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BMS150 test 2 > demyelinating disease in CNS (wk 5) > Flashcards

demyelinating disease in CNS (wk 5) Flashcards

1
Q

what does demyelinates in the CNS damage

A

oligodendrocytes or their processes that myeline axons

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2
Q

what does demyelinates in the PNS damage

A

Schwann cells

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3
Q

CNS damage in demyelinating disease

A

damage to oligodendrocytes or their processes that myelinate axons
* Most common mechanism of injury – damage to the processes, usually an autoimmune mechanism (multiple sclerosis)

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4
Q

PNS damage in demyelinating disease

A

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

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5
Q

what is the most common mechanism of injury when the CNS has demyelination

A

autoimmune- damage to processes that myelinate axons

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6
Q

what is MS

A
  • 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)

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7
Q

how is MS highly variable?

A

 can affect almost anywhere in the CNS (brain and spinal
cord)

 Motor, sensory, cognitive, and mood signs/symptoms

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8
Q

what gender is MS more freuqent in and at what age

A

3x women
20-40 yrs old

15X increased risk if a first degree relative, 150X increased risk if a monozygotic twin has it

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9
Q

what genes can cause MS

A

HLA2 gene (DRB1/DRB15)

Responsible for antigen presentation – responsible for 10%
of disease risk, gene most associated with the disease

 Pathophysiology uncertain

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10
Q

what cytokines in MS

A

IL-2, IL-7, IL-17

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11
Q

what other things is MS linked to

A

-viral infections (EBV?)
-sun exposure and vitamin D reduced levels
-another autoimmune history

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12
Q

progression of MS

A

MS progresses straight to a chronic inflammatory picture with no preceding acute inflammation

 Typical of most autoimmune diseases

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13
Q

what are the 2 phases of MS

A
  1. active plaques
  2. inactive plaques2
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14
Q

2 phases of MS

A

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
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15
Q

what does an MS brain look like

A
  • 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
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16
Q

what do helper T cells attack in active plaques in MS

A

myelin basic protein

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17
Q

how is myeline destroyed by active plaques in MS

A
  • 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
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18
Q

what are flares in MS

A
  • 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 B-cells 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
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19
Q

what are inactive plaque in MS

A

plaques without prominent inflammation

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20
Q

inactive plaques in MS

A
  • 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 calcium- mediated 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
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21
Q

what happens with action potnetial in MS

A

fewer APs

demyelinate so can saltatory conduction and need non-saltatory (continuous) condition) which needs more ATP

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22
Q

action potential in inactive plaques in MS

A

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
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23
Q

MS signs and symptoms

A

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

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
-or formication (feel bugs under skin)
-tingle, pins and needles
* 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

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

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

  • 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
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24
Q

motor Charcot triad in MS

A

dysarthria, nystagmus, tremor

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25
Q

what happens to deep tendons reflexes in MS

A

increase

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26
Q

l;hermittes phenomemon in MS

A

electrical shock running down back and limbs

27
Q

why do MS have heat and activity intolerance

A

action potential destabilization

28
Q

what is uhthoff sign in MS

A

hot shower or environment causes blurry vision

29
Q

what is the diagnosis for MS

A

Macdonalds criteria

characteristic lesion on brain

spinal MRI

antibodies in CSF (spinal tap)

30
Q

Macdonald criteria of MS

A

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

31
Q

MS treatment

A
  • 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
32
Q

what is the most common progression of MS

A

relapsing-remitting

33
Q

which MS progression has the best and worst prognosis

A

best- relapsing remitting
worse-primary progressive

  • In general, the prognosis is better for relapsing- remitting, 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)
34
Q

neuropathy

A

functional disturbance and/or pathological change in the PNS

35
Q

neuralgia

A

pain in the distribution of a particular nerve, usually in the absence of objective signs

36
Q

neuritis

A

inflammation of a nerve

37
Q

radiculopathy

A

pain along a dermatome, implying that the problem is at the level of the nerve root

38
Q

plexopathy

A

neuropathy of the entire plexus

39
Q

polyneuropathy vs mononeuropathy

symmetrical or not?

A

poly is symmetrical

mono is not symmetrical

40
Q

polyneuropathy

A

▪ Symmetrical distal weakness
▪ Symmetrical distal sensory loss (stocking & glove)
▪ Hyporeflexia

41
Q

multiple mononeuropathy

A

involves >1 nerve, but not in a symmetrical fashion
▪ Often due to toxins, diabetes, AIDS, chronic inflammatory disease (e.g. RA, SLE)

42
Q

causes of multiple mononeuropathy

A

toxins, diabetes, AIDS, chronic inflammatory disease (e.g. RA, SLE)

43
Q

Charcot marie tooth disease

hereditary

A

hereditary motor and sensory neuropathy

autosomal dominant inheritance (variable penetrance)

44
Q

what are the 2 genes in Charcot marie tooth disease

A

CMT1 and CMT2

  • 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)
45
Q

clinical presentation of Charcot marie tooth disease

A
  • 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
46
Q

how to diagnose Charcot marie tooth disease

A

Nerve biopsy and nerve conduction studies, as well as characteristic physical exam, history

47
Q

treatment of Charcot marie tooth disease

A

Massage – ROM to prevent contractures
▪ Anti-inflammatories, analgesics

48
Q

prognosis of Charcot marie tooth disease

A

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

49
Q

what is guillain barre syndrome (GBS)

A

Acute onset immune-mediated demyelinating neuropathy
* Uncommon disease, but most common cause of acute flaccid paralysis

  • 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.
  • 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.
50
Q

what causes guillain barre syndrome (GBS)

A

▪ 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

51
Q

what cells causes demyelination in guillain barre syndrome (GBS)

A
  • 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
52
Q

guillain barre syndrome (GBS) in the cells (DIAGRAM slide 43)

A

HMC2 in gut/peyers patch releases cytokines to activate B cell and IgG antibodies then circulate and attack myelin and Schwann cells in PNS

53
Q

clinical features of guillain barre syndrome (GBS)

A

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
54
Q

diagnosis of guillain barre syndrome (GBS)

A

Diagnosis mostly made by history and physical, EMG and nerve conduction studies are helpful

55
Q

treatment of guillain barre syndrome (GBS)

A

severe disease, can progress to loss of function including cervical spinal cord
▪ Protect airway, ventilation
▪ Plasmapheresis – removal of antibodies from the blood ▪ IV immunoglobulins

56
Q

prognosis of. guillain barre syndrome (GBS)

A
  • 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
57
Q

compressive neurological damage

in PNS, compression of nerve leads to…

A

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)

58
Q

theories of compressive nerve damage

A
  1. crush injury
  2. ischemia
  • 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
59
Q

bells palsy effect where?

A

Idiopathic paralysis of the facial nerve, most common cause of unlateral facial paralysis

60
Q

what causes bells palsy

A

herpes virus

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

61
Q

clinical features of bells palsy

A
  • 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
62
Q

diagnose, treat, prognosis of bells palsy

A

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
63
Q

polyneuropathy vs multiple mononeuropathy

A

seems like poly is symmetrical vs mono is asymmetrical?

Polyneuropathies usually denote a diffuse process affecting all nerves more or less symmetrically, showing length-dependent signs and symptoms. In mononeuropathy multiplex, the disease process affects one nerve at a time but eventually many of them, usually with considerable asymmetry.

BMS150 test 2 (18 decks)

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