Multiple Sclerosis: Symptoms and Causes

• Immediate emergency department referral is needed for suspected progressive multifocal leukoencephalopathy (PML), encephalitis, new-onset seizure, or symptomatic cardiac dysfunction.

Definition and Epidemiology

• Multiple sclerosis (MS) is a chronic, progressive inflammatory and neurodegenerative disease affecting the central nervous system (CNS).
• MS affects about 1 million people in the United States and 2.8 million worldwide.
• The cause of MS is unclear, but involves destruction of the myelin sheath from inflammation and demyelination, causing injury to the brain, optic nerves, and spinal cord.
• MS involves an interaction among the autoimmune system, genetic factors, and environmental factors.
• Over 110 genes are associated with MS.
• Vitamin D deficiency is a possible concern.
• Onset typically occurs between 20 and 40 years of age, but can occur in younger or older patients.
• MS affects twice as many women as men.
• MS is less common near the equator and more common in the Northern mid-latitudes.

Pathophysiology

• MS is considered an inflammatory and neurodegenerative disease affecting both white and gray matter of the CNS
• An environmental trigger likely activates an inflammatory process, causing gliosis, inflammation, and scarring (sclerosis) in the CNS.
• The inflammatory process involves T- and B-cell activity, macrophages, and natural killer cells.
• The blood–brain barrier degrades, allowing proinflammatory cytokines to penetrate the CNS.
• Reactivation of the inflammatory process in the CNS leads to demyelination and axonal destruction.
• Both inflammatory and degenerative processes occur early and simultaneously.
• Inflammation downregulates and neurodegeneration escalates as the disease progresses.
• Recovery in early disease occurs due to the CNS's ability to reorganize, compensate for axonal loss, and remyelinate.
• Remyelination is often incomplete, and axonal degradation leads to permanent disability over time.

Clinical Courses of Multiple Sclerosis

• Radiographically isolated syndrome (RIS): MRI lesions specific to MS without clinical symptoms; 65% convert to MS in 5.3 years.
• Clinically isolated syndrome (CIS): Acute or subacute neurologic event indicative of demyelination; up to 90% of MS patients have CIS on presentation.
• Relapsing-remitting MS (RRMS): Clinical relapses followed by remission; the most common type; 85% of patients have RRMS at diagnosis.
• Primary-progressive MS (PPMS): Accumulating disability from onset without defined relapses or remissions; about 10% of patients have PPMS.
• Secondary-progressive MS (SPMS): Progressive course with or without relapses, evolving from RRMS; 50% of RRMS cases convert to SPMS, and 90% after 25 years.
• Progressive-relapsing MS (PRMS): Steadily progressive from onset with acute attacks; about 5% of patients have this type.
• Benign: Expanded Disability Severity Scale (EDSS) score ≤3 for over 10 years; about 50% progress to EDSS scores ≥6.0 or SPMS within 20 years

Clinical Presentation and Physical Examination

• The four clinical courses of MS are: relapsing-remitting (RRMS), primary-progressive (PPMS), secondary-progressive (SPMS), and progressive-relapsing (PRMS).
• 15% to 30% of RRMS patients progress to SPMS within 15 to 20 years.
• At presentation, patients may have a clinically isolated syndrome (CIS) or first clinical episode, typically a focal neurologic deficit like eye pain or visual disturbances from optic neuritis.
• MRI can demonstrate multiple lesions consistent with MS, enabling early diagnosis and treatment.
• Radiographically isolated syndrome (RIS) involves MRI lesions specific to MS without clinical symptoms.
• Common presenting symptoms include visual disturbances, eye pain, neck or back pain, paresthesias or weakness of the limbs, or facial pain.
• Other symptoms include sensory issues, diplopia, nystagmus, unsteady gait, or bowel/bladder dysfunction.
• Associated findings include fatigue, temperature sensitivity, bandlike sensations around the waist (“MS hug”), dysarthria, muscle spasms, cognitive disturbances, and sexual dysfunction.
• Initial symptoms can be vague and go unrecognized, such as sensory distortion, bowel/bladder dysfunction, or cognitive impairment.
• Symptoms are unpredictable and variable.
• A complete neurologic examination is required for patients with suspected or confirmed MS.
• Neurologic examination findings may be normal, especially in early disease.
• Specific domains of the neurologic examination for MS include mental status, cranial nerves, motor testing, sensory examination, cerebellar function, and reflexes.
• Mental status assessment includes general conversation, speech fluidity, thought processing speed, integration of complex ideas, and following instructions; neuropsychiatric testing can reveal cognitive issues.
• Cranial nerve assessment includes extraocular movements, nystagmus, intranuclear ophthalmoplegia, ophthalmic examination for disc pallor, and trigeminal nerve assessment for allodynia.
• Motor testing may reveal limb weakness, clumsiness, decreased fine dexterity, increased tone, and clonus; gait evaluation should include evidence of circumduction, spasticity, or ataxia.
• The Timed 25-Foot Walk (T25FW) test is an important part of MS evaluation.
• Sensory examination should focus on pinprick, proprioception, and vibration testing to determine long-tract involvement; a sensory level may indicate spinal cord involvement.
• Cerebellar function is assessed via finger-to-nose and Romberg testing; patients often have ataxic gait.
• Reflexes are often brisk with upgoing toes, indicating CNS involvement.
• Documenting neurologic and functional baselines is essential for evaluating treatment response or exacerbation.
• Functional areas include driving, falls and injuries, work difficulties, interpersonal skills, financial capabilities, and activities of daily living (ADLs).
• The Expanded Disability Severity Scale (EDSS), Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), and T25FW can provide quantitative support for functional limitations.

Diagnostics

• MS diagnosis requires separation of time and space, with at least two distinct episodes lasting more than 24 hours occurring at least 30 days apart, and evidence of at least two different locations.
• Signs and symptoms must be consistent with inflammatory demyelinating disease, with no other identifiable cause.
• Ruling out other conditions is essential through clinical history, examination, and diagnostic studies.
• MRI is the gold standard for MS diagnosis, based on the McDonald Criteria (introduced in 2001, revised in 2005, 2010, and 2017).
• Visual evoked potentials, optical coherence tomography (OCT), spinal tap, and blood work are useful when diagnosis is unclear or MRI is not readily available.

Initial Diagnostics

• Laboratory tests are typically not specific for MS diagnosis.
• Standardized Brain MRI Protocol recommendations include: mandatory axial FLAIR, sagittal FLAIR, and axial T2 imaging; gadolinium contrast as indicated; optional sequences (3D high-resolution T1- and susceptibility-weighted); surveillance for progressive multifocal encephalopathy; spinal cord sequences; and judicious use of gadolinium.
• Additional diagnostic laboratory tests may include: complete blood count (CBC) with differential, chemistry profile, antinuclear antibodies (ANA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fluorescent treponemal antibody absorption test (FTA-ABS), HIV test, antiphospholipid antibodies (if ANA >1:320), prothrombin time/partial thromboplastin time (PT/PTT), angiotensin-converting enzyme (ACE), thyroid-stimulating hormone (TSH), vitamin D, Lyme titer, vitamin B12, and folate.
• Additional diagnostic imaging may include: brain, cervical spine, thoracic spine, and lumbar spine MRI.
• Additional studies may include: visual evoked potentials, optical coherence tomography, and lumbar puncture with cerebrospinal fluid analysis for proteins or inflammatory cells.

Differential Diagnosis

• Primary differentials include tumors, cerebral vascular events, encephalitis, toxic exposure, or metabolic deficiency.
• Other differentials include structural or anatomic issues, psychiatric disorders, toxin exposure, vascular conditions, metabolic disorders, genetic conditions, infections, inflammatory diseases, and other MS variants.

Physician Consultation

• Consultation with a neurologist, MS neurology expert, or MS center should be considered for diagnosis confirmation.

Interprofessional Collaborative Management

• Neurologist and MS specialist consultations are recommended for initial evaluation, DMT prescription, MS exacerbation, and difficult-to-manage symptoms.
• Management goals include addressing the disease, managing symptoms, and maximizing patient and family quality of life.
• A comprehensive approach involves the patient, family, and a collaborative care team (CCT).
• The CCT consists of a neurologist, advanced practice nurse, physician assistant, and/or a center specializing in MS, along with other specialists as needed.
• Long-term care may be managed by a neurology specialist or a primary care provider, but a team approach is essential.
• The CCT empowers the patient by encouraging an active role in developing and implementing the plan of care.

Management of MS

• Education about DMT aims to help patients and families understand the importance of early treatment.
• DMT goals are to decrease exacerbation rate, decrease MRI activity, and slow disability progression.
• DMT initiation starts early, usually with the first presentation of CIS.
• DMTs are classified based on administration methods: injectable, infusible, and oral.
• Injectable DMTs include interferons (Betaseron, Extavia, Avonex, Plegridy, Rebif), which require monitoring for depression, liver enzymes, and hematologic profiles.
• Copaxone, a synthetic protein given subcutaneously for relapsing MS, has varied adverse reactions like anxiety and injection site edema.
• Kesimpta, a newer injectable for relapsing MS, is an anti-CD monoclonal antibody requiring careful monitoring for infection.
• Infusible DMTs include Novantrone and Tysabri.
• Novantrone requires careful cardiac evaluation and monitoring due to risk of cardiac toxicity and leukemia.
• Tysabri, a monoclonal antibody with immunosuppressant effect, was recalled due to PML cases but returned under strict monitoring; increased PML risk remains.
• Other monoclonal antibody treatments include ocrelizumab, rituximab, ofatumumab, and alemtuzumab, each with different indications, contraindications, and risks.
• Oral therapies include Gilenya, Aubagio, Bafiertam (Tecfidera), Mavenclad, Mayzent, Ponvory, Vumerity, and Zeposia, each with individual risks and side effects.
• Other agents with immunosuppressant or immunomodulating effects, such as Imuran, Rheumatrex, Rituxan, Cytoxan, CellCept, plasmapheresis, and IVIG, have been used off-label with varying efficacy.
• Research into neuroprotection, remyelination, and stem cell transplantation is ongoing.
• Hypovitaminosis D is a considered a risk factor, and vitamin D may have an immunomodulatory beneficial effect.
• A healthy low-sodium diet and smoking cessation positively affect disease progression and severity.

Exacerbation

• Exacerbation is the acute onset of neurologic symptoms lasting over 24 hours, preceded by 30 days of stability, without underlying causes like infection.
• Exacerbation treatment typically involves high-dose intravenous steroids or adrenocorticotropic hormone (ACTH).
• Corticosteroids downregulate inflammatory lymphocytes and close the damaged blood–brain barrier.
• Most MS exacerbations are handled outpatient; hospitalization is needed for significant self-care deficits, complications, or infections.
• After an exacerbation, rehabilitation is necessary to address new deficits or functional loss.

Life Span Considerations

• A diagnosis of MS can bring relief or uncertainty due to its variability.
• People with MS can still work, and their lifespan can be similar to those without MS.
• Routine health screening and life planning should continue after diagnosis.
• Pregnancy may have a neuroprotective effect, with acute exacerbation common up to 6 months postpartum.
• DMTs are not recommended during pregnancy or breastfeeding; stopping DMTs 3 months before conception is advised.
• Ambulatory dysfunction, fatigue, and cognitive impairment are major contributors to loss of employment.
• Up to 70% of patients develop cognitive difficulties due to CNS lesions.
• Depression is common and increases the risk of vascular disease and death.
• Patients with MS are at higher risk for other autoimmune diseases, osteoporosis, sleep disorders, UTIs, pressure ulcers, obesity, and substance use.

Patient and Family Education and Health Promotion

• MS diagnosis can be overwhelming; support and education about the disease, its variability, and available therapies are essential.
• Emphasize the benefits of DMT, such as delayed disability, reduced exacerbations, and reduced MRI activity.
• Encourage adherence to DMT regimens and symptomatic treatment to optimize quality of life.
• Focus on raising awareness and promoting health, wellness, and safety, including preventive care, exercise, diet, lifestyle modifications, smoking cessation, and avoiding drug/alcohol abuse.
• Driving evaluations may be needed.
• Comprehensive issues include balancing normalcy with the demands of the disease, family planning, coping skills, caregiver issues, and relationship issues.
• Address concerns about confidentiality, insurance, employment, and disability issues.
• Remind patients and families that MS is often compared to a marathon, requiring support for long-term decision-making.

This lesson covers the symptoms, causes, and prevalence of multiple sclerosis (MS). It also discusses neurological and cardiac symptoms that require immediate referral. It also examines the blood-brain barrier degradation.