01: Reactions of CNS to Injury:

Normal histology & function 2) Simple atrophy

Shrunken morphology
Seen in amyotrophic lateral
sclerosis (ALS) !

3) Structural changes
Major pathological reactions alterations of both cytoskeleton and non-cytoskeleton
proteins
Neurons
Inclusions: abnormal protein aggregation and folding
Lethal injury (obviously irreversible) if proteosome/ubiquitin pathway overloaded or
1) Necrosis due to acute cell injury = oncosis damaged
Caused by: A) Alzheimers ! tau ! neurofibrillary tangles
Primary: tau is a component of
disruption of energy supply due to hypoxia, microtubules
hypoglycemia, toxins hyperphosphorylation
Secondary: involved in
pathogenesis of NFT’s
Excitotoxic injury:
microtubules fall apart
CNS injury causes: when tau misfolds !
! release of excitory aa’s (glutamate) cell dysfunction
! activation of ionotropic NMDA receptors
! Ca++ and Na++ into cell B) Parkinsons ! !-synuclein ! Lewy body
! production of free radicals & activation of
apoptotic mechanisms
Free radicals
Morphology:

" Nucleus: shrunken, C) Huntingtons ! huntingtin (polyglutamine repeats)

hyperchromasia, disintegration ! intranuclear inclusions
Cytoplasm: cytotoxic edema D) Prion disease ! PrP(sc) ! PrP(sc) amyloid fibrils
(vacuoles) loss of Nissl viral inclusions possible (i.e. herpes)
substance, eosinophilia (red storage material
neurons)
Astrocytes (potatoes)
2) Apoptosis 1) Normal histology & function:
Occurs in: are everywhere: cortex, GM, & WM
CNS embryogenesis immunostain for glial fibrilary acidic protein
corticosteroid-induced cell death (GFAP)
secondary effects of ischemic stroke (area surrounding involved in neuronal migration and connectivity
stroke = “penumbra”) during embryogenesis
neurodegenerative diseases (Pick’s disease)
important for synaptic growth & plasticity
Morphology:
DNA fragmentation typical have many metabolic functions
blood-brain barrier
Non-lethal injury
flid, electrolyte, neurotransmitter metabolism
1) Axonal reaction (central chromatolysis) nutritive & energy support for neurons
Wallerian degeneration: degeneration of distal nerve
following axonal injury 2) Reactive gliosis: the “universal reaction” to injury
Central chromatolysis: cell becomes very active in Morphology:
response to injury (4 days to 3 weeks)
Morphology: 1) hypertrophy of cytoplasmic
processes
" Cytoplasmic swelling 2) increased production of GFAP
dissolution of Nissl bodies (very (pink cytoplasm)
active, no longer “stacked”)

Pathophysiology: Why does gliosis occur?

When a neuron dies, it releases growth factors that
activate astrocytes
Gliosis maintains structural integrity
Astrocytes produce growth factors and cytokines
01: Reactions of CNS to Injury:
3) Alzheimer type 2 gliosis Microglial cells (red peppers)
Morphology: Normal function & Histology
enlargement of nucleus WITHOUT cytoplasmic
hypertrophy or ! GFAP
" Wilson’s disease
(due to abnormal copper
metabolism, leads to cirrhosis).
Notice enlarged nucleus,
unenlarged cytoplasm

Pathophysiology: Embryogenesis
Often specific to metabolic injury
NOT derived from neuroepithelial cells in neural tube
Associated with ! NH4 in liver disease
derived from bone marrow stem cells (mesoderm)
Alzheimer type 2 gliosis helps to detoxity ammonia seen
with severe cirrhosis Functions
Clinical Antigen presentation
cytokine production
hepatic encephalopathy = when a sick liver causes brain
damage due to ! NH4 phagocytic (limited activity)
causes pyramidal symptoms, “cloudiness,” finger flaps Reactions to injury
Oligodendrocytes (tomatoes) Microglial activation: ! number and size
Normal function: Myelination phagocytic: neuronophagia
HIV infects mainly microglial cells, not neurons
" Single oligodendrocyte
extending over SEVERAL axons
Examples of Microglia in action
After a cerebral infarct: Microglials transform into
In PNS, Schwann cells each macrophages
myelinate a single axon.

Stain for Myelin basic protein

Reaction to injury: Demyelination

Causes
Immune (e.g. MS) Nodules in viral infection
Viral (e.g. PML)
Progressive multifocal leukencephelopathy due to JC
papovavirus

Selective Vulerability
Definition
Different cell types (neurons or glia) or functional
areas of the CNS are susceptible to different injuries
Due to differences in:
Toxic/metabolic
Hypoxia/ischemia
connectivity, receptors expressed, vascular supply,
etc
Clinical example:
Hippocampus very susceptible to hypoxia
Selective involvement in degenerative disease
ALS, spinocerebellar degeneration
02: Blood-Brain Barrier, Brain Edema, Herniations:
Overview of Blood-Brain Barrier Pathophysiology of BBB Disruption
History Disruption of BBB: passage of free fluid &
Brain would not be stained when blood was stained, macromolecules from circulation into cerebral
and vice-versa extracellular space
Anatomy Can cause:
Course of blood vessels to brain 1) vasogenic edema
Blood vessels run in subarachnoid space 2) ! protein in CSF
Branches penetrate the cortex Can be caused by:
The area immediately surrounding the arterioles is tumors with abnormal vessels (e.g. glioblastoma)
NOT the BBB. This is the Virchow-Robbins (VR) MRI contrast enhancement with injected dye would show
abnormal vascular permeability
space
Abnormal tumor vessels are lacking tight junctions
inflammation ! cytokine mediated (e.g. MS,
abscess)
conditions with “immature” or leaky vessels (e.g.
granulation tissue around abscess, organizing
hematomas)
Blood-CSF barrier
History
When blood is stained, choroid plexus is stained, but
not brain
Morphology
tight junctions between epithelial cells of choroid
plexus
The capillary endothelium is the BBB

1) primary BBB ! Endothelium joined by tight

junctions
2) secondary BBB ! basement membrane and
astrocytic processes choroid plexus capillaries are fenestrated and will
Regions of brain lacking BBB allow passage of macromolecules into choroid
1) Pineal plexus stroma
dye travels through stroma of chorid plexus but it CANNOT
2) Medulla (area postrema) enter ventricle due to blood-CSF barrier
3) Hypothalamus choroid plexus cells secrete CSF
Function
Restrict macromolecules from entering cerebral
extracellular space
Selective transport of substances into CNS via
specific endothelial transport systems
endothelial cells are metabolically quite active
Both active & passive transport involved
02: Blood-Brain Barrier, Brain Edema, Herniations:
Brain Edema Brain herniations
1) Vasogenic Edema: ! ECF ! intracranial pressure (ICP)
Pathogenesis: Monro-Kellie doctrine
! capillary permeability In a closed system, total
Characteristics: volume available is
inconstant
Location: white matter, because there is more
room for expansion Very rapid rise of pressure
once you’ve passed critical
Composition: plasma filtrate + protein
volume
! Extracellular fluid volume ! enlarged
Consequences of ! ICP
extracellular space
brain herniations (3)
! Macromolecule permeability
a marker of “midline shift”
Clinical conditions
brain death (global
tumor, abscess, active demyelinating lesions, hypoxia-ischemia)
organizing hematomas, infarcts (later stage)
1) Subfalcine herniation
Detection: T2-weighted MRI
primary event: sliding of cigulate gyrus beneath falx
2) Cytotoxic Edema: cells swell up
secondary effect: compression of ACA ! infarction of
medial frontal lobe in middle cranial fossa
2) Transtentorial herniation
primary event: displacement of medial temporal lobe
(uncus) through tentorial notch
secondary effects: 4 things can happen
a) Stretching and compression of CN III
ipsilateral CN III paresis & pupillary dilatation
Pathogenesis: b) Compression of CONTRALATERAL cerebral
Cellular swelling due to " membrane ion pumps peduncle (kernohan’s notch) (more rare)
Characteristics: ipsilateral hemiparesis

Location: GM & WM c) Compression of PCA

(posterior cerebral artery)
Composition: intracellular water and sodium
" (slightly) Extracellular fluid volume
infarction of medial temporal-
normal macromolecule permeability occipital lobes !
Clinical conditions:
hypoxic-ischemic encephalopathy (i.e. due to d) Shearing of perforating vessels in upper
subarachnoid hemorrhage), infarcts (early stage), brainstem ! Duret hemorrhages
hypoosmolality
Detection:
Isodense appearance on CT: cannot easily
separate GM from WM
3) Interstitial Edema
Pathogenesis: brainstem shoved down
Mainly due to choroid plexus CSF outflow Basilar artery is fixed, but brainstem slides down
obstruction (! brain fluid due to impaired CSF ! COMA or LETHAL
circulation or resorption)
3) Cerebellar tonsillar herniation
Characteristics:
primary event: downard displacement of cerebellar
Location: primarily around ventricles tonsils through foramen magnum
(periventricular WM)
secondary event: Compression of medulla !
Composition: same as CSF dysfunction of respiratory and CV centers !
! Extracellular fluid volume cessation of respiration and death
normal macromolecule permeability Brain death
Clinical conditions: Pathogenesis
hydrocephalus (large ventricles on T2 MRI or CT) if ICP > BP, brain can’t be perfused ! global
e.g. Colloid cyst obstructing foramina of Monro (connects hypoxic-ischemic injury ! total necrosis
rd
lateral ventricles to 3 ventricle)
03: CSF in Health and Disease:
CSF Formation outpouchings of arachnoid membrane through
CSF Produced mainly by choroid plexus gaps in dura containing venous sinuses
about 500 mls formed/absorbed per day
CSF replenished 3-5 times/day
Many different factors influence CSF production
There are many ion pumps that can be inhibited by drugs
clinically, diuretics can be used to " CSF production
Anatomy
Choroid plexus in walls of lateral ventricles, and roof
of 3rd and 4th ventricles Factors affecting CSF drainage
subarachnoid bleed can impede CSF reabsorbtion
thrombosis of venous sinuses can also impede CSF
absorbtion
CSF Functions
Shock absorbant
cushions CNS and protects from traumatic injury
Nutrition
contains sugars and other elements which are used
by neurons and glia
Waste disposal
simple cuboidal epithelium
removes wasts products of metabolism
tight junctions in between cells
Communication
microvilli form a brush border
acts as a messaging system via cytokines,
cilia on apical surfaces help in CSF movement hormones, neurotransmitters, metabolites
CSF also produced by Ependymal lining and Hydrocephalus
Perivascular spaces (Virchow-Robbin)
Definition
CSF Circulation & Flow pathological increase in cerebral ventricular volume
Animation: http://www.sickkids.ca/childphysiology/cpwp/brain/csf.htm
can be due to ! production or " absorption
Types of hydrocephalus
1) communicating hydrocephalus
ventricular system still open
can be caused by SAH impeding arachnoid
granulation reabsorbtion
2) non-communicating hydrocephalus
3) obstructive hydrocephalus
4) arrested (compensated) hydrocephalus
5) normal pressure hydrocephalus
Route of Flow ! ventricular size
Lateral ventricles clinical triad:
! foramena of Monroe (interventricular foramina) 1) dementia
into Third ventricle 2) incontinence
3) gait disturbance
! aqueduct of Sylvius
into Fourth ventricle 6) Hydrocephalus ex vacuo
! Foramena of Luschka (Lateral foramina) consequence of stroke
! Foramen of Magendie (Median foramen) ventricle expands
into subarachnoid space and basal cisterns 7) External hydrocephalus
three main cisternae (thin potential spaces that pediatric
could get pathologically dilated): have dilation of subarachnoid space
cisterna interpeduncularis Extension of CSF to/around optic nerve leads to
cisterna pontis papiledema, which can signify hydrocephalus
cisterna cerebellomedullaris
CSF Reabsorbed by Arachnoid granulations
03: CSF in Health and Disease:
CSF Acquisition (Lumbar Puncture) ! protein
Indications: ! bilirubin in body
CNS infections ! carotenoid pigments
CNS inflammation Brown/Gray: CNS melanoma
CNS tumors Greenish: carcinomatous meningitis (lots of
SAH malignant cells)
MS Gram stain
GBS (?) Bacterial meningitis
CIDP (?) ~70% positive if untreated
Contraindications ~50% positive if partially treated
Bleeding or clotting disorders ~90% positive if Pneumococcal or Staph
skin infection Acid-Fast: TB
epidural abscess Wright or Giemsa: Toxoplasmosis
space occupying lesions (tumors, abscess, etc) Hyphae can be seen in Candida or other fungal
meningitis
Anatomy
Cells
Highest point of iliac crest identified, imaginary line
interesects space between L3 and L4 Normal:
Pressure WBC: No PMN’s, < 5 mononuclear cells
Normal RBC: No RBCs, except due to traumatic tap
700 RBCs account for 1 WBC
Normally 12-18 cm H20
Fluctuates with heart beat & respiration ! PMN’s: suggest meningitis
Queckenstedt test ! Mononuclear cells:
compress internal jugular to imitate venous block viral meningitis
should show ! CSF pressure early bacterial meningitis
if not, could be spinal block carcinomatous meningitis
Increased pressure connective tissue disorders
benign intracranial hypertension ( = pseudotumor ! RBC’s: traumatic or SAH
cerebri)
Protein
space occuping lesions
Sensitive, but non-specific marker which reflects BBB
venous sinus thrombosis permeability
diffuse cerebral inflammatory or toxic process Normal value: 30-45 mg/dL
Decreased pressure 1000 RBC’s = 1 mg increase in protein
spontaneous intracranial hypotension ! Protein
Complications CNS infections, inflammation, or tumor
herniation " Protein
Post LP headache young children
To reduce, use small needle size, bevel direction removal of lots of CSF
parallel to dural fibers, and replace stylet before
intracranial HTN (30% of cases)
withdrawal of needle
Oligoclonal bands: electrophoretic separation of
infection
protein on gel, each band represents a homogenous
epidural hematoma, SDH, SAH protein secreted by a single clone of plasma cells
implantation of epidermal tumor monoclonal
CSF Analysis normal CSF rarely has more than 1 band
Appearance oligoclonal (3-5 bands)
Clear, colorless: normal ~90% of MS patients have OCBs
Cloudy: ! protein or cells 100% of SSPE (subacute sclerosing pan encephalitis,
secondary to measles) have OCBs
Pink: traumatic vs SAH ~25% of other CNS inflammatory disorders have OCBs
Can take three tubes ! if blood decreases then polyclonal
it’s probably traumatic
Can also do RBC cytology to determine
Yellow: xanthochromia
03: CSF in Health and Disease:
Glucose
Normal
regulated by carrier-facilitated transport
CSF glucose should be # 2/3 of serum glucose
relationship lost if serum glucose > 400 mg/dL
! glucose
! glucose in serum
" glucose
bacterial meningitis
hypoglycemia
some cases of viral meningitis (HSV, Mumps)
carcinomatous meningitis
SAH
Bacterial antigens
60-100% sensitive for H. Influenzae
useful in partially treated meningitis
Culture
Bacterial meningitis, viruses (enterovirus, HSV), fungi, TB
PCR (DNA)
Very high sensitivity: 95-100%
Viral meningitis or encephalitis (HSV, EBV, Enterovirus, CMV), tuberculous meningitis
Cytology
Requires lots of CSF, 10-20 cc’s
May require serial LP’s since first one may be negative
Useful in suspected neoplasms of brain, meninges, spinal cord, or metastatic lesions
these days, CT/MRI is much more useful
CSF Profiles in Different Disease Conditions
Opening Protein Glucose Cells Gram Cultures Other
pressure
Bacterial ! ! " ! PMN’s + +
meningitis
Viral meningitis ! or normal ! normal ! - +/- PCR +
Mononuclear
HSV encephalitis ! or normal ! normal ! - +/- PCR +
Mononuclear
Multiple Sclerosis normal ! normal normal or OCB +
! IgG !
Mononuclear MBP +
Guillain-Barre ! or normal ! normal normal or Albuminocytologic
! dissociation +
Mononuclear
04: Neurological Exam:
Four main questions to be addressed examine resistance to passive movement
1) Is there a lesion? Where? Strength: MRC scale
2) What is its pathophysiology? 0 = no movement
3) What further studies are needed to elucidate the 1 = muscle belly moves but not sufficient to
diagnosis? move a joint
4) How will the problem be managed? 2 = movement of joint with gravity eliminated
Method of examination 3 = movement against gravity
Cranial nerves 4 = movement against some resistance
I: 5 = full strength
test each nostril separately using non-irritating movement
odor coordination
II: finger-nose
test visual fields and acuity heel-shin
pupillary light response (efferent requires CN III), gain and station
and observe fundus
ask patient to walk on heels, toes
III, IV, VI:
Romberg
extraocular motions and lids
reflexes
V:
Scale
0 = absent reflex
1 = reflex present only with reinforcement
2 = normal
3 = brisk
4 = clonus
Level
Biceps = C5/6
Brachioradials = C6
check touch and pain in all three divisions
Triceps = C7
corneal reflex (efferent is CN VII)
Quadriceps (knee jerk) = L4
jaw strength, and jaw jerk
Achilles (anke jerk) = S1
VII:
Check for symmetry of nasolabial folds during Other reflexes
smile Pathological
Check orbicularis oculi strength by resistance to Babinski, snout, grasp
forced eye closure Superficial
Check frontalis by asking patient to elevate abdominal, cremasteric
eyebrows Meningeal
VIII: Kernig
assess hearing Brudzinski

perform Weber and Rinne tests sensory system

IX, X: primary: touch, pinprick, vibration, position
assess gag reflex and soft palate strength cortical: stereognosis, graphesthesia, extinction,
point localization
listen for hoarseness
XI:
assess SCM & Trapezius strength
XII:
Assess ability to protrude tongue, push tongue
into cheeks, and move it back and forth rapidly
motor system
Observe
atrophy, bulk, fasciculations, tremor, chorea
Check tone
04: Neurological Exam:
Localization & Formulation Dermatomes
Four main segments of nervous system
1) Supratentorial
cerebral hemisheres, thalamus, hypothal, basal
ganglia, olfactory & optic nerves
2) Posterior fossa
nuclei of CN III through XII, cerebellum,
decussations of corticospinal tracts and medial
lemniscus
3) Spinal level
dorsal and ventral horns and roots, spino-
thalamic tract decussation
4) Peripheral level
peripheral nerves, plexi, muscles, NMJ
VINDICATE
Vascular
Infectious/Inflammatory
Neoplastic
Degenerative
Intoxication
Congenital
Autoimmune
Trauma
Endocrine
Pathway Review
Corticospinal

Spinothalamic & Posterior Columns

08: Cerebrovascular Disease:
Cerebral Ischemia Imaging of Acute Ischemic Stroke
Diffuse: hypoxic-ischemic encephalopathy CT scan
Focal: cerebral infarction/ischemic stroke insensitive to infarcts < 24 hrs old
Pathology of Ischemic stroke Can image occluded vessels
Molecular events in cerebral ischemia Good identification of hemorrhage
MRI (conventional)
Somewhat better than CT, but similar drawbacks
MRI (diffusion weighted = DWI): best
identifies cytotoxic edema
MRI (perfusion weighted = PWI)
measures blood flow
combined with DWI can image ischemic penumbra
Etiological Classification of Ischemic Stroke
1) Large Vessel: atherothrombotic
Affected vessels:
carotid, vertebrobasilar
Pathophysiology:
red neurons
in situ thrombosis due to plaque rupture or
Ischemic penumbra
severe stenosis
Definition:
atheromatous lesions most often at vessel
zone of viable tissue surrounding infarct where bifurcations
cells are at increased risk of irreversible injury
Pathology:
No cytotoxic edema (yet)
medium to large-sized cerebral infarcts, often in
Caused by: more than one vascular territory
spreading neuronal depolarization Location:
excitotoxic injury cerebral hemispheres (carotid), brainstem,
impaired microcirculation cerebellum (vertebrobasilar)
activation of neuronal apoptosis 2) Small vessel: hypertensive
Detected by: Affected vessels:
Diffusion-perfusion mismatch Small penetrating arteries arising at right angles
Subacute (2-13 days) from major arteries
lenticulostriate
liquefaction necrosis with macrophage infiltration
thalamostriate
(some from microglia, some from bloodstream)
Pathophysiology:
! BP ! destruction of vessel wall
(lipohyalinosis) ! occlusion OR rupture of
vessel

Old (>1 month)

end result: hole in brain

Lipohyalinosis is NOT atherosclerosis. It is damage to

structure of wall due to HTN
Vascular occlusion is NOT a thromus. It is a proliferative
injury due to HTN. tPA doesn’t work.
Gliosis (GFAP) in area surrounding stroke
Pathology:
GFAP is an intermediate filament
lacunar infarction (<1.5 cm), hemorrhage
NO collagen. Just a hole.
08: Cerebrovascular Disease:
Location: Hemorrhagic Stroke
basal ganglia, thalamus, pons, cerebellum, Pathogenesis
cerebral white matter embolic infarcts can be hemorrhagic
3) Embolic: can happen iatrogenically with tPA
Affected vessels: Classification by mechanism
smaller vessels, such as arterial branches of 1) HTN ! Hyertensive cerebral hemorrhage
circle of Willis, often at bifurcations or stenotic
Etiology:
areas
!BP
Pathology: ! degeneration of small penetrating arteries
! aneurysmal dilatation (Charcot-Bouchard
aneurysm)
ballooned-out points of susceptibility where vessel
wall is extremely weak

! Rupture!
C-B aneurysms occur @ level of penetrating
arteries
2) Ruptured berry aneurysm (or vascular
malformation) ! SAH
small or large infarcts; often in different arterial Location: Occur @ level of bifurcating arteries
territories Anterior >> posterior circulation
may be hemorrhagic due to reperfusion Most common sites:
Location: Anterior:
cerebral hemispheres (cortex, WM, rarely deep ICA-Post communicating
MCA
gray nuclei)
Anterior communicating
cerebellum
rarely brainstem Posterior:
Etiology/Pathophysiology: Basilar-PCA (top of basilar)
Cardiogenic
atrial fibrillation Pathogenesis:
valvular disease
cardiac mural thromba
patent foramen ovale
Non-cardiac
arterial (e.g. atherosclerotic plaques)
“foreign” materials (fat, air)
Pulmonary vascular malformation
Congenital defect in muscle wall (media) at arterial
4) Other (vasculitis, dissection, radiation injury, bifurcation
hypercoagulable state, etc) Hereditary: CT disorders, polycystic kidney disease
HTN may play secondary role
Complications
Early
! ICP ! herniation
Vasospasm ! infarction
rebleeding
Late
rebleeding
hydrocephalus
08: Cerebrovascular Disease:
3) Amyloid angiopathy (in elderly)
Most common cause of lobar hemorrhage in
elderly patients
Lobar Hemorrhage Definition:
hemorrhage within cortex and/or white matter of
cerebral hemispheres
Location:
In cerebral hemispheres
NOT in deep gray nuclei or brainstem
Etiology:
1) Amyloid angiopathy
2) Vascular malformation
Pathogenesis:
Deposition of $-amyloid in meningeal and cortical
vessels
blood vessels stain for $-amyloid
! degeneration of vessel wall
! hemorrhage
Affected patient may or may not have
Alzheimer’s
4) Vascular malformations
Arteriovenous malformation (AVM)

tangle of enlarged abnormally-formed arteries and veins

no elastic tissue in walls
very susceptible to bleeding
Could actually lead to ! CO heart failure
Cavernous angioma
similar to a hemangioma in liver
distended vascular channels with thin fibrous walls (not
arteries or veins)
propensity for bleeding
Venous angioma/capillary telangiectasis (almost
never bleed)
Strokes can also be classified by location
Intracerebral
deep gray nuclei stoke ! small vessel
pontine/thalamic/basal ganglia stroke ! HTN
Lobar hemorrhage ! amyloid angiopathy, AVM
Subarachnoid: berry aneurysm, trauma,
coagulopathy
Subdural/Epidural ! trauma
11: Demyelinating Disease:
Normal Myelin & Demyelination
Myelin Structure
plasma membrane of myelin-producing cell
encircles axon in concentric lamellar pattern
CNS: one oligodendrocyte myelinates multiple
internodes on multiple axons
therefore, the death of just a few oligo’s can Appearance
have a big impact
well-circumscribed areas of pink-gray discoloration found
PNS: one Schwann cell myelinates only one in (but not confined to) white matter
internode on a single axon Size
Demyelination: general points range from microscopic foci to large confluent regions of
hemispheric white matter
primary target of disease = myelin-forming cell
and/or myelin sheath Location
Generally perivenular, especially in walls of lateral
axons are relatively preserved
ventricles
distinguish from secondary loss of myelin due to junction of cerebral cortex and WM
axonal degeneration optic nerves, chiasm, and tracts
axonal injury is SECONDARY consequence of brainstem (especially pons)
demyelination spinal cord
if the reverse happened (axonal death) then you Active MS Plaque Histology
can’t have myelin sheathing nothing (myelin Active Plaque = very cellular plaque
would die too)
1) mononuclear cell inflammation
segmental loss of myelin sheath impairs axonal
transmission ! clinical deficits perivascular:
CD8+ T cells
Demyelinating disease: Numerous etiologies
B-cells
Immune mediated
plaque parenchyma
CNS: MS, acute disseminated encephalomyelitis CD4+ T cells
(post-viral encephalomyelitis)
PNS: Guillian-Barre syndrome 2) altered vascular permeability
Infectious (e.g. PML, SSPE) etiology
Toxic-metabolic interaction between endothelium and inflammatory cells
in plaque (cytokine effect)
acquired (central pontine myelinolysis)
radiology
hereditary (leukodystrophies)
BBB breakdown ! contrast enhancement of active
Vascular lesions
Multiple Sclerosis 3) active demyelination
Definition & Clinical Presentation a) destruction of oligodendrocyte
distinct episodes of neurologic deficits separated in
time attributable to white matter lesions separated
in space within the CNS
most typical form = chronic relapsing and
remitting disorder
most often affects young adults
Gross Pathology
Pathologic Hallmark = Plaque
cytokines
excitotoxic injury
apoptosis
b) destruction of myelin sheath
11: Demyelinating Disease:
Inactive (chronic) MS plaques

cytokine-mediated
antigen-antibody complement-mediated (MAC)
c) macrophage infiltration
d) reactive gliosis

Little or no inflammation
sharp margin with normal white matter
" cellularity ! mainly reactive astrocytes
reactive astrocytes have already laid down
GFAP and fibrillary processes, now they are
relatively quiescant
this has imparted the rigidity (“sclerosis”) to the
plaque
hypertrophic reactive astrocytes some loss of oligo’s
conspicuous feature of active plaques relative axonal sparing (some plaques may have
function: significant axonal loss)
APC (MHC II) Pathogenesis of MS
produce cytokines
e) axonal sparing
Observations
most axons spared in early active plaque
some axonal injury may be present (axonal
fragmentation and swellings)
significant axon loss may be present in older lesions
! irreversible deficits seen later in course of MS
Causes
collateral damage (cyokines, proteases,
excitotoxins, reactive O2 species)
loss of normal “trophic” or protective effect of myelin
sheath
An active MS plaque will stain:
1) Peripheral activation of autoreactive lymphocytes
positive for neurofilament protein (axons still there)
but negative for myelin
2) Homing to CNS
f) remyelination is possible 3) Adhesion to brain capillaries and extravasation
across BBB
4) Reactivation of T cells by exposed autoantigens
5) Secretion of cytokines
6) Activation of microglia and astrocytes
! act as APC’s
7) Stimulation of antibody cascade
! myelin specific antibodies
! membrane attack complex
occurs mainly at plaque margin END RESULT:
possible origin from oligodendroglial stem cell pool 8) Myelin destruction
migrates from periventricular area
9) Axonal degeneration
clinical effect: recovery of function following acute
episode?
13: Tumors:
Tumors – Classification examples: medulloblastoma, glioblastoma
primary tumors Extra-CNS (metastatic) spread
neuroectoderm very rare
glial cells ! astrocytoma, oligodendroglioma, most often seen in medulloblastoma (late);
ependymoma, glioblastoma rarely glioblastomal other gliomas
neurons ! ganglion cell tumors WHO Classification
embryonal cells ! medulloblastoma circumscribed
“Sheath” cells pilocytic astrocytoma (WHO grade I)
Arachnoid cell ! meningioma pilocytic = “hair-like”
Schwann cell ! schwannoma, neurofibroma diffusely infiltrating
Secondary tumors astrocytoma (WHO grade II)
metastatic ! carcinoma, sarcoma, melanoma anaplastic astrocytoma (WHO grade III)
hematopoietic ! leukemia, lymphoma glioblastoma (WHO grade IV)
Tumors: Age/Incidence/Location 1) Pilocytic astrocytoma
Adults most common astrocytoma in children
Supratentorial location
Most common: metastases > gliomas > “sheath” cerebellum (mainly)
tumors also 3rd ventricular region
Children biologic behavior
Infratentorial very slow growing
most common: neuroectodermal tumors excellent prognosis after surgical removal
astrocytoma, medulloblastoma, ependymoma only rarely malignant
Clinical effects of brain tumors pathology
space-occupying effects on brain parenchyma gross:
extraparenchymal tumor can compress brain
meningioma
schwannoma
tumor can invade parenchyma and destroy brain
circumscribed
pilocytic astrocytoma
metastatic tumors
infiltrating circumscribed, often cystic with mural nodule
most gliomas microscopic: WHO grade I
medulloblastoma
hemorrhage within tumor
edema ! ! ICP
impairment of CSF flow ! hydrocephalus
clinical presentation
focal neuro signs
seizures well-differentiated fibrillary astrocytes
generalized signs of ! ICP no features of anaplasia, well differentiated
herniations no mitotic activity, necrosis, or other features of
anaplasia. the cells look pretty much like normal
Neuroepithelial (neuroectoderm) tumors astrocytes
Spread compact and spongy areas
infiltration of normal brain structures
most common method of spread
examples: astrocytoma, glioblastoma,
medulloblastoma
Dissemination within CSF (subarachnoid space,
ventricles)
rosenthal fibers
uncommon microcysts
13: Tumors:
2) Diffusely infiltrating astrocytomas variegated appearance with hemorrhage and necrosis
may cross midline through corpus callosum – “butterfly
Atrocytoma + glioblastoma are 80% of primary brain
glioma”
tumors in adult
microscopic (WHO grade IV)
location: mostly cerebrum but can occur anywhere
biologic behavior:
diffuse infiltration of surrounding structures
recur
! tendency towards anaplasia over time
pathology
gross: highest grade of astrocytic tumors
ALWAYS have necrosis, but doesn’t always have
hemorrhage
very aggressive
marked nuclear atypia
mitoses
microvascular proliferation

left image: thalamus expanded, midline shift due to mass

effect
right image: not well circumscribed; involves frontal lobe
of brain; can find tumor cells even around border zone;
this one also has microcysts
diffusely infiltrative with indistinct borders
small cysts
Microscopic: high magnification of a blood vessel: "glomeruloid"
NO blood brain barrier - LEAKY in contast scans.
ABNORMAL microvascular proliferation.
Due to growth factors secreted by cancer cells.
necrosis (+/- pseudopalisading)
pseudopalisading: a lining up of cells around
necrotic area
hyperproliferative area
low-grade (WHO grade II)
cell density not high, but cells vary in size and shape
pleomorphic nuclei
no mitoses
Anaplastic (WHO grade III)
! cellularity
more pleomorphic, nuclear atypia
mitoses present
NO necrosis or vascular proliferation
Pathogenesis of gliomas: GENETICS
3) Glioblastoma
Behavior
highly malignant
very difficult to treat
may recur even after apparent total resection
because cells are all over the place
requires adjuvant therapy (radiation, chemo)
often fatal within 1 year
Pathology
gross:

p53 gene ! astrocytoma/glioblastoma

EGRF ! primary glioblastoma
13: Tumors:
4) Medulloblastoma
Age: mainly children and young adults, most
common neuroepithelial tumor in children.
location: cerebellum
origin:
primitive neuroectodermal cells in roof of 4th
ventricle or external granular layer of cerebellum
The only brain tumor we know of that
DEFINITELY comes from stem cell
biologic behavior:
diffuse spread via CSF, extra-CNS spread (late)
“Sheath” Cell tumors
Meningiomas
incidence: 15% of primary brain tumors
most common non-glial primary CNS tumor in
adults
cell of origin: meningothelial (arachnoid cap) cell
arise out of arachnoid villi?
location: falx and cerebral convexities, skull base,
tentorium, foramen magnum, ventricles, spinal cord

dark blue stuff in ventricle is tumor, spreads through

CSF
sensitive to radiation and/or chemo
> 50% 5-year survival
pathology biological behavior
gross: slow growing, usually benign
may recur if incompletely removed
may invade soft tissue and bone (but this
doesn’t imply malignancy)
possible hormonal influence on tumor growth
(i.e. estrogen/progesterone receptors?)
pathology
gross:

well-circumscribed, solid mass, may have hemorrhage

or necrosis
microscopic: WHO grade IV

well-circumscribed
attached to dura
compression – NOT INVASION – of adjacent brain
microscopic:

densely cellular small “blue cell” tumor

high rate of tumor cell proliferation and necrosis
many mitosis, high capacity to proliferate
may show neuronal (common) or glial differentiation, or
both
signs of EARLY differentiation lobules or whorls of meningothelial cells
repeat, they are stem cell tumors! Psammoma bodies
mature neurons rarely seen lack anaplastic features
13: Tumors:
Nerve Sheath Tumors Hematopoietic tumors
Schwannoma primary CNS lymphoma
cell of origin: schwann cell demographics:
normally, a schwann cell myelinates the axon males 50-60 yo, immunodeficient (much
younger with AIDS)
pathogenesis:
thought to be related to infection of B cells by
EBV: EBV genome gets into B cells and starts
proliferating. Actual steps involved in
transformation not well understood. B cells come
from periphery and migrate into brain (brain
doesn't normally have B cells sitting around). For
some reason the B cells become neoplastic
location: cranial & spinal sensory nerve roots once they're in the brain.
single or multiple location:
most intracranial schwannomas originate from mainly cerebral hemispheres, periventriclar, but
vestibular branch of CN VIII can be multicentric (many tumors arising at
old term: acoustic neuroma. New term: vestibular different sites)
schwannoma. Don't come from acoustic branch of VIII,
but can impinge on the acoustic branch and cause
deafness

note multifocal, periventricular locations

biologic behavior:
bilateral vestibular schwannomas – type 2 highly malignant (<2 yrs survival)
neurofibromatosis (NF2)
pathology
biologic behavior:
gross:
slow-growing, benign; treated by surgery Ill-defined or circumscribed masses
pathology: necrosis or hemorrhage
gross: microscopic:
perivascular distrubution of tumor cells
very anaplastic looking cells
most are large B cell lymphoma

discrete, encapsulated mass ! pushes on nerve

separate from nerve of origin
compress but do not invade brain or spinal cord
microscopic:
benign spindle cells confirm with immunohistochemistry
compact (Antoni A) and loose (Antoni B) areas
don’t worry too much about the histology, just know
that they’re spindle-shaped cells
13: Tumors:
Metastatic tumors Pathology:
Incidence: gross:
50-60% of all brain tumors well-circumscribed masses
10-20% of patients with extra-CNS carcinoma don’t infiltrate like gliomas do
develop brain mets predilection for gray-white junctions
most common primaries: necrosis, hemorrhage or cyst formation
lung (>50%) vasogenic edema
breast (15%) abnormal contrast
skin (melanoma) microscopic:
colon usually similar to primary tumor
kidney
tumors most likely to metastasize to brain:
melanoma
breast
lung
location:
brain parenchyma (75% in cerebral hemispheres)
dura
leptomeninges (meningeal carcinomatosis)
19: Pathophysiology & Neuropsychiatric Sequelae of Traumatic Brain Injury
Traumatic Brain Injury (TBI) caused by angular acceleration
Pathophysiology Features to remember
Hemorrhages 1) axonal swelling
2) retraction balls, which lead to

3) axon distruption in 12-24 hours

can also be called axon “shearing” BUT axons
Epidural NOT cut
Subdural Delayed deterioriation
SAH can take hours or years to manifest due to
Contusion DAI ! 24 hrs
Cerebral edema ! ~3 days
Delayed subdural hematoma
hypoxic/ischemic injury
hydrocephalus ! can take year(s)
Severity of TBI
Mild TBI
Coma + PTA (post-traumatic amnesia) < 20
mins
CGS initially 13-15
Coup Contusion no focal neuro deficits
at the sight of injury
Moderate TBI
Contre-coup Contusion Coma + PTA = 30 min to 1 week
opposite site of injury
Initial GCS 10-12
Microscopically: NOT diffuse, can see small
areas of focal hemorrhage Glasgow Coma Scale
Certain high-probability areas: Eye opening
1. none
2. to pain
3. to speech
4. spontaneous
Motor Response
1. none
2. extension
inferior orbitofrontal (where “personality” is)
3. abnormal flexion
anterior temporal
4. withdrawal
occipital
5. localize pain
Can be seen on MRI sometimes
6. obeys commands
Can been seen as “dysfunctional area” visible
on SPECT Verbal response
Years Later 1. none
Contusions can turn into Plaques Jaunes 2. incomprehensible
Diffuse axonal injury (DAI) 3. inappropriate
often normal CT 4. confused
but can be imaged by “GRASS” ! finds hemosiderin 5. oriented
DAI actually not diffuse, but has small foci
19: Pathophysiology & Neuropsychiatric Sequelae of Traumatic Brain Injury
Principle prognostic factors in TBI
1) Depth of coma (Glasgow Coma Scale)
2) Duration of coma
3) Duration of post-traumatic amnesia (PTA)
Concussion
Definition
acceleration-deceleration head injury with transient
impairment of consciousness but no macroscopic
brain damage
core symptoms
TBI: Behavioral Morbidity
1) Post-concussion syndrome
headache
diziness (+/- nausea/vomiting), vertigo
impaired attention
2) Post-TBI Epilepsy
risk factors
3) Post-TBI Personality Change
orbitofrontal
social disinhibition
impulsive, distractible
hyperactive
inappropriate jocularity
Phineus Gage
maybe someone else we all know?
dorsolateral prefrontal
“opposite” of orbitofrontal syndrome
apathetic, unmotivated
psychomotor slowing
“pseudodepressed”
mixed frontal syndrome
4) Affective disorders: depression & mania following
TBI
depression
acute depression: more frequent with left
dorsolateral frontal, basal ganglia, subcortical
lesions
late-onset depression: less relation to lesion
location
mania
onset after age 45 signifies neurological event
risk factors for post-TBI behavior %’s
age
premorbid personality
extent of injury
substance abuse, etc
Treatment
avoid drugs that are sedating or slow things
down
use low doses
20: Epilepsy
Epilepsy: Definitions 2) Generalized seizures ! no auras but can have
Epileptic Seizure prodrome
transient disturbance of cerebral function due to a) tonic-clonic (grand mal) seizure
extensive and hypersynchronous abnormal activity loss of consciousness
of cortical neurons ictus ( = the seizure itself)
Epileptic Disorder = “Epilepsy” fall
Chronic neurological condition characterized by muscular rigidity (tonic)
recurrent epileptic seizures inhibited respiration (cyanosis)
These disorders are “The Epilepsies” rhythmic jerking (clonic)
less than 2 mins duration
A single seizure is NOT epilepsy
incontinence
Suggests some type of underlying neurological
tongue biting common
defect (but can be many causes)
post-ictal confusion
“The Epilepsies”
b) absence (pronounced like you’re a Frenchy)
1) Partial (focal) seizures ! localized cortical
excitation almost always seen in children
onset before puberty
a) simple partial seizures
otherwise normal children
no impairment of consciousness
multiple lapses of consciousness under 10 secs
Aurus reflect stimulation of a certain cortical (frozen)
region
up to 100’s per day
can be motor
no aura
can be sensory
somatosensory no post-ictal confusions
visual seizures precipitated by hyperventilation
auditory multifactorial inheritance
olfactory good prognosis
can be autonomic
c) myoclonic
pallor, sweating
can be psychic very quick jerks
affective d) clonic
illusions e) tonic
structured hallucinations stiffening: assumption of rigid posture
cognitive
often seen w/development disabled
b) complex partial seizures
f) atonic (drop seizures)
with impairment of consciousness
3) Unclassified seizures
aura often present
a) Infantile spasms
unresponsive staring
VERY BAD
duration less than 2 minutes
very brief seizures involving bilateral symmetric
may be automatisms flexor or flexor-extensor spasms
post-ictal confusion usually present may occur hundreds of times per day
todd’s paresis: neurological deficit following usually begin between 3 months and 1 year of
seizure age
c) secondarily generalized seizures often associated with underlying cerebral
starts focally, spreads bilaterally disease
poor prognosis, mental retardation common
Complex Partial Seizure Absence Seizure outcome
4) Status epilepticus
1-2 min duration 10-30 secs duration A seizure lasting more than 30 minutes, or recurrent
May be aura no aura seizures w/o return to baseline neuro status
ictal automatisms rare automatisms can occur with all forms of seizures
post-ictal confusion immediate recovery generalized tonic-clonic status is neurological
focal spikes on EEG generalized 3 Hz emergency
spike/wave on
EEG 25% mortality
20: Epilepsy
Causes of Epilepsy Medications for Epilepsy
General Partial Seizures
NO pathognomonic lesion of epileptic brain Carbamezepine
many different types of metabolic abnormalities and Phenytoin
anatomical lesions can prouce seizures Valproate
Common causes by age Pheonobarbital
Infancy (0 ! 2 yo) Generalized Tonic-clonic seizures
intracranial birth injury Carbamezepine
acute infection Phenytoin
perinatal hypoxia & ischemia Valproate
metabolic disturbances (hypoglycemia, Pheonobarbital
hypocalcemia)
Absence Seizures
congenital malformations
Valproate
genetic disorders
Ethosuximide
Childhood (2 ! 10 yo)
NO Carba/Phenytoin!
idiopathic = genetic
Myoclonic Seizures
acute infection
Valproate
trauma
Clonazepam
febrile convulsions
Treatment of status epilepticus
Adolescence (10 ! 18 yo)
manage ABC’s
idiopathic = genetic
IV benzodiazepines
trauma
Surgical Treatment of medically refractory
drug, alcohol withdrawal
partial epilepsy
vascular malformation Commonly found after resective surgery
Early Adulthood (18 ! 35 yo) Mesial Temporal Sclerosis
trauma present in up to 75% of resected temporal lobe
drug, alchohol withdrawal specimens
idiopathic = genetic scars after epilepsy
tumor typically greater than 50% cell loss in CA1-4 of:
Middle age (35 ! 60 yo) hippocampus
tumor fascia dentata
prosubiculum
trauma
cerebrovascular dz
drug, alcohol withdrawal
Old age ( > 60)
Cerebrovascular dz
degenerative disease
tumor
Factors that may precipitate or provoke a seizure
systemic illness
fever
head trauma
“impact seizures” are one-time events, don’t
predispose to epilepsy
alcohol/sedative drug withdrawal
sleep deprivaion
matabolic derangements
psychological stress
25: ALS & Spinal Cord Disorders
Clinical Features of ALS specialized MRI protocols (diffusion-tensor MR
General Descriptions imaging) can also reveal corticospinal tract
impairment
age-dependent, progressive, lethal
Electrodiagnostic studies
loss of LMN ! skeletal denervation & atrophy
evidence of anterior horn (LMN) disfuction seen in
multiple nerve root distributions in at least 3 limbs
sensory is normal
Classification of ALS
Sporadic
peak incidence 55-75, M>F
Familial
<10% of ALS, usually autosomal dominant
corticospinal tract degeneration 20% with mutations in SOD1 (Cu/Zn superoxide
bottom images are ALS, top are normal dismutase)
loss of UMN (cortex) ! spasticity & hyperrelexia Western Pacific
non-motor systems (i.e. sensory) spared ALS is a complex disorder with multiple suspected
focal onset, then spread causes and phenotypic variation
Diagnosis interplay of environment, genes, and aging
“Rule out everything else” toxic exposure, excitotoxicity, protein misfolding,
Absense of: mitochondrial dysfunction, oxidative stress,
inflammation, monogenic defects, and polygenic
Electrophysiological, EMG, neuroimaing traits can all play a role
evidence of other diseases
Presence of:
ALS Differential Diagnosis
Polyradiculopathy/myelopathy
UMN & LMN degeneration
post-polio syndrome
progressive spread of deficit
motor neuropathy with anti-GM1 Ab
Specific Physical Findings
MND and gammopathy/paraproteinemia
Bulbar symptoms
heavy metal intoxication
CN V, VII, IX, X, XII
hexosaminidase-A deficiency
Dysarthria
paraneoplastic motor neuronopathy syndrome
Dysphagia
syringomyelia/syringobulbia
risk of aspiration pneumonia
ALS affects both UMN and LMN motor
Drooling
neurons
Pseudobulbar palsy UMN signs:
Respiratory symptoms spasticity, hyperreflexia, extensor plantar response
fatigue LMN signs:
weight loss muscle weakness, atrophy, fasciculations, cramps
May have significant clinical variablity atrophy can lead to deformities
weakness may be hemiparesis (one limb) or “Claw hand:” atrophy of both median and ulnar-
paraparesis (bibrachial paresis) nerve innervated muscles
may be limited to LMN, simulating nerve root or
plexus disorder
Progressive Muscular Atrophy
may be limited to UMN, simulating myelopathy
Primary Lateral Sclerosis
May primarily affect bulbar motor neurons Scapular Winging Tongue atrophy & fascic.
Primary Bulbar Palsy
Is often initially misdiagnosed!
MRI findings
MRI is often normal
corticospinal tract hyperintensity sometimes seen
represents gliosis
25: ALS & Spinal Cord Disorders
Anatomy Review: ALS Treatment
Median nerve Goal of treatment is to slow progression
Riluzole
inhibits release of glutamate and blocks
glutamate receptors, extends survival by several
months
Other agents in trials
Possible role for stem cells
Supporting Therapy
Gastric feeding tube
non-invasive ventilation
! survival, ! quality of life
physical therapy, etc
Ulnar Nerve
Motor Neuron Disorders of Infancy &
Childhood
Spinal Muscular Atrophy (SMA)
Description
progressive weakness & atrophy
degeneration of anterior horn cells (LMN)
NO UMN signs
recessive Survival Motor Neuron (SMN) gene on
chrom 5
95% have deletions that prevent expression
gene product required for mRNA splicing and assembly
of snRNPs
Pathogenesis/Pathology of ALS
Many factors may contribute to preferential Werdnig-Hoffman
vulnerability of motor neurons floppy infant < 6 mo, death within 2 yrs
Kugelberg-Welander
onset in childhood, milder, survival to 5th decade
Pathogenesis
Spinal Cord Compression
Cervical Spondylosis can compress cord & cervical
roots

large size
extensive dendritic tree
! neurofilaments, prone to aggregation
weak induction of stress proteins (HSP70)
motor neurons interact closely with their neighbors
and may be vulnerable to specific stresses degenerative dz
etc. narrows spinal canal and intervertebral foramen
Inclusions can cause:
role in ALS still unclear, but presence suggests that injury of spinal cord (myelopathy)
neurons are stressed injury to roots (radiculopathy)
axonal spheroids: packed with phosphorylated (or both)
neurofilaments
hyaline inclusions & ubiquitinated inclusions
25: ALS & Spinal Cord Disorders
Transverse myelopathy Brown-Sequard
epidural cord compressed by metastasis Cord hemisection

Anatomy of spinal cord

Clinical
ipsilateral findings below level of injury
UMN signs
loss of proprioception, vibration
ipsilateral findings at level of injury
paresthesias and radicular pain
contralateral findings
Localize the following lesions: loss ot pain and temperature extending to ~2
Ipsilateral UMN findings and " JPS with contralateral " dermatomes below level of injury
in pain/temp sensation Syringomyelia
Dissociated sensory loss, weakness, areflexia of upper Cavity in central spinal gray matter
extremities
sensory level with paraparesis and bladder
incontinence
B12 deficiency = subacute combined
degeneration
Clinical
Ataxia from sensory loss
gait disturbance: must look at ground while walking
positive romberg sign Clinical
Anatomy Dissociated sensory loss
loss of pain & temp in cape-like distribution with
other sensory modalities spared
frequent burns/injuries to arm (pt can’t feel pain)
Segmental paresis w/LMN signs
Horner’s (if lesion is in thoracic cord)
Sacral sparing

Posterior column involvement

loss of proprioception and vibration sense
+ romberg
Corticospinal tract involvement
peripheral neuropathy
optic atrophy
spinothalamic tract is OK
25: ALS & Spinal Cord Disorders
Tabes Dorsalis Review of spinal lesions
Degeneration of posterior columns

Clinical
develops 10-20 yrs after syphilis
posterior roots affected in addition to posterior
columns
Classic triad of symptoms:
1) “lightening” pains
2) ataxia
3) bladder disturbance
signs:
loss of proprioception (sensory ataxia)
areflexia
argyll-robertson pupils
only react to accomodation, not to light

Anterior Spinal Artery Syndrome

Infarction in anterior 2/3 of cord

Clinical
Flaccid paraplegia below level of lesion
dissociated sensory loss
loss of pain/temp below level of lesion
intact proprioception and vibration
dorsal columns spared ! supplied by posterior spinal
artery
occurs in watershed distribution (~T4)
associated with atherosclerosis, hypotension,
dissecting aneurysism, or repair of aortic
aneurysims
26: Muscle Disorders
Classification TSH
Inherited Electrolytes: screen for readily treatable
Muscular dystrophies disturbances
Duchenne’s EMG
Myotonic Dystrophy Look for “electrical signature” confirming weakness
is localized to muscle (vs NMJ, nerve, anterior horn,
Metabolic myopathies
etc)
mitochondrial
Useful in determining if myopathy has necrosis
Kearns-Sayre
myopathy with necrosis will have fibrillation
glycogen storage disease
potential activity
McArdle’s
Muscle Biopsy
Acquired
generally confirms diagnosis of myopathy and may
Idiopathic inflammatory myopathies reveal specific category
Dermatomyositis
Pathological Examples
endocrine Muscle Fiber Necrosis
Hypothyroid myopathy
toxic
Colchicine myopathy
myopathy of intensive care
infectious
Trichinosis
General Features of Muscle Disease
Proximal muscle weakness seen in many of the dystrophies caused by loss or
deficiency of sarcolemmal proteins
neck, pelvic girdle, humeral, femoral muscle
weakness inflammatory myopathies, toxic myopathies,
hypothyroid myopathy, etc.
head drop (head ptosis) from neck extensor
weakness Muscle Fiber Atrophy
Cranial nerve weakness rare
DTR’s normal
Clues in diagnosis
Location of involvement
ocular muscle involvement
mitochondrial myopathy
distal muscle weakness Above shows atrophy of Type II (dark) & Type I
(light)
myotonic dystrophy
typical of neurogenic atrophy
pharyngeal muscle weakness
Type II atrophy
inflammatory myopathy
corticosteroid myopathy or disuse atrophy
respiratory muscle weakness
Perivascular interfascicular inflammation and Fiber
myopathy of intensive care Necrosis
rash & arthralgia
suggests CT dz, like inflammatory myopathy
syncopy/lightheadedness
cardiomyopathy
Role of studies in diagnosis
Lab Values
CK: sensitive but nonspecific sign of muscle Perivascular & interfascicular inflammation
involvement characteristic of dermatomyositis
may be ! in neurogenic dz (ALS)
some myopathies (non-necrotizing) have normal
CK (corticosteroid myopathy)
ESR, CBC: screen for systemic disorder
26: Muscle Disorders
Variation, Vacuoles, Splits The Dystrophinopathies (Duchenne’s &
Becker’s)
X-linked diseases
Duchenne’s Muscular Dystrophy
Physical
bilateral winging of scapulas
marked hypertrophy of calf muscles
Gower’s maneuver
Trichinella spiralis larva places hands on knees to rise from floor
Clinical observations
no abnormality at birth
early toddler clumsiness doesn’t go away
firm & rubbery muscles
can’t run properly, tightness across several
joints
By age 5-6, stair climbing difficult w/o railing
Mitochondial myopathy Age 2-5, apparent improvement
natural development a step ahead of muscle weakness
Age 6-7, sudden falls
Age 8-10, must use wheelchair
Pathogenesis
"" or loss of Dystrophin (D)
mutation in DMD gene
deletion/duplication/small insertion/point
in HIV patient treated w/Zidovidine
very large gene & rod-shaped protein
inner surface of plasma membrane
provides mechanical stability
forms skeleton of muscle fiber
Damaged D !
damaged membrane due to exercise
satellite cells form myoblasts, plug hole
after ~ 60 divisions, satellite cells can no longer divide
crystalline inclusions in mitochondria larger muscles subjected to ! stress, hence more
affected
The case of the 34 yo homemaker
HPI Pathology
1 yr history of weakness
Exam
weakness of neck extensors, arm abductors, elbow
flexors & extensors, hip flexors, knee extensors
Labs
CK !!!
** rounded, opaque, pre-necrotic fibers
EMG NF necrotic fibers
fibrillation potentials in weak muscles RF clusters of regenerating fibers
potentials recruit early, are short in duration, " in CT excessive connective tissue deposition
amplitude, polyphasic in form Immunostain for dystrophin shows D is
Biopsy irregularly distributed, significantly reduced
scattered necrotic & regenerating fibers Diagnosis in proband with clinical symptoms
increased variation Elevated CK (up to 100x normal)
mononuclear cells surround non-necrotic muscle First step: Molecular testing of DMD gene
fibers If positive, diagnosis is made
Diagnosis If negative, muscle biopsy for western blot &
immunohistochemical studies of dystrophin
Inflammatory myopathy: polymyositis
26: Muscle Disorders
Management Weakness
keep joints loose facial, neck muscles
hand intrinsic muscles
stretch muscles
Percussion myotonia: slow tonic contraction after
night splints percussion of thenar eminence, take several
leg braces, spine stabilization seconds to resolve
distal leg muscles
corticosteroids allows 1-3 yrs of continued
proximal muscle involvement not prominent (but
ambulation
possible)
Becker’s Muscular Dystrophy Infantile myotonic dystrophy
Much more mild form than DMD, ambulation may hypotonia, facial paralysis, club feet
continue for decades
inverted “V’ of upper lip
Some fibers express dystrophin
EMG
waxing & waning of discharge frequency and
amplitude

Systemic features
" IQ
cardiac conduction defects
Clinical spectrum of dystrophinopathies
early cataracts
Consider additional phenotypes without much
weakness testicular atrophy, uterine hypotonia
" exercise tolerance Low IgG
muscle cramps & myoglobinuria insulin resistance
late onset benign muscle weakness heightened sensitivity to anesthesia
isolated ! CK smooth muscle involvement
congestive cardiomyopathy w/o weakness cholecystitis/constipation

isolated cognitive dysfunction Laboratory features

Myotonic Dystrophies CK: mildly !
Autosomal dominant diseases EMG: myotonic discharges
Myotonic Dystrophy (Type I) biopsy: variation in fiber size, fiber splitting,
typical features: elongated face, temporal & internalized nuclei
masseter wasting, narrow neck Pathogenesis
Complex multisystem disorder expansion of unstable trinucleotide repeat (CTG)
myotonia sequence on 3’ end of chromosome 19
length of repeat directly correlates w/ severity
delayed relaxation of striated muscle following
contraction Management
variability in severity watch cardiac, respiratory, sleep apnea
range from nearly asymptomatic adult to hypotonic infant easy myotonia
Autosomal dominant careful w/anesthesia
Clinical features in moderate dz monitor blood glucose
characteristic facial appearance physical therapy, etc
frontal balding, elongated face, temporal & masseter
wasting, narrow neck
Comes to medical attention due to:
mental retardation
disabling distal weakness
myotonia
Myotonic Dystrophy (Type II)
Different genetic defect
NO chromosome 19 CTG expansion
Chromosome 3 defect
26: Muscle Disorders
Type II is different from type I: Metabolic Myopathies (AR)
no congenital form Caused by an absence/deficiency in an enzyme
no mental retardation important to the metabolism of glycogen (e.g.
McArdles’disease) or fat (e.g.
less central hypersomnia
carnitinepalmitoyltransferase deficiency)
less symptomatic distal, facial, and bulbar
final common pathway: not enough production of
weakness
ATP
less pronounced muscle atrophy
abnormality can reside in glycolytic pathway, fat
Comes to medical attention due to: metabolism, or mitochondrial function
muscle pain, stiffness, fatigue w/proximal Acquired Myopathy
weakness Idiopathic inflammatory myopathies (Dermatomyositis)
Pathogensis of myotonic dystrophies Endocrine (Hypothyroid myopathy)
abnormally large expanded repeats in RNAs cause Toxic (Colchicinemyopathy; myopathy of intensive
both Type I and II care)
mutant mRNAs containg huge repeat expansions Infectious (Trichinosis)
accumulate in nucleus
Inflammatory Myopathies
Other inherited Myopathies Dermatomyositis
Dystrophinopathies (X-linked)
Clinical features
Myotonic Dystrophies (AD)
time-course: weeks to months
Oculopharyngeal Muscular Dystrophy (AD)
distribution of weakness
proximal muscles & neck flexors
dysphagia in 30%
weakness may be subtle
Rash
heliotrope, V sign, gottron’s sign
has childhood form
Associated diseases
malignancy
Emery Dreifuss Dystrophy (X-linked) CT disease (scleroderma)
pronounced elbow scapular winging interstitial lung disease (20%)
contractures and lumbar cardiomyopathy (10%)
lordosis
Diagnosis: straightforward
Responds to immunosuppressive treatment
Polymyositis
similar to DM above, but complex to diagnose w/
broad ddx
Inclusion body myositis
Clinical
time-course: weeks to months
distribution of weakness
proximal muscles & neck flexors
Facioscapularhumeral Dystrophy (AD) distal, asymmetrical
volar forearm & quads
Limb Girdle Dystrophies (AR, AD)
young person (1st through 4th decade) onset limb- other organ involvement rare
girdle weakness Associated diseases
M=F NOT malignancy
spares face CT disease
! CK Diagnosis: often difficult, simulates ALS
muscle biopsy resembles duchenne: Responds poorly to immunosuppressive treatment
necrosis/regeneration
Distal Muscular Dystrophies (AR)
26: Muscle Disorders
Laboratory
! CK
EMG shows evidence for necrosis & small motor
units
muscle biopsy: degeneration and regeneration &
inflammation
General Principles*
Muscle disease tends to have a limb girdle or proximal
predominance of weakness
Neuropathies tend to have a predilection for the distal
muscles (served by the longest axons)
Neuromuscular junction disease affects primarily
cranial nerve-innervated muscles and is characterized
by fatigability
*Watch out for the exceptions
Sample Questions
27: NMJ Disorders
Anatomy & Physiology of NMJ MG
Demographics
F 10-40, M 50-70 (thymoma)
Inheritance
sporatic
small percentage have FH
more than half of relatives of MG patients have
EMG abnormality and AchR Ab
Associated autoimmune dz:
thyroid dz, pernicious anemia
Three main clinical features
1) fluctuating weakness
varies from day to day or during course of day
fatigability with exercise
2) characteristic distribution
ocular
ptosis/diplopia is common initial presentation
pattern of weakness doesn’t conform to anatomical
distribution of nerves
Synthesis of Ach: Choline acetyltransferase
bulbar
acetate + choline ! Ach
affecting facial expression, mastication, swallowing,
Degradation speech
AchE (reverse of above rxn) jaw can sag open
Physiology Bell’s phenomenon when trying to close eyes (can’t
close them properly)
Two types of Ach release
limbs/trunk
1) spontaneous release ! MEPP erector spinae most frequently affected
due to release of single vesicle (quantum), 10K Ach neck extensors weak ! heads can flow forward
molecules
3) Response to cholinergic drugs
2) evoked ! EPP
in response to nerve AP, many vesicles are released Other clinical features
Events of NMJ transmission pain and sensory symptoms uncommon
Presynaptic nerve impulse ! Ach release ! smooth/cardiac, respiratory muscles uninvolved
EPP ! muscle AP minimal atrophy, normal DTR’s
Neuromuscular Disease Classification pupils spared
Can be classified by location Morphological changes at the NMJ
presynaptic disorders
Lambert-Eaton (LE)
postsynaptic disorders
MG
Can be classified by etiology
immune-mediated
LE, MG 1) " # AchR
toxic-metabolic 2) junction folds sparse & shallow, synaptic space
botulism, snake poisoning, hyperMg widened
congenital myasthenic syndromes Etiology & Pathogenesis
defects in Ach synthesis, AchE, or AchR autoimmune: AchR antibodies
Common clinical features cause rapid turnover of AchR
fluctuating weakness & fatigability AchR Abs synthesized by B cells in thymus
generally are pure motor syndromes thymus almost always abnormal in MG patients
affects proximal, bulbar, or extraocular muscles (hyperplasia, or thymomas)
preferentially thymectomy often results in improvement
MG is most common NMJ disorder Bacterial or viral Ag may be similar to AchR
27: NMJ Disorders
EMG Further Workup
Compound muscle AP (CMAP) 1) PFT’s
measure of # of muscle fibers activated by nerve 2) Rule out factors that can exacerbate MG
impulse 3) Chest CT: r/o thymoma, infection
How does EMG study help to study features of 4) r/o associated immuological dz (SLE, FR, TSH)
MG?
5) PPD skin test before giving immunosuppressive
repetitive nerve stimulation at low rate shows treatment
decremental response to CMAPs
6) review medication list, avoid drugs that may
Pathophysiology exacerbate MG
penicillamine, aminoglycoside, polymixin, $-
blockers, thyroid hormones, lithium,
chlorpromazine, etc
Treatment
1) AchE inhibitors
pyridostigmine, neostigmine
2) Immunosuppression
steroids, cyclosporine, mycophenolate mefetil
Presynaptic events are normal
3) Plasma exchange
normal # of quanta
4) Thymectomy
normal release process
But response to quanta is small
Ach binds to fewer receptors
Size of EP proportional to amount of Ach that
binds AchR
Fatigability
successive " in # of quanta released after
repetitive AP’s leads to " in size of EPP and
failure of NMJ transmission
decremental response with repetitive nerve
stimulation @ 3 Hz
Diagnosis
Pharmacological
tensilon test
give edrophonium
Physiological
EMG with repetitive stimulation at low rate to
show decremental response
Can also do single fiber testing in difficult case
+ in 90% of cases
Immunological
AchR Ab
+ in 90% of patients w/ generalized MG
+ in 50% of patients with ocular MG
4 different Ab’s
three against AchR and one against muscle
29: Peripheral Nerve Disorders
Clinical features of peripheral nerve disease 1) Axonal Neuropathy
Distinguishing between other peripheral disorders Description
In contrast to muscle, NMJ, and AHC disorders, stocking glove distribution of sensory loss
Peripheral nerve disorders have " sensory distal to proximal gradient
sensory Ankle DTR’s lost before knee DTR’s
positive: prickling, tingling, burning upper limb reflexes affected last
negative: loss of sensation, proprioception EMG: Nerve conduction studies (NCS)
motor " sensory and motor amplitudes
weakness (distal > proximal) conduction velocities normal or mildly reduced
muscle atrophy EMG: Needle electrode examination (NEE)
autonomic evidence of nerve irritability
orthostatic hypotension positive sharp waves
cardiac arrhythmia fibrillation potential activity

Electrodiagnostic studies voluntary activation: " # of large amplitude motor

unit potentials firing rapidly
2) Demyelinating Neuropathy
Description
loss of reflexes early in course, but muscle bulk
relatively well presevered despite weakness
proximal muscles involved early, may involve
nerve conduction studies facial muscles
evaluates sensory & motor fibers enlarged palpable nerves (familial)
repeated episodes of demyelination followed by
patients feel a shock remyelination
needle electrode examination EMG: Nerve conduction studies (NCS)
evaluates lower motor unit " sensory & motor amplitudes
needle in nerve and muscle " nerve conduction velocities
Axonal vs Demyelinating Neuropathy inherited: uniform slowing
Basis of classification acquired – dispersed responses, conduction block
two major pathological rxns to peripheral nerves: prolonged F waves
1) axonal degeneration (“dying back”) EMG: Needle electrode examination (NEE)
few abnormalities: minimal fibrillation or positive
waves
" # of motor unit potentials
Anatomic Classification of Peripheral
Neuropathy

1) Symmetrical Generalized Polyneuropathies

“initial appearance of histological %’s in axon followed by a) distal axonopathies: target of disease is axon
myelin degeneration and muscle denervation” toxic:
axonal degeneration continues in a distal ! proximal
drugs, chemicals
direction
longest nerves affected first: first have symptoms in toes, metabolic:
then progressively have symptoms move proximally uremia, diabetes, porphyria, endocrine
Wallerian degeneration: axonal degeneration occurring deficiency:
distal to the site of nerve fiber trauma
thiamine, pyridoxine
2) demyelination
genetic:
“initial appearance of histological %’s in myelin or
Schwann cell, followed by demyelination of several or charcot-marie tooth dz (II)
multipe internodal segments” malignancy:
small cell CA of lung, myeloma
29: Peripheral Nerve Disorders
b) myelinopathies: target of disease is myelin nadir of weakness within 2 weeks
toxic: ascending paralysis
diphtheria, buckthorn but can be descending at times (cranial nerves
immunologic: to arms/legs)
acute: Guillain-Barré, chronic: CIDP (chronic proximal muscle involvement early
inflammatory demyelinating polyradiculoneuropathy)
often have facial / oropharyngeal weakness
genetic:
can have respiratory failure
charcot-marie tooth dz (I), metachromatic
leukodystrophy often have dysautonomia (arrhythmias,
c) neuronopathies: target of disease is not axon orthostatic hypotension, HTN, bladder probs, etc)
or myelin, but cell body of neuron Lab Studies
somatic motor: ! CSF protein w/o cells (albuminocytological
ALS, hereditary motor neuronopathies dissociation)
somatic sensory EMG: multifocal demyelination
infectious: herpes zoster " conduction velocity
malignancy: carcinomatous sensory neuronopathy dispersed motor responses
toxic: pyridoxine sensory neuronopathy
conduction block
autonomic
Pathogenesis
hereditary dysautonomia
preceding viral infections may trigger autoimmune
2) Focal & Multifocal: sensory #’s and weakness in an
response
asymmetric and patchy distribution
cell-mediated immune rxn against myelin
ischemia
components
vasculitis (polyarteritis, RA), diabetes
infiltration of endoneurium by mononuclear cells –
infiltration periventricular distribution
leukemia, lymphoma, granuloma, schwannoma ! segmental demyelination
physical injuries
compression (carpel tunnel), crush, transection
immunological
CIDP variant, multifocal motor neuropathy
Steps to diagnose peripheral disorders
1) generalized or focal/multifocal?
based on location of signs/symptoms
2) axonopathy or myelinopathy?
based on history, physical, EMG A word on Guillain-Barré Syndrome (GBS)
3) additional lab studies ! diagnosis in the past, GBS = AIDP
AIDP (Acute Inflammatory Demyelinating Now, several forms of GBS are recognized:
Polyradiculoneuropathy) Demyelinating form: AIDP
Description Axonal variants (more common in northern
primarily a myelinopathy: multifocal demyelination China): AMAN, AMSAN
Symmetrical Generalized Polyneuropathy AMAN = acute motor axonal neuropathy
AMSAN = acute motor sensory axonal neuropathy
Acquired disorder of peripheral nerves & nerve
roots AIDP: Treatment
immune-mediated prevent complications, plasmapheresis, IV Ig
Clinical features AIDP: Prognosis
Triad of features: 75% good recovery by 6-12 months
1) motor weakness (variable extent) 11% wheelchair bound or chronic course
2) areflexia ~5% mortality
3) paresthesias with mild distal sensory loss poor prognostic factors:
2/3 have antecent event (URT illness/surgery) old age (>60)
associated with CMV & campylobacter jejuni need for ventilatory support
rapidly (days) progressive symmetric weakness time to plateau < 7 days
weakness does not progress > 4 weeks low mean distal motor amplitude
29: Peripheral Nerve Disorders
AIDP variant: Fisher syndrome Pathogenesis of DM neuropathy
ophthalmoplegia
ataxia
areflexia
Distal Symmetrical Polyneuropathy DDx
Uremia, B12 deficiency, EtOH/nutritional, amyloid,
collagen vascular dz, hypothyroid, vasculitis, diabetes
Diabetic Neuropathy
Most common complication of DM
most frequent peripheral nerve disorder worldwide Treatment
excluding traumatic neuropathies glycemic control!
Classification treatment of pain
distal symmetrical polyneuropathy NSAIDs
proximal symmetrical polneuropathy anticonvulsants
polyradiculoneuropaty gabapentin, lamotrigine, carbamazepine
diabetic amyotrophy TCA’s
thoracic radiculopathy tramadol
multiple mononeuropathies capsaicin cream
cranial mononeuropathies aldose reductase inhibitors
distal symmetrical polyneuropathy antioxidants
clinical features antiglycation agents
gradual onset PKC $ inhibitors
paresthesias
burning, aching, tingling
begin distal ! spread proximal
stocking-glove sensory loss distribution
when symptoms reach above knees, fingers and
hands affected
advanced: anterior chest and abdomen affected
" or absent DTR’s
mild motor weakness in distal muscles
autonomic involvement
small pupils
anhidrosis of lower extremities
orthostatic hypotension
fiber involvement
small fiber involvement
! impaired touch, pain, temp
large fiber involvement
! impaired proprioception and vibration ! ataxia
! susceptibility to unnoticed injuries
! foot ulcers, joint destruction
Pathology
axonal degeneration pathologically
EMG
absent sensory responses in legs
low motor amplitudes
fibrillation potential activity in distal > proximal
muscles (foot muscles)
Lecture List:
1. Cellular Neuropathology
2. Blood-brain barrier / Brain Edema / Herniations
3. CSF in Health and Disease
4. Adult Neurologic Exam
5. Localization in Neurological Diagnosis
6. Coma
7. Disorders of Higher Cortical Function
8. Cerebrovascular Pathology
9. Cerebrovascular – Clinical
10. Histology Lab #1 (Normal, Strokes)
11. Demyelinating Disease Pathology
12. Demyelinating Disease – Clinical
13. Tumor Pathology
14. Tumor – Clinical
15. Histology Lab #2 (MS, Tumors)
16. Adult Neurology small groups #1
17. CNS Malformations
18. Acquired Brain Injuries in Children
19. Traumatic Brain Injuries & Neuropsychiatric Sequelae
20. Epilepsy
21. Headache
22. Pain
23. Dementia
24. Basal Ganglia / Movement Disorders
25. ALS and Spinal Cord Disorders
26. Muscle Disorders
27. NMJ Disorders
28. Histology Lab #3 (Alzheimers, Parkinson’s, ALS)
29. Peripheral Nerve Disorders
30. Sleep
31. ANS Disorders
32. Adult Neurology small groups #2
33. Neurorehabilitation
34. Dizziness