Muscle And Nmj Dzs

NEUROLOGY MUSCLE AND NEUROMUSCULAR JUNCTION DISORDERS

 Acquired

History  Weakness Acute/Chronic/Episodic (Neuromuscular junction) Proximal (Arm, shoulders, pelvic girdle)(Patient will have no problem walking on smooth surfaces or reaching out for something but will experience difficulty on combing the hair or climbing up the stairs)  Swallowing (Laryngeal muscle)/Speech (Tongue)/EOM (Diplopia at certain gaze)  Respiratory/Cardiac  No Sensory Loss: Involves only the motor fibers  Muscle pain/cramps  Twitches: Not common in motor fiber disease, common only in diseases involving the anterior horn cells  Abnormal posture: If the problem started much younger

Family

History: important, even if negative there is still need for investigation  Past Medical History: Other problems in the body especially thyroid and/or lung diseases

Drug

abuse/Substance abuse: Statins & alcohol can cause myopathy

Physical Examination Muscle Disorders Proximal weakness Normal/ Late loss Pseudohypertrophy (late atrophy) Muscle tenderness not present all the time, tenderness only when being held by the examiner) No sensory loss

Nerve Disorders Distal weakness (Difficulty on holding on to things) Early hypo/ areflexia Atrophy Dysesthesias (Really painful even when not being examined) Sensory loss

Diagnostics

Muscle

enzymes: CPK (available in the Philippines),

aldolase

Electromyogram/Nerve Conduction tests: Normal NCV in muscle disease, or may see fibrillations or positive waves, small motor units will recruit very fast (Early recruitment of motor units)  Radiologic X-rays, MRI, Neuromuscular series (NMS)  Muscle biopsy  Disease specific examinations: Tests related to other diseases  Gene analysis: Analysis for Dystrophin Classification of Primary Neuropathies  Inherited Usually called dystrophy progressive) Duchenne & Beckers Congenital myotonic Limb girdle Fascioscapulohumeral CHRABI Page 1 of 10

Proteins & Associated Disease

Dystrophin: Duchenne/Becker Actin, Troponin, α-actinin: Nemaline Myopathy Myoblin: LGMD1 Titin: LGMD2I Sarcoglycans: LGMD2C,D,E,F Extrajunctional Muscle Membrane  These are the specific proteins involved in the various muscle disease that are found in the muscle membrane:  Dystrophin Found in the cytoplasm of muscle cell Acts together with F-actin Important for cytoskeletal support Duchenne & Becker  Dystrophin associated glycoprotein: Sarcloglycans, syntrophins, alpha-dystobrevin, sarcospan

Dystroglycan:

Congenital

myotonic

muscle

dystrophies

Sarcoglycan: Limb-girdle dystrophy Laminin & agrin: Connects sarcolemma to outside portion of basal lamina Histology  Normal muscle fibers may stain differently based on the type. Type 2 muscle fibers take up more stain. Atrophic fibers appear small angulated. Hypertrophic fibers show variation in fiber size and are thick and splitting. A group of fibers that shrink is termed “Small Group Atrophy” or “Large group Atrophy” depending on how much is loss. If the atrophy appears only in the center of the fiber, the term use is Core Atrophy (Congenital myotonic muscle dystrophy)  Ragged red fibers  Necrotic Fibers Poorly stained Loss of internal structure Macrophage  Regenerating Fibers Small Basophilic Large Pale nuclei Duchenne Muscular Dytrophy (1986)  Onset: < 5 years (3-5 y/o)

Male > Female  Progressive weakness of the girdle muscles

Calf hypertrophy: Hypertrophy of muscle – calf first… (Degenerative

&

becomes weak...later infiltrated w/ contractures…then scoliosis…then difficulty…finally, cardiac failure  IQ not too good, patient not too mobile  Respiratory failure in their 20’s-30’s  Genotype: Dystrophin deficiency 96% with frameshift mutation

fat cells… respiratory

30% with new mutation  Clinical Manifestations: Weakness Proximal > Distal Symmetric Legs & Arms (Legs first) Adductor magnus of the legs (most affected) Gracilis & Sartorius (relatively spared) Duchenne established the diagnostic criteria: Weakness with onset on the legs Hyperlordosis with wide-based gait Hypertrophy of weak muscles Progressive course over time Reduce muscle contractility on electric stimulation Absence of bladder/bowel dysfunction Course Reduced motor function by 2-3 years Steady decline in strength after 6-11 years Gower’s sign: Standing up with the aid of hands pushing on the knees Failure to walk: 9-13 years “Waddle when they walk, straddle when they stand” Muscle Hypertrophy evident: Especially in the calf May be generalized Increases with age Most commonly due to muscle fibrosis Some relatively spared muscles may have true hypertrophy Other Clinical Features Dilated Cardiomyopathy (> 15 years) Mental Retardation (Mean IQ ~88) Night blindness Altered response to flashes of light in dark adapted state ERG: b-wave, reduced amplitude Dp260: Isoform of dystrophin in retina Death Most common between 15-25 years Respiratory or Cardiac failure Life prolonged by ~ 6 years to 25 years with respiratory support Life shortened by 2 years if cardiomyopathy appears early.  Laboratory exams CK is very high Troponin I: Elevated beyond normal but not to levels comparable to cardiac ischemia Liver enzymes: High AST/ALT Biopsy NADH Stain: Pale necrotic fibers H&E Stain: Phagocytosis: Invasion of fibers by macrophages Dystrophin stains around the rim of the muscle fibers Degeneration & regenerating muscle fibers  Treated using steroids (Prednisone)  X-linked disorder CHRABI Page 2 of 10

Becker’s Muscle Dystrophy  Dystrophin mutation Deletion: in 70% of patients Frameshift mutation New mutations are rare Worse Cases: Additional mutation in myogenic factors  Clinical features Onset > 7 years old Weakness Not as bad as in Duchenne Symmetric Proximal > Distal; legs and arms May be especially prominent in quadriceps or hamstrings Slowly progressive Severity & onset age correlate with muscle dystrophin levels Calf pain on exercise Muscle hypertrophy: prominent in the calves and is painful after exercise. Failure to walk: 16-80 years Systemic Clinical manifestations: Joint contractures: Ankles & others Cardiomyopathy: may occur before severe weakness Mental retardation Associated with deletion of Dp140 transcription unit Dystrophin deficiency (because it is found also in the brain tissue)  Serum CK is very high: 5,00 – 20,000 (Lower levels with increasing age and disability)  Muscle Biopsy: Myopathic Varied muscle fiber size Endomysial connective tissue increased Myopathic grouping: < 12 years of age Degeneration/Regeneration Reduced dystrophin (Provides support for muscle during contraction & relaxation) staining  Older patients: Findings are typical of chronic dystrophies Increased endomysial connective tissue Variable fiber size: small muscle fibers are rounded Internal nuclei The largest muscle fibers are hypertrophied Occasional fibers: Degeneration; regeneration; hypocontracting; split Mosaicism for Dystrophin

Asymptomatic & symptomatic female carriers Majority are females: Larger calves with overt muscle weakness  Female heterozygous carriers  Increase CK with proximal muscle weakness

Myonuclei capable & dystrophin negative Sarcoglycanopathy (Limb-Girdle Muscular Dystrophy)  Shoulder or pelvic weakness

Walton & Nattrass Definition (1954)

 Expression in either male or female sex  Onset usually in the late first or second decade of life (but also middle age)

Usually

autosomal recessive & less frequently autosomal dominant  Involvement of shoulder or pelvic girdle muscles with variable rates of progression  Severe disability within 20-30 years

Muscular

pseudohypertrophy &/or contractures are uncommon  Basic division of LGMD Autosomal Dominant (LGMD 1) Autosomal Recessive (LGMD 2)

Classification

uses an alphabetical lettering system spanning A-E in LGMD 1 & A-J in LGMD 2: The letter delineates the order in which each LGMD was linked to a chromosomal locus (ie. LGMD 1A was mapped to a chromosome prior to LGMD 1B, etc.)

Hip-girdle weakness is most prominent in the gluteus

maximus & hip adductors. Along with abdominal weakness, this leads to a wide-based, lordotic gait  Atrophy is often prominent (Very early)

Progression tends to be slow & wheelchair use begins 11-28 years after the onset of the symptoms

Fascioscapulohumeral Dystrophy  Autosomal dominant, 4q35 with childhood onset. NL lifespan

Facial,

neck, proximal shoulder & scapular muscles involved, rare in cardiac  Ankle dorsiflexores  Slowly progressive course  Histopath similar to Duchenne’s but milder. Shows muscle fibers of different sizes.  PE: downward sloping of clavicles, elevated scapula, pectoralis is atrophic, no anterior axillary fold, patient can’t abduct arms w/o help

Diagnosis:

Weakness in facial muscles, scapular muscles & later in ankle dorsiflexors  Different sizes of muscle fibers Myotonic Dystrophy (Types 1-3)  Caused by a defective gene on chromosome 19q13.2

The

muscle weakness is accompanied by myotonia (delayed relaxation of muscles after contraction) & by a variety of abnormalities in addition to those of the muscle  Other names: Steinert’s disease Dystrophia myotonica  Onset: Neonatal to late adulthood Congenital onset: Floppy infant, but no myotonia yet, respiratory weakness Children: Mental retardation & motor delay Adults Myopathic discharge Seen on EMG & clinically Especially 2nd to 4th decades Weakness: Finger flexors, neck flexors & face Motonia: Grip CHRABI Page 3 of 10

Older adult (with minimal DM1; onset of > 60) present with cataracts Age of onset correlates with length of repeat when CTG number is less than ~ 400  Can grasp hand but cannot relax  Contraction for a long time on tapping thenar muscle  Dive bomber sound??  (+)percussion contraction ( depression in the skin after percussion)

Hooded eyes, hollowed masseter & temples; inverted V mouth  Chronic changes in MD Type 1 (Most common form) H&E stain Numerous internal nuclei Longitudinal chains Myopathic changes: Fiber size variation Other signs/symptoms: cataracts, endocrine problems like DM, myoglobinuria, respiratory/cardiac problems Congenital Myopathy  Central Core Disease Nemaline rods Centronuclear (Myotubular) Myopathy: Infant with A long slender body Long fingers & toes Elongated head Floppy Shifting of bones due to poor muscle tone Frog-leg posture Swallowing difficulties Very fatal course Metabolic Myopathy  Myophosphorylase Defect Defect in glycogen metabolism Absent to reduced muscle phosphorylase Exercise intolerance Myoglobinuria Muscle weakness in ~ 70% Forearm exercise test: no rise in lactate CK: High  Thyrotoxic Myopathy Proximal weakness with EMG; abnormalities in 90% Percussion may give fascies associated with Myasthenia gravis or PP. Fatty deposit around the eyes create exopthalmos Recti muscles hypertrophies Periodic hypokalemic paralysis  Hypothyroidism Percussion provokes prolonged contraction with slow release (+) percussion contracture Weakness, stiffness, cramps, pseudomyotonia, increased CPK  Periodic Paralysis Hypo, hyper, euklaemic Autosomal dominant with male predominance Molecular mechanism is a mutation of the voltage gated sodium channel Triggered by CHO load, exercise, cold

Sudden attacks In patients w/ hyperthyroidism, can’t move in the morning, signs & symptoms precipitated by high CHO intake, patient is hypokalemic, more common in males than in females Treatment: Give potassium supplements  Alcoholic Myopathy Insidious proximal weakness, low CPK Acute rhabdomyolysis may accompany binge drinking with renal failure.  Myoglobinuria Massive muscle lysis as seen in trauma, burns, snake-bites, drug toxicitiy, infections Dramatic CPK elevations Acute tubular necrosis may supervene fatally Inflammatory Muscle Disease  Most important: polymyositis (PM), dermatomyositis (DM), inclusion body disease (IBM, sarcoidosis, scleroderma, focal infection)

Group

of muscle disease that cause inflammation & degeneration of the skeletal muscle tissues

Heterogenous

group of subacute, chronic & rarely

acute acquired  Autoimmune

Muscle

weakness + skin signs & symptoms in dermatomyositis; but signs & symptoms may be transient.  Myopathy is a muscle disease  Inflammation is a response to cell damage

The

inflammatory process  Destruction of muscle tissue  Weakness & pain  Loss of muscle bulk (Atrophy)  Classification Idiopathic IM: Largest group Secondary In association with other systemic or CTD In association with bacterial, viral or parasitic infection Infantile/Childhood Miscellaneous forms  Characterisitic symptom: Muscular Weakness  Frequency: Incidence of 0.5-8.4/million Pevalence of 5-10/million  M:F ratio Polymyositis (PM) 1:1 Dermatomyositis (DM) 1:2 Inclusion Body Myositis (IBM) 3:1  Age: DM has a bimodal pattern (3-10 and 45-50 years) PM 45-60 years IBM > 50 years  Race: More frequent among Afro-Americans  Genetic predisposition  T-Cell mediated myotoxicity  Complement mediated microangiopathy

IBM: Autoimmune + degenerative features Myonuclear abnormalities CHRABI Page 4 of 10

Vacuolation Amyloid deposition Mitochondiral proliferation  Etiologies Multifactorial Genetic Predisposition Do not accumulate among family members HLA-association: A1, B8, DR3, DR5, DR7, HLADRB1*0301-DQA1*0501 Environmental factors/triggers Infectious: Coxsackie B, HIV, HTLV-1, HBV, Influenza, echovirus, Adenovirus, Toxoplasma, Borrelia U-V Light  Overall clinical features: 1 in 100,000 cases Common myopathy Symmetrical muscle weakness Subacutely to chronic progression Difficulty in getting up from chair, climbing stairs, lifting objects & combing hair PM/DM : Affects mostly proximal muscles IBM: Affects distal muscles & proximal legs (Quadriceps selected weakeness) Distal weakness first (hand flexors), w/ wasting, later quads become atrophic

Dermatomyositis:

Rashes on the shoulder (Shawl Sign), hands & neck, dysphagia are common Heliotrope Rash Red-purple edematous ± erythema (maculopapular) Distribution: Face & upper eyelids, Symmetric A dark lilac discoloration or is violaceous to dusky erythematous rash with or without edema in a symmetrical distribution involving the periorbital area

This rash may follow the course of myositis or it may wax/wane discordantly with the disease activity Gottron’s Sign Red-purple keratotic, atrophic erythema, or macules Found on extensor surface of the joints: especially MCP, PIP and DIP (Knuckles)  V-neck Sign: Violaceous macular erythema on the chest

Mechanic’s Hands/Nailfold lesions: Raised scaly & dry

on the extensor surfaces of the finger joints  Electromyography findings Fibrillation potentials Positive sharp waves Complex repetitive discharges Short-duration, small amplitude, polyphasic motor units with early recruitment but normal frequency  Muscle biopsy Findings: H&E stain Necrotic & regenerating perifascicular regions Muscle fiber size is variable  Treatment Options

muscle

fibers

in

Severe cases: Initiate treatment with IV methyprednisolone 20-30 mg. per kg/day or every other day for 3-5 days Usual treatment: Prednisone 1.5 mg/kg/day (up to 100 mg) in a morning dose. In 2-4 weeks, it can often be changes to alternate day regimen Dose taper: No more than 5 mg every 2-4 weeks Exacerbation: Double the dose of prednisone (up to 1.5 mg/kg or 100 mg.) Calcium: 1000 – 1500 mg/day Vitamin D: 400-800 IU/day Physical therapy: Axial exercise to reduce the risk of osteoporosis. Exercise also reduces steroid induce myopathy Estrogen therapy in post-menopausal women Weight control Monitor the BP, glucose, potassium & eyes (glaucoma & cataract) Only polymyositis & dermatomyositis respond to steroids Secondary Inflammatory Myopathies  Myopathies will get better & patient will be stronger once the infection is better  Retroviruses In humans infected with HIV & HTLV-1 Inflammatory myopathy (HIV-polymyositis) can occur as either an isolated clinical phenomenon or concurrently with the other manifestations of HIV Very weak or early atrophy (Maybe due to poor intake with decrease muscle mass)  Other Viral Infections They have been associated with acute & chronic myositis Molecular mimicry especially with Coxsackie virus to Jo-1 antibody PCR is unable to detect these viruses Examples: Coxsackie, Influenza, Paramyxovirus, CMV, EBV  Nonviral Microbial Myositis Parasites  Protozoa: Toxoplasma, Trypanosoma  Cestodes: Cysticerci  Nematodes: Trichinae

 May

produce diifuse myositis  Parasitic polymyositis Trichinosis  Infection derived by eating infected pork  Biopsy may reveal the following: Empty cysts Cyst containing inflammatory cells Cyst containing calcifications Surrounding muscle has no inflammation or active myopathic changes  Juveniles of the parasitic nematode Trichinella spiralis are exncysted in human muscle tissue  Humans acquire the infection by eating undercooked infected pork or other meat with juvenile worms encysted in the muscle tissue.  Within the human intestine, the juveniles develop into sexually mature adults. Females burrow into the intestinal muscles and produce CHRABI Page 5 of 10

more juveniles, which bore through the body or travel in lymphatic vessels to other organs, including skeletal muscles where they encyst.  Bacterial infections Staphylococcus aureus myositis Usually focal, unless patient immunocompromised Fluctuant mass  Yersinia spp  Streptococcus spp  Anaerobes  Bacteria causes a suppurative form of myositis Tropical myyositis Pyomyositis

is

Collagen Vacular Diseases  Muscle ischemia  Cachexia  Peripheral nerve involvement

Musculoskeletal deformities  Systemic sclerosis (associated with DM)  SLE (PM in 5-8%)  In Sjogren’s Syndrome (DM and IBM)  Same pathological features as that found in the idiopathic forms  Treatment: Steroid (However, high doses of steroid can cause myopathy especially in high doses) Miscellaneous Forms  Granulomatous myopathy

In hypersensitivity vasculitis: Eosinophilic syndromes  Macrophagic myofascitis Localized form With pipe stem capillaries  Drug induced  Graft versus host reaction  Combined with mitochondrial myopathy Drugs causing Drug induced Forms  Amiodarone: For arrhythmias  Amphetamines  Chloroquine  Cimetidine  Cocaine

Colchicine: Anti-gout medications  Corticosteroids: Even if you have weakness, must still continue giving drugs because the weakness may disappear  Cyclosporin  Danazol  Epsilon amino-caproic acid  Ethanol  Fibric acid derivatives  Heroin  Hydralazine  Hydroxychloroquine  Hydroxyurea  Ipecac (emetine)  Levodopa  Nicotinic acid

 Pancuronium  Penicillamine  Pentazone  Phenylbutazone  Phenytoin  Procainamide  Rifampin  Statin drugs Newer statins causes more myopathy (Atorvastatin) Older statins (Simvastatin) causes myopathy as well but at a lesser rate than the newer statins  Sulfonamides  Tiopronin  Vecuronium bromide  Vincristine  Zidovudine (AZT) Toxic Myopathies  Mitochondrial  Myosin Deficiency Myopathies Critical illness myopathy  Given steroids & neuromuscular blockers  Improved but quadriplegic due to muscle necrosis  Sometimes the reason why the patient cannot be removed from the respiratory  Rhabdomyolysis  Muscle overactivity syndrome

Drug & toxin induced Neuroleptic Malignant Syndrome  Precipitated by succinylcholine Introduction  Neuromuscular Transmission Process by which action potential in a motor nerve axon leads to an action potential in the relevant twitch fiber of a vertebrate skeletal muscle Particularly relevant to a range of different diseases NMJ is the target for many neurotoxins

Motor nerve unit consists of:  Motor neuron cell body in the spinal cord  Motor nerve axon that arises from it Branches when it reaches the surface of the muscle, and each branch loses its myelin sheath just before forming the motor nerve terminals that synapse on the surface of each muscle fiber. The NMJ:  Oval in shape  30-50 µm in its largest dimension  Runs parallel to the length of the fiber

 Easily

demonstrated in muscle tissue by fixing & staining for AchE Each nerve terminal expansion (bouton) is a thin extension of a Schwann Cells Schwann cell extension express high levels of proteins: NCAM & S-100 (Covers the axon & appears to protect & nourish the axon before it reaches the muscle) Muscle surface at the point of contact between the nerve & muscle is often raised, but the terminal branches are sunk into synaptic depressions where the sarcolemma forms post-synaptic folds In between the muscle and the nerve terminal, the basal lamina (a distance of ~50 nm) can be seen. Basal Lamina  Extends as a double layer into each of the folds  Appears to be amorphous but contains many essential molecules: Collagen IV Laminins Heparan SO4 proteoglycans  At the NMJ, it forms a network or scaffold that anchors the NMJ-specific proteins: AchE S-laminin (synapse-specific laminin) Agrin (AchR-aggregating molecule) Neuroregulin

 All

are involved in the development, maintenance & function of the NMJ.

Envenomation: Cause of neuromuscular failure (Due to specificity for NMJ proteins, many of the toxins have been helpful in the study of neuromuscular transmissions and its disorders)  Neuromuscular Junction A chemical synapse

On EM, you can see a large number of small synaptic

Transmission depends on release of Ach from the motor nerve terminal & its interaction with AchR’s on the postsynaptic muscle surface End-Plate Potential (EPP)  Generation of a local potential change in the post-synaptic membrane

Where the voltage-gated Calcium Channels are located & where the synaptic vesicles fuse with the plasma membrane to release their contents

 Induces

a regenerating action potential by activating voltage-gated sodium channels

When sufficient VGSCs are opened, resulting depolarization leads to a regenerative action potential that can propagate along the muscle fiber

Nature

and Development of the NMJ (Microscopic Structure) A special structure of the nerve muscle synapse

CHRABI Page 6 of 10

vesicles concentrated on the membrane opposite to the post-synaptic folds  Active Zones (Cytoplasmic densities) Cluster along the nerve terminal opposite the entrance to the folds

α-bungarotoxin: snake toxin Binds specifically & irreversibly to the AchR’s, increased density corresponds to the location of AchR’s, present at > 10,000/µm2 post-synaptic membrane In contras, AchR’ density outside the NMJ in mature muscle falls to ~10/ µm2

VGSCs

& NCAM are located in the lower 2/3 of the post-synaptic folds

Below

the post-synaptic folds, within the cytoplasm of the myofibril, are several nuclei, which are responsible for producing the proteins involved in post-synaptic structure & function

Molecular Architecture of the Post-synaptic Nerve Terminal  Receptors are on the trough  AchR’s purified from the electric fish Torpedo marmorata were associated with a 43kDa protein that was qubsequently called RAPsyn (Receptor aggregating proteins at the synapse)

Synapsin

binds to actin, before releasing acetylcholine, synapsin must 1st release actin  RAPsyn: Cytoplasmic protein of ~400 aa residues that appears to be essential for the localization of AchR’s & many other NMJ-specific proteins Highly concentrated at the tops of the folds, beneath the AchR’s Important for aggregation of AchR on the junctional folds Protein involved on congenital myasthenic syndrome  Utrophin Protein that shows extensive homology to the dytrophin but which in normal muscle is highly concentrated at the NMJ at the tops of the junctional folds, with a similar distribution to the AchR’s & RAPsyn Thought to link the AchR/α-dystrobrevin complex to actin filaments

α-dystrobrevin 1: Col-localizes with AchR’s  Dystrophin Present at the base of the folds & throughout the sarcolemma At the NMJ, it associates with α-dystrobrevin 2, ankyrin and β-spectrin. Myasthenia Gravis  History of Myasthenia Gravis Thomas Willis: first myasthenia gravis

written

description

of

English physician (1621-1675) Wrote about a woman who temporarily lost her power of speech & became mute as a fish. This has been interpreted as being the first written description of myasthenia gravis  Is the most common primary disorder of neuromuscular transmission

The

usual cause is an acquired immunological abnormality

A

chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body (but may also involve cardiac & smooth muscle). The name myasthenia gravis, which is Latin & Greek in origin, literally means “grave muscle weakness”

CHRABI Page 7 of 10

The

hallmark of myasthenia gravis is a muscle weakness that increases during periods of activity & improves after periods of rest

Certain

muscles such as those that control eye & eyelid movement, facila expression, chewing, talking & swallowing are often, but not always, involved in the disorder

The

muscles that control breathing & neck & limb movements may also be affected  Clinical Presentation Ocular motor disturbances, ptosis or diplopia (double-vision), are the initial symptom of MG in 2/3’s of patients, almost all had both symptoms within 2 years Levator palpebra is involved, but other muscles supplied by cranial nerve 3 is not affected Involvement from rostrocaudal direction: Lid → muscles for extraocular eye movement → facial muscle → Respiratory muscles → Leg muscles Ptosis is initially one-sided & only partially involved, then becomes complete, after a few months it becomes bilateral Ptosis is described as “No ptosis in the morning, ptosis only apparent at the end of the day” Size & reactivity of the pupils is normal Oropharyngeal muscle weakness, difficulty chewing, swallowing, or talking, is the initial symptom in 1/6 of the patients. Limb weakness in only 10% Initial weakness is rarely limited to single muscle groups such as neck or finger extensors or hips flexors (Spotty involvement of the muscle) The severity of weakness fluctuates during the day, usually being least severe in the morning & worse as the day progresses, especially after prolonged use of affected muscles Facial weakness is obvious, in that the corners of the mouth do not rise, the eyebrows are raised & the forehead is wrinkled in an effort to compensate for partial right-sided ptosis & almost incomplete left-sided ptosis Masseter: Manifested as difficulty chewing & jaw will open if not held up The course of the disease is variable but usually progressive Weakness is restricted to the ocular mscules in about 10% of cases The rest have progressive weakness during the first 2 years that involved the oropharyngeal & limb muscles Maximum weakness occurs during the first year in 2/3 of patients In the era before corticosteroids were used for treatment, approximately 1/3 of patients improved spontaneously, 1/3 became worse & 1/3 died of the disease Spontaneous improvement frequently occurred early in the course (During the active phase, can do a lot for the patient)

During the inactive stage or fixed stage, patient may not need to take medications Onset is bimodal  Females have earlier onset  Male: Peak happens later in life Factors that worsen MG symptoms:  Emotional upset  Systemic illness (especially respiratory infections)  Hypothyroidism or Hyperthyroidism  Pregnancy  The menstrual cycle  Drugs affecting the neuromuscular transmission  Increase body temperature Symptoms fluctuated over a relatively short period of time & then became progressively severe for several years (active stage) The active stage is followed by an inactive state in which fluctuations in strength still occurred but are attributable to fatigue, intercurrent illness, or other identifiable factors. After 15-20 years, weakness often becomes fixed & the most severely involved muscles are frequently atrophic (burnt-out stage) Deep tendon reflexes are present even if weakness is severe as long as there is no muscle atrophy (In muscle & neuromuscular junction disorders, deep tendon reflexes are normal)  Pathophysiology of MG Problem is post synaptic The normal NMJ releases acetylcholine (Ach) from the motor nerve terminal in discrete packlages (quanta) The Ach quanta diffuse accross the synaptic cleft & bind to receptors on the folded muscle end-plate membrane Stimulation of the motor nerve releases many Ach quanta that depolarize the muscle end plate region & then the muscle membrane causing muscle contraction In acquired myasthenia gravis, the post-synaptic muscle membrane is distorted & simplified, having lost its normal folded shape The concentration of Ach receptors on the mscule end-plate membrane is reduced & antibodies are attached to the membrane Ach is released normally, but its effect on the postsynaptic membrane is reduced. The post-juctional membrane is less sensitive to applied Ach, & the probability that any nerve impulse will cause a muscle action potential is reduced MuSK: Muscle specific… tyrosine kinase protein: Sometimes affected in MG  The Thymus in MG The thymus contains all the necessary elements for the pathogenesis of MG:  Myoid cells that express AchR antigens  Antigen presenting cells  Immunocompetent T-cells

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Thymic abnormalities are clearly associated with myasthenia gravis but the nature of the association is uncertain 10% of patients with MG have a thymic tumor & 70% have hyperplastic changes (germinal centers) that indicate an active immune response. These are areas within the lymphoid tissue where B-cells interact with helper T-cells to produce antibodies Because the thymus is the central organ for immunological self-tolerance, it is reasonable to suspect that thymic abnormalities cause the breakdown in tolerance that causes an immune mediated attack on AchR in MG. Patients with thymoma usually have more severe disease, higher levels of AchR’s antibodies & more severe EMG abnormalities than patients without thymoma Almost 20% of patients with MG whose symptoms began between the ages of 30 & 60 years have thymoma, the frequency is much lower when symptom onset is after age of 60 Even in patients without thymoma, treatment is still thymectomy to remove antibody source  Diagnostic Procedures The Endrophonium Chloride (Tensilon) Test: Weakness caused by abnormal neuromuscular transmission characteristically improves after IV administration of endrophonium chloride. Antibodies against AchR  Gold standard

 74%

of patients with acquired generalized MG & 54% with ocular myatshenia have serum antibodies that bind human AchR

 The serum concentration of AchR antibody varied

widely among patients with similar degrees of weakness & cannot predict the severity of disease in individual patients.

Repetitive Nerve Stimulation

 Decrementing response (Decrease in amplitude)  Significant > 10% - consitient with neuromuscular transmission defect. Single Fiber EMG  Action potential of motor fiber supplied by 1 motor nerve

 Most

sensitive clinical test of neuromuscular transmission & shows increased jitter

 Jitter

is greatest in weak muscles but may be abnormal even in muscles with normal strength

 Patients

with mild of purely ocular muscle weakness may have increased jitter only in facial muscles RNS vs SFEMG in MG  In generalized MG, RNS is sensitive  In ocular MG, RNS is not so sensitive depending on the muscle tested.

 SFEMG

is indicated & helpful in patients with normal RNS

 If

RNS is abnormal, practically, SFEMG is not needed because it will almost always be abnormal  Treatment Treatment decisions should be based on knowledge of the natural history of disease in each patient & the predicted response to a specific form of therapy Treatment goals must be individualized according to the severity of the disease, the patient’s age & sex & the degree of functional impairment Cholinesterase inhibitors (pyridostigmine: Mestinon)  Mainstay

 Adverse effects of ChE inhibitors may result from Ach accumulation at muscarinic receptors on smooth muscle & autonomic glands & at nicotinic receptors or skeletal muscle (Salivation, cramps, diarrhea & bradycardia)  Frank muscle weakness: Difficult to depolarize  GI complaints are common

 Increased

bronchial & oral secretions are a serious problem in patients with swallowing or respiratory insufficiency

 Symptoms

of muscarinic overdose may indicate that nicotinic overdosage (weakness) is also occurring Corticosteroid Therapy

 Marked

improvement or complete relief of symptoms occurs in more than 75% of patients treated with prednisone & same improvement occurs with most of the rest

 Much

of the improvement occurs in the first 6-8 weeks, but strength may increase to total remission in the months that follow  The best response occurs in patients with recent onset of symptoms, but patients with chronic disease may also respond.

 Patients

with thymoma have an excellent response to prednisone before or after removal of the tumor  The most predictable response to prednisone occurs when treatment begins with a daily dose of 1.5-2 mg/kg/day

 About

1/3 of patients become weaker temporarily after starting prednisone, usually within the first 7-10 days & lasting for up to 6 days  Treatment can be started at low dose to minimize exarcebations; the dose is then slowly increased until improvement occurs.

 Exacerbations may also occur

with this approach & the response is less predictable.

 The

major disadvantages of chronic steroid therapy are the side effects (Diabetes, hypertension, hypokalemia & osteoporosis) Immunosuppressive drugs (azathioprine, cyclosporine, mycophenolate, methotrexate) IVIG

CHRABI Page 9 of 10

 Several groups have reported a favorable response to high-dose (2 g/kg infused over 2-5 days) of IVIG.

 Possible

mechanisms of action include donwregulation of antibodies directed against AchR & the introduction of anti-idiotypic antibodies. Improvement occurs in 50-100% of patients, usually beginning within 1 week & lasting for several weeks or months.

Plasmapheresis: Plasma exchange is used as a short-term intervention for patients with sudden worsening of MG symptoms for any reason, to rapidly improve strength before surgery & as a chronic intermittent treatment for patients who are refractory to all other treatments (Maybe stabilized after 5 treatments) Thymectomy  Very invasive procedure  Because of variable course, not sure if resolution is due to thymectomy or because of remission Avoid aminoglycosides & tetracycline which can cause myasthenia crises Congenital Myasthenic Syndromes  Electrophysiology Decrement on RNS  Common at 2Hz stimulation  Absent with CMG with episodic apnea when asymptomatic. Repetitive CMPA to single stimulus Patients taking high doses of AchE inhibitors  Decrement on RNS not corrected by endrophonium  Syndromes are differentiated by anatomic location of mutated protein Presynaptic  Defects in evolved release of Ach aunta or Ach resynthesis (ChAT mutations)  Frequency 8% Synaptic Basal Lamina  Defect caused by mutations in collagen tail of AchE  Frequency 16% Postsynaptic  Most caused by mutations in subunits of AchRs  Other: Syndromes caused by plectin ort RAPsyn mutations  Frequency: 76% Neonatal Myasthenia Gravis  Mother has myasthenia gravis: Antibody will go to the placenta & cause transient fetal myasthenia  This is different from congenital myasthenia gravis in which the mother has no myasthenia & the problem last for life Myasthenic Syndromes (Lambert-Eaton)  Epidemiology Prevalence: 1 in 100,000 Males slightly more common than females Age: 17-75 years; onset younger without associated neoplasm.  Clinical features

Onset  Weakness (82%), epsecially legs  Age: Range = 7-80 years  Usually precedes CA: >80% Weakness  Proximal > Distal

 Legs (98%) & Arms (82%)  Neck (30%)  Respiratory (15%): Rarely severe.  Bulbar: Dysphagia (22-56%); Dystarthia (up to 80%)  Improves with: Brief sustained exercise  May worsen with: Sustained exercise; heat or fever  Fatigability (33%) Extraocular muscles  Not involved at presentation  Rarely involved on examination  Occassional ptosis (30-50%)  Symptomatic diplopia in ~40% (transient) Muscle pain – occasional Sensory neuropathy: Distal/ symmetric (Limb muscles) Autonomic neuropathy  Association stronger with cancer than with LEMS  Dry mouth > eyes  Impotence among males

 Other

(10-50%): Bladder/ Constipation/ Hyperhydrosis  Diagnosis Electrophysiology (RNS)  Increment After rapid (50Hz) RNS or Sustained muscle contraction Prolonged by cooling Muscles with most increment after 10 seconds manximal voluntary contracture Most specific test for LEMS when > 100% in several muscles or >400% in one muscle Abductor digiti minimi; abductor policis brevis; anconeus  Decrement on slow (5 Hz) RNS: especially in small band muscles.  Pathophysiology Usually related with a malignancy: Small cell carcinoma of the lung: may manifest even prior to symptoms of lung malignancy) Presynaptic disorder

 Reduced

numbers of P/Q Ca++ channels on presynaptic terminals  Ultrastructure: active zone presynaptic terminals reduced  Physiology Reduced K+ stimulated Ca++ influx into presynaptic terminals Reduced Ca++ dependennt quantal Ach release Botulism  Intoxication usually follows food ingestion, some cases follow wound inoculation CHRABI Page 10 of 10

 Results in long lasting severe muscle paralysis  Symptoms Nausea & vomiting are the 1st symptoms Neuromuscular features appear in 12-36 hours Initial symptoms: Blurring of vision, dysphagia, dysarthia Dilated pupils: Descending weakness progresses for 4-5 days then plateaus (As compared to GBS, in which the paralysis is ascending) Respiratrory paralysis may occur rapidly Most havve autonomic dyysfunction  Treatment Trivalent (A,B,E) antitoxin Antibiotics are not effective Supportive therapy increase respiratory assistance ChE inhibitors are NOT BENEFICIAL Guanidine or DAP may improve strength Recovery takes many months but it is usually complete (Weakness can last for a while) VINCE CHRABI