demyelinating disease in CNS (wk 5)

Question 1

what does demyelinates in the CNS damage

Answer 1

oligodendrocytes or their processes that myeline axons

Question 2

what does demyelinates in the PNS damage

Answer 2

Schwann cells

Question 3

CNS damage in demyelinating disease

Answer 3

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

Question 4

PNS damage in demyelinating disease

Answer 4

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

Question 5

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

Answer 5

autoimmune- damage to processes that myelinate axons

Question 6

what is MS

Answer 6

• 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)

Question 7

how is MS highly variable?

Answer 7

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

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

Question 8

what gender is MS more freuqent in and at what age

Answer 8

3x women
20-40 yrs old

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

Question 9

what genes can cause MS

Answer 9

HLA2 gene (DRB1/DRB15)

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

 Pathophysiology uncertain

Question 10

what cytokines in MS

Answer 10

IL-2, IL-7, IL-17

Question 11

what other things is MS linked to

Answer 11

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

Question 12

progression of MS

Answer 12

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

 Typical of most autoimmune diseases

Question 13

what are the 2 phases of MS

Answer 13

1. active plaques
2. inactive plaques2

Question 14

2 phases of MS

Answer 14

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

Question 15

what does an MS brain look like

Answer 15

• 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

Question 16

what do helper T cells attack in active plaques in MS

Answer 16

myelin basic protein

Question 17

how is myeline destroyed by active plaques in MS

Answer 17

• 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

Question 18

what are flares in MS

Answer 18

• 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

Question 19

what are inactive plaque in MS

Answer 19

plaques without prominent inflammation

Question 20

inactive plaques in MS

Answer 20

• 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

Question 21

what happens with action potnetial in MS

Answer 21

fewer APs

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

Question 22

action potential in inactive plaques in MS

Answer 22

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

Question 23

MS signs and symptoms

Answer 23

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

Question 24

motor Charcot triad in MS

Answer 24

dysarthria, nystagmus, tremor

Question 25

what happens to deep tendons reflexes in MS

Answer 25

increase

Question 26

l;hermittes phenomemon in MS

Answer 26

electrical shock running down back and limbs

Question 27

why do MS have heat and activity intolerance

Answer 27

action potential destabilization

Question 28

what is uhthoff sign in MS

Answer 28

hot shower or environment causes blurry vision

Question 29

what is the diagnosis for MS

Answer 29

Macdonalds criteria characteristic lesion on brain spinal MRI antibodies in CSF (spinal tap)

Question 30

Macdonald criteria of MS

Answer 30

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

Question 31

MS treatment

Answer 31

* 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

Question 32

what is the most common progression of MS

Answer 32

relapsing-remitting

Question 33

which MS progression has the best and worst prognosis

Answer 33

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)

Question 34

neuropathy

Answer 34

functional disturbance and/or pathological change in the PNS

Question 35

neuralgia

Answer 35

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

Question 36

neuritis

Answer 36

inflammation of a nerve

Question 37

radiculopathy

Answer 37

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

Question 38

plexopathy

Answer 38

neuropathy of the entire plexus

Question 39

polyneuropathy vs mononeuropathy symmetrical or not?

Answer 39

poly is symmetrical mono is not symmetrical

Question 40

polyneuropathy

Answer 40

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

Question 41

multiple mononeuropathy

Answer 41

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

Question 42

causes of multiple mononeuropathy

Answer 42

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

Question 43

Charcot marie tooth disease hereditary

Answer 43

hereditary motor and sensory neuropathy autosomal dominant inheritance (variable penetrance)

Question 44

what are the 2 genes in Charcot marie tooth disease

Answer 44

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)

Question 45

clinical presentation of Charcot marie tooth disease

Answer 45

* 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

Question 46

how to diagnose Charcot marie tooth disease

Answer 46

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

Question 47

treatment of Charcot marie tooth disease

Answer 47

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

Question 48

prognosis of Charcot marie tooth disease

Answer 48

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

Question 49

what is guillain barre syndrome (GBS)

Answer 49

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.

Question 50

what causes guillain barre syndrome (GBS)

Answer 50

▪ 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

Question 51

what cells causes demyelination in guillain barre syndrome (GBS)

Answer 51

* 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

Question 52

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

Answer 52

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

Question 53

clinical features of guillain barre syndrome (GBS)

Answer 53

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

Question 54

diagnosis of guillain barre syndrome (GBS)

Answer 54

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

Question 55

treatment of guillain barre syndrome (GBS)

Answer 55

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

Question 56

prognosis of. guillain barre syndrome (GBS)

Answer 56

* 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

Question 57

compressive neurological damage in PNS, compression of nerve leads to...

Answer 57

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)

Question 58

theories of compressive nerve damage

Answer 58

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

Question 59

bells palsy effect where?

Answer 59

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

Question 60

what causes bells palsy

Answer 60

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

Question 61

clinical features of bells palsy

Answer 61

* 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

Question 62

diagnose, treat, prognosis of bells palsy

Answer 62

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

Question 63

polyneuropathy vs multiple mononeuropathy

Answer 63

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.