the underlying disease.
CLINICAL PEARLS
|
▶ MS is a demyelinating disease with
lesions separated over time and space.
▶ MS patients can have lesions on brain
MRIs without associated clinical complaints directly related to those
lesions.
▶ Visual compromise and weakness are
frequent presenting symptoms in MS.
▶ The symptoms of MS seem to worsen
with elevation of temperature or fever, known as Uhthoff phenomenon.
▶ While acute relapses are managed with
steroids, the long-term management of the disease is through
disease-modifying agents. There are now oral therapies in addition to
subcutaneous, intramuscular, and intravenous options. |
REFERENCES
Carrithers MD. Update on disease-modifying treatments for multiple sclerosis. Clin Ther. 2014; 36(12):1938-1945.
Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol. 2014;122:269-290.
Genzyme, Inc. Lemtrada (alemtuzumab) prescribing information. Issued November 2014. http://products.sanofi.us/lemtrada/lemtrada.pdf. Accessed February 13, 2015.
Katz Sand IB, Lublin FD. Diagnosis and differential diagnosis of multiple sclerosis. Continuum (Minneap Minn). 2013;19(4):922-943.
Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, et. al. For the ORATORIO Clinical Investigators. N Engl J Med. 2017;376:209-220.
Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn). 2013;19(4):901-921.
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