Multiple Sclerosis
Internists rarely start disease-modifying therapy, but they are the ones who see the first attack, the patient who looks like they are relapsing when they are actually infected, and the immunosuppression complications years later. The diagnosis needs lesions separated in space and time, the commonest "relapse" on the ward is a pseudorelapse from fever or infection, and the single most consequential distinction is MS versus the antibody-mediated diseases that look like it and are made worse by the wrong treatment.
🔍 Overview
What It Is
Multiple sclerosis is a chronic immune-mediated demyelinating disease of the central nervous system, producing inflammatory demyelination and axonal loss in the brain, spinal cord and optic nerves. It typically presents between 20 and 40 years of age, is more common in women, and rises in incidence with distance from the equator. Risk associations include low vitamin D, smoking, obesity in adolescence, and Epstein-Barr virus exposure.
Disease Courses
- Relapsing-remitting (RRMS) -the great majority at onset. Discrete attacks with partial or complete recovery between them.
- Secondary progressive -gradual accumulation of disability after an initially relapsing course, with or without superimposed relapses.
- Primary progressive -a minority, with progression from onset and no distinct relapses; presents later, often with a progressive myelopathy, and affects men and women more equally.
- Clinically isolated syndrome -a first demyelinating attack that does not yet meet full criteria; MRI findings determine whether it will be treated as MS, and early treatment delays conversion.
Presentations Worth Recognizing
- Optic neuritis -subacute monocular visual loss with pain on eye movement, dyschromatopsia (colors appear washed out, red desaturation) and a relative afferent pupillary defect. The disc is usually normal on fundoscopy because the inflammation is retrobulbar.
- Partial transverse myelitis -sensory level, bandlike truncal sensations, limb weakness, bladder dysfunction. MS typically causes a partial, asymmetric cord lesion spanning fewer than three vertebral segments.
- Brainstem and cerebellar syndromes -diplopia from internuclear ophthalmoplegia (a highly suggestive finding in a young patient), vertigo, ataxia, dysarthria, and trigeminal neuralgia in someone young.
- Lhermitte sign (electric sensation down the spine on neck flexion) and the Uhthoff phenomenon -transient worsening of existing symptoms with heat, exercise or fever, which is a conduction effect rather than a new attack.
- The invisible symptoms that dominate quality of life: fatigue, cognitive slowing, depression, bladder dysfunction, spasticity and pain. These are what patients report as most disabling, and they are frequently unaddressed.
🧪 Diagnosis
The Core Principle: Dissemination in Space and Time
- The diagnosis requires evidence of CNS demyelinating lesions separated in space (different locations) and in time (different points in the disease course), with no better explanation. The McDonald criteria formalize this.
- Dissemination in space: lesions in at least two of the four characteristic regions -periventricular, cortical/juxtacortical, infratentorial, and spinal cord.
- Dissemination in time: a new lesion on follow-up imaging, simultaneous enhancing and non-enhancing lesions on a single scan (which demonstrates lesions of different ages at one sitting), or CSF-specific oligoclonal bands, which can substitute for dissemination in time.
- MRI brain and spinal cord with and without gadolinium is the central investigation; periventricular ovoid lesions perpendicular to the ventricles (Dawson fingers) are characteristic.
- Lumbar puncture -CSF-specific oligoclonal bands (present in serum-paired testing) support the diagnosis; typical CSF shows normal or mildly raised protein with a mild lymphocytic pleocytosis.
A marked CSF pleocytosis argues against MS. Cell counts substantially above the low tens, high protein, or a neutrophilic predominance should redirect you toward infection, neurosarcoidosis, or an antibody-mediated disease rather than MS -a fact worth knowing before an LP result is over-interpreted as confirmatory.
The Distinction That Changes Treatment
- Test aquaporin-4 (AQP4) IgG and MOG IgG when the presentation is atypical: longitudinally extensive transverse myelitis spanning three or more vertebral segments, severe or bilateral optic neuritis, area postrema syndrome (intractable hiccups, nausea and vomiting), or a severe first attack.
- ⚠ Why it matters enormously: neuromyelitis optica spectrum disorder and MOG antibody disease are treated differently, and several MS disease-modifying therapies make NMOSD worse -interferon beta and some others can precipitate severe relapses. Getting this wrong is not a labeling error, it is a treatment harm.
- Other mimics to consider: neurosarcoidosis, Behçet disease, SLE and Sjögren with CNS involvement, B12 deficiency and copper deficiency (both cause subacute combined degeneration), CNS lymphoma, small vessel ischemic disease in older patients, and infections including HIV, syphilis and Lyme.
- Baseline screening labs to exclude mimics: CBC, CMP, ESR/CRP, B12, TSH, ANA, and HIV, syphilis and Lyme serology where the epidemiology fits.
🚨 Management
Before treating any apparent relapse, exclude a pseudorelapse. Infection (especially urinary tract infection), fever, heat, metabolic derangement, and even severe stress can transiently unmask or worsen existing deficits without any new inflammatory activity -the Uhthoff phenomenon at work. Check for infection and treat it first; the deficits resolve as the temperature and the infection settle. Giving steroids for a pseudorelapse treats nothing and risks harm, and this is the single commonest MS error on a general medical ward.
Acute Relapse
- High-dose glucocorticoids -typically intravenous methylprednisolone 1 g daily for 3 to 5 days, or an equivalent high-dose oral regimen, which has comparable efficacy. Steroids speed recovery from a relapse but do not change long-term disability, which is why they are reserved for functionally significant attacks rather than every symptom flare.
- Plasma exchange for severe relapses that do not respond to steroids.
- Mild sensory relapses may need no acute treatment at all -the honest position is that the benefit is speed of recovery, not the eventual outcome.
Disease-Modifying Therapy (what the internist should know)
- DMTs reduce relapse rate and new MRI lesion formation in relapsing disease; they do not repair existing damage, which is why early treatment matters and why delay is costly.
- The broad classes: injectables (interferon beta, glatiramer acetate), orals (dimethyl fumarate, teriflunomide, fingolimod and related sphingosine-1-phosphate modulators, cladribine), and monoclonal antibodies (natalizumab, ocrelizumab and other anti-CD20 agents, alemtuzumab). Higher-efficacy agents carry higher risk.
- The complications an internist will actually meet:
- Anti-CD20 agents (ocrelizumab, rituximab): hypogammaglobulinemia and infection risk, and hepatitis B reactivation -screen HBsAg and anti-HBc before starting, exactly as in the viral hepatitis topic.
- Natalizumab: progressive multifocal leukoencephalopathy (PML), with risk stratified by JC virus antibody status, prior immunosuppression and treatment duration. New or subacute cognitive, behavioral or focal deficits in a natalizumab patient are PML until proven otherwise.
- Fingolimod and S1P modulators: first-dose bradycardia requiring monitoring, macular edema, lymphopenia, and rebound disease activity on abrupt discontinuation.
- Live vaccines are contraindicated on most DMTs, so vaccination status should be brought up to date before starting.
- Ocrelizumab is the agent with evidence in primary progressive disease (ORATORIO, 2017), though the effect is a modest slowing rather than arrest -roughly a 24% relative reduction in confirmed disability progression, which is worth saying plainly before starting an infusion therapy. Progressive forms otherwise respond poorly to immunomodulation, and management shifts toward symptom control and rehabilitation.
Symptom Management (where most quality of life is won)
- Fatigue -the commonest and most disabling symptom. Screen for and treat the reversible contributors first: depression, poor sleep, sleep apnea, anemia, thyroid disease and deconditioning. Exercise helps.
- Spasticity -baclofen or tizanidine, physiotherapy and stretching; botulinum toxin for focal spasticity. Look for the trigger: infection, constipation, pressure ulcer or an ingrown toenail can all worsen spasticity.
- Bladder dysfunction -check a post-void residual before prescribing, because an anticholinergic given to a patient with incomplete emptying causes retention. Treat urgency with antimuscarinics or mirabegron, and retention with intermittent catheterization.
- Neuropathic pain -gabapentinoids, duloxetine or a tricyclic; carbamazepine for trigeminal neuralgia.
- Depression is common and undertreated, and independently worsens fatigue and cognition. Screen for it deliberately.
- Vitamin D repletion, smoking cessation, exercise and heat avoidance -smoking accelerates disability accumulation, making cessation a disease-modifying intervention in its own right.
- Bone health -reduced mobility plus recurrent steroid courses is an osteoporosis risk profile, linking directly to that topic's secondary-cause workup.
🏥 Rounds
Pimp Questions
❓ An admitted MS patient with a UTI develops worsening leg weakness. Do you give steroids?
No -treat the infection first, because this is almost certainly a pseudorelapse. Fever, infection, heat and metabolic derangement transiently impair conduction in already-demyelinated axons (the Uhthoff phenomenon), unmasking or worsening old deficits without any new inflammatory activity. The deficits resolve as the temperature and infection settle. Steroids treat nothing here and add harm -hyperglycemia, worsened infection, delirium. This is the single commonest MS error on a general medical ward. If deficits persist after the infection clears, reassess for a true relapse.
❓ A patient has transverse myelitis spanning five vertebral segments. Why does that change your workup urgently?
Because longitudinally extensive transverse myelitis (three or more vertebral segments) is atypical for MS and characteristic of neuromyelitis optica spectrum disorder -MS usually causes partial, asymmetric cord lesions under three segments. Send AQP4-IgG and MOG-IgG. The distinction is not academic: several MS disease-modifying therapies, including interferon beta, can make NMOSD substantially worse and precipitate severe relapses. Treating NMOSD as MS is a treatment harm, not a labeling error. Severe or bilateral optic neuritis and area postrema syndrome (intractable hiccups, nausea, vomiting) should trigger the same testing.
❓ What does "dissemination in space and time" mean, and how can a single MRI satisfy both?
Space means lesions in at least two characteristic CNS locations -periventricular, cortical/juxtacortical, infratentorial, spinal cord. Time means lesions arising at different points in the disease. A single scan can demonstrate both if it shows simultaneous enhancing and non-enhancing lesions, because gadolinium enhancement lasts only weeks -so an enhancing lesion beside a non-enhancing one proves two different ages at one sitting. Alternatively, CSF-specific oligoclonal bands can substitute for dissemination in time, which is why the LP still earns its place in an equivocal case.
❓ A patient on natalizumab develops subacute confusion and a new focal deficit. What is the concern?
Progressive multifocal leukoencephalopathy (PML) from JC virus reactivation -the defining serious risk of natalizumab, with risk stratified by JC virus antibody status, prior immunosuppressant exposure, and duration of treatment beyond about two years. Unlike an MS relapse, PML tends to progress subacutely over weeks with cognitive and behavioral change rather than presenting as a discrete attack. Stop the drug, get urgent MRI and CSF JC virus PCR, and involve neurology immediately. Any new neurologic change in a natalizumab patient is PML until proven otherwise.
❓ Before prescribing an anticholinergic for urinary urgency in MS, what must you check?
A post-void residual. MS bladder dysfunction can be a storage problem (urgency, frequency), an emptying problem (retention from detrusor-sphincter dyssynergia), or both -and they are indistinguishable by symptoms alone, because incomplete emptying causes overflow urgency that looks exactly like an overactive bladder. Giving an antimuscarinic to a patient who is already retaining precipitates frank retention and recurrent UTIs -which then cause pseudorelapses. Check the residual first: high means intermittent catheterization, low means the urgency can be treated pharmacologically.
Sample Presentation
Ms. Lindqvist is a 28-year-old woman with five days of blurred vision in the right eye and pain on eye movement. Exam: reduced visual acuity, red desaturation, a right relative afferent pupillary defect, and a normal-appearing optic disc. She recalls a two-week episode of numbness in both legs about a year ago that resolved without evaluation.
Key Points: (1) This is optic neuritis -the normal disc is expected because the inflammation is retrobulbar -and the prior sensory episode raises the possibility of a second event in space and time. MRI brain and spinal cord with and without gadolinium is the key test; simultaneous enhancing and non-enhancing lesions would establish dissemination in time on a single scan. (2) Because the presentation is unilateral and not severe, it fits MS -but severe or bilateral optic neuritis, or a cord lesion spanning three or more segments, would demand AQP4-IgG and MOG-IgG testing before any DMT, since interferon beta can worsen NMOSD. (3) Send the mimic screen (B12, TSH, ANA, HIV, syphilis), consider LP for oligoclonal bands if the MRI is equivocal, and treat the acute attack with high-dose steroids to speed recovery while stating honestly that they do not change the eventual outcome.
Ward & Clinic Checklist
- Apparent relapse: infection and fever excluded first -pseudorelapse is commoner than relapse on a medical ward.
- Atypical features screened: long cord lesion, severe or bilateral optic neuritis, area postrema syndrome -send AQP4 and MOG antibodies.
- Mimics excluded: B12, TSH, ANA, ESR/CRP, HIV, syphilis, Lyme where relevant.
- DMT identified and its specific risk known: anti-CD20 (hepatitis B reactivation, hypogammaglobulinemia), natalizumab (PML), S1P modulators (bradycardia, rebound on stopping).
- Hepatitis B screening documented before anti-CD20 therapy.
- Vaccinations updated before starting a DMT -live vaccines are contraindicated on most.
- Post-void residual checked before any anticholinergic for bladder symptoms.
- Fatigue, mood, bone health and vitamin D addressed -these carry most of the quality-of-life burden and are the parts most often skipped.
📋 Summary
Summary
Space and Time Define the Diagnosis
Lesions separated in space (two of: periventricular, cortical/juxtacortical, infratentorial, spinal cord) and in time, with no better explanation. A single MRI can satisfy both when enhancing and non-enhancing lesions appear together, since enhancement lasts only weeks -proving two different ages at one sitting. CSF-specific oligoclonal bands can substitute for dissemination in time.
Recognize the Classic Attacks
Optic neuritis (subacute monocular loss, pain on eye movement, red desaturation, RAPD, normal disc because the lesion is retrobulbar), partial transverse myelitis, and brainstem syndromes including internuclear ophthalmoplegia in a young patient. Lhermitte sign and the Uhthoff phenomenon are characteristic but are conduction effects, not new attacks.
Pseudorelapse Before Relapse
Infection -especially UTI- fever, heat and metabolic derangement transiently unmask old deficits without new inflammation. Treat the infection first; the deficits resolve as the temperature settles. Steroids for a pseudorelapse treat nothing and add hyperglycemia, worsened infection and delirium. This is the commonest MS error on a general medical ward.
The Distinction That Causes Harm If Missed
Longitudinally extensive myelitis (3+ segments), severe or bilateral optic neuritis, or area postrema syndrome means sending AQP4-IgG and MOG-IgG, because several MS therapies including interferon beta make NMOSD substantially worse and can precipitate severe relapses. MS causes partial cord lesions under three segments. This is a treatment harm, not a labeling error.
Exclude the Mimics Deliberately
B12 and copper deficiency (subacute combined degeneration), neurosarcoidosis, Behçet, SLE and Sjögren, CNS lymphoma, small vessel disease in older patients, and HIV, syphilis and Lyme. A marked CSF pleocytosis argues AGAINST MS and should redirect toward infection, sarcoid or antibody-mediated disease before an LP result is over-read as confirmatory.
Steroids Speed Recovery, Not Outcome
High-dose methylprednisolone (IV or equivalent high-dose oral) for 3-5 days shortens a relapse but does not change long-term disability -so reserve it for functionally significant attacks and say the limitation plainly. Plasma exchange for steroid-refractory severe relapses. Mild sensory relapses may need no acute treatment at all.
Know the DMT Complications You Will Meet
Anti-CD20 (ocrelizumab, rituximab): hypogammaglobulinemia, infection, and hepatitis B reactivation -screen HBsAg and anti-HBc before starting. Natalizumab: PML, risk-stratified by JC virus antibody, prior immunosuppression and duration -any new subacute cognitive or focal change is PML until disproven. S1P modulators: first-dose bradycardia, macular edema, and rebound activity on abrupt stopping. Live vaccines are contraindicated on most DMTs.
The Invisible Symptoms Carry the Burden
Fatigue, cognition, depression, bladder dysfunction, spasticity and pain determine quality of life more than the relapse count, and are the parts most often unaddressed. Check a post-void residual before any anticholinergic -incomplete emptying mimics an overactive bladder, and treating it pharmacologically causes retention and the UTIs that then trigger pseudorelapses. Smoking accelerates disability accumulation, so cessation is itself a disease-modifying intervention; add vitamin D, exercise, and bone health given steroid exposure and reduced mobility.
