Multiple Sclerosis

Multiple Sclerosis: Definition

Epidemiology » PEAK INCIDENCE: 20 to 40 years of age. » PREVALANCE: MS is more common in people raised in northern latitudes and in certain genetic clusters. » PREDOMINANT SEX & AGE: Female/male ratio is 2 to 3:1 » GENETICS: Frequency of MS in Dizygotic Twins & Monozygotic twins. (Department of Neurology and Research)

» Higher prevalence in northern latitudes. » Cultural Considerations » White populations > than Asian or African Populations

» The precise etiology of MS is uncertain. There is evidence that autoimmunity (autoreacitve T cells and B cells) plays an important role. It is believed that an interaction between multiple genes influencing the immune system and environmental factors such as certain viruses e.g. Epstein-Barr virus and human herpes virus 6, low Vitamin D level, smoking, and sun exposure are important factors. (Ferri’s, 2013).

» Immune System: Malfunction causes destruction of body’s cells » Immune Response: Is driven by T- Lymphocytes and B- Lymphocytes » Lymphocytes breakdown and cross the blood brain barrier

Pathology Progression

Pathology » MS is a nerve disorder caused by destruction of the insulating layer surrounding neurons in the brain and spinal cord. Myelin helps electrical signals pass quickly and smoothly between the brain and the rest of the body. When the Myelin is destroyed, nerve messages are sent more slowly and less efficiently. » Oligodendrocytes-Glial Cells » Nerve Cells Disruption

»Subtypes include: Most Common  Relapsing-Remitting MS (RRMS), Most Common  Secondary Progressive MS (SPMS)  Primary Progressive MS (PPMS)  Progressive Relapsing MS (PRMS)  Neuromyelitis Optica (NMO: Devic’s Disease)  Marburg’s Disease (Malignant MS)  Balo’s Concentric Sclerosis  Schilder’s Diffuse Sclerosis  Relapsing Optic Neuritis ( Ferri’s, 2013)

Physical Findings & Clinical Presentation » Common: both vague and nonspecific » Visual Abnormalities: Horizontal Nystagmus, visual field defects Marcus Gunn Pupil Internuclear Ophthalmoplegia

Physical Findings and Clinical Presentation » Corticospinal Tract Involvement » Sensory Loss » Ataxia » Bladder Dysfunction » Lhermitte’s Sign » Uhtoff’s Phenomenon

Symptoms » Early: Numbness in 1or more limbs, partial paralysis, double or blurred vision in 1 eye » Later: Loss of coordination, loss of ability to walk of bladder or bowel control » Mental Symptoms: Depression, forgetfulness, loss of concentration

Symptoms are unique to each individual but a typical patient presents as a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution.

Differential Diagnosis » Autoimmune: Acute Disseminated Encephalomyelitis (ADEM), Postvaccination Encephalomyelitis » Degenerative: Subacute Combined Degeneration of the cord (B-12 deficiency), Amyotrophic lateral sclerosis » Infections: Lyme’s Disease, Neurosyphillis, HIV, Tropical Spastic Paraparesis, Progressive Multifocal Leukoencephalopahty, Whipple’s Disease » Inflammatory: Systemic Lupus, Erythematosus, Vasculitis, Sarcoidosis, » Sjogren’s Disease, Behcet’s Disease, Celiac Disease » Mitochondrial: Leber’s Hereditary Optic Neuropathy, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes

» MS is a clinical diagnosis, based on symptoms of an “attack”. » An MS attack (also called a relapse or exacerbation) is defined by the McDonald criteria as patient- reported or objectively observed event typical of an acute inflammatory demyelinating event in the CNS, and can be either current or historical, with duration of at least 24 hours, in the absence of fever or infection. » MRI of brain and spine is then done and the McDonald’s criteria, based on symptoms and lesions found and their location a supportive diagnosis of Multiple Sclerosis can be made. » MS is a clinical diagnosis, based on symptoms of an “attack”. » An MS attack (also called a relapse or exacerbation) is defined by the McDonald criteria as patient- reported or objectively observed event typical of an acute inflammatory demyelinating event in the CNS, and can be either current or historical, with duration of at least 24 hours, in the absence of fever or infection. » MRI of brain and spine is then done and the McDonald’s criteria, based on symptoms and lesions found and their location a supportive diagnosis of Multiple Sclerosis can be made.

» OLD CARTS » Family history of MS? » Smoker? » Past medical history of cerebral spinal fluid problems? » EXAM: ˃Neurologic ˃HEENT ˃Respiratory ˃Cardiac ˃Musculoskeletal ˃Genitourinary ˃Abdominal ˃Psychiatric ˃Constitutional » OLD CARTS » Family history of MS? » Smoker? » Past medical history of cerebral spinal fluid problems? » EXAM: ˃Neurologic ˃HEENT ˃Respiratory ˃Cardiac ˃Musculoskeletal ˃Genitourinary ˃Abdominal ˃Psychiatric ˃Constitutional

» RRMS: At least two relapses-two clinical lesions distinctly separated in space and time or one clinical lesion plus paraclinical testing » PPMS: Insidious progression of disability with a positive CSF and either dissemination in both space and time or ongoing progression for at least 1 year. » RRMS: At least two relapses-two clinical lesions distinctly separated in space and time or one clinical lesion plus paraclinical testing » PPMS: Insidious progression of disability with a positive CSF and either dissemination in both space and time or ongoing progression for at least 1 year.

» Lumbar Puncture: All first-line relapses and all cases in which the DX of MS is not DEFINITE. » Serum: Complete Blood Count (CBC), Sedimentation Rate (Sed-rate), CHEM 7, Liver function tests (LFT’s), Antinuclear Antibody, and Vit.-B 12. » Consider: Anti-SS-A antibody, Anti-SS-B antibody, Neuromyelitis Optica IgG antibody, Lyme Titer, Angiotension-Coverting Enzyme, TSH, Free T-4, Anti- Thyroglobulin antibody, Very Long-Chain Fatty Acid, Arylsulfatase A, and Possibly Heavy Metal Screening (Urine) » Head Imaging (CT or MRI) is strongly recommended. » Lumbar Puncture: All first-line relapses and all cases in which the DX of MS is not DEFINITE. » Serum: Complete Blood Count (CBC), Sedimentation Rate (Sed-rate), CHEM 7, Liver function tests (LFT’s), Antinuclear Antibody, and Vit.-B 12. » Consider: Anti-SS-A antibody, Anti-SS-B antibody, Neuromyelitis Optica IgG antibody, Lyme Titer, Angiotension-Coverting Enzyme, TSH, Free T-4, Anti- Thyroglobulin antibody, Very Long-Chain Fatty Acid, Arylsulfatase A, and Possibly Heavy Metal Screening (Urine) » Head Imaging (CT or MRI) is strongly recommended.

MRI: Dawson’s Fingers Treatment Includes » Patient education regarding disease characteristics, treatment options, and prognosis should be given. Advise patient to schedule intermittent rest periods on a daily basis and avoid exposure to heat as much as possible. Provide encouragement regarding improved quality of life with new disease modifying drug options. Recommend physical therapy for spasticity/disability. (Ferri’s, 2013). » Patient education regarding disease characteristics, treatment options, and prognosis should be given. Advise patient to schedule intermittent rest periods on a daily basis and avoid exposure to heat as much as possible. Provide encouragement regarding improved quality of life with new disease modifying drug options. Recommend physical therapy for spasticity/disability. (Ferri’s, 2013).

» Relapses: High-Dose IV Methylprednisone (3 to 5 days), alternative is 15 mg/kg/day), followed by a 7-10 day prednisone taper. » If marked acute disability and acute corticosteroid therapy has failed, plasma exchange (5-7 exchanges on alternate days) have shown benefit. (Ferri’s, 2013) » Relapses: High-Dose IV Methylprednisone (3 to 5 days), alternative is 15 mg/kg/day), followed by a 7-10 day prednisone taper. » If marked acute disability and acute corticosteroid therapy has failed, plasma exchange (5-7 exchanges on alternate days) have shown benefit. (Ferri’s, 2013)

» Disease Modifying Therapy: Includes Interferon Beta-1a (IM Avonex, SC Rebif), Interferon Beta-1b (SC Betaseron), and Glatiramer Acetate (SC Copaxone). Interferon's require routine CBC and LFT monitoring (initially at 1-month then ever 3-months). Occasionally check TSH, Interferon's can cause flu-like symptoms. » Fingolimod: Approved first oral disease modify agent. » Dalfampridine: (Ampyra), a potassium channel blocker- improves walking speed in patients. » Cytotoxic: Methotrexate or azathioprine is occasionally used in PPMS or RRMS. » Monoclonal Antibodies: Natalizumab (Tysabril) is approved for RRMS in the form of monthly infusions. » Disease Modifying Therapy: Includes Interferon Beta-1a (IM Avonex, SC Rebif), Interferon Beta-1b (SC Betaseron), and Glatiramer Acetate (SC Copaxone). Interferon's require routine CBC and LFT monitoring (initially at 1-month then ever 3-months). Occasionally check TSH, Interferon's can cause flu-like symptoms. » Fingolimod: Approved first oral disease modify agent. » Dalfampridine: (Ampyra), a potassium channel blocker- improves walking speed in patients. » Cytotoxic: Methotrexate or azathioprine is occasionally used in PPMS or RRMS. » Monoclonal Antibodies: Natalizumab (Tysabril) is approved for RRMS in the form of monthly infusions.

Chronic Continued » Pain: Carbamazepine, Gabapentin, or Amitriptyline » Fatigue: Consider Amantadine 100mg BID, Modafinil (most effective for somnolence), or Fluoxetine

Referral » Referral to neurology on DX is highly recommended. » Consider referrals for PT, and OT to prevent/minimize disability. » Consider referral to urology if post-void residual by bladder scan is more than 100 ml. » Referral to MS specialist should be strongly considered in case of poor response to therapy, possibility of cytotoxic treatment, and /or concern regarding accuracy of diagnosis (Ferri’s, 2013)

Question # 1 Multiple Sclerosis » A 34 y/o female has been recently DX with Multiple Sclerosis (MS). When providing primary care for this patient, you consider that MS: A.Has a predictable course of progressive decline in intellectual and motor function. B.Manifests with a classic pattern of Myalgia, blurred vision, and Ataxia. C.Is often seen with a variable pattern of exacerbation and remissions. D.Is accompanied by classic central nervous system lesions detectable on skull films. ANSWER: C

» Treatment options in MS to attenuate disease progression include: A.Interferon beta- 1b B.Methylprednisolo ne C.Ribavirin D.Phenytoin ANSWER: A