Multiple Sclerosis

Definition and Epidemiology

Definition

Multiple sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor (MS) is an immune-mediated disease resulting in demyelination of the nerves of the CNS.

• Leads to degeneration of axons Axons Nerve fibers that are capable of rapidly conducting impulses away from the neuron cell body. Nervous System: Histology in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy
• Typically a waxing and waning course with alternating periods of flares and remissions

Epidemiology

• Most common inflammatory disease of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy
• One of the most common causes of long-term disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment in young patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
• Seen in all ethnic groups, but most common in Caucasians
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: 50–300 per 100,000 people (depending on region)
• Female to male ratio: 2–3:1 
• Age of symptom onset: 20–40 years

Etiology and Pathophysiology

Etiology

The exact etiology of MS is unknown. The disease is thought to be multifactorial with genetic predisposition and environmental factors playing contributive roles.

Genetic factors:

• No specific inherited gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics; likely polygenetic influences 
• Mutations in MHC class II are associated with 2–4 times higher risk.
• Interleukin receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors polymorphism Polymorphism The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site to large nucleotide sequences visible at a chromosomal level. Basic Terms of Genetics also appears to increase the risk.
• Presence of the HLA-DRB1*15 allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics appears to increase risk.
• Presence of the HLA-A HLA-A Polymorphic class I human histocompatibility (HLA) surface antigens present on almost all nucleated cells. At least 20 antigens have been identified which are encoded by the a locus of multiple alleles on chromosome 6. They serve as targets for t-cell cytolytic responses and are involved with acceptance or rejection of tissue/organ grafts. Organ Transplantation*02 allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics appears to decrease risk and confer protective effects. 
• Female gender Gender Gender Dysphoria and family history Family History Adult Health Maintenance of disease appear to increase risk.
• Concurrence of disease amongst monozygotic twins Monozygotic twins Result from the division of a single zygote; share the same genetic material Multiple Pregnancy is approximately 35%.
• Concurrence of disease amongst 1st-degree relatives is 3%–4%.

Environmental factors:

• Factors increasing disease risk:
  • Smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases tobacco 
  • Living at higher altitudes
  • History of EBV EBV Epstein-barr virus (EBV) is a linear, double-stranded DNA virus belonging to the herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • History of HHV-6 HHV-6 Human herpesvirus (HHV)-6 and HHV-7 are similar double-stranded DNA viruses belonging to the Herpesviridae family. Human herpesviruses are ubiquitous and infections are commonly contracted during childhood. Human Herpesvirus 6 and 7 infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity in early adolescence
  • Low vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies levels
• Factors decreasing disease risk:
  • Increased exposure to sunlight 
  • High vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies levels
• Geographic distribution suggests that the prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency increases with an increase in the distance from the equator.

Pathogenesis

• Immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs self-attacks oligodendrocytes that form a protective myelin sheath around nerve fibers Nerve Fibers Slender processes of neurons, including the axons and their glial envelopes (myelin sheath). Nerve fibers conduct nerve impulses to and from the central nervous system. Nervous System: Histology → inflammatory reaction → damage and oligodendrocyte Oligodendrocyte A class of large neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal (not the same as satellite cells, perineuronal of ganglia) according to their location. They form the insulating myelin sheath of axons in the central nervous system. Nervous System: Histology death → demyelination (loss of the protective myelin sheath) in the CNS (i.e., brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy, optic nerves)
• Axonal damage and degeneration → irreversible decay of nerve fibers Nerve Fibers Slender processes of neurons, including the axons and their glial envelopes (myelin sheath). Nerve fibers conduct nerve impulses to and from the central nervous system. Nervous System: Histology → impairment of effective transmission of action potentials
• Sites that are most likely to undergo demyelination:
  • Periventricular white matter White Matter The region of central nervous system that appears lighter in color than the other type, gray matter. It mainly consists of myelinated nerve fibers and contains few neuronal cell bodies or dendrites. Brown-Séquard Syndrome
  • Optic nerve Optic nerve The 2nd cranial nerve which conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. The 12 Cranial Nerves: Overview and Functions
  • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem
  • Cerebellar peduncles
  • Corpus callosum
  • Spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord: Anatomy

Clinical Presentation

Clinical forms

• Clinically isolated syndrome (CIS):
  • Episode lasting 24 hours and accompanied by neurologic symptoms typically seen in MS
  • In some cases, this is the earliest manifestation of MS. 
  • Affected individuals may or may not develop MS.
• Relapsing-remitting MS:
  • Most common form
  • Characterized by relapses or recurrences of symptoms followed by periods of remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches of symptoms
  • During relapses, existing symptoms worsen and/or new symptoms may occur.
  • Disease is stable between relapses.
• Secondary progressive MS (SPMS):
  • Develops in about 50% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with relapsing-remitting MS
  • Characterized by ongoing relapses and remissions with progressive worsening of disease and development of new CNS lesions between relapses
• Primary progressive MS (PPMS):
  • Least common form (approximately 15% of cases)
  • Characterized by steady progression and the worsening of disease and symptoms 
  • Acute exacerbations may still occur with worsening of symptoms or the appearance of new symptoms.

Signs and symptoms

• Acute exacerbations are defined as transient dysfunction lasting for at least 24 hours.
• Relapses are characterized by symptoms lasting at least 24 hours with remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches > 30 days since the last relapse Relapse Relapsing Fever.
• Uhthoff phenomenon: Exacerbation of symptoms occurs with increased body temperature Body Temperature The measure of the level of heat of a human or animal. Heatstroke ( fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, exercise, hot baths).
• Constitutional symptoms Constitutional Symptoms Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis:
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
  • Headaches
• Sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology disturbances: 
  • Dysesthesia Dysesthesia Complex Regional Pain Syndrome (CRPS) (altered, unpleasant, and/or painful sensation to touch)
  • Hypoesthesia (complete or partial loss of sensation)
  • Loss or impaired vibration Vibration A continuing periodic change in displacement with respect to a fixed reference. Neurological Examination sense 
  • Neuralgia (burning, stabbing pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways) 
  • Lhermitte’s sign: a feeling of sudden electrical impulses shooting through the spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy and extremities, which are typically elicited by neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess flexion Flexion Examination of the Upper Limbs
• Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology abnormalities:
  • Muscle weakness 
  • Spasticity Spasticity Spinal Disk Herniation
  • Hyperreflexia
  • Disrupted fine motor Fine Motor Developmental Milestones and Normal Growth skills
  • Positive Babinski sign Babinski sign A reflex found in normal infants consisting of dorsiflexion of the hallux and abduction of the other toes in response to cutaneous stimulation of the plantar surface of the foot. In adults, it is used as a diagnostic criterion, and if present is a neurologic manifestation of dysfunction in the central nervous system. Posterior Cord Syndrome (big toe extends up and smaller toes fan out)
  • Absent abdominal reflex (absence of abdominal muscle contraction upon anterior abdominal wall Abdominal wall The outer margins of the abdomen, extending from the osteocartilaginous thoracic cage to the pelvis. Though its major part is muscular, the abdominal wall consists of at least seven layers: the skin, subcutaneous fat, deep fascia; abdominal muscles, transversalis fascia, extraperitoneal fat, and the parietal peritoneum. Surgical Anatomy of the Abdomen stimulation)
• Ocular abnormalities:
  • Optic or retrobulbar neuritis Retrobulbar neuritis Inflammation of the optic nerve. Commonly associated conditions include autoimmune disorders such as multiple sclerosis, infections, and granulomatous diseases. Clinical features include retro-orbital pain that is aggravated by eye movement, loss of color vision, and contrast sensitivity that may progress to severe visual loss, an afferent pupillary defect (Marcus-Gunn pupil), and in some instances optic disc hyperemia and swelling. Inflammation may occur in the portion of the nerve within the globe (neuropapillitis or anterior optic neuritis) or the portion behind the globe (retrobulbar neuritis or posterior optic neuritis). Cranial Nerve Palsies (common early manifestation):
    • Often unilateral
    • May present with vision Vision Ophthalmic Exam impairment, color blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, and pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways with eye movements
    • Marcus Gunn pupil Marcus Gunn Pupil Pupil: Physiology and Abnormalities may be seen: pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities does not react appropriately to light as it should; a type of relative afferent Afferent Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities defect 
  • Internuclear ophthalmoplegia Ophthalmoplegia Paralysis of one or more of the ocular muscles due to disorders of the eye muscles, neuromuscular junction, supporting soft tissue, tendons, or innervation to the muscles. Orbital and Preseptal Cellulitis:
    • More often bilateral than unilateral
    • Occurs due to lesion in medial longitudinal fasciculus Medial Longitudinal Fasciculus Internuclear Ophthalmoplegia
    • Results in impaired conjugate horizontal movements of the eyes 
    • Weakened medial rectus Medial rectus Orbit and Extraocular Muscles: Anatomy muscle ipsilateral to the lesion impairs adduction Adduction Examination of the Upper Limbs in that eye with nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism seen in the contralateral abducting eye with lateral gaze.
  • Hazy vision Vision Ophthalmic Exam
  • Central scotoma Central Scotoma The Visual Pathway and Related Disorders
  • Painless loss of vision Vision Ophthalmic Exam for hours or days
  • Double vision Vision Ophthalmic Exam
  • Monocular vision Vision Ophthalmic Exam
• Autonomic dysfunction Autonomic Dysfunction Anterior Cord Syndrome: 
  • Bowel or bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess incontinence
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Residual urine buildup
  • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
  • Vaginal dryness 
• Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem/cerebellar symptoms: 
  • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo/ dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia/impaired walking
  • Loss of balance or coordination Coordination Cerebellar Disorders
  • Dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease
  • Charcot’s triad:
    • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
    • Scanning speech
    • Volitional tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies (can be arrested by an act of will)
• Psychological symptoms:
  • Depressed mood
  • Emotional changes
  • Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment deficits
  • Concentration deficits
  • Cognitive impairment (late manifestation)

Diagnosis

The diagnosis of MS is that of exclusion, meaning that neurological symptoms that cannot be better explained by a condition other than MS are excluded. The diagnosis is obtained with the following:

• History and physical examination
• Imaging of the entire CNS with MRI of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy is the gold standard:
  • Reveals multiple sclerotic plaques most commonly in the periventricular areas related to oligodendrocyte Oligodendrocyte A class of large neuroglial (macroglial) cells in the central nervous system. Oligodendroglia may be called interfascicular, perivascular, or perineuronal (not the same as satellite cells, perineuronal of ganglia) according to their location. They form the insulating myelin sheath of axons in the central nervous system. Nervous System: Histology loss/demyelination and reactive gliosis
  • T1 sequence: hypointense Hypointense Magnetic Resonance Imaging (MRI) lesions (“black holes”) seen (poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas)
  • T2 sequence or fluid-attenuated inversion recovery Fluid-Attenuated Inversion Recovery Magnetic Resonance Imaging (MRI) ( FLAIR FLAIR Magnetic Resonance Imaging (MRI)) sequence: hyperintense Hyperintense Magnetic Resonance Imaging (MRI) (bright) lesions seen
  • MRI with contrast ( gadolinium Gadolinium An element of the rare earth family of metals. It has the atomic symbol gd, atomic number 64, and atomic weight 157. 25. Its oxide is used in the control rods of some nuclear reactors. Magnetic Resonance Imaging (MRI)): Contrast enhancement of active lesions is indicative of acute inflammation Acute Inflammation Inflammation for up to 6 weeks after an exacerbation.
• EEG EEG Seizures:
  • Visual evoked potentials have the ability to detect inactive lesions in up to 70% of cases.
  • Shows delayed optic nerve Optic nerve The 2nd cranial nerve which conveys visual information from the retina to the brain. The nerve carries the axons of the retinal ganglion cells which sort at the optic chiasm and continue via the optic tracts to the brain. The largest projection is to the lateral geniculate nuclei; other targets include the superior colliculi and the suprachiasmatic nuclei. Though known as the second cranial nerve, it is considered part of the central nervous system. The 12 Cranial Nerves: Overview and Functions conduction with increased latency (delayed response to stimulation)
• Lumbar puncture Lumbar Puncture Febrile Infant/CSF examination:
  • ↑ Leukocyte count (lymphocytic pleocytosis Pleocytosis Tick-borne Encephalitis Virus)
  • ↑ Myelin basic protein
  • Presence of multiple oligoclonal bands is indicative of intrathecal IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis synthesis Synthesis Polymerase Chain Reaction (PCR) and is diagnostic (also indicates poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas if seen early in the disease course).
• McDonald criteria: based on temporal and spatial dissemination of CNS lesions
  • Considers the presence of new lesions and/or exacerbations over time, AND
  • Objective evidence of lesions in different areas of the CNS

Management

Currently, there is no cure for MS. The goals of management are to improve symptoms, slow disease progression, and maintain the quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life.

Treatment for acute exacerbations of MS

• Oral or IV corticosteroids Corticosteroids Chorioretinitis (e.g., methylprednisolone Methylprednisolone A prednisolone derivative with similar anti-inflammatory action. Immunosuppressants) 
• Plasmapheresis Plasmapheresis Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. Stevens-Johnson Syndrome, if unresponsive to steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors

Disease-modifying agents used to prevent relapses and slow disease progression

• Monoclonal antibodies Monoclonal antibodies Antibodies produced by a single clone of cells. Ebolavirus and Marburgvirus:
  • Examples:
    • Natalizumab Natalizumab A humanized monoclonal immunoglobulin g4 antibody to human integrin alpha4 that binds to the alpha4 subunit of integrin alpha4beta1 and integrin alpha4beta7. It is used as an immunologic factor in the treatment of relapsing-remitting multiple sclerosis and Crohn’s disease. Crohn’s Disease
    • Ocrelizumab Ocrelizumab Immunosuppressants
    • Rituximab Rituximab A murine-derived monoclonal antibody and antineoplastic agent that binds specifically to the cd20 antigen and is used in the treatment of leukemia; lymphoma and rheumatoid arthritis. Immunosuppressants
    • Ofatumumab
    • Ublituximab
    • Alemtuzumab
  • Risk of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, including progressive multifocal Multifocal Retinoblastoma leukoencephalopathy (often fatal brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification infection)
• Sphingosine 1-phosphate receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (S1PR) modulators:
  • Alter migration and sequestration of lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology
  • Examples:
    • Fingolimod
    • Siponimod
    • Ozanimod
    • Ponesimod
• Other immunomodulators:
  • Interferon beta: risk of hepatotoxicity Hepatotoxicity Acetaminophen
  • Glatiramer acetate: suppresses the Th1 Th1 A subset of helper-inducer T-lymphocytes which synthesize and secrete interleukin-2; interferon-gamma; and interleukin-12. Due to their ability to kill antigen-presenting cells and their lymphokine-mediated effector activity, th1 cells are associated with vigorous delayed-type hypersensitivity reactions. T cells: Types and Functions arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy of the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs
  • Dimethyl fumarate Fumarate Citric Acid Cycle
  • Teriflunomide
  • Cladribine Cladribine An antineoplastic agent used in the treatment of lymphoproliferative diseases including hairy-cell leukemia. Antimetabolite Chemotherapy

Management of related symptoms

• Spasticity Spasticity Spinal Disk Herniation: tizanidine Tizanidine Spasmolytics, baclofen Baclofen A gamma-aminobutyric acid derivative that is a specific agonist of gaba-b receptors. It is used in the treatment of muscle spasticity, especially that due to spinal cord injuries. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. Spasmolytics, botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism, cannabis
• Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways: anticonvulsants ( carbamazepine Carbamazepine A dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties. First-Generation Anticonvulsant Drugs, gabapentin Gabapentin A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of partial seizures; neuralgia; and restless legs syndrome. Second-Generation Anticonvulsant Drugs, pregabalin Pregabalin A gamma-aminobutyric acid (gaba) derivative that functions as a calcium channel blocker and is used as an anticonvulsant as well as an anti-anxiety agent. It is also used as an analgesic in the treatment of neuropathic pain and fibromyalgia. Second-Generation Anticonvulsant Drugs), tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants ( amitriptyline Amitriptyline Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the reuptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines. Tricyclic Antidepressants),  duloxetine Duloxetine A thiophene derivative and selective neurotransmitter uptake inhibitor for serotonin and noradrenaline (SNRI). It is an antidepressant agent and anxiolytic, and is also used for the treatment of pain in patients with diabetes mellitus and fibromyalgia. Serotonin Reuptake Inhibitors and Similar Antidepressants
• Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia: amantadine Amantadine An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. Antivirals for Influenza, modafinil Modafinil Stimulants, selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants
• Gait Gait Manner or style of walking. Neurological Examination disorder: fampridine
• Bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess disorder:
  • Overactive bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess/detrusor overactivity: anticholinergics Anticholinergics Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs ( oxybutynin Oxybutynin Anticholinergic Drugs, tolterodine Tolterodine An antimuscarinic agent selective for the muscarinic receptors of the bladder that is used in the treatment of urinary incontinence and urinary urge incontinence. Anticholinergic Drugs)
  • Voiding disorder: alpha-blockers Alpha-blockers Drugs that bind to but do not activate alpha-adrenergic receptors thereby blocking the actions of endogenous or exogenous adrenergic agonists. Adrenergic alpha-antagonists are used in the treatment of hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma. Antiadrenergic Drugs ( phenoxybenzamine Phenoxybenzamine An alpha-adrenergic antagonist with long duration of action. It has been used to treat hypertension and as a peripheral vasodilator. Antiadrenergic Drugs, prazosin Prazosin A selective adrenergic alpha-1 antagonist used in the treatment of heart failure; hypertension; pheochromocytoma; raynaud disease; prostatic hypertrophy; and urinary retention. Antiadrenergic Drugs)
  • Urinary retention Urinary retention Inability to empty the urinary bladder with voiding (urination). Delirium: intermittent self-catheterization
• Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction: tadalafil Tadalafil A carboline derivative and phosphodiesterase 5 inhibitor that is used primarily to treat erectile dysfunction; benign prostatic hyperplasia and primary pulmonary hypertension. Phosphodiesterase Inhibitors, sildenafil Sildenafil A phosphodiesterase type-5 inhibitor; vasodilator agent and urological agent that is used in the treatment of erectile dysfunction and primary pulmonary hypertension. Phosphodiesterase Inhibitors
• Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation: stool softeners, laxatives Laxatives Laxatives are medications used to promote defecation. Most often, laxatives are used to treat constipation or for bowel preparation for certain procedures. There are 4 main classes of laxatives: bulk-forming, stimulant, osmotic, and emollient. Laxatives
• Depression: selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( citalopram Citalopram A furancarbonitrile that is one of the serotonin uptake inhibitors used as an antidepressant. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia in preference to tricyclic antidepressants, which aggravate dyskinesia. Serotonin Reuptake Inhibitors and Similar Antidepressants, sertraline Sertraline A selective serotonin uptake inhibitor that is used in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants, paroxetine Paroxetine A serotonin uptake inhibitor that is effective in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants)

Nonpharmacological interventions

• PT
• Occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder
• Speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies
• Prepregnancy counseling

Differential Diagnosis

• Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus): an autoimmune condition that can affect virtually any organ system. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship typically suffer from kidney disease and photosensitivity Photosensitivity Tetracyclines and can also present with neurological symptoms of numbness, tingling Tingling Posterior Cord Syndrome, headaches, and confusion. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus commonly test positive for ANA with double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions. Management is with immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants. 
• Neurosyphilis Neurosyphilis Infections of the central nervous system caused by treponema pallidum which present with a variety of clinical syndromes. The initial phase of infection usually causes a mild or asymptomatic meningeal reaction. The meningovascular form may present acutely as brain infarction. The infection may also remain subclinical for several years. Late syndromes include general paresis; tabes dorsalis; meningeal syphilis; syphilitic optic atrophy; and spinal syphilis. General paresis is characterized by progressive dementia; dysarthria; tremor; myoclonus; seizures; and argyll-robertson pupils. Syphilis: a manifestation of tertiary syphilis Tertiary Syphilis Syphilis caused by the spirochete Spirochete Treponema is a gram-negative, microaerophilic spirochete. Owing to its very thin structure, it is not easily seen on Gram stain, but can be visualized using dark-field microscopy. This spirochete contains endoflagella, which allow for a characteristic corkscrew movement. Treponema, Treponema pallidum Treponema pallidum The causative agent of venereal and non-venereal syphilis as well as yaws. Treponema. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with neurosyphilis Neurosyphilis Infections of the central nervous system caused by treponema pallidum which present with a variety of clinical syndromes. The initial phase of infection usually causes a mild or asymptomatic meningeal reaction. The meningovascular form may present acutely as brain infarction. The infection may also remain subclinical for several years. Late syndromes include general paresis; tabes dorsalis; meningeal syphilis; syphilitic optic atrophy; and spinal syphilis. General paresis is characterized by progressive dementia; dysarthria; tremor; myoclonus; seizures; and argyll-robertson pupils. Syphilis may present with headaches, mood disturbances, and memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment impairment. Demyelination can also occur with neurosyphilis Neurosyphilis Infections of the central nervous system caused by treponema pallidum which present with a variety of clinical syndromes. The initial phase of infection usually causes a mild or asymptomatic meningeal reaction. The meningovascular form may present acutely as brain infarction. The infection may also remain subclinical for several years. Late syndromes include general paresis; tabes dorsalis; meningeal syphilis; syphilitic optic atrophy; and spinal syphilis. General paresis is characterized by progressive dementia; dysarthria; tremor; myoclonus; seizures; and argyll-robertson pupils. Syphilis, specifically demyelination of the dorsal column Dorsal column Spinal Cord: Anatomy of the spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy, which leads to ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia (referred to as tabes dorsalis Tabes dorsalis Parenchymatous neurosyphilis marked by slowly progressive degeneration of the posterior columns, posterior roots, and ganglia of the spinal cord. The condition tends to present 15 to 20 years after the initial infection and is characterized by lightning-like pains in the lower extremities, urinary incontinence; ataxia; severely impaired position and vibratory sense, abnormal gait, optic atrophy; Argyll-Robertson pupils, hypotonia, hyperreflexia, and trophic joint degeneration. Syphilis). The 1st-line treatment for neurosyphilis Neurosyphilis Infections of the central nervous system caused by treponema pallidum which present with a variety of clinical syndromes. The initial phase of infection usually causes a mild or asymptomatic meningeal reaction. The meningovascular form may present acutely as brain infarction. The infection may also remain subclinical for several years. Late syndromes include general paresis; tabes dorsalis; meningeal syphilis; syphilitic optic atrophy; and spinal syphilis. General paresis is characterized by progressive dementia; dysarthria; tremor; myoclonus; seizures; and argyll-robertson pupils. Syphilis is penicillin Penicillin Rheumatic Fever.
• Neurosarcoidosis: a condition where sarcoidal granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis are deposited within the CNS. Neurosarcoidosis most commonly presents with cranial nerve defects or visual disturbances. Diagnosis is made using imaging studies by detecting granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis and obtaining a tissue diagnosis with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.
• Vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 ( cobalamin Cobalamin A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12) deficiency: a condition presenting with mild neurological symptoms, such as numbness and tingling Tingling Posterior Cord Syndrome of the extremities. As the deficiency becomes more severe, patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship can develop mental confusion, psychiatric changes, and ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia. Vitamin B12 deficiency Vitamin B12 deficiency A nutritional condition produced by a deficiency of vitamin B12 in the diet, characterized by megaloblastic anemia. Since vitamin B12 is not present in plants, humans have obtained their supply from animal products, from multivitamin supplements in the form of pills, and as additives to food preparations. A wide variety of neuropsychiatric abnormalities is also seen in vitamin B12 deficiency and appears to be due to an undefined defect involving myelin synthesis. Folate and Vitamin B12 can be treated using intramuscular vitamin B12 Vitamin B12 A cobalt-containing coordination compound produced by intestinal microorganisms and found also in soil and water. Higher plants do not concentrate vitamin B 12 from the soil and so are a poor source of the substance as compared with animal tissues. Intrinsic factor is important for the assimilation of vitamin B 12. Folate and Vitamin B12 repletion.