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Multiple sclerosis.ppt

  1. 1. Multiple sclerosis By:- Jwan Ali Ahmed AlSofi
  2. 2. • Multiple sclerosis (MS) is a chronic disease characterized by 1. inflammation, 2. demyelination, 3. gliosis (plaques or scarring), 4. neuronal loss. • MS plaques typically occur at different times and in different CNS locations. • MS is said to be disseminated in time and space. • 5 million individuals worldwide. • Manifestations of MS vary from a benign illness to a rapidly evolving and incapacitating disease requiring profound lifestyle adjustments.
  3. 3. Epidemiology and causes • MS is approximately threefold more common in women than men. • The age of onset is typically between 20 and 40 years • Prevalence of MS is 0.1–0.2%. • The cause of MS is unknown; however, it is believed to occur as a result of some combination of genetic and environmental factors such as infectious agents. • Risk factors:- 1. Geographicly the highest known prevalence for MS in north of Scotland. In other temperate zone areas • Moving at an early age from one location in the world to another alters a person's subsequent risk of MS. 2. Vitamin D deficiency is associated with an increase in MS risk . • ongoing deficiency may increase the relapse rate in established MS. 3. a protective effect of sun exposure. 4. any microbes have been proposed as triggers of MS, but none have been confirmed. 5. Smoking has been shown to be an independent risk factor for MS. 6. Stress may be a risk factor although the evidence to support this is weak.
  4. 4. Pathogenesis:- Pathology of MS Stage of Inflammation Stage of Demyelination Stage of Gliosis/Scarring
  5. 5. 1- Stage of inflammation:- • Perivenular cuffing with inflammatory mononuclear cells (T cells & macrophages) with infiltration of surrounding white matter • Disruption of blood brain barrier (but vessel wall is preserved, a contrast to vasculitis syndromes where vessel wall is damaged)
  6. 6. 2- Stage of demyelination:- • Demyelination is the hallmark of the pathology • Cell-mediated immunity • T-lymphocytes against Myelin Basic Protein (MBP) • Humoral immunity • Myelin specific antibodies • presence of elevated levels of locally synthesized immunoglobulins and oligoclonal antibodies, derived from clonally restricted CNS B cells and plasma cells, in the CSF are also characteristic of MS.
  7. 7. 3- Stage of Gliosis/Scarring:- • Astrocytic proliferation (gliosis) • Relative sparing of axons is typical of MS • Partial or total axonal destruction can also occur, especially within highly inflammatory lesions • MS Plaques - Oligodendrocyte precursor cells survive and in many lesions are present in even greater numbers than in normal tissue but fail to differentiate into mature myelin- producing cells - Partial remyelination of surviving naked axons by surviving oligodendrocytes appearing as ‘shadow plaques’
  8. 8. Multiple sclerosis types 1.Relapsing remitting MS 2.Primary progressive MS 3.2nd progressive MS 4.Progressive relapsing MS
  9. 9. 1- Relapsing Remitting MS • It occurs more than 85% of the cases • is characterized by discrete attacks of neurological dysfunction that generally evolve over days to weeks (rarely over hours). • There is often complete recovery over the ensuing weeks to months. • Approximately half will fail to improve. • Between attacks, patients are neurologically stable.
  10. 10. 2- Primary Progressive MS • accounts for ∼ 15% of cases. • These patients do not experience attacks but only a steady functional decline from disease onset • The sex distribution is more even, • The disease begins later in life (mean age ∼ 40 years), • Disability develops faster (relative to the onset of the first clinical symptom).
  11. 11. 3- Secondary Progressive MS • SPMS always begins as RRMS. • At some point, however, the clinical course changes so that the patient experiences a steady deterioration in function unassociated with acute attacks (which may continue or cease during the progressive phase). • SPMS produces a greater amount of fixed neurologic disability than RMS. • For a patient with RMS, the risk of developing SPMS is ~2% each year, meaning that the great majority of RMS ultimately evolves into SPMS. • As such, SPMS appears to represent a late stage of the same underlying illness as RMS.
  12. 12. 4- Progressive/relapsing MS • (PRMS) overlaps PPMS and SPMS • accounts for ∼ 5% of MS patients • Like patients with PPMS, these patients experience a steady deterioration in their condition from disease onset. • However, like SPMS patients, they experience occasional attacks superimposed upon their progressive course.
  13. 13. CLINICAL MANIFESTATIONS • The onset of MS may be abrupt or insidious. • Symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. • Symptoms of MS are extremely varied and depend on the location and severity of lesions within the CNS  Sensory symptoms  Motor symptoms  Visual symptoms  Sphincter disturbance  Cognitive impairment  Ataxia and vertigo  Double vision
  14. 14. 1- Motor symptoms • Weakness of the limbs may manifest as  loss of strength, , speed, or dexterity, as fatigue  a disturbance of gait  heaviness • Exercise-induced weakness is a characteristic symptom of MS. • The weakness is of the upper motor neuron type. • Usually accompanied by other pyramidal signs such as spasticity, hyperreflexia, and Babinski signs. • A tendon reflex may be lost (simulating a lower motor neuron lesion) if an MS lesion disrupts the afferent reflex fibers in the spinal cord.
  15. 15. 2- Spasticity • Is commonly associated with spontaneous and movement- induced muscle spasms. • More than 30% of MS patients have moderate to severe spasticity, especially in the legs. • This is often accompanied by painful spasms interfering with ambulation, work, or self-care. • Occasionally, spasticity provides support for the body weight during ambulation, and in these cases, treatment of spasticity may actually do more harm than good.
  16. 16. 3- Facial weakness • Due to a lesion in the pons. • May resemble idiopathic Bell’s palsy. • Unlike Bell’s palsy, facial weakness in MS is usually NOT associated with : - Ipsilateral loss of taste sensation - Retroauricular pain.
  17. 17. 4- Sensory symptoms • Include both 1. Paresthesias (e.g., tingling, prickling sensations, formications, “pins and needles,” or painful burning) 2. Hypesthesia (e.g., reduced sensation, numbness, or a “dead” feeling). • Unpleasant sensations (e.g., feelings that body parts are swollen, wet, raw, or tightly wrapped) are also common. • Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) indicates that the spinal cord is the origin of the sensory disturbance. • It is often accompanied by a band-like sensation of tightness around the torso. • Pain is a common symptom of MS:- • experienced by >50% of patients. • Pain can occur anywhere on the body and can change locations over time.
  18. 18. 5- Optic neuritis (ON) Presents as • Periorbital pain (aggravated by eye movement) often precedes or accompanies the visual loss. • Diminished visual acuity, • Dimness, • Decreased color perception (desaturation) in the central field of vision. • These symptoms can be mild or may progress to severe visual loss. • Rarely, there is complete loss of light perception. • Central visual loss (central scotoma) • Visual symptoms are generally monocular but may be bilateral. • An afferent pupillary defect is usually present. • Funduscopic examination:- • may be normal • optic disc swelling (papillitis). • Pallor of the optic disc (optic atrophy) commonly follows ON. • Uveitis is uncommon and should raise the possibility of alternative
  19. 19. 6- Visual blurring • May result from 1. Optic neuritis (ON) 2. Diplopia – if the symptom resolves when either eye is covered, the cause is diplopia. • Diplopia may result from  Internuclear ophthalmoplegia (INO)  OR from palsy of the 6th cranial nerve (rarely the 3rd or 4th). • An INO is an impairment in horizontal eye movement characterized by:- o impaired adduction of affected eye o abduction nystagmus of the contralateral eye o due to a lesion in the ipsilateral medial longitudinal fasciculus. • A bilateral INO is particularly suggestive of MS. • Other common gaze disturbances in MS include 1. a horizontal gaze palsy, 2. a “one and a half” syndrome (horizontal gaze palsy plus an INO), 3. acquired pendular nystagmus.
  20. 20. Oculomotor circuitry • During horizontal eye movement • The paramedian pontine reticular formation (PPRF) sends a signal to the abducens nucleus, which contains 2 sets of neurons 1. neuronal axons that innervate the ipsilateral rectus muscle and cause abduction 2. abducens interneurons decussate to form the medial longitudinal fasciculus (MLF) and innervate the medial rectus subnucleus • axons from the medial rectus subnucleus innervate the ipsilateral medial rectus muscle adduction
  21. 21. 7- Ataxia • usually manifests as cerebellar tremors. • Ataxia may also involve - the head - Trunk - the voice – producing a characteristic cerebellar dysarthria (scanning speech).
  22. 22. 8- Vertigo and Hearing loss • may appear suddenly from a brainstem lesion, superficially resembling acute labyrinthitis. • Hearing loss may also occur in MS but is uncommon.
  23. 23. Lhermitte’s symptom:- • is an electric shock–like sensation • that radiates down the back into the legs. • Rarely, it radiates into the arms. • Typically induced by flexion or other movements of the neck • It is generally self-limited but may persist for years. • Lhermitte’s symptom can also occur with other disorders of the cervical spinal cord (e.g., cervical spondylosis).
  24. 24. Heat sensitivity:- • Refers to neurologic symptoms produced by an elevation of the body’s core temperature. • For example, unilateral visual blurring may occur during a hot shower or with physical exercise (Uhthoff’s symptom). • It is also common for MS symptoms to worsen transiently, sometimes dramatically, during febrile illnesses. • Such heat-related symptoms probably result from transient conduction block.
  25. 25. Trigeminal neuralgia Hemifacial spasm Glossopharyngeal neuralgia • can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, seventh, and ninth cranial nerve, respectively. • Trigeminal neuralgia (tic douloureux) is a very brief lancinating facial pain often triggered by an afferent input from the face or teeth. • Most cases of trigeminal neuralgia are not MS related; • Atypical features that should raise the possibility that MS:- 1. onset before age 50 years, 2. bilateral symptoms, 3. objective sensory loss 4. Nonparoxysmal pain
  26. 26. Facial myokymia • Consists of either persistent rapid flickering contractions of the facial musculature (especially the lower portion of the orbicularis oculus) • or a contraction that slowly spreads across the face. • It results from lesions of 1. the corticobulbar tracts 2. or brainstem course of the facial nerve.
  27. 27. • Bladder dysfunction  is present in >90% of MS patients,  in a third of patients, dysfunction results in weekly or more frequent episodes of incontinence • Cognitive dysfunction • can include memory loss, impaired attention, difficulties in executive functioning, memory, problem solving, slowed information processing, and problems shifting between cognitive tasks • Depression , experienced by approximately half of patients • Fatigue is experienced by 90% of patients; this symptom is the most common reason for work-related disability in MS. • Sexual dysfunction may manifest as decreased libido, impaired genital sensation, impotence in men, and diminished vaginal lubrication or adductor spasms in women. • Constipation occurs in >30% of patients. • Fecal urgency or bowel incontinence is less common (<15%) but can be socially debilitating.
  28. 28. Diagnosis • There is no definitive diagnostic test for MS. • Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS. • Symptoms must 1. last for >24 h 2. occur as distinct episodes 3. that are separated by a month or more. • In patients who have only one of the two required signs on neurologic examination, the second may be documented by abnormal tests such as MRI or evoked potentials (EPs).
  29. 29. 1- 2- 3-
  30. 30. 1- DIAGNOSTIC TESTS- MRI • Characteristic abnormalities are found in >95% of patients, although more than 90% of the lesions visualized by MRI are asymptomatic.  T1 C+ (gadolinium): active lesions show enhancement. • MS  a breakdown of the BBB  increase in vascular permeability  leakage of IV (Gd) into the parenchyma. • Such leakage occurs early in the development of an MS • a useful marker of inflammation. • Gd enhancement typically persists for <1 month, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on T2-weighted images. • Older lesions show no enhancement  T1 : lesions are typically iso- to hypointense (T1 black holes). • Black holes may be a marker of irreversible demyelination and axonal loss.  T2 : lesions are typically hyperintense
  31. 31. Brain magnetic resonance imaging in multiple sclerosis. Multiple high-signal lesions (arrows) seen particularly in the paraventricular region on T2 image.
  32. 32. In T1 image with gadolinium enhancement, recent • lesions (A arrows) show enhancement, suggesting active inflammation (enhancement persists for 4 weeks); • older lesions (B arrows) show no enhancement but low signal, suggesting gliosis.
  33. 33. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS.
  34. 34. Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image in which the high signal of cerebrospinal fluid (CSF) has been suppressed. CSF appears dark, whereas areas of brain edema or demyelination appear high in signal, as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease.
  35. 35. Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the midthoracic spinal cord.
  36. 36. Sagittal T1-weighted image obtained after the intravenous administration of gadolinium DTPA reveals focal areas of blood-brain barrier disruption, identified as high-signal- intensity regions (arrows).
  37. 37. 2- DIAGNOSTIC TESTS- Evoked potentials • Visual evoked potentials (VEP) about 85% of people with definite MS have an abnormal VEP. • Somatosensory evoked potential (SSEP) about 77% of people with definite MS have an abnormal SSEP. • Brain stem Auditory evoked potential (BAEP) about 60% of people with definite MS have an abnormal BAEP.
  38. 38. 3- DIAGNOSTIC TESTS- CSF - Suggestive of MS: 1. Normal opening pressure. 2. Normal sugar. 3. Total CSF protein is usually normal or slightly elevated (less than 100 mg/dL). 4. Mononuclear pleocytosis. 5. Oligoclonal band. 6. Increase level of intrathecally synthesized IgG. - The followings raise the concern that MS is not the diagnosis: - A pleocytosis of >75 cells/μL, - the presence of polymorphonuclear leukocytes, - a protein concentration >1 g/L (>100 mg/dL) in CSF
  39. 39. Cerebrospinal fluid
  40. 40. • The specific tests required to exclude alternative diagnoses will vary with each clinical situation; • The followings should probably be obtained in all patients with suspected MS:- 1. ESR, 2. serum B12 level, 3. anti-nuclear antibodies, 4. treponemal antibody
  41. 41. DISORDERS THAT CAN MIMIC MS • Acute disseminated encephalomyelitis (ADEM) • Neuro myelitis optica • Antiphospholipid antibody syndrome • Behçet’s disease • Neoplasms (e.g., lymphoma, glioma, meningioma) • Sarcoidosis • Stroke and ischemic cerebrovascular disease
  42. 42. Treatment of Multiple Sclerosis • Therapy for MS can be divided into several categories: 1. treatment of acute attacks 2. Treatment with disease-modifying agents that reduce the biological activity of MS, 3. Symptomatic therapy
  43. 43. ACUTE ATTACKS OR INITIAL DEMYELINATING EPISODES • When patients experience acute deterioration, it is important to consider whether this change reflects new disease activity or a “pseudoexacerbation” resulting from an increase in ambient temperature, fever, or an infection. • When the clinical change is thought to reflect a pseudoexacerbation, glucocorticoid treatment is inappropriate.
  44. 44. ACUTE ATTACKS OR INITIAL DEMYELINATING EPISODES • Glucocorticoids are used to manage:- 1. first attacks 2. acute exacerbations. • When patients experience an acute deterioration, glucocorticoid treatment is administered as IV methylprednisolone 500 to 1000 mg/d for 3 to 5 days followed by a course of oral prednisone beginning at a dose of 60 to 80mg/d and gradually tapered over 2 weeks. • IV immunoglobulin and plasma exchange when 1. relapses are sever (Acute MS) 2. when corticosteroids are contraindicated.
  45. 45. DISEASE-MODIFYING THERAPIES FOR RELAPSING FORMS OF MS (RRMS, SPMS WITH EXACERBATIONS) • In relapsing-remitting and relapsing secondary progressive MS these disease modifying drugs reduce the relapse rate by about 30%.
  46. 46. IFN-B • IFN-B is a class 1 interferon. • Efficacy in MS, however probably results from immunomodulatory properties (reduce inflammatory activity). • There is one 1b (Betaferon/Betaseron) and two 1a (Avonex and Rebif) formulation of interferon-beta. • Common side effects of INF-B therapy : • Flu-like-symtom , • lymphopenia , • elevated liver function tests. • Hypothyrodism , • depression , • increased spasticity . • Cognitive change have been reported.
  47. 47. Glatiramer acetate • Is asynthetic , random polypeptide composed of four amino acid . • 20 mg is administered by subcutaneous injection every day. • Side effects include: flushing, chest tightness, dyspnoea, palpitation. • Safe in pregnancy • Prevent 50% of MS
  48. 48. Dimethyl fumarate • Twice daily oral medication. • Reduce relapse. • Se: flushing and diarrhea.
  49. 49. Teriflunomide • this once daily medication can reduce relapse rate. • SEs: hair loss and liver damage.
  50. 50. NATALIZUMAB • Its administered as IV infusion every 4 weeks. • Side effects include: hypersensitivity and progressive multifocal • leukoencephalopathy.
  51. 51. MITOXANTRONE HYDROCHLORIDE • Its antineoplastic drug, Its administered by IV infusion every every 3 months • Side effects include: bone marrow suppression and cardiomyopathy.
  52. 52. • Other immunomodulatory agents: like azathioprine, methotrexate, cyclophosphamide, intravenous immunogiobuline are occasionally used in aggressive secondary progressive MS.
  53. 53. Symptomatic Therapy • Weaknees  • Potassium channel blockers e.g. 4- aminopyridine 10 to 40 mg/d may be helpful. • Ataxia and tremor  Clonazepam. • Spasticity spasm  improve by Baclofen, tizanidine, and dantroline. • Pain  treated by anticonvulsant (carbamazepine, gabapentin) • Bladder dysfunction • urinary incontinence by oxybutynin • urinary retention by bethanecol. • Depression  SSRI (e.g. fluoxitine) • Fatigue  improve with modafenil or pemoline Or amantadine • Sexual dysfunction  helped by Sildenafil.
  54. 54. CLINICAL VARIANTS OF MS • Neuromyelitis optica (NMO), or Devic’s syndrome, is an aggressive inflammatory disorder consisting most typically of attacks of acute ON and myelitis • Attacks of ON can be bilateral (rare in MS) or unilateral • myelitis can be severe and transverse (rare in MS) and is typically longitudinally extensive, involving three or more contiguous vertebral segments • The brain MRI was classically thought to be normal at the onset of NMO • Up to 40% of patients have a systemic autoimmune disorder, often systemic lupus erythematosus, Sjögren’s syndrome, myasthenia gravis, Hashimoto’s thyroiditis • highly specific autoantibody directed against the water channel protein aquaporin-4 is present in the sera of 60–70% of patients who have a clinical diagnosis of NMO
  55. 55. THE END

Notas do Editor

  • Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin.