Compressive and Demyelinating Illness in the CNS (Neurology - Week 5) Flashcards
True or False: Demyelination can occur in the peripheral or central nervous system
True
Demyelination in the ____________ (peripheral/central) nervous system affects oligodendrocytes or their processes
central
Demyelination in the ____________ (peripheral/central) nervous system affects Schwann cells
peripheral
What is the most common mechanism of injury to oligodendrocytes?
Damage to processes typically via an autoimmune mechanism (e.g., multiple sclerosis)
What are the most common mechanisms of injury for Schwann cells
1) genetic deficits (impair their ability to compact together or produce myelin sheath)
2) autoimmune mechanisms including self-reactive antibodies, antibody complexes or cytotoxic T cell damage to Schwann cells
_______________ is an immune-mediated disease directed against the CNS, which involves the loss of myelin (eventually leading to the loss of axons)
multiple sclerosis
What are some characteristic findings associated with multiple sclerosis?
- chronic inflammatory findings
- white matter lesions throughout brain and spinal cord
- pathological specimens/(lesions?) are firm and hard in areas of white matter loss
- highly variable (can affect anywhere in the CNS; can cause motor, sensory, cognitive, and mood-related signs/symptoms)
True or False: Multiple sclerosis (MS) is the most common demyelinating illness.
True
Note: MS has a prevalence of about 1/1000 in North America and Europe, is 3x more likely in women, and tends to begin in young adulthood/middle age (peak incidence between 20 and 40)
About how many people in Canada are affected by MS?
100, 000 (now)
130, 000 (estimated by 2031)
MS is polygenetic. What does this mean?
Polygenetic = multiple genes are involved/affected
For MS in particular, they are HLA-II genes (DRB1/DRB15; gene most associated with the disease) and the genes for IL-2, IL-7, and IL-17
What is the risk of developing MS if a first-degree (e.g., mother, father, sibling) relative is diagnosed?
15x higher risk
What is the risk of developing MS if your monozygotic twin is diagnosed?
150x higher risk
If it’s not genetic, what else could cause MS?
- viral infections (e.g., EBV)
- limited sun exposure and low vitamin D
- history of other autoimmune disease
Does MS have an acute inflammation phase before chronic inflammation?
No – goes straight to chronic inflammation
What are the two phases of MS pathogenesis?
1) First Phase = Active Plaques: presence of typical leukocytes found during chronic inflammation –> destruction of myelin/oligodendrocytes
2) Second Phase = Inactive Plaques: loss of axons (and eventually neurons) with limited to no leukocytic infiltration and prominent gliosis
What are the major leukocytes involved in the first phase of MS pathogenesis?
- CD4+ Th cells (primarily Th1 and Th17)
- cytotoxic T cells
- B cells
- macrophages
Where do MS plaques form?
Typically adjacent to…
- lateral ventricles
- optic tracts
- brainstem
- cerebellum
- and spinal cord
True or False: cerebral atrophy may result over time in an individual with MS
True
Note: loss of neurons = loss of brain tissue therefore shrinks
True or False: leukocytes are recruited and cross the blood-brain-barrier (BBB) during the active phase of MS
True
Note: there should be very few to no leukocytes in a normal CNS
Helper T cells initiate an immune response against __________________ during the active phase of MS
myelin basic protein (MBP)
note: MBP helps to compact the layers of myelin sheath
Leukocytes that have crossed the BBB in the active phase of MS, then recruit other leukocytes (e.g., cytotoxic T cells and macrophages) into ____________ and activate them
white matter
Which leukocyte attacks the oligodendrocytes in MS?
cytotoxic T cells
Recap: the helper T cells (and B cells) are attacking the myelin itself, while the cytotoxic T cells are attacking the oligodendrocytes
Other than helper T cells, what other leukocyte can destroy the myelin sheath in the active phase of MS?
MBP-specific B-lymphocytes
What is a period of worsened neurological symptoms (in MS)?
flare
Note: in between flares, there are fewer chronic inflammatory cells
Areas where lymphocytes reside “permanently” as flares continue are called what?
lymphocytic follicles
Note: these are prominent around the meninges and blood vessels
Inactive plaques are plaques without prominent _____________
inflammation
What happens to axons as they lose their “blanket”?
- degeneration
- fewer action potentials
- and eventually neuronal cell death
How do axons compensate for demyelination?
Redistribution of sodium channels to aid action potential conduction
Note: since we don’t have anymore myelin, the signal is not travelling as fast, so we need a way to speed things up/help the axon
What are the most common initial symptoms of MS?
- paresthesias (tingling/numbness) in one or more extremities, the trunk, or one side of the face
- weakness or clumsiness of a leg or hand
- visual disturbances (e.g., partial loss of vision, optic neuritis pain, diplopia, scotomas, nystagmus, dizziness)
What is the most common initial symptom of MS?
sensory loss
What is/are the most common cognitive sign/symptom(s) of MS?
fatigue and depression
What is L’hermitte’s phenomenon?
L’hermitte’s phenomenon = sensation of an electrical shock running down the back and along the limbs
Note: it is one of the signs/symptoms of MS but is NOT sensitive or specific for MS
True of False: Pain is present in about 50% of MS patients
True
What are some motor symptoms of MS?
- bilateral spastic weakness (mostly in lower extremities)
- increased deep tendon reflexes (3+ or 4+)
- charcot triad: dysarthria, nystagmus, tremor
- facial twitching (myokymia)
- slurred speech
What are some brainstem and spinal cord findings of MS?
- dizziness
- bladder dysfunction
- constipation
- erectile dysfunction (men) or genital anesthesia (women)
- frank urinary and fecal incontinence (advanced cases)
What are some sensory signs/symptoms of MS?
- paresthesia (abnormal sensations on skin, e.g., numbness, tingling, burning)
- pain (in 50% of cases)
- L’hermitte’s phenomenon (electrical “shock”)
True or False: Other signs/symptoms of MS include heat and activity intolerance.
True
Note: hotter environments = APs going faster and if we don’t have myelin, it’s going to take more ATP
What is Uhthoff sign?
when a hot environment/shower/physical exertion leads to blurry vision, due to a transient worsening of neurological function in response to increases in core body temp
How do you diagnose MS?
1) a symptom and history checklist (known as MacDonald’s criteria)
Aided by…
2) characteristic lesions on brain and spinal cord (via MRI)
3) presence of certain antibodies in CSF (via spinal tap)
Describe the simplified MacDonald criteria
Requires:
- documentation of two or more episodes of symptoms + two or more signs
- pathology in anatomically noncontiguous white matter tracts of CNS
- symptoms last for more than 24h
- must occur as distinct episodes that are separated by a month or more
- MRI can take place of second occurrence of 2 signs/2 symptoms
Is there a cure for MS?
No
What is the prognosis for MS?
- relapsing-remitting = most common (90% of patients first presenting with MS)
- secondary progressive (1% of patients with MS develop this type each year)
- primary progressive (10% of patients first presenting with MS)
How do we treat MS?
- immunomodulators for chronic treatment (e.g., Natalizumab, copaxone, interferon-like drugs)
- steroids for acute flares
Is the prognosis better or worse for relapsing-remitting MS vs. primary progressive MS?
primary progressive is worse compared to relapsing-remitting
True or False: secondary progressive MS is often more responsive to immunomodulatory drugs
False.
Secondary progressive MS is less responsive to immunomodulatory drugs.
Mortality is _________ (common/uncommon) in MS, and significant functional disability is __________ (normal/not normal).
uncommon, normal (30-50% even with therapies)
The functional disturbance and/or pathological change in the PNS is known as
neuropathy
Pain in the distribution of a particular nerve, usually in the absence of objective signs is known as
neuralgia
Inflammation of a nerve is called
neuritis
Pain along a dermatome (implying that the problem is at the level of the nerve root) is known as
radiculopathy
Neuropathy of the entire plexus is called
plexopathy
True or False: Neuropathies can be sensory, motor, autonomic, or a combination
True
How does polyneuropathy present?
- symmetrical distal weakness
- symmetrical distal sensory loss (stocking and glove)
- hyporeflexia
How does multiple mononeuropathy present?
- involves more than 1 nerve, but NOT in a symmetrical fashion
Note: often due to toxins, diabetes, AIDS, chronic inflammatory disease (e.g., RA, SLE)
Charcot-Marie-Tooth (CMT) Disease is also known as
hereditary motor and sensory neuropathy (HMSN)
True or False: Charcot-Marie-Tooth Disease is the most common inherited neurologic disorder
True
prevalence = 1/2500
True or False: Charcot-Marie Tooth Disease has an autosomal dominant inheritance pattern with variable penetrance (not the same severity in everyone)
True
CMT1/HMSN1 pathophysiology
demyelination of peripheral nerves due to abnormal myelin production, damage to nerves, and thickened palpable myelin sheaths
Note: the proteins involved in myelin compaction are defective, leading to demyelination/remyelination cycles
CMT2/HMSN2 pathophysiology
axonal death and degeneration without a primary defect in myelin (aka your myelin is fine but for some reason axons are still dying)
Note: less common
How does Charcot-Marie-Tooth Disease present clinically?
- both sensory and motor symptoms
- slowly progressive distal symmetrical muscle weakness and atrophy (champagne bottle legs)
- diminished DTRs, foot drop, pes cavus (high arches even with weight) with hammer toes
- proprioception and touch affected (less pain and temperature sensation)
- nerves can become enlarged and palpable with cycles of myelination and remyelination
How do you diagnose CMT?
- nerve biopsy and nerve conduction studies
- physical exam
- history
How do you treat CMT?
- massage, ROM to prevent contractures
- anti-inflammatories
- analgesics
What is the prognosis for CMT?
- most have normal life expectancy
- involvement of phrenic nerve (diaphragm) or cranial nerves is very rare
- usually exclusively affects the lower leg
Acute onset immune-mediated demyelinating neuropathy is known as
Guillain-Barre Syndrome (GBS)
Note: it is an uncommon disease
Although it is an uncommon disease, what is the most common cause of Guillain-Barre Syndrome (GSB)?
acute flaccid paralysis
1.5/100, 000 per year
What is the pathogenesis of GBS?
- usually occurs after infection (2/3 with flu-like symptoms)
- usually related to infections of Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae, OR prior vaccinations
- T-lymphocytes that presumably recognize myelin cause segmental demyelination
- macrophages and antibodies also involved in nerve damage
- nerve conduction is slowed and may be blocked completely
- after 2-3 weeks of demyelination, the Schwann cells begin to proliferate, inflammation subsides, and re-myelination begins
How does GBS present clinically?
- acute, rapid, progressive inflammatory polyradiculopathy
- involves mostly MOTOR symptoms
- ascending symptoms (weakness starts in lower limbs, then progresses to higher regions of the body)
- sphincters tend to be spared
Note: flaccid paralysis can be life-threatening if it progresses to involve the phrenic nerve (C3, C4, C5)
How do you diagnose GBS?
- history and physical
- EMG and nerve conduction studies are also helpful
How do you treat GBS?
- protect airway, ventilation
- plasmapheresis (removal of antibodies from the blood)
- IV immunoglobulins
What is the prognosis of GBS?
If the patient survives the initial disease, the prognosis is good. However, some have prolonged functional deficits for 2 years or more.
If not recognized and treated = very high mortality
What does compression of a nerve in the PNS lead to?
- pain (very common)
- reduction or loss of function (motor - weakness or flaccid paralysis; sensory - numbness/anaesthesia/tingling, pins-and-needles/dysaesthesia)
Pathological theories of compressive nerve damage include… ?
1) Direct mechanical damage to the nerve (crush injury); death of the nerve likely only in severe cases
2) Ischemia (compression of the blood vessels in the perineurium = decreased blood flow and reduced function in the nerve); again, nerve usually survives unless very severe…. this is the more important mechanism
Idiopathic paralysis of the facial nerve is known as what?
Bell’s Palsy
note: the most common cause of unilateral facial paralysis (23/100, 000 per year)
True or False: Bell’s Palsy tends to occur in children
False.
Tends to occur in adults
Bell’s Palsy is thought to be compression of the facial nerve caused by edema/inflammation cause by ____________
herpes virus
Note: normally lies dormant in the cell body of neurons, but can reactivate and lead to edema of the facial nerve (CN7)
What are some of the clinical features of Bell’s Palsy?
- acute onset of unilateral upper and lower facial paralysis (over 48 hour period)
- posterior auricular pain
- earache
- decreased tearing or epiphora (excess tears)
- hyperacusis (reduced tolerance to sound)
- taste disturbances
- otalgia (ear pain)
- poor eyelid closure
How do you diagnose Bell’s Palsy?
Mainly clinical (signs and symptoms)
How do you treat Bell’s Palsy?
Steroids and antivirals have limited value
Surgery in stubborn cases
What is the prognosis for Bell’s Palsy?
Tends to resolve on it’s own over time (more than 80% of cases)
