PATHOPHYSIOLOGY CLINICAL FEATURES AND

DIFFERENTIAL DIAGNOSES

Myasthenia gravis Myasthenia gravis

Dr JISHANTH MProf Dr A Gowrishankar’s Unit

Dept. of Internal Medicine

INTRODUCTIONINTRODUCTION

• The most significant development:The demonstration of An Immunologic Mechanism operative at the neuromuscular junction

• Result is a failure of effective neuromuscular transmission on the postsynaptic side

THE NEUROMUSCULAR JUNCTION

PATHOPHYSIOLOGY

1. Antibodies to AChR protein:85 % of patients with generalized myasthenia and 60% of those with ocular myasthenia shows AChR Antibodies

2. Anti-MuSK Ab(40% of seronegative cases)An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with “AChR clustering”

How do these antibodies act?

1. Blocks the binding of ACh to the AChR.2. INCREASES THE DEGRADATION rate of AChR

ANTIBODIES→ CROSS LINKING OF RECEPTORS → →CLUSTERING → ENDOCYTOEIS → DEGRADATION

3. A complement-mediated destruction of the postsynaptic folds.

The latter two mechanisms would be expected to reduce the number of AChR at the synapse.

Myasthenia GravisMyasthenia Gravis

AChRs

Antibodies

Simplified Motor Endplates

PATHOLOGY

• The muscle fibers are generally intact • In fatal cases with extensive paralysis,

“Segmental necrosis with variable regeneration” • Scattered aggregates of lymphocytes, “Lymphorrhages”

especially associated with thymomas

MOTOR END PLATE: 1. a reduction in the area of the nerve terminal, 2. a simplification of the postsynaptic region (sparse, shallow,

abnormally wide or absent secondary synaptic clefts) 3. a widening of the primary synaptic cleft

PRESYNAPTIC VESICLES AND NERVE TERMINALS ARE NORMAL

THYMIC AND OTHER ASSOCIATED DISORDERS

• Thymus is abnormal in ~75% of patients with MG• In ~65% the thymus is "hyperplastic,"

(a nonneoplastic lymphofollicular hyperplasia of the thymic medulla) with the presence of active germinal centers detected histologically

• 10% of patients have thymic tumors (“ neoplastic”)

• Thymomas with malignant characteristics may spread locally• Upon distant spread, the lungs and liver are usually

affected.

Muscle-like cells within the thymus (myoid cells) which bear AChRs on their surface may trigger immune response

Pathologic Features of the Thymus• Hyperplasia of the medulla characterized by lymphoid follicles with active

germinal centers. The cells in the centers of the follicles are histiocytes;• Immunoglobulin G (IgG) is elaborated in the germinal follicles. • These resemble the cellular reaction that is observed in the thyroid of

Hashimoto thyroiditis.

THYMOMASTwo forms have been described:

1. Composed of histiocytic cells like the reticulum cells in the center of the follicles

2. Predominantly lymphocytic and considered to be lymphosarcomatous

• The immune effector cells in myasthenia gravis are both T and B cells.

• Sensitized T cells and complement play a role in continued stimulation of B cells and in cell mediated post synaptic destruction

CLINICAL FEATURES• Prevalence: 1-7 in 10,000• Affect all age groups• Usual age at onset: BIMODAL PEAK• 20-30 yrs(young women), 50-60 yrs(older men)• < 10% occur in children <10 yrs• When <40 yrs f:m = 2-3:1, males more affected in elderly(3:2)• Overall F:M = 3:2

• Familial occurrence is known, but rare• More common is a family history of one or the other autoimmune

diseases, and suggests partial genetic predisposition• Reports of the concurrence of myasthenia and MULTIPLE

SCLEROSIS

CLINICAL PRESENTATION

• Repeated or persistent activity of a muscle group exhausts its contractile power(fatigability), leading to a progressive paresis, and rest partially restores strength

• There is special vulnerability of certain muscles ( the eyelids and the muscles of the eyes, face, jaws,

throat, and neck, are the first to be affected )

• Limb muscle weakness as the initial complaint is less frequent.

CLINICAL PRESENTATION

• Fluctuating weakness increased by exertionWeakness increases during the day and improves with rest

• Levator palpebrae &Extraocular muscle weaknessPtosis/diplopia is presenting symptom in 50% of patients and ↑ during the course of disease in 90%If associated with weakness of closure—almost diagnostic if “PUPILS ARE SPARED”

• Head extension and flexion weaknessMore sensitive in demonstrating generalised disease

OSSERMAN Classification

1. Class I Any ocular muscle weakness

2. ClassII Mild weakness other than ocularIIa Predominantly limb,axial, or bothIIb Predominantly orpharyngeal/respiratory

3. Class III Moderate weakness other than ocularIIIa Predominantly limb,axial, or both

IIIb Predominantly orpharyngeal/respiratory4. Class IV Severe weakness other than ocular

IVa Predominantly limb,axial, or bothIVb Predominantly orpharyngeal/respiratory

5. Class V Intubation with/without ventilation

PROGRESSION OF DISEASE

Mild to severe…..over weeks to months

• Spreads from ocular to facial to bulbar to truncal and limb muscles

• Symptoms may remain limited to EOM and eyelid muscles for yrs• The disease remains ocular in 16% of patients

REMISSIONS

• Spontaneous remissions rare, most remissions with treatment occur within the first three years

• If remission lasts >1 yr and recurs disease tend to be progressive.• Isolated ocular myasthenia > 1 yr, subsequent generalisation is

only 16%• The course is altered by thymectomy (even drug free remissions)

BASIC PHYSICAL EXAMINATION

Sensory examination and DTR’s are normal

1. Muscle strength testing2. Recognize patients who may develop respiratory failure

(i.e. difficult breathing)

CLINICAL PRESENTATION

MUSCLE STRENGTH

Ocular muscle weakness Facial muscle weakness Bulbar muscle weakness Limb muscle weakness Respiratory weakness

Bulbar Muscles

1. OCULAR MUSCLE WEAKNESS

• ASYMMETRIC• Usually affects more than one extraocular muscle and is

not limited to muscles innervated by one cranial nerve• Weakness of lateral and medial recti may produce a

pseudo internuclear opthalmoplegia

• Ptosis is caused by Levator palpebrae weakness• “Sustained upward gaze for 30 seconds”• Diplopia is very common• “Lid-twitch” sign, Repeated ocular versions• Bright sunlight aggravate the ocular signs and COLD

improves them

2. FACIAL MUSCLE WEAKNESS

• Facial muscle weakness is almost always present• bilateral facial muscle weakness• Sclera below limbus may be exposed due to weak lower lids• Muscles of facial expression

3. BULBAR MUSCLE WEAKNESS

• Bulbar muscle weakness( more in Anti MuSK Ab positive cases)

Palatal muscles• “Nasal voice”, nasal regurgitation• Chewing may become difficult• Severe jaw weakness may cause jaw to hang open• Swallowing may be difficult and aspiration may occur with

fluids—coughing and choking while drinking

Neck muscles• Neck flexors affected more than extensors

4. LIMB MUSCLE WEAKNESS

• Upper limbs more common than lower limbs• Proximal > than distal muscles• Usually asymmetric weakness

Upper ExtremitiesDeltoidsWrist extensorsFinger extensorsTriceps > Biceps

Lower ExtremitiesHip flexors (most common)QuadricepsHamstringsFoot dorsiflexorsPlantar flexors

5. RESPIRATORY MUSCLE WEAKNESS

• Weakness of the intercostal muscles and the diaphragm may result in CO2 retention due to hypoventilation• May cause a neuromuscular emergency

• Weakness of pharyngeal muscles may collapse the upper airway

• Monitor negative inspiratory force, vital capacity and tidal volume

• Do NOT rely on pulse oximetry• Arterial blood oxygenation may be normal while CO2 is

retained

• As the disease progresses it can involve the external sphincters of bowel and bladder.

• A temporary increase in weakness may follow vaccination, menstruation and exposure to extremes of temperature

• Weakened muscles “NEVER GO FOR ATROPHY”

• Tendon reflexes are retained till late• Smooth and cardiac muscles are not involved

• Tongue may display a central and 2 lateral longitudinal furrows “trident tongue”

• Symptoms may appear first during pregnancy, puerperium or in response to drugs used during anesthesia.

• Transient NEONATAL MYASTHENIA

CO-EXISTING AUTOIMMUNE DISEASES

1. Hashimoto’s thyroiditis/thyrotoxicosis• Occurs in 5-10%% MG patients• Weakness may not improve with treatment of MG

alone in patients with co-existing hyperthyroidism2. Rheumatoid arthritis3. Scleroderma4. Lupus erythematosus, 5. Sjӧgren syndrome, 6. mixed connective tissue disease7. anticardiolipin antibody 8. polymyositis

MYASTHENIC CRISIS

• A rapid and severe deterioration of myasthenia called “myasthenic crisis” can bring patient to the brink of respiratory failure and quadriparesis in hours

• A respiratory infection or a sedative medication with NM block may be the reason

• It can develop at any time after the diagnosis of myasthenia• Anticipate if patient is restless, anxious with diaphoresis and

develops tremor.• Require respiratory support

NEUROLOGIC CONDITIONS MIMICKING MYASTHENIA GRAVIS

CONDITION SIGNS AND SYMPTOMS

ALS Asymmetric muscle weakness and atrophyBotulism Generalized limb weaknessGuillain-Barré syndrome Ascending limb weaknessInflamm. muscle disorders Proximal symmetric limb weakness Lambert-Eaton syndrome Proximal symmetric limb weakness Multiple sclerosis Bilateral internuclear ophthalmoplegiaPeriodic paralysis Intermittent generalized muscle weakness

Thyroid diseaseCongenital myasthenic syndromesBrainstem syndromes/encephalitis

LAMBERT-EATON SYNDROME

• Presynaptic disorder of NMJ• Antibodies against P/Q type calcium channels at the motor

nerve terminals ( +ve in 85%)• Impaired release of Ach from nerve terminals• Muscle weakness similar t MG ( proximal>distal, CN

involvement >70%)• “Warming up” phenomenon

Depressed/absent reflexesAutonomic changesIncremental response to RNS

• Associated with Ca Lung(small cell Ca).. “paraneoplastic”• Treatment: Immunosuppression; plasmapheresis;

3,4-DAP; pyridostigmine

DRUGS PRECIPITATING MYASTHENIA

Anti-infective Agents Cardiovascular Agents Other Agents

Aminoglycosides Propranolol ChloroquineAmpicillin Verapamil CorticosteroidsCiprofloxacin Quinidine “d-penicillamine”Erythromycin Procainamide Phenytoin Imipenem Propafenone MydriaticsKanamycin Acebutolol Trihexyphenidyl Pyrantel Practolol Interferon

Timolol TrimethadioneOxyprenolol

Prognosis

• Long-term outlook better for children than adults• Life expectancy slightly reduced• Most favorable outcome for bulbar weakness• Drug free remissions possible with thymectomy• Death rate reduced from 30% to <5% with

pharmacotherapy and surgery

Differential diagnoses• Lambert-Eaton Myasthenic Syndrome• Oaculopharyngeal muscular dystrophy• Multiple Sclerosis• Botulism• Brainstem syndromes• Brainstem gliomas• Thyroid disease• Sarcoidosis and Neuropathy• Amyotropic Lateral Sclerosis• Basilar Artery Thrombosis• Cavernous sinus syndromes• Dermatomyositis• Congenital myasthenic syndromes• Drugs/Antibiotics