DIFFERENTIAL DIAGNOSIS OF NEUROGENIC DISORDERS & MYOPATHIES · DIFFERENTIAL DIAGNOSIS OF NEUROGENIC...
Transcript of DIFFERENTIAL DIAGNOSIS OF NEUROGENIC DISORDERS & MYOPATHIES · DIFFERENTIAL DIAGNOSIS OF NEUROGENIC...
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DIFFERENTIAL DIAGNOSIS OF NEUROGENIC DISORDERS & MYOPATHIES
NEUROPATHY MYOPATHY
Weakness distal proximalWeakness distal proximal
Sensory dysfunction + 0
Loss of reflexes early late
Serum enzymes +/- +++
CSF protein may be elevated normal
Electromyography neurogenic myopathic
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CLASSIFICATION OF PERIPHERALNERVE DISEASESNERVE DISEASES
Myelinopathyy p yAcute inflammatory polyneuropathy (Guillain-Barré
syndrome or GBS)Chronic inflammatory demyelinating polyneuropathyChronic inflammatory demyelinating polyneuropathy
(CIDP)Charcot-Marie-Tooth, type 1 (CMT-1)
AxonopathyWallerian degeneration (trauma, vasculitis etc.)g ( )Distal axonopathies (dying back neuropathies)
NeuronopathyNeuronopathy Amyotrophic lateral sclerosis (ALS)
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CLINICAL ROLE OF NERVE BIOPSY IS VERY LIMITED
• Identify the cause of a neuropathy(vasculitis, amyloidosis).( , y )
• Nerve conduction studies are moreNe ve co duct o stud es a e o euseful than nerve biopsy for dis-tinguishing between a demyelinatingtinguishing between a demyelinatingneuropathy and an axonal disorder.
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PATHOLOGICAL ANALYSIS OF SURAL NERVE BIOPSY
• ROUTINE HISTOLOGY
• SEMITHIN PLASTIC SECTIONS
• TEASED MYELINATED FIBERS
ELECTRON MICROSCOPY• ELECTRON MICROSCOPY
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SURAL NERVE, SEMITHIN PLASTIC SECTION (TOLUIDINE BLUE)
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TEASED MYELINATED FIBER:TEASED MYELINATED FIBER:NORMAL
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PERIPHERAL NERVE, ELECTRON MICROGRAPH
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SEQUENCE OF SEGMENTAL DEMYELINATION & REMYELINATION
Prox. Dist.
Conductionblock ofaction po-
Conduction
ptentials
Conductionslowing
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NERVE STIMULATION EVOKES ACTION POTENTIAL IN HAND MUSCLE
J N l N P hi t 2005 76 1269 1272J. Neurol. Neurosurg. Psychiatry 2005;76;1269-1272
NORMAL COMPOUND MUSCLE ACTION POTENTIAL
REDUCED AMPLITUDE OF CMAP
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TEASED MYELINATED FIBER:TEASED MYELINATED FIBER:SEGMENTAL REMYELINATION
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SAME TEASED FIBER ATSAME TEASED FIBER AT HIGHER MAGNIFICATION
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SEQUENCE OF SEGMENTAL AXONAL DEGENERATION & REGENERATION
Proximal Distal
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TEASED MYELINATED FIBER:AXONAL DEGENERATION
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CLASSIFICATION OF PERIPHERALNERVE DISEASESNERVE DISEASES
Myelinopathyy p yAcute inflammatory polyneuropathy (Guillain-Barré
syndrome or GBS)Chronic inflammatory demyelinating polyneuropathyChronic inflammatory demyelinating polyneuropathy
(CIDP)Charcot-Marie-Tooth, type 1 (CMT-1)
AxonopathyWallerian degeneration (trauma, vasculitis etc.)g ( )Distal axonopathies (dying back neuropathies)
NeuronopathyNeuronopathy Amyotrophic lateral sclerosis (ALS)
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ACUTE INFLAMMATORY POLYNEUROPATHY(G A A S O O G S)(GUILLAIN-BARRE SYNDROME OR GBS)
• Rapidly progressive neuropathy chiefly motor reachingRapidly progressive neuropathy, chiefly motor, reachingmaximum weakness usually within 1 to 2 weeks.
S i t k i j d d• Severe respiratory weakness is a major danger and mayrequire treatment in an intensive care unit.
• An acute infectious illness precedes weakness in two thirds,consisting of influenza-like symptoms or diarrhea. The res-piratory disorder is linked to infection by viruses whereaspiratory disorder is linked to infection by viruses whereasdiarrhea is often caused by Campylobacter jejuni.
R t k k th P t h di• Recovery takes weeks or months. Permanent handicap occurs in 15%-20% of patients.
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GBS: DIAGNOSIS & TREATMENT
• Electrophysiology: early block of conduction of action po-tentials along motor nerves. Slowing of conduction veloc-ity develops later as segmental remyelination appearsity develops later as segmental remyelination appears.
• Electrodiagnostic studies often show evidence of co-existingaxonal degeneration, usually of mild degree.
• Cerebrospinal fluid typically has mildly elevated pro-p yp y y ptein and no cells.
• Sural nerve biopsy does not have a role in diagnosis but• Sural nerve biopsy does not have a role in diagnosis buthas provided information about etiology and pathogenesis.
• Plasmapheresis or intravenous gamma globulin speeds re-covery.
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PATHOLOGY OF GUILLAIN-BARRÉ SYNDROME
• Immune complexes (C3, IgG, IgM) are detectable on thesurface of myelin sheaths in the early stagesurface of myelin sheaths in the early stage.
• Sparse T cells, chiefly CD4 subset, infiltrate endoneurium.
• Monocytes and macrophages appear to attack myelin shea
• Myelinated fibers show segmental demyelination during thefirst few days. Segmental remyelination occurs subsequently.
• The lesions have a perivenular distribution and tend to af-fect the DRG, nerve roots and adjacent nerves where bloodnerve barrier is normally more permeable than elsewhere.
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GBS, DORSAL ROOT GANGLION, H&E
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GBS, MOTOR NERVE, H&E
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GBS, MOTOR NERVE, SEMITHIN SECTION
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GBS, ELECTRON MICROGRAPH
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GBS, SEGMENTAL REMYELINATION
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GBS, C3 COMPONENT ON MYELIN SHEATHS
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EVIDENCE FOR AUTOIMMUNE ETIOLOGY IN GUILLAIN BARRE SYNDROMEIN GUILLAIN-BARRE SYNDROME
• Demyelinating neuropathy can be induced in experimentali l b i i ti ith li ifi d lianimals by immunization with myelin, purified myelin pro-
tein or galactocerebroside.
• Antibody titers to nerve myelin in patients correlate with disease activity.
• The antibodies recognize specific glycolipids or glycopro-teins of peripheral myelin in a minority of patients.
• Immune complexes are found at surface of myelin sheaths
• Plasmapheresis or intravenous gamma globulin speedsrecovery when treatment is started early.
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AXONAL VARIANT OF GUILLAIN-BARRE SYNDROME
• Clinical syndrome resembles Guillain-Barre syndrome, but is foften purely motor.
• It is common in Asia and other countries but accounts for onlyy5% of patients in the US or Europe.
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AXONAL VARIANT OF GBS,P ibl l l i iPossible molecular mimicry
• The patients often have elevated serum autoantibodies
that recognize the terminal oligosaccharide of GM1& GD1a ganglioside& GD1a ganglioside.
• The chemical structure of lipopolysaccharide of C.j j i h th li h id h ijejuni has the same oligosaccharide chainpresent in GD1a and GM1.
• This suggests that the immune response to C. jejuni
induces antibodies that crossreact to a self-induces antibodies that crossreact to a selfantigen
of the axolemma. This axonal variant of t i
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CLASSIFICATION OF PERIPHERALNERVE DISEASESNERVE DISEASES
Myelinopathyy p yAcute inflammatory polyneuropathy (Guillain-Barré
syndrome or GBS)Chronic inflammatory demyelinating polyneuropathyChronic inflammatory demyelinating polyneuropathy
(CIDP)Charcot-Marie-Tooth, type 1 (CMT-1)
AxonopathyWallerian degeneration (trauma, vasculitis etc.)g ( )Distal axonopathies (dying back neuropathies)
NeuronopathyNeuronopathy Amyotrophic lateral sclerosis (ALS)
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CHRONIC INFLAMMATORY DEMYELINAT-ING POLYNEUROPATHY (CIDP)ING POLYNEUROPATHY (CIDP)
• Chronic progressive or relapsing neuropathy, motor > sensory.
• An antecedent infectious illness is uncommon.
• Electrophysiology: conduction block and slowing of velocity.
• Pathology: segmental demyelination and remyelination, onion gy g y y ,bulbs, fibrosis and little or no lymphocytic infiltration of tissue.
• Probably an autoimmune disorder of myelin but pathogenesis• Probably an autoimmune disorder of myelin but pathogenesis is not well understood.
• Patients respond to plasmapheresis, intravenous gamma globu-lin or corticosteroid treatment.
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ONION BULB
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CIDP WITH ONION BULBS
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CLASSIFICATION OF PERIPHERALNERVE DISEASESNERVE DISEASES
Myelinopathyy p yAcute inflammatory polyneuropathy (Guillain-Barré
syndrome or GBS)Chronic inflammatory demyelinating polyneuropathyChronic inflammatory demyelinating polyneuropathy
(CIDP)Charcot-Marie-Tooth, type 1 (CMT-1)
AxonopathyWallerian degeneration (trauma, vasculitis etc.)g ( )Distal axonopathies (dying back neuropathies)
NeuronopathyNeuronopathy Amyotrophic lateral sclerosis (ALS)
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CHARCOT-MARIE-TOOTH, TYPE I
• Slowly progressive distal limb weakness begins in first dec-ade with great variation in onset; few sensory complaints.
• Autosomal dominant, mutations commonly affect PMP22.
• Neurological exam:Atrophy of distal leg muscles (stork leg appearance).Palpable nerve enlargement in 50%Palpable nerve enlargement in 50%.Pes cavus and hammer toes is common.
El t h i l U if l i f d ti l it• Electrophysiology: Uniform slowing of conduction velocity.No conduction block.
• Pathology: similar to CIDP.
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Lou Gehrig
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AMYOTROPHIC LATERAL SCLEROSIS(LOU GEHRIG’S DISEASE)
• Progressive weakness, muscle wasting and fasciculations; often asymmetrical in the beginning.
• Symptoms usually begin after the age of 40.Symptoms usually begin after the age of 40.
• Hyperactive tendon reflexes, clonus and Babinski signs.
• Electromyogram: Signs of denervation in muscle.Normal or slightly reduced conductions.
• Most are sporadic; about 10% are familial.
• Death occurs usually within 3 to 5 years from onset.
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ALS: FASCICULATIONS & BABINSKY REFLEXES
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ALS: LOWER MOTOR NEURON PATHOLOGY
• Loss of motor neurons in ventral horns and• Loss of motor neurons in ventral horns andnuclei of cranial nerve V, VII, IX-XII.
S i f t l i f i l III• Sparing of motor nuclei of cranial nerves III,IV & VI and Onuf’s nucleus.
• Surviving motor neurons show atrophy & inclusions.
• Few chromatolytic-like nerve cells.
Littl id f l ti• Little or no evidence of axonal regeneration.
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ALS: LOSS OF MOTOR NEURONS IN VENTRAL HORN
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ALS & SARCOIDOSIS, SPINAL CORD, TDP-43
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ALS, SKEIN-LIKE INCLUSIONS, UBIQUITIN
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SKEIN-LIKE INCLUSIONS
I t t l i t f l d• Intracytoplasmic aggregates of granules and loosely- arranged fibrils (skein-like inclusions) occur in motor neurons of spinal cord and brain pstem. Rare in Betz motor cells of precentral gyrus.
• Invisible in routine histology (H&E) and are notargyrophilic.
• The inclusions are composed of TDP-43, a proteinp
that is normally expressed in the nucleus.
• The skein-like inclusions are ubiquinatedThe skein-like inclusions are ubiquinated.
• Sensitivity: 90-100%; specificity: >95%.
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ALS, NEUROFILAMENT PROTEIN
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ALS: UPPER MOTOR NEURON PATHOLOGYALS: UPPER MOTOR NEURON PATHOLOGY
L f B t ll ( t ) i• Loss of Betz cells (upper motor neurons) in pre-central gyrus.
• Pyramidal degeneration with gradually increasingmyelin pallor in a caudal direction due to loss ofy paxons.
Th d i i k d b h• The tract degeneration is marked by macrophages(removing myelin debris) and numerous activatedmicrogliamicroglia.
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ALS, MYELIN PALLOR IN PYRAMIDAL TRACT, LFB-PAS
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ALS, PYRAMIDAL TRACT, CD68
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PATHOGENESIS OF ALS
Mutations of the Cu/Zn superoxide dismutase (SOD1)cause ALS of 20% of familial cases Expression ofcause ALS of 20% of familial cases. Expression of mutant human SOD1 in transgenic mice produces MNDby a toxic or gain of function mechanism. This mouse model has yielded two major hypotheses of toxicity:
aberrant oxidation intracellular aggregatesgg g
glutamate toxicity disruptedglutamate toxicity, disruptedcalcium homeostasis, abnormalnitration and glycation of proteins,apoptotic death
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AIMS OF MUSCLE BIOPSY
• Distinguish a neurogenic disorderfrom a myopathyfrom a myopathy.
S i h it d thi f• Screen inherited myopathies formolecular analysis.
• Subclassify acquired myopathies.y q y p
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CRYOSECTIONS OF SKELETAL MUSCLE, H&E
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CRYOSECTIONS OF SKELETAL MUSCLE, ATPase
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MODIFIED GOMORI TRICHROME
SUCCINATE DE-HYDROGENASE
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DIAGNOSTIC HISTOLOGICAL FEATURESOF A NEUROGENIC DISORDER
• LARGE GROUPS OF ATROPHIC FIBERS• LARGE GROUPS OF ATROPHIC FIBERS
• FIBER TYPE GROUPING
• TARGET FIBERS
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GROUPS OF ATROPHIC MYOFIBERS, H&E
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FIBER TYPE GROUPING
NADH-DEHY-DROGENASE
ATPaseDROGENASE
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TARGET FIBERS, NADH DEHYDROGENASE
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DIAGNOSTIC HISTOLOGICAL FEATURES OF MYOPATHIES
• ABSENCE OF NEUROGENIC ABNORMALITIES
• NECROTIC MUSCLE FIBERS
• BASOPHILIC (REGENERATING) MYOFIBERS
• FIBROSIS OF THE ENDOMYSIUM
• SPECIAL PATHOLOGICAL FEATURES (INFLAMMATORY• SPECIAL PATHOLOGICAL FEATURES (INFLAMMATORYCELLS, RAGGED RED FIBERS ETC.)
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NECROTIC FIBER, H&E
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REGENERATING FIBER, H&E
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GOWER’S SIGN
Gowers, 1879
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DUCHENNE MUSCULAR DYSTROPHYDUCHENNE MUSCULAR DYSTROPHY
• X-linked recessive inheritance
O t f k ti bl t 2 5• Onset of weakness noticeable at 2-5 years of age.
• Progressive weakness, proximal>distal
• Hypertrophy of calvesHypertrophy of calves
• High serum creatine kinase activity
• Fatal in 3rd decade
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DUCHENNE DYSTROPHY, H&E
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DUCHENNE DYSTROPHY, LATER STAGE
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DUCHENNE MUSCULAR DYSTROPHYDUCHENNE MUSCULAR DYSTROPHY
• Dystrophin is a 427 kD protein that binds toDystrophin is a 427 kD protein that binds tothe inner face of the surface membrane.
The protein has amino acid seq ence similari• The protein has amino acid sequence similari-ties with alpha-actinin, an actin binding protein.
• The protein links actin to the surface membrane
and the basal lamina acting through dystrogly-and the basal lamina acting through dystroglycan and merosin (alpha 2-laminin).
Interrupting this linkage causes the surface• Interrupting this linkage causes the surface mem-
brane to be unstable leading to fiber injury.
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Duggan et al. Mutations in the sarcoglycan genes in patients with myopathy. N Engl J Med 1997;336:618
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DUCHENNE DYSTROPHY, SPECTRIN
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DUCHENNE DYSTROPHY, DYSTROPHIN
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INFLAMMATORY MYOPATHIESINFLAMMATORY MYOPATHIES
• Polymyositis
• Inclusion body myositis
• Dermatomyositis
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POLYMYOSITISPOLYMYOSITIS
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DIAGNOSTIC FEATURES OF POLYMYOSITIS
• Subacute progressive weakness, proximal>distal.Usually adults, women more common than men.y ,
• Elevated serum creatine kinase activity.
• Electromyogram: myopathic potentials, spon-taneous activity.
• Muscle biopsy: inflammatory myopathy affect-ing chiefly the endomysium.g y y
• Usually respond to glucocorticoids.
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POLMYOSITIS, H&E
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POLMYOSITIS, PARAFFIN SECTION, H&E
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POLMYOSITIS, IMMUNOPEROXIDASE, CD8
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POLYMYOSITIS: PATHOLOGY
• Necrotic fibers and regenerating fibersrandomly distributed throughout the muscle specimen.
• CD8 cytotoxic cells infiltrate pre-d i tl th d i ith idominantly the endomysium with in-vasion of rare myofibers.
• Little fibrosis or myofiber hypertrophy, consistent with a subacute disorder.co s ste t w t a subacute d so de .
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INCLUSION BODYMYOSITIS
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DIAGNOSTIC FEATURES OF IBM
• Most common inflammatory myopathy in patients over the age of 50 years and affects mostly men.the age of 50 years and affects mostly men.
• Slowly progressive weakness, proximal and distal.
• Mildly elevated serum creatine kinase or normal.
• Electromyogram: myopathic potentials, spon-taneous activity.
• Muscle biopsy: resembles polymyosits, but chronic and exhibits rimmed vacuoles and amyloid inclusions.
• Usually does not respond to glucocorticoids.
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INCLUSION BODY MYOSITIS, H&E
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IBM, RIMMED VACUOLES, H&E
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IBM, EOSINOPHILIC INCLUSION IN A RIMMED VACUOLE
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IBM, CONGO RED, FLUORESCENCE, RHODAMINE OPTICS
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ELECTRON MICROSCOPY, 15-20 nm FILAMENTS
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IBM PATHOLOGY
• IBM resembles polymyositis but has hyper-trophic fibers and prominent endomysial fibrosis indicating it is chronic.
• Rimmed vacuoles.
• Congophilic fibrillar inclusions composed• Congophilic fibrillar inclusions, composedof abnormal (? paired-helical) filaments.
• Lymphocytic infiltration suggests an auto-immune disorder, but disorder is usually , yunresponsive to immunosuppression.
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DERMATOMYOSITISDERMATOMYOSITIS
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DIAGNOSTIC FEATURES OF DERMATOMYOSITIS
• Subacute progressive weakness, proximal>distal.Children and adults, women more common than men.,
• Characteristic rash on face, chest & extensor surfaces.
• Elevated serum creatine kinase activity.
El hi i l• Electromyogram: myopathic potentials, spontaneousactivity.
• Muscle biopsy: inflammatory myopathy affectingchiefly the perimysium with perifascicular atrophy.
• Usually respond to glucocorticoids or IVGG.
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DERMATOMYOSITIS, PERIFASCICULAR ATROPHY, H&E
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DERMATOMYOSITIS: LYMPHO-DERMATOMYOSITIS: LYMPHOCYTE PHENOTYPES
CD4 T ll d B ll l t d hi fl• CD4 T cells and B cells located chieflyin connective tissue and around vesselsof perimysiumof perimysium.
• Inconstant and usually sparse CD8 T cellsy plocated mainly in endomysium.
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DM, IMMUNE COMPLEXES (C5b-9) IN BLOOD VESSEL WALL
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TUBULORETICULAR AGGREGATE IN ENDOTHELIAL CELL
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DERMATOMYOSITIS: PATHOLOGY
• Perifascicular atrophy of muscle fibers, with or with-i fib i fibout necrotic fibers or regenerating fibers.
• Immune complexes of immunoglobulins and comple-p g pment components in the walls of blood vessels.
• Endothelial tubuloreticular aggregatesEndothelial tubuloreticular aggregates.
• Reduced number of capillaries at periphery of fascicle.
• Lymphocytes are often sparse and located in chiefly perimysium.p y
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INFLAMMATORY MYOPATHIES:INFLAMMATORY MYOPATHIES:PATHOPHYSIOLOGY
• Polymyositis and inclusion body myositis (IBM) haveautoaggressive CD8 lymphocytes that appear to attackautoaggressive CD8 lymphocytes that appear to attack myofibers and suggest an autoimmune role. However, a major question exists about the etiology and patho-
i f IBMgenesis of IBM.
• Dermatomyositis is thought to be caused by auto-y g yantibodies, possibly targeting an antigen of theendothelium. The pathological findings suggest that myofiber injury may be caused by ischemiathat myofiber injury may be caused by ischemia.
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HYPOTONIA IN INFANCYHYPOTONIA IN INFANCY
DISEASE INHERITED PROGNOSIS
Werdnig-Hoffmann Autosomal Fataldisease recessivedisease recessive
Central core disease Autosomal Not pro- dominant
gressiveNemaline myopathy Variabley p y
Variable
Mitochondrial disorder Maternal or VariableMitochondrial disorder Maternal or Variableautosomal
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WERDNIG-HOFFMANN DISEASE
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CENTRAL CORE DISEASE, NADH DEHYDROGENASE
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MITOCHONDRIALMITOCHONDRIALMYOPATHY
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MUTATIONS OF mtDNA RAGGED “RED” FIBER
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CYTOCHROME C OXIDASE DEFICIENT MYOFIBER
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RRF, SUCCINATE DEHYDROGENASE