Updated BMS150 Demyelinating Conditions PDF

Neurology Compressive and Demyelinating Illness in the Central Nervous System BMS 150 : Week 5 Instructor: Dr Albert Iarz, ND, RMT Objectives Describe the pathophysiologic mechanisms of demyelination and the consequences of demyelination on neuronal function Develop a model of the pathophysiology of...

Neurology Compressive and Demyelinating Illness in the Central Nervous System BMS 150 : Week 5 Instructor: Dr Albert Iarz, ND, RMT Objectives Describe the pathophysiologic mechanisms of demyelination and the consequences of demyelination on neuronal function Develop a model of the pathophysiology of MS, incorporating pathological findings, immunological mechanisms, and known etiological factors Describe the general epidemiology, common clinical features, and key diagnostic aspects of MS Describe the time course of MS by: Distinguishing between the three major patterns of MS progression Identifying the major signs and symptoms that are typical of early MS Comparing the clinical features of flares and periods in between flares Distinguishing between the pathologic appearance of an active and an active plaque Objectives Define the following terms: Neuropathy, neuralgia, neuritis, radiculopathy, polyneuropathy, multiple mononeuropathy Describe the basic epidemiology, pathogenesis, major clinical features, and prognosis of the hereditary sensory and motor neuropathies Describe the basic epidemiology, pathogenesis, major clinical features, and prognosis of Guillain-Barre syndrome Describe the pathophysiologic mechanisms by which nerve compression leads to neurological damage Describe the basic epidemiology, pathogenesis, major clinical features, and prognosis of Bell’s palsy Demyelinating Disease - Overview Demyelination can occur in the peripheral or central nervous system ▪ Central – damage to oligodendrocytes or their processes that myelinate axons Most common mechanism of injury – damage to the processes, usually an autoimmune mechanism (multiple sclerosis) ▪ Peripheral – damage to Schwann cells; common mechanisms include: Genetic deficits that impair the ability of Schwann cells to compact or produce myelin sheaths Autoimmune – self-reactive antibodies, antibody complexes, or cytotoxic T-cells damage Schwann cells Multiple Sclerosis - Overview Immune-mediated disease directed against the CNS ! loss of myelin and eventual loss of axons ▪ Chronic inflammatory findings (typical of autimmunity) ▪ White matter lesions throughout the brain and spinal cord ▪ Pathological specimens are firm and indurated in areas of white matter loss (sclerosis) Highly variable ▪ can affect almost anywhere in the CNS (brain and spinal cord) ▪ Motor, sensory, cognitive, and mood signs/symptoms Multiple Sclerosis - Epidemiology Most common demyelinating illness ▪ Prevalence is ~1/1000 in North America and Europe 3x more frequent in women Tends to begin during young adulthood/middle age ▪ Peak incidence between 20 and 40 ▪ How common is it in Canada? About 100,000 people affected now ▪ By 2031 there will be over 130,000 affected ▪ Cost on the Canadian healthcare system ! over $16,000/person/year MS - Etiology Genetic Polygenetic etiology ▪ Candidate genes: HLA-II gene (DRB1/DRB15) ▪ Responsible for antigen presentation – responsible for 10% of disease risk, gene most associated with the disease ▪ Pathophysiology uncertain IL-2, IL-7, IL-17 Genetic variations have not been linked to phenotypic variations (110 genetic variations identified so far) ▪ 15X increased risk if a first degree relative, 150X increased risk if a monozygotic twin has it MS - Etiology Other factors: Link to viral infections (EBV?) ▪ B cells may find their way into the CNS during a viral infection ▪ There are often many activated B-lymphocytes found within the CNS that are not specific for myelin – may disrupt immune regulation in the CNS once they’re established Sun exposure and vitamin D ▪ Some epidemiological evidence that reduced levels of vitamin D may contribute History of another autoimmune disease MS - Pathogenesis MS progresses straight to a chronic inflammatory picture with no preceding acute inflammation ▪ Typical of most autoimmune diseases Two phases: 1st phase (active plaques): presence of typical leukocytes found during chronic inflammation ▪ Destroy myelin and oligodendrocytes that form it, though new oligodendrocytes can still be generated ▪ Major leukocytes: CD4+ Th (likely mostly Th1 and Th17) and B-cells Macrophages (recruited and derived from microglia) and cytotoxic T-cells 2nd phase (inactive plaques): loss of axons (and eventually neurons) with limited to no leukocytic infiltration and prominent gliosis MS - Gross Pathology Multiple well-circumscribed, irregularly shaped plaques that are firmer than the surrounding tissues Commonly occur adjacent to the lateral ventricles, optic tracts, brainstem, cerebellum, spinal cord More prominent in areas rich in white matter Over time, a degree of cerebral atrophy may be noted MS Pathogenesis: Active Plaques Leukocytes are recruited from the circulation, across the BBB (there should be few to no leukocytes in the normal CNS) Helper T-cells initiate an immune response against myelin (likely a component of myelin basic protein) ▪ MBP helps to compact the many layers of the myelin sheath These helper T cells recruit other leukocytes into white matter (cytotoxic T-cells, macrophages) and activate them ▪ Cytotoxic T-cells seem to attack oligodendrocytes MBP-specific B-lymphocytes are also recruited into the CNS and produce anti-MBP antibodies – these also seem to help destroy the myelin sheath MS Pathology: Active Plaques MS Pathology: Active Plaques Inflammation in MS Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells These infiltrates are composed of activated T cells, B cells and macrophages MS Pathogenesis: Acute Flares Flare = period of worsened neurological symptoms ▪ build-up of helper T-cells and cytotoxic T-cells in the CNS that attack white matter components and Bcells that produce myelin-specific antibodies ▪ In between flares, fewer chronic inflammatory cells detected As flares continue, there seem to be areas where lymphocytes reside “permanently” – these are called lymphocytic follicles ▪ Prominent around the meninges and blood vessels MS Pathogenesis: Inactive Plaques Inactive plaques = plaques without prominent inflammation With loss of myelin and oligodendrocytes, axons tend to degenerate ▪ “destabilization” of action potentials (see next slide) ▪ Fewer action potentials ! reduced trophic support for neurons – leading to neuronal cell death ▪ Expression of NMDA receptors on “naked” axons and calciummediated cytotoxicity – glutamate is also toxic to oligodendrocytes In many (most?) patients, over time MS can progress with very limited inflammation ▪ White matter, axons, and neurons can all be lost in areas with minimal chronic inflammatory findings ▪ Prominent gliosis (astrocytes and microglia), no new oligodendrocyte production MS Pathogenesis: Inactive Plaques Following demyelination, additional sodium channels are redistributed along the axon, allowing action potential conduction ▪ Changes in temperature and activity can impair the conduction along the demyelinated segment, though – destabilization of APs Non-saltatory (continuous) conduction of APs requires more ATP; may have long-term neuronal metabolism consequences MS - Signs and Symptoms Most common initial symptoms: Paresthesias in one or more extremities, the trunk, or one side of the face Weakness or clumsiness of a leg or hand Visual disturbances ▪ Partial loss of vision and pain due to optic neuritis ▪ Diplopia ▪ Scotomas ▪ Nystagmus and dizziness MS - Signs and Symptoms - early MS - Signs and Symptoms Cognitive Fatigue and depression are common and disabling (~75%) Many patients report that MS impairs (slows) their cognition and has prominent effects on memory Sensory Paresthesia and loss of any type of sensation L’hermitte’s phenomenon ▪ Sensation of an “electrical shock” running down the back and along the limbs (usually unpleasant) ▪ Not sensitive or specific for MS MS - Signs and Symptoms Sensory Paresthesia and loss of any type of sensation ▪ Paresthesias include tingling, prickling, “pins and needles” feelings, and are very common Can also include a restless feeling or feeling like bugs are on or under the skin (formication) Pain, whether as a part of paresthesias or chronic pain, is present in 50% L’hermitte’s phenomenon ▪ Sensation of an “electrical shock” running down the back and along the limbs (usually unpleasant) ▪ Not sensitive or specific for MS MS - Signs and Symptoms Motor Bilateral, spastic weakness, mostly in the lower extremities ▪ Spasticity is a common spinal cord manifestation Increased deep tendon reflexes Charcot triad: dysarthria, nystagmus, tremor Facial twitching (myokymia) Slurred speech MS - Signs and Symptoms Brainstem and spinal cord findings: Dizziness Bladder dysfunction (e.g. urinary urgency or hesitancy, partial retention of urine, mild urinary incontinence) – very common Constipation Erectile dysfunction in men or genital anesthesia in women Frank urinary and fecal incontinence in advanced cases MS - Signs and Symptoms Other: Heat and activity intolerance ▪ May be linked to “action potential destabilization” ▪ Uhthoff sign – hot environment or shower ! blurry vision ▪ a transient worsening of neurologic function (initially described as blurry vision after a hot bath), with heat exposure, physical exhaustion (exercise), infection, or dehydration is very common in MS patients. ▪ Heat causes transient worsening of many symptoms of MS and can cause fatigue. Temporary, short-lived (less than 24 hours), and stereotyped worsening of neurological function among multiple sclerosis patients in response to increases in core body temperature. ▪ Symptoms and signs often worsen in hot environments and with intense activity – can even precipitate flares MS - Diagnosis Clinical diagnosis ▪ A symptom and history checklist, known as the MacDonald’s criteria Aided by characteristic lesions on a brain and spinal MRI ▪ these lesions are not specific, though they are pretty sensitive Presence of certain types of antibodies in the CSF MS - MacDonald criteria simplified Requires: documentation of two or more episodes of symptoms + two or more signs ▪ pathology in anatomically noncontiguous white matter tracts of the CNS ▪ Symptoms must last for >24 h ▪ Must occur as distinct episodes that are separated by a month or more Revision allows for imaging (MRI) to add additional data in place of a second occurrence of 2 signs + 2 symptoms MS - Treatment Treatment and Prognosis No cure ▪ Immunomodulators can be used for chronic treatment (Natalizumab, copaxone, interferon-like drugs) ▪ Steroids for acute flares Progression: ▪ Relapsing-remitting: most common 90% of patients first presenting with MS ▪ Secondary progressive About 1% of MS patients develop secondary progressive MS/year ▪ Primary progressive 10% of patients first presenting with MS MS - Prognosis In general, the prognosis is better for relapsingremitting, and worse for primary progressive ▪ Many relapsing-remitting patients progress to secondary progressive ▪ Secondary proressive is often less responsive to immunomodulatory drugs Mortality is uncommon, but significant functional disability is the norm (likely 30 – 50% even with disease-modifying therapies) MS - Prognosis A. Relapsing/remitting B. Secondary progressive C. Primary progressive MS Therapies ! FYI … are complicated and some have a pretty much unknown mechanism of action Agents that prevent immune cell migration ▪ Natalizumab (anti-integrin) ▪ Fingolimod (keeps lymphocytes sequestered in lymph nodes vs. migrating to peripheral tissues, may also shift macrophages to M2 phenotype) ▪ interferons (reduces T-cell penetration through the BBB, not sure why) Agents that deplete immune cells ▪ Ocrelizumab, rituximab, cladribine, alemtuzumab, mitoxantrone Agents that nobody really understands ▪ Copaxone (glatiramer), dimethylfumarate There’s a lot of others Peripheral Neuropathies Terminology: Neuropathy: functional disturbance and/or pathological change in the PNS Neuralgia: pain in the distribution of a particular nerve, usually in the absence of objective signs Neuritis: inflammation of a nerve Radiculopathy: pain along a dermatome, implying that the problem is at the level of the nerve root Plexopathy: neuropathy of the entire plexus Peripheral Neuropathies Neuropathies can be sensory, motor, autonomic or a combination Polyneuropathy: often presents as: ▪ Symmetrical distal weakness ▪ Symmetrical distal sensory loss (stocking & glove) ▪ Hyporeflexia Multiple mononeuropathy: involves >1 nerve, but not in a symmetrical fashion ▪ Often due to toxins, diabetes, AIDS, chronic inflammatory disease (e.g. RA, SLE) Charcot-Marie-Tooth Disease AKA Hereditary motor and sensory neuropathy ▪ HMSN Autosomal dominant inheritance ▪ Penetrance is variable – not the same severity in everyone The most common inherited neurologic disorder ▪ Prevalence: 1/2500 (quite common) Charcot-Marie-Tooth Disease Pathophysiology CMT1 – demyelination of peripheral nerves due to abnormal myelin production, damage to nerves, and thickened, palpable myelin sheaths ▪ Proteins involved in myelin compaction are defective, resulting in demyelination/remyelination cycles CMT2 – axonal death and degeneration without a primary defect in myelin (less frequent) Charcot-Marie-Tooth Disease Clinical Presentation Both sensory and motor symptoms Slowly progressive distal symmetric muscle weakness and atrophy (champagne bottle legs) ▪ Diminished DTRs, foot drop, pes cavus (High arch) with hammer toes common Proprioception and touch mainly affected ▪ Less pain and temperature, since these are unmyelinated Nerves can become enlarged and palpable with cycles of myelination and re-myelination Charcot-Marie-Tooth Disease Charcot-Marie-Tooth Disease Diagnosis, Treatment, Prognosis Nerve biopsy and nerve conduction studies, as well as characteristic physical exam, history Treatment: ▪ Massage – ROM to prevent contractures ▪ Anti-inflammatories, analgesics Most have normal life expectancy ▪ Involvement of phrenic nerve or cranial nerves is very rare ▪ For reasons not well understood, usually exclusively affects the lower leg Guillain-Barre Syndrome (GBS) Acute onset immune-mediated demyelinating neuropathy Uncommon disease, but most common cause of acute flaccid paralysis ▪ 1.5/100,000/year Pathogenesis: ▪ Typically occurs after an infection (2/3 of cases involve identifiable previous flu-like symptoms) ▪ Infections with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae, or prior vaccination are shown to be associated Guillain-Barre Syndrome Pathogenesis cont… T-lymphocytes that presumably recognize myelin cause a segmental demyelination ▪ Macrophages are also found within lesions and are thought to aid destruction of nerves ▪ Antibodies also likely mediate some damage; plasmapheresis improves symptoms Guillain-Barre Syndrome The body's immune system begins to attack the body itself The immune response causes a cross-reaction with the neural tissue. When myelin is destroyed, destruction is accompanied by inflammation. These acute inflammatory lesions are present within several days of the onset of symptoms. Guillain-Barre Syndrome Nerve conduction is slowed and may be blocked completely. Even though the Schwann cells that produce myelin in the peripheral nervous system are destroyed, the axons are left intact in all but the most severe cases. After 2-3 weeks of demyelination, the Schwann cells begin to proliferate, inflammation subsides, and re-myelination begins. Guillain-Barre Syndrome Guillain-Barre Syndrome Clinical features: Acute, rapid, progressive inflammatory polyradiculopathy ▪ Unlike other conditions discussed previously, develops rapidly and typically involves predominantly motor symptoms Ascending symptoms – weakness starts in the lower limbs, progresses to higher regions of the body ▪ Sensory loss can also occur but weakness is prominent ▪ Flaccid paralysis that can threaten life if it progresses to involve the phrenic nerve (C3, C4, C5) Sphincters tend to be spared Guillain-Barre Syndrome Diagnosis, treatment, prognosis: Diagnosis mostly made by history and physical, EMG and nerve conduction studies are helpful Treatment – severe disease, can progress to loss of function including cervical spinal cord ▪ Protect airway, ventilation ▪ Plasmapheresis – removal of antibodies from the blood ▪ IV immunoglobulins If patients survive the initial disease, prognosis is good ▪ Some have prolonged functional deficits for 2 years or more ▪ If not recognized and treated, very high mortality Compressive Neurological Damage In the peripheral nervous system, compression of a nerve often leads to: ▪ Pain – very common, feature of most compressive neuropathies ▪ Reduction or loss of function Loss of motor function ! weakness or flaccid paralysis ▪ Sometimes loss of autonomic nervous system function (i.e. urinary retention, erectile dysfunction) Loss of sensory function ! numbness (anaesthesia) or tingling, pins-and-needles sensation (dysaesthesia) Compressive Neurological Damage – General Pathophysiology Theories of compressive nerve damage: Direct mechanical damage to the nerve ! loss of axonal function (crush injury) ▪ Death of the nerve likely only in severe cases ▪ Less severe ! compressive defects in axonal transport necessary for transporting proteins from cell body to axon Ischemia ▪ Compression of the vessels in the perineurium ! decreased blood flow and reduced function in the nerve Usually nerve survives unless compression is severe Likely the most important mechanism of damage Impingement of the nerve ! inability to “glide” along its course may explain symptoms that are dependent on position Common Compressive Disorders – Peripheral Nerves FYI – to be covered in your Biomed/Phys Med class: Carpal tunnel syndrome Ulnar nerve entrapment Thoracic outlet syndrome Suprascapular nerve entrapment Disk herniation ! radiculopathy Sciatica Meralgia paresthetica Peroneal nerve compression Bell’s Palsy Idiopathic paralysis of the facial nerve, most common cause of unlateral facial paralysis ▪ 23/100,000/year (close to MS incidence; common) ▪ Tends to occur in adults (slightly more common in older adults) Thought to be compression of the facial nerve caused by edema/inflammation caused by herpes virus ▪ Herpes virus normally lies dormant in the cell body of neurons ▪ Pathophysiology: Herpes virus reactivation ! Edema of the facial nerve (CN7) during inflammation ! compression of the nerve in the very narrow compartment of the petrous portion of the temporal bone where the nerve runs Studies suggest that this compartment is more narrow on the affected side than on the contralateral side Bell’s Palsy Clinical Features Acute onset of unilateral upper and lower facial paralysis (over a 48 hour period) Posterior auricular pain, earache Decreased tearing or epiphora Hyperacusis Taste disturbances Otalgia Poor eyelid closure Bell’s Palsy Diagnosis, treatment, prognosis Diagnosis is mainly clinical (signs and symptoms) Steroids and antivirals have limited value ▪ Surgery in stubborn cases Tends to self resolve (>80% of cases) over time