Mais conteúdo relacionado



  1. Dr. Anzil Mani Singh Maharjan Resident Phase- B Department of Neurology BSMMU
  2. Myelin  Myelin forms a layer, the myelin sheath around the axon of a neuron  It is an outgrowth of a type of glia cell
  3. Myelin composition  Cholesterol is an essential constituent of myelin  Myelinated axons appear white, hence the the term "white matter" of the brain  Some of the proteins are myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein  The intertwining hydrocarbon chains of sphingomyelin serve to strengthen the myelin sheath
  4. Myelination  The production of the myelin sheath is called myelination  In humans, myelination begins in the 14th week of fetal development  During infancy, myelination occurs quickly and continues through the adolescent stages of life  Schwann cells supply the myelin for peripheral neurons  Oligodendrocytes myelinate the axons of the CNS neurons
  5. Myelin Function  Propagate nerve impulses rapidly in a saltatory fashion  Voltage-gated Na+ channels found at the nodes of Ranvier  Na+ influx  Current cannot flow outward in myelinated internodal segments • Provides insulation
  6. Myelin Diseases  Demyelination is the process of damage to the myelin or oligodendroglial cell ◦ Autoimmune- MS ◦ Infectious- PML ◦ Toxic and metabolic ◦ Vascular processes – Binswanger  Dysmyelination - a primary biochemical abnormality of myelin formation exists ◦ Hereditary disorders- Leukodystrophies
  7. Classification of the Inflammatory Demyelinative Diseases I. Multiple sclerosis Chronic relapsing encephalomyelopathic form Acute multiple sclerosis (Marburg disease) Primary and secondary progressive types Diffuse cerebral sclerosis (Schilder disease and concentric sclerosis of Balo
  8. Classification of the Inflammatory Demyelinative Diseases IV. Acute and subacute necrotizing hemorrhagic encephalitis A. Acute encephalopathic form B. Subacute encephalitis III. Neuromyelitis optica (Devic disease) II.Acute disseminated encephalomyelitis A.Postinfectious: Following measles, chickenpox, smallpox, mumps, rubella, influenza,Mycoplasma B.Postvaccinal : Following rabies or smallpox
  9. Introduction  British as “disseminated sclerosis”  French as “sclérose en plaques”  MS is a chronic condition characterized clinically by episodes of focal disorders of the: ◦ Optic nerves ◦ Spinal cord ◦ Brain  remit to a varying extent and recur over a period of many years
  10. Pathology
  11. Pathology  Hallmark of MS is the cerebral or spinal plaque, which consists of a discrete region of demyelination  Relative preservation of axons  Atrophy and ventricular dilatation  Disruption of BBB but vessel wall is preserved
  12. Pathology (Gross)  Active plaques appear whitish yellow or pink with somewhat indistinct borders  Older plaques appear translucent with a blue-gray discoloration and sharply demarcated margins  Plaques are small (1-2 cm) but may become confluent, generating large plaques  Develop in a perivenular distribution  Most frequently in the periventricular white matter, brainstem, and spinal cord
  13. Pathology (Gross) Brain - Coronal Section Spinal Cord
  14. Histopathology  Active plaques reveals perivascular infiltration of lymphocytes (predominantly T cells) and macrophages, with occasional plasma cells  In the plaque, myelin is disrupted, resulting in myelin debris found in clumps or within lipid- laden macrophages  Reactive astrocytes are prominent in plaques Venule Demyelination area
  16. Epidemiology  Age of Onset ◦ Mean and median age of onset in relapsing forms of MS is age 29 to 32 ◦ Primary progressive MS (PPMS) has a mean age of onset of 35 to 39 ◦ Can occur as late as the seventh decade ◦ 5% of cases of MS have their onset before age 18  Sex Distribution ◦ F>M ◦ 2 : 1
  17. Epidemiology Geographical Distribution  MS is a location-related illness with a latitude gradient  High-frequency areas with prevalence of 60 -100 per 100,000 or more, include ◦ All of Europe (including Russia) ◦ Southern Canada ◦ Northern United States ◦ New Zealand ◦ SE portion of Australia  The highest reported rate of 300 per 100,000 occurring in the Orkney Islands
  18. Epidemiology Race  Determinant of MS risk  White extraction, especially from Northern Europe are the most susceptible  People of Asian, African, or Amerindian origin have the lowest risk  Other groups are variably intermediate  Migration after puberty no increased risk  Migration before childhood increased risk
  19. Pathogenesis
  20. Pathogenesis  The cause of MS remains undetermined  Possible Etiologies include ◦ Infection ◦ Enviromental factors ◦ Autoimmunity ◦ Genetic Susceptibility
  21. Pathogenesis Infection  Little direct evidence supports the concept of a role for viral infection  Human T-cell lymphotropic virus type 1 [HTLV1]  Human herpesvirus 6 (HHV6)  Epstein-Barr virus (EBV)  Chlamydia pneumoniae Environmental Factors  Sunlight exposure during growth  Vitamin D  Epidemiological data supportive
  22. Pathogenesis Autoimmunity  Break down of tolerance (unresponsiveness of the immune system)  By means of molecular mimicry between self- antigens and foreign antigens  Myelin basic protein (MBP), the target for autoimmune attack  T cells that respond to MBP are found in the peripheral blood possibly at higher levels in MS patients with active disease
  23. Pathogenesis Genetic susceptibility  The risk of familial recurrence in MS is 15%  Highest risk in first-degree relatives (age-adjusted risk): 4–5% for siblings and 2–3% for parents or offspring  Monozygotic twins have a concordance rate of 30%  The genes that predispose to MS are incompletely defined  Inheritance appears to be polygenic, with influences from ◦ Genes for human leucocyte antigen (HLA) typing ◦ Interleukin receptors ◦ CLEC16A (C-type lectin domain family 16 member A) ◦ CD226 genes
  25. Clinical Manifestations  Multiple sclerosis is classically described as a relapsing remitting disorder  MS may display marked clinical heterogeneity. This variability includes ◦ age of onset ◦ mode of initial manifestation ◦ frequency ◦ severity ◦ sequelae of relapses ◦ extent of progression ◦ Cumulative deficit over time  High degree of variability and the difficulty in predicting the course and severity make MS one of the most puzzling CNS disease
  26. Clinical Manifestations Early symtoms and signs Symptoms and Signs in the Established Stage of the Disease Disability
  27. Clinical Manifestations Early Symptoms  Onset over hours or days  Motor or sensory system involvement in 50 % of patients  Symptoms of tingling of the extremities and tight band- like sensations around the trunk  Dragging or poor control of one or both legs to a spastic or ataxic paraparesis Early Signs  The tendon reflexes are retained and later become hyperactive  Extensor plantar reflexes  Disappearance of the abdominal reflexes  Varying degrees of deep and superficial sensory loss may be associated
  28. Clinical Manifestations  The patient will complain of weakness, incoordination, or numbness and tingling in one lower limb  But the examination will reveal ◦ Bilateral Babinski signs ◦ Bilateral corticospinal tract signs ◦ Posterior column disease
  29. Clinical Manifestations Several syndromes typical of MS and may be the initial manifestation : (1) Optic neuritis (2) Transverse myelitis (3) Cerebellar ataxia - nystagmus and ataxia (4) Various brainstem syndromes (vertigo, facial pain or numbness, dysarthria, diplopia) ◦ These syndromes may pose a diagnostic dilemma as these do occur in other diseases too
  30. Clinical Manifestations  Paresthesia or numbness of an entire arm or leg  Facial pain often simulating tic douloureux  Disorders of micturition  Cervical myelopathy- slowly progressive with weakness and ataxia
  31. Clinical Manifestations Diplopia ◦ Medial longitudinal fasciculi ◦ Internuclear ophthalmoplegia ◦ Paresis of the medial rectus on attempted lateral gaze, with a coarse nystagmus in the abducting eye ◦ Usually bilateral The presence of bilateral internuclear ophthalmoplegia in a young adult is virtually diagnostic of MS
  32. Clinical Manifestations  Myokymia or paralysis of facial muscles  Deafness, tinnitus, unformed auditory hallucinations (because of involvement of cochlear connections)  Vomiting (vestibular connections), and, rarely, stupor and coma  Vertigo of central type  Dull, aching low back pain  Sharp, burning, poorly localized, or lancinating radicular pain, localized to a limb or discrete part of the trunk
  33. Clinical Manifestations Lhermitte sign  Flexion of the neck may induce a tingling, electric shock like feeling down the shoulders and back  Frequent occurrence of this phenomenon in MS  Due to an increased sensitivity of demyelinated axons to the stretch or pressure on the spinal cord induced by neck flexion
  34. Clinical Manifestations Uhthoff phenomenon  Transient worsening of function with increased body temperature  Due to a drop below the safety threshold for conduction because of physiological changes involving the partially demyelinated axon
  35. Clinical Manifestations Established Stage of the Disease  50 % will manifest a clinical picture of mixed or generalized type with signs pointing to involvement of the optic nerves, brainstem, cerebellum, and spinal cord  30 to 40 % will exhibit only varying degrees of spastic ataxia and deep sensory changes in the extremities, i.e., essentially a spinal form of the disease  5 % have a predominantly cerebellar or brainstem– cerebellar form occurs
  36. Clinical Manifestations Cognitive impairment  Progressive decline, is present in perhaps one- half of patients with long-standing MS  Reduced attention  Diminished processing speed and executive skills  Memory decline  Language skills and other intellectual functions are preserved
  37. Clinical Manifestations  The most characteristic clinical course of MS is the occurrence of relapses  Relapses can be defined as ◦ acute or subacute onset of clinical dysfunction ◦ that usually reaches its peak from days to several weeks, ◦ followed by a remission during which the symptoms and signs usually resolve partially or completely  The minimum duration for a relapse has been arbitrarily established at 24 hours
  38. Clinical Manifestations (Course) 1. Relapsing-remitting (RRMS): Clearly defined relapses with full recovery or with sequelae and residual deficit on recovery The periods between disease relapses are characterized by a lack of disease progression 2. Secondary progressive (SPMS): Initial relapsing remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus 3. Primary progressive (PPMS): Disease progression from onset, with occasional plateaus and temporary minor improvements allowed 4. Progressive relapsing (PRMS): Progressive disease from onset, with clear acute relapses with or without full recovery The periods between relapses are characterized by continuing progression
  39. Clinical Manifestations
  40. Disease progression
  42. CSF ANALYSIS Cytology  In 1/3 of with an acute onset or an exacerbation, there may be a slight to moderate mononuclear pleocytosis (6 to 20 or less than 50 cells/mm3)  In rapidly severe demyelinating disease of the brainstem, the total cell count may reach or exceed 100, and rarely 1,000, cells/mm3  In the hyperacute cases, the greater proportion of these may be polymorphonuclear leukocytes
  43. CSF ANALYSIS Protein  40 % of patients, the total protein content of the CSF is increased slightly  Not more than 100 mg/dL  In two-thirds of patients, the proportion of gamma globulin (mainly IgG) is increased (greater than 12 percent of the total protein)  IgG index obtained by measuring albumin and gamma globulin in both the serum and CSF
  44. CSF ANALYSIS Oligoclonal bands  Gamma globulin proteins in the CSF of patients with MS are synthesized in the CNS  They migrate in agarose electrophoresis as abnormal discrete populations, so- called oligoclonal bands  The most widely used CSF test for the confirmation of the diagnosis  Show several bands in the CSF in more than 90 percent of cases of MS  But they are not always found with the first attack or even in the later stages of the disease
  45. Magnetic Resonance Imaging  MRI is the most helpful ancillary examination in the diagnosis of MS  Reveal asymptomatic plaques in the cerebrum, brainstem, optic nerves, and spinal cord  T2-weighted images show : ◦ Hyperintense well-demarcated lesions ◦ Multiple and asymmetrical ◦ Periventricular surface in location
  46. Magnetic Resonance Imaging Axial images showing multiple hyperintense lesions in the white matter
  47. Magnetic Resonance Imaging  The presence lesions in the corpus callosum is diagnostically useful  This structure is spared in many other disorders Midsagittal FLAIR image
  48. Magnetic Resonance Imaging  In sagittal images extension of the lesion outward from the corpus callosum in a fimbriated pattern and have been termed “Dawson fingers”  These areas may extend into the centrum semiovale and may reach the convolutional white matter Sagittal FLAIR image
  49. Magnetic Resonance Imaging Sagittal fat-suppressed image Sagittal T1-weighted postcontrast image
  50. Newer Imaging Tecniques  MAGNETIC RESONANCE SPECTROSCOPY ◦ a tool that derives MRI signal from multiple metabolites ◦ A high choline (Cho) peak is indicative of an increase in membrane turnover, as can be seen in demyelination and remyelination  DIFFUSION TENSOR IMAGING  HIGH-FIELD-STRENGTH MRI
  51. Evoked Potentials  EPs are CNS electrical events generated by peripheral stimulation of a sensory organ  Are useful ◦ To determine abnormal function that may be clinically unapparent ◦ When the clinical data point to only one lesion in the CNS mainly in the early stages of the disease or in the spinal form Commonly used EPs are 1. Visual Evoked response (VEPs) 2. Somatosensory evoked potentials (SSEPs) 3. Brainstem auditory-evoked responses (BAER)
  52. Comparison of Sensitivity of Laboratory Testing Investigations Sensitivity VER 80%-85% BAER 50%-65% SSEP 65%-80% OCB 85%-95% MRI 90%-97%
  53. Revised McDonald et al. (2005) Diagnostic Criteria for MS
  54. McDonald (2011) Diagnostic Criteria for MS
  55. Differential diagnosis  The differential diagnosis of MS in the setting of a young adult with two or more clinically distinct episodes of CNS dysfunction with at least partial resolution is limited  Problems arise with ◦ Atypical presentations ◦ Monophasic episodes ◦ Progressive illness ◦ The unusual nature of some sensory symptoms may result in a misdiagnosis of conversion disorder
  56. Differential diagnosis Inflammatory Diseases  Granulomatous angiitis, SLE, Sjogren disease, Behcet disease,PAN  Paraneoplastic encephalomyelopathies  ADEM, postinfectious encephalomyelitis Infectious Diseases  Lyme neuroborreliosis,  HTLV, HIV  PML  Neurosyphilis Granulomatous Diseases • Sarcoidosis • Wegener granulomatosis • Lymphomatoid granulomatosis Diseases of Myelin • MLD (juvenile and adult) •Adrenomyeloleukodystrophy Miscellaneous • Spinocerebellar disorders • Arnold-Chiari malformation
  58. Treatment Treatment of the MS patient should be directed toward these basic goals:  Relief or modification of symptoms  Shortening the duration or limiting the residual effects of an acute relapse  Reducing the frequency of relapses  Preventing disability progression or slowing its pace  Supporting family and patient, alleviating social and economic effects, and advocating for the disabled or handicapped
  59. Symptomatic Treatment Spasticity  Baclofen a GABA agonist Daily divided doses of 20 to 120 mg and occasionally .Intrathecal baclofen via an implanted pump  Tizanidine a centrally active α2-noradrenergic agonist, gradually increased starting with 2 mg at bedtime  Benzodiazepines  Dantrolene sodium rarely  4-Aminopyridine and 3,4-diaminopyridine (3,4-DAP) block potassium channels in the axolemma  Botulinum toxin type A (Botox) injections into spastic or contracted muscles may also be effective in selective cases
  60. Symptomatic Treatment Tremor  Weighted wrist bracelets and specially adapted utensils are nonpharmaceutical options  Most attempts at pharmacological amelioration of tremor fail  Isoniazid  Primidone  Carbamazepine  Gabapentin  Topiramate  Clonazepam  Propranolol  Ondansetron
  61. Symptomatic Treatment Fatigue  Amantadine 100 mg twice a day  Modafinil - a wakefulness promoting agent  Methylphenidate 10 to 60 mg/day in 2 to 3 divided dose  SSRIs  Fluoxetine 10 to 20 mg once twice daily  Bupropion
  62. Symptomatic Treatment Bladder Dysfunction  Initial steps in managing bladder dysfunction include ◦ fluid management, ◦ timed voiding ◦ use of a bedside commode  Hyperreflexic bladder without outlet obstruction ◦ Oxybutynin,Tolterodine,Trospium,Darifenacin,solifenacin, Desmopressin  Imipramine for enuresis  Detrusor hyperreflexia with outlet obstruction may respond Credé maneuvers terazosin hydrochloride  Intermittent catheterization  Chronic indwelling catheterization may be required  Surgical correction-augmentation of bladder capacity with an exteriorized loop of bowel
  63. Symptomatic Treatment Depression  SSRIs are the medications of choice  Fluoxetine  Amitriptyline, 25 to 100 mg daily Sexual Dysfunction  Sildenafil 25 to 100 mg 1 hour before sexual intercourse for erectile dysfunction
  64. Symptomatic Treatment Cognitive Impairment  Interferon beta-1a SC  L-amphetamine  Modafinil  Donepezil  Cognitive-behavioral therapy  Family and individual counseling  Strategies to improve day-to-day function  Job modifications and accommodations
  65. Treatment of Acute Attacks  Acute attacks are typically treated with corticosteroids  Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurological impairment  Short courses of IV methylprednisolone – 500 to 1000 mg daily for 3 to 5 days ◦ With or without a short prednisone  S/Es include psychiatric changes, predilection for infections,GI disturbances,anaphylactoid reactions, Increased incidence of fracture
  66. Disease-Modifying Treatments  INTERFERONS ◦ A recombinant interferon beta-1b SC ◦ interferon beta-1a IM injections  SYNTHETIC POLYMER ◦ Glatiramer acetate (GA) - a synthetic polypeptide SC  MONOCLONAL ANTIBODY ◦ Natalizumab ◦ Fingolimod (FTY720)
  67. Disease-Modifying Treatments Emerging Therapies  Laquinimod Orally active synthetic immunoregulator  Oral fumarate/BG-12 Induces apotosis of activated T cells  Teriflunomide Is a metabolite of leflunomide  Alemtuzumab Humanized monoclonal anti-body against CD52 antigen expressed in all lymphocytes  Rituximab A chimeri murine-human monoclonal antibody directed against CD30 antigen on B lymphocytes
  68. Treatment-Rehabilitation  Referral to physical,occupational and speech therapists 1.Physical therapy  Evaluate and train the patient in appropriate exercise programs to : ◦ decrease spasticity ◦ maintain range of motion ◦ strengthen muscles ◦ improve coordination  Mechanical aids, such as ankle-foot orthoses, also can be useful in spasticity management.
  69. Treatment-Rehabilitation 3.Occupational therapy • Assessment of the patient's functional abilities in completing activities of daily living •Evaluate for adaptive equipment and assistive technology needs 2. Speech therapy
  70. Treatment Strategies
  71. Prognosis Prognostic indicators:  MS appears to follow a more benign course in women than in men  Onset at an early age is a favorable factor, whereas onset at a later age carries a less favorable prognosis RRMS is more common in younger patients, and PPMS and SPMS are more common in the older age group  Relapsing form of the disease is associated with a better prognosis than progressive disease  Among initial symptoms, impairment of sensory pathways or ON has a favorable prognostic feature  Pyramidal and particularly brainstem and cerebellar symptoms carry a poor prognosis  Devic disease, Baló concentric sclerosis, and particularly Marburg disease are more fulminant variants of MS, with early disability and even death