01: Reactions of CNS to Injury:
2) Simple atrophy
Normal histology & function
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) 1) Necrosis due to acute cell injury = oncosis
if proteosome/ubiquitin pathway overloaded or damaged A) Alzheimers
Caused by:
!
tau ! neurofibrillary tangles tau is a component of microtubules
Primary: disruption of energy supply due to hypoxia, hypoglycemia, toxins
hyperphosphorylation involved in pathogenesis of NFT’s
Secondary: Excitotoxic injury:
microtubules fall apart when tau misfolds ! cell dysfunction
CNS injury causes: ! release of excitory aa’s
(glutamate)
! 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, hyperchromasia, disintegration
C) Huntingtons ! huntingtin (polyglutamine repeats) ! intranuclear inclusions
Cytoplasm: cytotoxic edema (vacuoles) loss of Nissl substance, eosinophilia (red neurons)
D) Prion disease
"
!
PrP(sc) ! PrP(sc) amyloid fibrils
viral inclusions possible (i.e. herpes) storage material
Astrocytes (potatoes) 1) Normal histology & function:
2) Apoptosis
are everywhere: cortex, GM, & WM
Occurs in: CNS embryogenesis corticosteroid-induced corticosteroid-induced cell death secondary effects of ischemic stroke (area surrounding stroke = “penumbra”) neurodegenerative diseases (Pick’s disease) Morphology: DNA fragmentation typical
immunostain for glial fibrilary acidic protein (GFAP) involved in neuronal migration and connectivity during embryogenesis important for synaptic growth & plasticity have many metabolic functions blood-brain barrier
Non-lethal injury 1) Axonal reaction (central ch romatolysis) Wallerian degeneration: degeneration of distal nerve following axonal injury Central chromatolysis: cell becomes very active in response to injury (4 days to 3 weeks) Morphology:
flid, electrolyte, neurotransmitter metabolism nutritive & energy support for neurons
2) Reactive gliosis: the “universal reaction” to injury Morphology: 1) hypertrophy of cytoplasmic processes
"
Cytoplasmic swelling
dissolution of Nissl bodies (very active, no longer “stacked”)
2) increased production of GFAP (pink cytoplasm)
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 ! or ! GFAP "
Wilson’s disease
(due to abnormal copper metabolism, leads to cirrhosis). Notice enlarged nucleus, unenlarged cytoplasm
Pathophysiology: Often specific to metabolic injury
Embryogenesis NOT derived from neuroepithelial cells in neural tube
Associated with ! NH4 in liver disease Alzheimer type 2 gliosis helps to detoxity ammonia seen with severe cirrhosis
derived from bone marrow stem cells (mesoderm)
Functions Antigen presentation
Clinical
cytokine production
hepatic encephalopathy = when a sick li ver causes brain damage due to ! NH4 causes pyramidal symptoms, “cloudiness,” finger flaps
Oligodendrocytes (tomatoes) Normal function: Myelination
phagocytic (limited activity)
Reactions to injury Microglial activation: ! number and size phagocytic: neuronophagia HIV infects mainly microglial cells, not neurons
Single oligodendrocyte extending over SEVERAL axons
"
In PNS, Schwann cells each myelinate a single axon.
Examples of Microglia in action After a cerebral infarct: Microglials transform into macrophages
Stain for Myelin 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 Toxic/metabolic Hypoxia/ischemia
Due to differences in: connectivity, receptors expressed, vascular supply, etc Clinical example: Hippocampus very susceptible to hypoxia Selective involvement in degenerative disease ALS, spinocerebellar degeneration
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 ! or ! GFAP "
Wilson’s disease
(due to abnormal copper metabolism, leads to cirrhosis). Notice enlarged nucleus, unenlarged cytoplasm
Pathophysiology: Often specific to metabolic injury
Embryogenesis NOT derived from neuroepithelial cells in neural tube
Associated with ! NH4 in liver disease Alzheimer type 2 gliosis helps to detoxity ammonia seen with severe cirrhosis
derived from bone marrow stem cells (mesoderm)
Functions Antigen presentation
Clinical
cytokine production
hepatic encephalopathy = when a sick li ver causes brain damage due to ! NH4 causes pyramidal symptoms, “cloudiness,” finger flaps
Oligodendrocytes (tomatoes) Normal function: Myelination
phagocytic (limited activity)
Reactions to injury Microglial activation: ! number and size phagocytic: neuronophagia HIV infects mainly microglial cells, not neurons
Single oligodendrocyte extending over SEVERAL axons
"
In PNS, Schwann cells each myelinate a single axon.
Examples of Microglia in action After a cerebral infarct: Microglials transform into macrophages
Stain for Myelin 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 Toxic/metabolic Hypoxia/ischemia
Due to differences in: 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 History Brain would not be stained when blood was stained, and vice-versa
Pathophysiology of BBB Disruption Disruption of BBB: passage of free fluid & macromolecules from circulation into cerebral extracellular space Can cause:
Anatomy Course of blood vessels to brain Blood vessels run in subarachnoid space Branches penetrate the cortex The area immediately surrounding the arterioles is NOT the BBB. This is the Virchow-Robbins (VR) space
1) vasogenic edema 2) ! protein in CSF Can be caused by: tumors with abnormal vessels (e.g. glioblastoma) MRI contrast enhancement with injected dye would show abnormal vascular permeability 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 junctions
!
Endothelium joined by tight
2) secondary BBB ! basement membrane and astrocytic processes Regions of brain lacking BBB 1) Pineal 2) Medulla (area postrema) 3) Hypothalamus 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
choroid plexus capillaries are fenestrated and will allow passage of macromolecules into choroid plexus stroma dye travels through stroma of chorid plexus but it CANNOT enter ventricle due to blood-CSF barrier
choroid plexus cells secrete CSF
02: Blood-Brain Barrier, Brain Edema, Herniations:
Brain Edema
Brain herniations
1) Vasogenic Edema: ! ECF
! intracranial pressure (ICP)
Pathogenesis:
Monro-Kellie doctrine
! capillary permeability Characteristics: Location: white matter, because there is more room for expansion Composition: plasma filtrate + protein ! Extracellular fluid volume extracellular space
!
enlarged
! Macromolecule permeability Clinical conditions tumor, abscess, active demyelinating lesions, organizing hematomas, infarcts (later stage) Detection: T2-weighted MRI 2) Cytotoxic Edema: cells swell up
In a closed system, total volume available is inconstant Very rapid rise of pressure once you’ve passed critical volume Consequences of ! ICP brain herniations (3) a marker of “midline shift”
brain death (global hypoxia-ischemia) 1) Subfalcine herniation primary event: sliding of cigulate gyrus beneath falx 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: Cellular swelling due to " membrane ion pumps Characteristics: Location: GM & WM Composition: intracellular water and sodium " (slightly) Extracellular fluid volume normal macromolecule permeability
b) Compression of CONTRALATERAL cerebral peduncle (kernohan’s notch) (more rare) ipsilateral hemiparesis
c) Compression of PCA (posterior cerebral artery) infarction of medial temporaloccipital lobes !
Clinical conditions: hypoxic-ischemic encephalopathy (i.e. due to subarachnoid hemorrhage), infarcts (early stage), hypoosmolality
d) Shearing of perforating vessels in upper brainstem ! Duret hemorrhages
Detection: Isodense appearance on CT: cannot easily separate GM from WM 3) Interstitial Edema Pathogenesis: Mainly due to choroid plexus CSF outflow obstruction (! brain fluid due to impaired CSF circulation or resorption) Characteristics: Location: primarily around ventricles (periventricular WM) Composition: same as CSF ! Extracellular fluid volume normal macromolecule permeability Clinical conditions: hydrocephalus (large ventricles on T2 MRI or CT) e.g. Colloid cyst obstructing foramina of Monro (connects rd lateral ventricles to 3 ventricle)
brainstem shoved down Basilar artery is fixed, but brainstem slides down !
COMA or LETHAL
3) Cerebellar tonsillar herniation primary event: downard displacement of cerebellar tonsils through foramen magnum secondary event: Compression of medulla ! dysfunction of respiratory and CV centers ! cessation of respiration and death Brain death Pathogenesis if ICP > BP, brain can’t be perfused ! global hypoxic-ischemic injury ! total necrosis
03: CSF in Health and Disease:
CSF Formation CSF Produced mainly by choroid plexus
outpouchings of arachnoid membrane through 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 rd th of 3 and 4 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 simple cuboidal epithelium tight junctions in between cells microvilli form a brush border cilia on apical surfaces help in CSF movement CSF also produced by Ependymal lining and Perivascular spaces (Virchow-Robbin)
CSF Circulation & Flow Animation: http://www.sickkids.ca/childphysiology/cpwp/brain/csf.htm
Waste disposal removes wasts products of metabolism Communication acts as a messaging system via cytokines, hormones, neurotransmitters, metabolites
Hydrocephalus Definition pathological increase in cerebral ventricular volume 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 Lateral ventricles !
foramena of Monroe (interventricular foramina)
into Third ventricle !
aqueduct of Sylvius
into Fourth ventricle !
Foramena of Luschka (Lateral foramina)
!
Foramen of Magendie (Median foramen)
into subarachnoid space and basal cisterns three main cisternae (thin potential spaces that could get pathologically dilated): cisterna interpeduncularis cisterna pontis cisterna cerebellomedullaris
CSF Reabsorbed by Arachnoid granulations
! ventricular size clinical triad: 1) dementia 2) incontinence 3) gait disturbance
6) Hydrocephalus ex vacuo consequence of stroke ventricle expands 7) External hydrocephalus pediatric have dilation of subarachnoid space Extension of CSF to/around optic nerve leads to papiledema, which can signify hydrocephalus
03: CSF in Health and Disease:
! protein
CSF Acquisition (Lumbar Puncture) Indications:
! bilirubin in body
CNS infections
! carotenoid pigments
CNS inflammation
Brown/Gray: CNS melanoma
CNS tumors
Greenish: carcinomatous meningitis (lots of malignant cells)
SAH
Gram stain
MS GBS (?)
Bacterial meningitis ~70% positive if untreated
CIDP (?)
~50% positive if partially treated
Contraindications
~90% positive if Pneumococcal or Staph
Bleeding or clotting disorders 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 Highest point of iliac crest identified, imaginary line interesects space between L3 and L4
Cells Normal: WBC: No PMN’s, < 5 mononuclear cells
Pressure Normal Normally 12-18 cm H20
RBC: No RBCs, except due to traumatic tap 700 RBCs account for 1 WBC
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 benign intracranial hypertension ( = pseudotumor cerebri) space occuping lesions
connective tissue disorders ! RBC’s: traumatic or SAH Protein
venous sinus thrombosis
Sensitive, but non-specific marker which reflects BBB permeability
diffuse cerebral inflammatory or toxic process
Normal value: 30-45 mg/dL
Decreased pressure spontaneous intracranial hypotension Complications herniation Post LP headache To reduce, use small needle size, bevel direction parallel to dural fibers, and replace stylet before withdrawal of needle infection epidural hematoma, SDH, SAH implantation of epidermal tumor
CSF Analysis Appearance
1000 RBC’s = 1 mg increase in protein ! Protein CNS infections, inflammation, or tumor " Protein young children removal of lots of CSF intracranial HTN (30% of cases) Oligoclonal bands: electrophoretic separation of protein on gel, each band represents a homogenous protein secreted by a single clone of plasma cells monoclonal normal CSF rarely has more than 1 band
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 Can take three tubes ! if blood decreases then it’s probably traumatic Can also do RBC cytology to determine Yellow: xanthochromia
~25% of other CNS inflammatory disorders have OCBs
polyclonal
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 pressure
Protein
Glucose
!
!
"
! PMN’s
+
+
Viral meningitis
! or normal
!
normal
! Mononuclear
-
+/-
PCR +
HSV encephalitis
! or normal
!
normal
! Mononuclear
-
+/-
PCR +
Multiple Sclerosis
normal
!
normal
normal or ! Mononuclear
OCB + IgG ! MBP +
! or normal
!
normal
normal or ! Mononuclear
Albuminocytologic dissociation +
Bacterial meningitis
Guillain-Barre
Cells
Gram
Cultures
Other
04: Neurological Exam:
Four main questions to be addressed 1) Is there a lesion? Where?
examine resistance to passive movement Strength: MRC scale
2) What is its pathophysiology?
0 = no movement
3) What further studies are needed to elucidate the diagnosis?
1 = muscle belly moves but not sufficient to move a joint
4) How will the problem be managed?
2 = movement of joint with gravity eliminated
Method of examination Cranial nerves I:
3 = movement against gravity 4 = movement against some resistance 5 = full strength
test each nostril separately using non-irritating odor II:
movement coordination finger-nose
test visual fields and acuity pupillary light response (efferent requires CN III), and observe fundus III, IV, VI: extraocular motions and lids V:
heel-shin gain and station ask patient to walk on heels, toes Romberg reflexes Scale 0 = absent reflex 1 = reflex present only with reinforcement 2 = normal 3 = brisk 4 = clonus Level Biceps = C5/6
check touch and pain in all three divisions corneal reflex (efferent is CN VII) jaw strength, and jaw jerk VII: Check for symmetry of nasolabial folds during smile Check orbicularis oculi strength by resistance to forced eye closure Check frontalis by asking patient to elevate eyebrows VIII: assess hearing perform Weber and Rinne tests IX, X: assess gag reflex and soft palate strength 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
Brachioradials = C6 Triceps = C7 Quadriceps (knee jerk) = L4 Achilles (anke jerk) = S1 Other reflexes Pathological Babinski, snout, grasp
Superficial abdominal, cremasteric
Meningeal Kernig Brudzinski
sensory system primary: touch, pinprick, vibration, position cortical: stereognosis, graphesthesia, extinction, point localization
04: Neurological Exam:
Localization & Formulation 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, spinothalamic 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
Dermatomes
08: Cerebrovascular Disease:
Cerebral Ischemia Diffuse: hypoxic-ischemic encephalopathy Focal: cerebral infarction/ischemic stroke
Pathology of Ischemic stroke Molecular events in cerebral ischemia
Imaging of Acute Ischemic Stroke CT scan insensitive to infarcts < 24 hrs old Can image occluded vessels 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 red neurons Ischemic penumbra Definition: zone of viable tissue surrounding infarct where cells are at increased risk of irreversible injury No cytotoxic edema (yet) Caused by: spreading neuronal depolarization excitotoxic injury impaired microcirculation activation of neuronal apoptosis Detected by: Diffusion-perfusion mismatch Subacute (2-13 days) liquefaction necrosis with macrophage infiltration (some from microglia, some from bloodstream)
Pathophysiology: in situ thrombosis due to plaque rupture or severe stenosis atheromatous lesions most often at vessel bifurcations Pathology: medium to large-sized cerebral infarcts, often in more than one vascular territory Location: cerebral hemispheres (carotid), brainstem, cerebellum (vertebrobasilar) 2) Small vessel: hypertensive Affected vessels: Small penetrating arteries arising at right angles from major arteries lenticulostriate thalamostriate
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
Gliosis (GFAP) in area surrounding stroke GFAP is an intermediate filament NO collagen. Just a hole.
Vascular occlusion is NOT a thromus. It is a proliferative injury due to HTN. tPA doesn’t work.
Pathology: lacunar infarction (<1.5 cm), hemorrhage
08: Cerebrovascular Disease:
Location: basal ganglia, thalamus, pons, cerebellum, cerebral white matter 3) Embolic: Affected vessels: smaller vessels, such as arterial branches of circle of Willis, often at bifurcations or stenotic areas Pathology:
Hemorrhagic Stroke Pathogenesis embolic infarcts can be hemorrhagic can happen iatrogenically with tPA Classification by mechanism 1) HTN ! Hyertensive cerebral hemorrhage Etiology: !BP !
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 territories may be hemorrhagic due to reperfusion
Location: Occur @ level of bifurcating arteries Anterior >> posterior circulation Most common sites:
Location:
Anterior: ICA-Post communicating MCA
cerebral hemispheres (cortex, WM, rarely deep 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
4) Other (vasculitis, dissection, radiation injury, hypercoagulable state, etc)
Congenital defect in muscle wall (media) at arterial bifurcation 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 have a big impact PNS: one Schwann cell myelinates only one internode on a single axon Demyelination: general points primary target of disease = myelin-forming cell and/or myelin sheath axons are relatively preserved distinguish from secondary loss of myelin due to axonal degeneration axonal injury is SECONDARY consequence of demyelination if the reverse happened (axonal death) then you can’t have myelin sheathing nothing (myelin would die too) segmental loss of myelin sheath impairs axonal transmission ! clinical deficits Demyelinating disease: Numerous etiologies Immune mediated CNS: MS, acute disseminated encephalomyelitis (post-viral encephalomyelitis) PNS: Guillian-Barre syndrome Infectious (e.g. PML, SSPE) Toxic-metabolic acquired (central pontine myelinolysis) hereditary (leukodystrophies) Vascular
Multiple Sclerosis Definition & Clinical Presentation
Appearance well-circumscribed areas of pink-gray discoloration found in (but not confined to) white matter
Size range from microscopic foci to large confluent regions of hemispheric white matter
Location Generally perivenular, especially in walls of lateral ventricles junction of cerebral cortex and WM optic nerves, chiasm, and tracts brainstem (especially pons) spinal cord
Active MS Plaque Histology Active Plaque = very cellular plaque 1) mononuclear cell inflammation perivascular: CD8+ T cells B-cells
plaque parenchyma CD4+ T cells
2) altered vascular permeability etiology interaction between endothelium and inflammatory cells in plaque (cytokine effect)
radiology BBB breakdown lesions
!
contrast enhancement of active
3) active demyelination 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 conspicuous feature of active plaques function: APC (MHC II)
some loss of oligo’s relative axonal sparing (some plaques may have significant axonal loss) 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 O 2 species) loss of normal “trophic” or protective effect of myelin sheath An active MS plaque will stain: positive for neurofilament protein (axons still there) but negative for myelin
f) remyelination is possible
1) Peripheral activation of autoreactive lymphocytes 2) Homing to CNS 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 clinical effect: recovery of function following acute episode?
9) Axonal degeneration
13: Tumors:
examples: medulloblastoma, glioblastoma
Tumors – Classification primary tumors
Extra-CNS (metastatic) spread
neuroectoderm
very rare
glial cells ! astrocytoma, oligodendroglioma, ependymoma, glioblastoma neurons ! ganglion cell tumors embryonal cells ! medulloblastoma “Sheath” cells
most often seen in medulloblastoma (late); rarely glioblastomal other gliomas WHO Classification circumscribed pilocytic astrocytoma (WHO grade I)
Arachnoid cell ! meningioma Schwann cell ! schwannoma, neurofibroma
pilocytic = “hair-like”
diffusely infiltrating astrocytoma (WHO grade II)
Secondary tumors metastatic ! carcinoma, sarcoma, melanoma
anaplastic astrocytoma (WHO grade III)
hematopoietic ! leukemia, lymphoma
glioblastoma (WHO grade IV)
Tumors: Age/Incidence/Location
1) Pilocytic astrocytoma most common astrocytoma in children
Adults
location
Supratentorial Most common: metastases > gliomas > “sheath” tumors Children
cerebellum (mainly) rd
also 3 ventricular region biologic behavior
Infratentorial
very slow growing
most common: neuroectodermal tumors
excellent prognosis after surgical removal
astrocytoma, medulloblastoma, ependymoma
Clinical effects of brain tumors space-occupying effects on brain parenchyma
only rarely malignant pathology 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
microscopic: WHO grade I
most gliomas 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
Neuroepithelial (neuroectoderm) tumors Spread
no mitotic activity, necrosis, or other features of anaplasia. the cells look pretty much like normal astrocytes compact and spongy areas
infiltration of normal brain structures most common method of spread examples: astrocytoma, glioblastoma, medulloblastoma Dissemination within CSF (subarachnoid space, ventricles) uncommon
rosenthal fibers microcysts
13: Tumors:
2) Diffusely infiltrating astrocytomas Atrocytoma + glioblastoma are 80% of primary brain tumors in adult location: mostly cerebrum but can occur anywhere
variegated appearance with hemorrhage and necrosis may cross midline through corpus callosum – “butterfly glioma”
microscopic (WHO grade IV)
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
low-grade (WHO grade II)
hyperproliferative area
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
3) Glioblastoma
Pathogenesis of gliomas: GENETICS
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
“Sheath” Cell tumors Meningiomas
Age: mainly children and young adults, most common neuroepithelial tumor in children.
incidence: 15% of primary brain tumors
location: cerebellum
most common non-glial primary CNS tumor in adults
origin: th
primitive neuroectodermal cells in roof of 4 ventricle or external granular layer of cerebellum
cell of origin: meningothelial (arachnoid cap) cell
The only brain tumor we know of that DEFINITELY comes from stem cell
location: falx and cerebral convexities, skull base, tentorium, foramen magnum, ventricles, spinal cord
arise out of arachnoid villi?
biologic behavior: diffuse spread via CSF, extra-CNS spread (late)
dark blue stuff in ventricle is tumor, spreads through CSF
sensitive to radiation and/or chemo > 50% 5-year survival pathology
biological behavior slow growing, usually benign
gross:
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:
location: cranial & spinal sensory nerve roots
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 once they're in the brain. location:
single or multiple most intracranial schwannomas originate from vestibular branch of CN VIII old term: acoustic neuroma. New term: vestibular schwannoma. Don't come from acoustic branch of VIII, but can impinge on the acoustic branch and cause deafness
mainly cerebral hemispheres, periventriclar, but can be multicentric (many tumors arising at different sites)
note multifocal, periventricular locations
biologic behavior: bilateral vestibular schwannomas – type 2 neurofibromatosis (NF2) biologic behavior: slow-growing, benign; treated by surgery pathology:
highly malignant (<2 yrs survival) pathology gross: Ill-defined or circumscribed masses 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 compact (Antoni A) and loose (Antoni B) areas don’t worry too much about the histology, just know that they’re spindle-shaped cells
confirm with immunohistochemistry
13: Tumors:
Metastatic tumors Incidence: 50-60% of all brain tumors 10-20% of patients with extra-CNS carcinoma develop brain mets most common primaries: lung (>50%) breast (15%) skin (melanoma) colon kidney tumors most likely to metastasize to brain: melanoma breast lung location: brain parenchyma (75% in cerebral hemispheres) dura leptomeninges (meningeal carcinomatosis)
Pathology: gross: well-circumscribed masses don’t infiltrate like gliomas do
predilection for gray-white junctions necrosis, hemorrhage or cyst formation vasogenic edema abnormal contrast
microscopic: usually similar to primary tumor
19: Pathophysiology & Neuropsychiatric Sequelae of Traumatic Brain Injury
caused by angular acceleration
Traumatic Brain Injury (TBI) 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 NOT cut
Epidural 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
Microscopically: NOT diffuse, can see small areas of focal hemorrhage
Initial GCS 10-12
Glasgow Coma Scale Eye opening
Certain high-probability areas:
1. none 2. to pain 3. to speech 4. spontaneous Motor Response 1. none 2. extension
inferior orbitofrontal (where “personality” is) anterior temporal
4. withdrawal
occipital
Can be seen on MRI sometimes Can been seen as “dysfunctional area” visible on SPECT
5. localize pain 6. obeys commands Verbal response 1. none
Years Later Contusions can turn into Plaques Jaunes
Diffuse axonal injury (DAI)
2. incomprehensible 3. inappropriate
often normal CT but can be imaged by “GRASS”
3. abnormal flexion
4. confused !
finds hemosiderin
DAI actually not diffuse, but has small foci
5. oriented
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
2) Generalized seizures ! no auras but can have prodrome
Epilepsy: Definitions Epileptic Seizure transient disturbance of cerebral function due to extensive and hypersynchronous abnormal activity of cortical neurons Epileptic Disorder = “Epilepsy”
a) tonic-clonic (grand mal) seizure loss of consciousness ictus ( = the seizure itself) fall
Chronic neurological condition characterized by recurrent epileptic seizures These disorders are “The Epilepsies” A single seizure is NOT epilepsy Suggests some type of underlying neurological defect (but can be many causes)
“The Epilepsies” 1) Partial (focal) seizures ! localized cortical excitation
muscular rigidity (tonic) inhibited respiration (cyanosis) rhythmic jerking (clonic) less than 2 mins duration incontinence tongue biting common
post-ictal confusion b) absence (pronounced like you’re a Frenchy) almost always seen in children onset before puberty
a) simple partial seizures no impairment of consciousness Aurus reflect stimulation of a certain cortical region can be motor
otherwise normal children
multiple lapses of consciousness under 10 secs (frozen) up to 100’s per day
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
very quick jerks
can be psychic affective
d) clonic
illusions
e) tonic
structured hallucinations
stiffening: assumption of rigid posture
cognitive
often seen w/development disabled
b) complex partial seizures with impairment of consciousness aura often present
f) atonic (drop seizures) 3) Unclassified seizures a) Infantile spasms
unresponsive staring duration less than 2 minutes
VERY BAD
may be automatisms
very brief seizures involving bilateral symmetric flexor or flexor-extensor spasms
post-ictal confusion usually present
may occur hundreds of times per day
todd’s paresis: neurological deficit following seizure
usually begin between 3 months and 1 year of age
c) secondarily generalized seizures starts focally, spreads bilaterally Complex Partial Seizure
Absence Seizure
often associated with underlying cerebral disease poor prognosis, mental retardation common outcome 4) Status epilepticus
1-2 min duration
10-30 secs duration
May be aura
no aura
A seizure lasting more than 30 minutes, or recurrent seizures w/o return to baseline neuro status
ictal automatisms
rare automatisms
can occur with all forms of seizures
post-ictal confusion
immediate recovery
focal spikes on EEG
generalized 3 Hz spike/wave on EEG
generalized tonic-clonic status is neurological emergency 25% mortality
20: Epilepsy
Causes of Epilepsy General
Medications for Epilepsy Partial Seizures
NO pathognomonic lesion of epileptic brain
Carbamezepine
many different types of metabolic abnormalities and anatomical lesions can prouce seizures
Phenytoin
Common causes by age Infancy (0 ! 2 yo)
Valproate Pheonobarbital Generalized Tonic-clonic seizures
intracranial birth injury
Carbamezepine
acute infection
Phenytoin
perinatal hypoxia & ischemia
Valproate
metabolic disturbances (hypoglycemia, hypocalcemia)
Pheonobarbital
congenital malformations genetic disorders Childhood (2 ! 10 yo) idiopathic = genetic acute infection trauma febrile convulsions Adolescence (10 ! 18 yo) idiopathic = genetic trauma drug, alcohol withdrawal vascular malformation Early Adulthood (18 ! 35 yo) trauma
Absence Seizures Valproate Ethosuximide NO Carba/Phenytoin! Myoclonic Seizures Valproate Clonazepam
Treatment of status epilepticus manage ABC’s IV benzodiazepines
Surgical Treatment of medically refractory partial epilepsy Commonly found after resective surgery Mesial Temporal Sclerosis
drug, alchohol withdrawal
present in up to 75% of resected temporal lobe specimens
idiopathic = genetic
scars after epilepsy
tumor
typically greater than 50% cell loss in CA1-4 of:
Middle age (35 ! 60 yo) tumor 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
hippocampus fascia dentata prosubiculum
25: ALS & Spinal Cord Disorders
Clinical Features of ALS General Descriptions age-dependent, progressive, lethal loss of LMN ! skeletal denervation & atrophy
specialized MRI protocols (diffusion-tensor MR imaging) can also reveal corticospinal tract impairment Electrodiagnostic studies 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 bottom images are ALS, top are normal
loss of UMN (cortex)
!
spasticity & hyperrelexia
non-motor systems (i.e. sensory) spared focal onset, then spread Diagnosis “Rule out everything else” Absense of: Electrophysiological, EMG, neuroimaing evidence of other diseases Presence of: UMN & LMN degeneration progressive spread of deficit Specific Physical Findings Bulbar symptoms CN V, VII, IX, X, XII Dysarthria Dysphagia risk of aspiration pneumonia Drooling Pseudobulbar palsy Respiratory symptoms fatigue weight loss May have significant clinical variablity weakness may be hemiparesis (one limb) or paraparesis (bibrachial paresis) may be limited to LMN, simulating nerve root or plexus disorder
20% with mutations in SOD1 (Cu/Zn superoxide dismutase) Western Pacific ALS is a complex disorder with multiple suspected causes and phenotypic variation interplay of environment, genes, and aging toxic exposure, excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation, monogenic defects, and polygenic traits can all play a role
ALS Differential Diagnosis Polyradiculopathy/myelopathy post-polio syndrome motor neuropathy with anti-GM1 Ab MND and gammopathy/paraproteinemia heavy metal intoxication hexosaminidase-A deficiency paraneoplastic motor neuronopathy syndrome syringomyelia/syringobulbia
ALS affects both UMN and LMN motor neurons UMN signs: spasticity, hyperreflexia, extensor plantar response LMN signs: muscle weakness, atrophy, fasciculations, cramps atrophy can lead to deformities “Claw hand:” atrophy of both median and ulnarnerve innervated muscles
Progressive Muscular Atrophy
may be limited to UMN, simulating myelopathy Primary Lateral Sclerosis
May primarily affect bulbar motor neurons Primary Bulbar Palsy
Is often initially misdiagnosed! MRI findings MRI is often normal corticospinal tract hyperintensity sometimes seen represents gliosis
Scapular Winging
Tongue atrophy & fascic.
25: ALS & Spinal Cord Disorders
Anatomy Review: Median nerve
ALS Treatment 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
Ulnar Nerve
physical therapy, etc
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
Pathogenesis/Pathology of ALS Many factors may contribute to p referential vulnerability of motor neurons
gene product required for mRNA splicing and assembly of snRNPs
Werdnig-Hoffman floppy infant < 6 mo, death within 2 yrs Kugelberg-Welander th
onset in childhood, milder, survival to 5 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 n eighbors 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 neurons are stressed
injury of spinal cord (myelopathy)
axonal spheroids: packed with phosphorylated neurofilaments
(or both)
hyaline inclusions & ubiquitinated inclusions
injury to roots (radiculopathy)
25: ALS & Spinal Cord Disorders
Transverse myelopathy epidural cord compressed by metastasis
Brown-Sequard 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: Ipsilateral UMN findings and " JPS with contralateral " in pain/temp sensation Dissociated sensory loss, weakness, areflexia of upper extremities
loss ot pain and temperature extending to ~2 dermatomes below level of injury
Syringomyelia Cavity in central spinal gray matter
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 Anatomy
Clinical Dissociated sensory loss loss of pain & temp in cap e-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 artery
!
supplied by posterior spinal
occurs in watershed distribution (~T4) associated with atherosclerosis, hypotension, dissecting aneurysism, or repair of a ortic aneurysims
26: Muscle Disorders
Classification Inherited Muscular dystrophies Duchenne’s Myotonic Dystrophy Metabolic myopathies mitochondrial Kearns-Sayre
glycogen storage disease McArdle’s
Acquired Idiopathic inflammatory myopathies Dermatomyositis endocrine
TSH Electrolytes: screen for readily treatable disturbances EMG Look for “electrical signature” confirming weakness is localized to muscle (vs NMJ, nerve, anterior horn, etc) Useful in determining if myopathy has necrosis myopathy with necrosis will have fibrillation potential activity Muscle Biopsy generally confirms diagnosis of myopathy and may reveal specific category
Pathological Examples Muscle Fiber Necrosis
Hypothyroid myopathy toxic Colchicine myopathy myopathy of intensive care infectious Trichinosis
General Features of Muscle Disease Proximal muscle weakness neck, pelvic girdle, humeral, femoral muscle weakness head drop (head ptosis) from neck extensor weakness
seen in many of the dystrophies caused by loss or deficiency of sarcolemmal proteins inflammatory myopathies, toxic myopathies, hypothyroid myopathy, etc. Muscle Fiber Atrophy
Cranial nerve weakness rare DTR’s normal
Clues in diagnosis Location of involvement ocular muscle involvement mitochondrial myopathy distal muscle weakness myotonic dystrophy pharyngeal muscle weakness inflammatory myopathy respiratory muscle weakness myopathy of intensive care
Above shows atrophy of Type II (dark) & Type I (light) typical of neurogenic atrophy Type II atrophy corticosteroid myopathy or disuse atrophy Perivascular interfascicular inflammation and Fiber 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 involvement may be ! in neurogenic dz (ALS) some myopathies (non-necrotizing) have normal CK (corticosteroid myopathy) ESR, CBC: screen for systemic disorder
Perivascular & interfascicular inflammation characteristic of dermatomyositis
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
in HIV patient treated w/Zidovidine
deletion/duplication/small insertion/point 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
The case of the 34 yo homemaker HPI
larger muscles subjected to ! stress, hence more affected
Pathology
1 yr history of weakness Exam weakness of neck extensors, arm abductors, elbow flexors & extensors, hip flexors, knee extensors Labs CK !!! EMG fibrillation potentials in weak muscles potentials recruit early, are short in duration, " in amplitude, polyphasic in form Biopsy scattered necrotic & regenerating fibers
** rounded, opaque, pre-necrotic fibers NF necrotic fibers RF clusters of regenerating fibers CT excessive connective tissue deposition
Immunostain for dystrophin shows D is irregularly distributed, significantly reduced Diagnosis in proband with clinical symptoms
increased variation
Elevated CK (up to 100x normal)
mononuclear cells surround non-necrotic muscle fibers
First step: Molecular testing of DMD gene
Diagnosis Inflammatory myopathy: polymyositis
If positive, diagnosis is made If negative, muscle biopsy for western blot & immunohistochemical studies of dystrophin
26: Muscle Disorders
Management
Weakness
keep joints loose
facial, neck muscles
stretch muscles
hand intrinsic muscles Percussion myotonia: slow tonic contraction after percussion of thenar eminence, take several seconds to resolve
night splints leg braces, spine stabilization
distal leg muscles
corticosteroids allows 1-3 yrs of continued ambulation Becker’s Muscular Dystrophy Much more mild form than DMD, ambulation may continue for decades Some fibers express dystrophin
proximal muscle involvement not prominent (but possible)
Infantile myotonic dystrophy hypotonia, facial paralysis, club feet inverted “V’ of upper lip EMG waxing & waning of discharge frequency and amplitude
Systemic features " IQ Clinical spectrum of dystrophinopathies Consider additional phenotypes without much weakness " exercise tolerance muscle cramps & myoglobinuria
cardiac conduction defects early cataracts testicular atrophy, uterine hypotonia Low IgG insulin resistance
late onset benign muscle weakness
heightened sensitivity to anesthesia
isolated ! CK
smooth muscle involvement
congestive cardiomyopathy w/o weakness isolated cognitive dysfunction
Myotonic Dystrophies
cholecystitis/constipation
Laboratory features CK: mildly !
Autosomal dominant diseases
EMG: myotonic discharges
Myotonic Dystrophy (Type I)
biopsy: variation in fiber size, fiber splitting, internalized nuclei
typical features: elongated face, temporal & masseter wasting, narrow neck Complex multisystem disorder myotonia delayed relaxation of striated muscle following contraction
variability in severity range from nearly asymptomatic adult to hypotonic infant
Autosomal dominant Clinical features in moderate dz characteristic facial appearance frontal balding, elongated face, temporal & masseter wasting, narrow neck
Pathogenesis expansion of unstable trinucleotide repeat (CTG) sequence on 3’ end of chromosome 19 length of repeat directly correlates w/ severity
Management watch cardiac, respiratory, sleep apnea easy myotonia careful w/anesthesia monitor blood glucose physical therapy, etc 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: no congenital form no mental retardation less central hypersomnia less symptomatic distal, facial, and bulbar weakness less pronounced muscle atrophy Comes to medical attention due to: muscle pain, stiffness, fatigue w/proximal weakness Pathogensis of myotonic dystrophies abnormally large expanded repeats in RNAs cause both Type I and II mutant mRNAs containg huge repeat expansions accumulate in nucleus
Other inherited Myopathies Dystrophinopathies (X-linked)
Metabolic Myopathies (AR) Caused by an absence/deficiency in an enzyme important to the metabolism of glycogen (e.g. McArdles’disease) or fat (e.g. carnitinepalmitoyltransferase deficiency) final common pathway: not enough production of ATP abnormality can reside in glycolytic pathway, fat metabolism, or mitochondrial function
Acquired Myopathy Idiopathic inflammatory myopathies (Dermatomyositis) Endocrine (Hypothyroid myopathy) Toxic (Colchicinemyopathy; myopathy of intensive care) Infectious (Trichinosis)
Inflammatory Myopathies Dermatomyositis Clinical features
Myotonic Dystrophies (AD) Oculopharyngeal Muscular Dystrophy (AD)
time-course: weeks to months 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) pronounced elbow contractures and lumbar lordosis
scapular winging
CT disease (scleroderma) interstitial lung disease (20%) cardiomyopathy (10%) 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
Limb Girdle Dystrophies (AR, AD)
volar forearm & quads
st
th
young person (1 through 4 decade) onset limbgirdle weakness
other organ involvement rare Associated diseases
M=F
NOT malignancy
spares face
CT disease
! CK
Diagnosis: often difficult, simulates ALS
muscle biopsy resembles duchenne: necrosis/regeneration
Responds poorly to immunosuppressive treatment
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
