PERIPHERAL NERVES, MUSCLE AND EYE

PERIPHERAL NEUROPATHIES• GUILLAIN-BARRE SYNDROME

• RAPIDLY PROGRESSIVE ACUTE DEMYELINATING DISORDER AFFECTING MOTOR AXONS,

RESULTING IN ASCENDING WEAKNESS THAT CAN LEAD TO DEATH FROM FAILURE OF

RESPIRATORY MUSCLES WITHIN DAYS OF ONSET OF SYMPTOMS

• TRIGGERED BY AN INFECTION OR VACCINATION THAT BREAKS DOWN SELF-TOLERANCE

LEADING TO AN AUTOIMMUNE RESPONSE

• CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY (CIDP)

• CHARACTERIZED BY SYMMETRICAL MIXED SENSORIMOTOR POLYNEUROPATHY THAT

PERSISTS FOR 2 MONTHS OR MORE (RELAPSING/REMITTING OR PROGRESSIVE COURSE)

• BOTH MOTOR AND SENSORY ABNORMALITIES ARE COMMON

• IMMUNE MEDIATED LIKE GUILLAIN-BARRE SYNDROME

• PERIPHERAL NERVES SHOW SEGMENTS OF DEMYELINATION AND REMYELINATION; CAN

ALSO SEE CONCENTRIC ARRANGEMENT OF MULTIPLE SCHWANN CELLS AROUND

INDIVIDUAL AXONS PRODUCING ONION BULB-LIKE STRUCTURES

• DIABETIC PERIPHERAL NEUROPATHY

• THE MOST COMMON CAUSE OF PERIPHERAL NEUROPATHY SEEN WITH LONGSTANDING

DISEASE

• CONSTELLATION OF FINDINGS INCLUDE AUTONOMIC NEUROPATHY, LUMBOSACRAL

RADICULOPATHY AND DISTAL SYMMETRIC SENSORIMOTOR POLYNEUROPATHY

NEUROMUSCULAR JUNCTION DISORDERS• MYASTHENIA GRAVIS

• AUTOIMMUNE DISEASE WITH FLUCTUATING MUSCLE WEAKNESS THAT IS CAUSED BY

AUTOANTIBODIES THAT TARGET THE NEUROMUSCULAR JUNCTION

• MOST COMMON ANTIGENIC TARGET IS THE POSTSYNAPTIC ACETYLCHOLINE RECEPTOR

• SHOW A BIMODAL AGE DISTRIBUTION WITH DISTINCTIVE CLINICAL FEATURES:

• EARLY ONSET – MORE COMMON IN FEMALES AND ASSOCIATED WITH THYMIC

HYPERPLASIA

• LATE ONSET – EQUAL GENDER DISTRIBUTION AND ASSOCIATED WITH THYMOMA

• DISEASE MANIFESTS WITH PTOSIS AND/OR DIPLOPIA AND REPETITIVE FIRING OF MUSCLES

MAKES THE WEAKNESS MORE SEVERE

• EFFECTIVE TREATMENTS INCLUDE CHOLINESTERASE INHIBITORS, IMMUNOSUPPRESSION,

PLASMAPHERESIS AND THYMECTOMY

• LAMBERT-EATON SYNDROME

• CAUSED BY AUTOANTIBODIES THAT INHIBIT THE FUNCTION OF PRESYNAPTIC CALCIUM

CHANNELS THEREBY REDUCING THE RELEASE OF ACETYLCHOLINE INTO THE SYNAPTIC CLEFT

• PATIENTS EXPERIENCE IMPROVEMENT IN WEAKNESS WITH REPETITIVE STIMULATION

• OFTEN ARISES AS A PARANEOPLASTIC DISORDER, PARTICULARLY SMALL CELL CARCINOMA

• CHOLINESTERASE INHIBITORS ARE NOT EFFECTIVE TREATMENT

PERIPHERAL NERVE SHEATH TUMORS• SCHWANNOMAS

• BENIGN ENCAPSULATED TUMORS THAT MAY OCCUR IN SOFT TISSUES, INTERNAL

ORGANS OR SPINAL NERVE ROOTS

• MOST COMMONLY AFFECTED IS THE 8TH CRANIAL NERVE

• MOST ARE SPORADIC BUT 10% ARE ASSOCIATED WITH NEUROFIBROMATOSIS

TYPE 2 (NF2)

• NF2 PATIENTS ARE AT RISK OF DEVELOPING MULTIPLE SCHWANNOMAS (BILATERAL

VESTIBULAR SCHWANNOMA), MENINGIOMAS AND EPENDYMOMAS; DO NOT DEVELOP

NEUROFIBROMAS

• DUE TO LOSS OF FUNCTION MUTATION IN THE MERLIN GENE ON CHROMOSOME 22

• MORPHOLOGICALLY, TUMORS ARE COMPOSED OF SCHWANN CELLS AND SHOW

AN ADMIXTURE OF DENSE AND LOOSE AREAS REFERRED TO AS ANTONI A AND

ANTONI B

• ANTONI A – COMPOSED OF BLAND SPINDLE CELLS WITH BUCKLED NUCLEI ARRANGED

INTO INTERSECTING FASCICLES; THESE CELLS OFTEN ALIGN TO PRODUCE NUCLEAR

PALISADING RESULTING IN ALTERNATING BANDS OF NUCLEAR AND ANUCLEAR AREAS

(VEROCAY BODIES)

• ANTONI B– SPINDLE CELLS ARE SPREAD APART BY A PROMINENT MYXOID

EXTRACELLULAR MATRIX; THICK-WALLED HYALINIZED VESSELS OFTEN ARE PRESENT

SCHWANNOMA

PERIPHERAL NERVE SHEATH TUMORS

• NEUROFIBROMAS

• BENIGN TUMORS GROUPED INTO THREE SUBTYPES:

• LOCALIZED CUTANEOUS NEUROFIBROMAS – ARISE AS SUPERFICIAL NODULAR OR POLYPOID TUMORS;

OCCUR AS EITHER SOLITARY SPORADIC LESIONS OR AS MULTIPLE LESIONS IN THE SETTING OF

NEUROFIBROMATOSIS TYPE I (NF1)

• PLEXIFORM NEUROFIBROMAS – GROW DIFFUSELY WITHIN THE CONFINES OF A NERVE OR NERVE PLEXUS

AND VIRTUALLY PATHOGNOMONIC FOR NF1; HARBOR A SMALL RISK OF MALIGNANT TRANSFORMATION

(MALIGNANT PERIPHERAL NERVE SHEATH TUMOR)

• DIFFUSE NEUROFIBROMAS – INFILTRATING PROLIFERATIONS THAT CAN TAKE THE FORM OF LARGE,

DISFIGURING SUBCUTANEOUS MASSES (OFTEN ASSOCIATED WITH NF1)

• NEUROFIBROMATOSIS TYPE 1 (NF1)

• AUTOSOMAL DOMINANT DISORDER CAUSED BY MUTATIONS IN THE TUMOR SUPPRESSOR NEUROFIBROMIN

ENCODED ON THE LONG ARM OF CHROMOSOME 17 (NEGATIVE REGULATOR OF RAS)

• CLINICAL FINDINGS INCLUDE NEUROFIBROMAS, MALIGNANT PERIPHERAL NERVE SHEATH TUMORS, OPTIC

GLIOMAS, PIGMENTED NODULES OF THE IRIS (LISCH NODULES) AND PIGMENTED SKIN LESIONS

• MORPHOLOGY:

• NOT ENCAPSULATED; THEY MAY APPEAR CIRCUMSCRIBED OR MAY EXHIBIT DIFFUSELY INFILTRATIVE

GROWTH

• THE NEOPLASTIC SCHWANN CELLS ARE ADMIXED WITH OTHER CELL TYPES INCLUDING MAST CELLS,

FIBROBLAST- LIKE CELLS AND PERINEURAL-LIKE CELLS

• BACKGROUND STROMA OFTEN CONTAINS LOOSE WAVY COLLAGEN BUNDLES (SHAVED CARROT

APPEARANCE) BUT CAN ALSO BY MYXOID OR CONTAIN DENSE COLLAGEN

NEUROFIBROMA

DUCHENNE AND BECKER MUSCULAR DYSTROPHY

• X-LINKED DISEASES CAUSED BY MUTATIONS THAT DISRUPT THE FUNCTION OF THE LARGE

STRUCTURAL PROTEIN DYSTROPHIN

• DUCHENNE MUSCULAR DYSTROPHY (DMD)

• BECOMES EVIDENT EARLY IN CHILDHOOD AND FOLLOWS AN INVARIABLY FATAL COURSE

• OFTEN HAVE DELETIONS OR FRAMESHIFT MUTATIONS OF DYSTROPHIN OFTEN LEADING TO

COMPLETE ABSENCE OF DYSTROPHIN ON MUSCLE BIOPSY

• CLINICAL FEATURES:

• WEAKNESS BEGINS IN THE PELVIC GIRDLE AND THEN IN THE SHOULDER GIRDLE

• CALF PSEUDOHYPERTROPHY IS A COMMON EARLY FINDING

• CARDIAC MUSCLE DAMAGE AND FIBROSIS MAY LEAD TO HEART FAILURE AND ARRHYTHMIAS

• HIGH SERUM CREATINE KINASE LEVELS ARE PRESENT AT BIRTH AND PERSIST THROUGH THE 1ST DECADE OF LIFE

• DEATH RESULTS FROM RESPIRATORY INSUFFICIENCY, PNEUMONIA AND CARDIAC DECOMPENSATION

• BECKER MUSCULAR DYSTROPHY (BMD)

• LESS COMMON AND LESS SEVERE THAN DMD (CAN HAVE A NEARLY NORMAL LIFE SPAN)

• OFTEN HAVE POINT MUTATIONS OF DYSTROPHIN OFTEN LEADING RESIDUAL BUT DEFECTIVE FORMS

OF DYSTROPHIN

• MORPHOLOGY:

• ALTERATIONS IN DMD AND BMD ARE SIMILAR BUT MILDER IN BMD

• ONGOING MYOFIBER NECROSIS AND REGENERATION

• PROGRESSIVE REPLACEMENT OF MUSCLE TISSUE BY FIBROSIS AND FAT

• MUSCLES TYPICALLY SHOW MARKED VARIATION IN MYOFIBER SIZE AND ABNORMAL INTERNALLY

PLACED NUCLEI

DUCHENNE MUSCULAR DYSTROPHY

OTHER INHERITED DISORDERS OF SKELETAL MUSCLE• MYOTONIC DYSTROPHY

• MYOTONIA, THE SUSTAINED INVOLUNTARY CONTRACTION OF A GROUP OF MUSCLES, IS THE

CARDINAL NEUROMUSCULAR SYMPTOM

• A NUCLEOTIDE REPEAT EXPANSION DISEASE (CTG REPEATS) INVOLVING MUTATIONS IN THE GENE

THAT ENCODES THE DYSTROPHIA MYOTONICAPROTEIN KINASE (DMPK)

• MALIGNANT HYPERTHERMIA

• AN ION CHANNEL MYOPATHY CHARACTERIZED BY TACHYCARDIA, TACHYPNEA, MUSCLE SPASMS

AND HYPERPYREXIA

• TRIGGERED WHEN PATIENTS CARRYING MUTATIONS IN THE RYANODINE RECEPTOR RYR1, A

CALCIUM EFFLUX CHANNEL, RECEIVE HALOGENATED ANESTHETIC AGENTS OR SUCCINYLCHOLINE

DURING SURGERY

• ON EXPOSURE TO ANESTHETIC, THE MUTATED RECEPTOR LEADS TO INCREASED EFFLUX OF CALCIUM FROM

THE SARCOPLASMIC RETICULUM, PRODUCING TETANY AND EXCESSIVE HEAT PRODUCTION

• MITOCHONDRIAL MYOPATHIES

• STEM FROM MUTATIONS IN EITHER MITOCHONDRIAL OR NUCLEAR GENOMES BECAUSE BOTH

ENCODE PROTEINS AND RNA THAT ARE CRITICAL FOR MITOCHONDRIAL FUNCTION

• MANIFEST IN EARLY ADULTHOOD WITH PROXIMAL MUSCLE WEAKNESS AND SEVERE INVOLVEMENT

OF THE OCULAR MUSCULATURE

• SOME ARE ASSOCIATED WITH NORMAL MUSCLE MORPHOLOGY; OTHERS SHOW AGGREGATES OF

ABNORMAL MITOCHONDRIA WHICH IMPART A BLOTCHY RED APPEARANCE IN SPECIAL STAINS

(RAGGED RED FIBERS)

INFLAMMATORY MYOPATHIES

• POLYMYOSITIS

• AUTOIMMUNE DISORDER ASSOCIATED WITH INCREASED EXPRESSION OF MHC CLASS I MOLECULES ON

MYOFIBERS

• CHARACTERIZED BY ENDOMYSIAL INFLAMMATORY INFILTRATES CONTAINING CD8+ CYTOTOXIC T-

CELLS AND MYOFIBER NECROSIS

• TREATED WITH CORTICOSTEROIDS OR OTHER IMMUNOSUPPRESSIVE AGENTS

• DERMATOMYOSITIS

• MOST COMMON INFLAMMATORY MYOPATHY IN CHILDREN

• OFTEN MANIFESTS AS A PARANEOPLASTIC DISORDER IN ADULTS

• ASSOCIATED WITH SKIN MANIFESTATIONS AND SYSTEMIC MANIFESTATIONS

• MORPHOLOGICALLY, IT IS ASSOCIATED WITH PERIVASCULAR MONONUCLEAR CELL INFILTRATES WITH

PLASMA CELLS, DROPOUT OF CAPILLARIES, TUBULORETICULAR INCLUSIONS IN ENDOTHELIAL CELLS AND

MYOFIBER DAMAGE IN A PARASEPTAL OR PERIFASCICULAR PATTERN

• RELATIVELY SPECIFIC ANTIBODIES INCLUDE THOSE AGAINST MI-2, P155 AND P140

• INCLUSION BODY MYOSITIS

• MOST COMMON INFLAMMATORY MYOPATHY IN PATIENTS OLDER THAN 60 YEARS OF AGE

• MORPHOLOGIC HALLMARK IS THE PRESENCE OF RIMMED VACUOLES THAT CONTAIN AGGREGATES OF

THE SAME PROTEINS THAT ACCUMULATE IN THE BRAINS OF PATIENTS WITH NEURODEGENERATIVE

DISEASES

• FOLLOWS A CHRONIC PROGRESSIVE COURSE AND GENERALLY DOES NOT RESPOND WELL TO

IMMUNOSUPPRESSIVE AGENTS

INFLAMMATORY MYOPATHIES

CORNEAL DEGENERATIONS AND DYSTROPHIES• BAND KERATOPATHIES

• SERVE AS EXAMPLES OF CORNEAL DEGENERATIONS

• CALCIFIC BAND KERATOPATHY – CHARACTERIZED BY DEPOSITION OF CALCIUM IN BOWMAN’S LAYER

• MAY COMPLICATE CHRONIC UVEITIS ESPECIALLY IN PATIENTS WITH CHRONIC JUVENILE RHEUMATOID ARTHRITIS

• ACTINIC BAND KERATOPATHY – EXTENSIVE SOLAR ELASTOSIS DEVELOPS IN THE SUPERFICIAL LAYERS OF THE CORNEAL

COLLAGEN

• DEVELOPS IN PATIENTS WHO ARE EXPOSED CLINICALLY TO HIGH LEVELS OF ULTRAVIOLET LIGHT

• THE SUN-DAMAGED COLLAGEN APPEARS YELLOW (OIL-DROPLET KERATOPATHY)

• KERATOCONUS

• CHARACTERIZED BY PROGRESSIVE THINNING AND ECTASIA OF THE CORNEA WITHOUT EVIDENCE OF INFLAMMATION OR

VASCULARIZATION GIVING THE CORNEA A CONICAL SHAPE

• IS TYPICALLY BILATERAL AND IS SOMETIMES ASSOCIATED WITH DOWN SYNDROME, MARFAN SYNDROME AND ATOPIC

DISORDERS

• MORPHOLOGY:

• THINNING OF THE CORNEA WITH BREAKS IN BOWMAN’S LAYER ARE CHARACTERISTIC

• CORNEAL HYDROPS – RUPTURE OF DESCEMET’S MEMBRANE WITH AQUEOUS HUMOR GAINING ACCESS TO THE CORNEAL

STROMA CAUSING SUDDEN LOSS OF VISION

• FUCHS ENDOTHELIAL DYSTROPHY

• EARLY, ENDOTHELIAL CELLS PRODUCE DROPLIKE DEPOSITS OF ABNORMAL BASEMENT MEMBRANE MATERIAL (GUTTATA)

• WITH PROGRESSION, THERE IS A DECREASE IN THE TOTAL NUMBER OF ENDOTHELIAL CELLS

• CONSEQUENTLY, THE STROMA BECOMES EDEMATOUS AND THICKENS, ACQUIRES A GROUND GLASS APPEARANCE

CLINICALLY AND LEADS TO BLURRY VISION AND VISION LOSS

• WITH INCREASING STROMAL EDEMA, THE EPITHELIUM UNDERGOES HYDROPIC CHANGE WITH DETACHMENT OF THE

EPITHELIUM FROM BOWMAN’S LAYER PRODUCING EPITHELIAL BULLAE

KERATOCONUS

FUCHS DYSTROPHY

THE ANTERIOR SEGMENT AND GLAUCOMA

• THE ANTERIOR SEGMENT CONSISTS OF THE CORNEA, ANTERIOR CHAMBER, POSTERIOR

CHAMBER, IRIS AND LENS

• GLAUCOMA – CHARACTERIZED BY DISTINCTIVE CHANGES IN THE VISUAL FIELD AND IN THE CUP

OF THE OPTIC NERVE, AND ARE OFTEN ASSOCIATED WITH ELEVATED INTRAOCULAR PRESSURE;

CLASSIFIED INTO TWO MAJOR CATEGORIES:

• OPEN ANGLE GLAUCOMA – THE AQUEOUS HUMOR HAS COMPLETE PHYSICAL ACCESS TO THE

TRABECULAR MESHWORK AND THE ELEVATION IN IN INTRAOCULAR PRESSURE RESULTS FROM AN

INCREASED RESISTANCE TO AQUEOUS OUTFLOW IN THE OPEN ANGLE

• PRIMARY OPEN ANGLE GLAUCOMA – MOST COMMON FORM OF GLAUCOMA; MUTATIONS IN THE

GLC1A GENE ENCODING MYOCILIN COMMONLY IMPLICATED

• SECONDARY OPEN ANGLE GLAUCOMA – MULTIPLE CAUSES INCLUDING SENESCENT RED BLOOD CELLS

AFTER TRAUMA (GHOST CELL GLAUCOMA), IRIS PIGMENT EPITHELIAL GRANULES (PIGMENTARY

GLAUCOMA) AND NECROTIC TUMORS (MELANOMALYTIC GLAUCOMA)

• ANGLE CLOSURE GLAUCOMA – THE PERIPHERAL ZONE OF THE IRIS ADHERES TO THE TRABECULAR

MESHWORK AND PHYSICALLY IMPEDES THE EGRESS OF AQUEOUS HUMOR FROM THE EYE

• PRIMARY ANGLE CLOSURE GLAUCOMA – TYPICALLY DEVELOPS IN EYES WITH SHALLOW ANTERIOR

CHAMBERS, OFTEN FOUND IN PATIENTS WITH HYPEROPIA

• SECONDARY ANGLE CLOSURE GLAUCOMA – MULTIPLE CAUSES INCLUDING NEOVASCULAR

GLAUCOMA AND IRIDOCORNEAL ENDOTHELIAL SYNDROME

THE ANTERIOR SEGMENT AND GLAUCOMA

THE RETINA

• RETINAL DETACHMENT – SEPARATION OF THE NEUROSENSORY RETINA FROM THE RETINAL

PIGMENT EPITHELIUM

• RHEGMATOGENOUS RETINAL DETACHMENT – ASSOCIATED WITH A FULL-THICKNESS RETINAL

DEFECT

• NON-RHEGMATOGENOUS RETINAL DETACHMENT – NOT ASSOCIATED WITH A RETINAL BREAK

OR TEAR WHERE THE SUBRETINAL SPACE IS FILLED WITH PROTEIN-RICH EXUDATE

• RETINAL VASCULAR DISEASE

• MALIGNANT HYPERTENSION – THICKENING AND DAMAGE TO CHOROIDAL VESSELS MAY

PRODUCE FOCAL CHOROIDAL INFARCTS SEEN CLINICALLY AS ELSCHNIG’S SPOTS

• CLINICALLY, THE VESSELS APPEAR NARROWED AND THE COLOR OF THE BLOOD COLUMN MAY

CHANGE FROM BRIGHT RED TO COPPER OR SILVER DEPENDING ON THE DEGREE OF VASCULAR

WALL THICKNESS

• DIABETES MELLITUS – ASSOCIATED WITH RETINAL MICROANGIOPATHY WHICH IS CLASSIFIED

INTO:

• BACKGROUND (PREPROLIFERATIVE) DIABETIC RETINOPATHY – CONSISTS OF BASEMENT

MEMBRANE THICKENING OF RETINAL BLOOD VESSELS, MICROANEURYSMS, MACULAR EDEMA AND

HEMORRHAGIC EXUDATES

• PROLIFERATIVE DIABETIC RETINOPATHY – THE APPEARANCE OF NEW VESSELS THAT SPROUT FROM

EXISTING VESSELS (NEOVASCULAR MEMBRANE)

AGE-RELATED MACULAR DEGENERATION (ARMD)

• MOST COMMON CAUSE OF IRREVERSIBLE VISUAL MORBIDITY IN THE UNITED

STATES

• ETIOLOGY OF THE CONDITION IS UNCLEAR BUT SMOKING, NUTRITIONAL

FACTORS, ATHEROSCLEROSIS AND HYPERTENSION HAVE ALL BEEN IMPLICATED

• CHARACTERIZED CLINICALLY BY LOSS OF VISION IN THE CENTER OF THE VISUAL

FIELD

• ATROPHIC (DRY) ARMD - DIFFUSE OR DISCRETE DEPOSITS IN BRUCH’S MEMBRANE

AND GEOGRAPHIC ATROPHY OF THE RETINAL PIGMENT EPITHELIUM

• EXUDATIVE (WET) ARMD – CHARACTERIZED BY THE DEVELOPMENT OF CHOROIDAL

NEOVASCULAR MEMBRANES (ASSOCIATED WITH MORE SEVERE VISION LOSS)

• CHOROIDAL NEOVASCULARIZATION – DEFINED BY THE PRESENCE OF ANGIOGENIC

VESSELS THAT PRESUMABLY ORIGINATE FROM THE CHORIOCAPILLARIS AND PENETRATE

THROUGH BRUCH’S MEMBRANE; THE VESSELS MAY LEAK AND THE EXUDED BLOOD

ORGANIZED BY RETINAL PIGMENT EPITHELIAL CELLS INTO MACULAR SCARS