demyelinating disease in CNS (wk 5) Flashcards
what does demyelinates in the CNS damage
oligodendrocytes or their processes that myeline axons
what does demyelinates in the PNS damage
Schwann cells
CNS damage in demyelinating disease
damage to oligodendrocytes or their processes that myelinate axons
* Most common mechanism of injury – damage to the processes, usually an autoimmune mechanism (multiple sclerosis)
PNS damage in demyelinating disease
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
what is the most common mechanism of injury when the CNS has demyelination
autoimmune- damage to processes that myelinate axons
what is MS
- 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)
how is MS highly variable?
can affect almost anywhere in the CNS (brain and spinal
cord)
Motor, sensory, cognitive, and mood signs/symptoms
what gender is MS more freuqent in and at what age
3x women
20-40 yrs old
15X increased risk if a first degree relative, 150X increased risk if a monozygotic twin has it
what genes can cause MS
HLA2 gene (DRB1/DRB15)
Responsible for antigen presentation – responsible for 10%
of disease risk, gene most associated with the disease
Pathophysiology uncertain
what cytokines in MS
IL-2, IL-7, IL-17
what other things is MS linked to
-viral infections (EBV?)
-sun exposure and vitamin D reduced levels
-another autoimmune history
progression of MS
MS progresses straight to a chronic inflammatory picture with no preceding acute inflammation
Typical of most autoimmune diseases
what are the 2 phases of MS
- active plaques
- inactive plaques2
2 phases of MS
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
what does an MS brain look like
- 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
what do helper T cells attack in active plaques in MS
myelin basic protein
how is myeline destroyed by active plaques in MS
- 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
what are flares in MS
- 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
what are inactive plaque in MS
plaques without prominent inflammation
inactive plaques in MS
- 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
what happens with action potnetial in MS
fewer APs
demyelinate so can saltatory conduction and need non-saltatory (continuous) condition) which needs more ATP
action potential in inactive plaques in MS
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
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
motor Charcot triad in MS
dysarthria, nystagmus, tremor
what happens to deep tendons reflexes in MS
increase
l;hermittes phenomemon in MS
electrical shock running down back and limbs
why do MS have heat and activity intolerance
action potential destabilization
what is uhthoff sign in MS
hot shower or environment causes blurry vision
what is the diagnosis for MS
Macdonalds criteria
characteristic lesion on brain
spinal MRI
antibodies in CSF (spinal tap)
Macdonald criteria of MS
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
- 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
what is the most common progression of MS
relapsing-remitting
which MS progression has the best and worst prognosis
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)
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
polyneuropathy vs mononeuropathy
symmetrical or not?
poly is symmetrical
mono is not symmetrical
polyneuropathy
▪ 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)
causes of multiple mononeuropathy
toxins, diabetes, AIDS, chronic inflammatory disease (e.g. RA, SLE)
Charcot marie tooth disease
hereditary
hereditary motor and sensory neuropathy
autosomal dominant inheritance (variable penetrance)
what are the 2 genes in Charcot marie tooth disease
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)
clinical presentation of Charcot marie tooth disease
- 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
how to diagnose Charcot marie tooth disease
Nerve biopsy and nerve conduction studies, as well as characteristic physical exam, history
treatment of Charcot marie tooth disease
Massage – ROM to prevent contractures
▪ Anti-inflammatories, analgesics
prognosis of Charcot marie tooth disease
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
what is guillain barre syndrome (GBS)
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.
what causes guillain barre syndrome (GBS)
▪ 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
what cells causes demyelination in guillain barre syndrome (GBS)
- 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 (GBS) in the cells (DIAGRAM slide 43)
HMC2 in gut/peyers patch releases cytokines to activate B cell and IgG antibodies then circulate and attack myelin and Schwann cells in PNS
clinical features of guillain barre syndrome (GBS)
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
diagnosis of guillain barre syndrome (GBS)
Diagnosis mostly made by history and physical, EMG and nerve conduction studies are helpful
treatment of guillain barre syndrome (GBS)
severe disease, can progress to loss of function including cervical spinal cord
▪ Protect airway, ventilation
▪ Plasmapheresis – removal of antibodies from the blood ▪ IV immunoglobulins
prognosis of. guillain barre syndrome (GBS)
- 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 PNS, compression of nerve 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)
theories of compressive nerve damage
- crush injury
- 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
bells palsy effect where?
Idiopathic paralysis of the facial nerve, most common cause of unlateral facial paralysis
what causes bells palsy
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
clinical features of bells palsy
- 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
diagnose, treat, prognosis of bells palsy
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
polyneuropathy vs multiple mononeuropathy
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.
