MYASTHENIA GRAVIS-

RE-EMRGENCE OF AN
OLD FOE
PRESENTED BY UNIT 5
HOU- PROF . DR RAJESH KASHYAP
AP - DR RAJENDER NEGI
 CASE REPORT
• PATIENT NAME – PREMA DEVI
• AGE- 48 / FEMALE
• PROFESSION – SWEEPER
• RESIDENT OF DHARAMPUR

COMPLAINTS OF –
PARTIAL DROOPING OF EYELIDS (L>R) - 1 YEAR
DIFFICULTY IN CHEWING / SWALLOWING – 2 MONTHS
DIFFICLUTY IN SPEAKING – 2 MONTHS
 DROOPING OF EYELIDS
(LEFT>RIGHT)
• Insidious in onset gradually progressive over the past one year.
• Very less/non existent in the morning and starts to develop and progressing in
trend towards the evening , with peak drooping after noon time and in the
evenings .
• Also associated with double vision (objects side by side) which progressed
during the day and was negligible in the morning .
• Both these complaints had worsened over the past year.
• No h/o any facial deviation, change in color vision, painless/painful loss of
vision, floaters or spots in eyes, protrusion/intrusion of eyeball, loss of sweating
and lacrimation on same side of face ,severe headache , fever , trauma or FND
• These complaints were associated with a significant decrease in
strength to perform all daily activities where earlier she could
perform all her daily tasks easily but now she would get easily tired
and had to rest while performing the tasks or leave them.

• She felt significant difficulty in combing and kneading her hair ,

keeping her arms over her head , however there was no difficulty in
turning in bed , in getting up from squatting position , climbing the
stairs , wearing or loosening of slippers while walking.

• No history of any gait or postural abnormalities , difficulty in getting

up from bed and walking.
 Difficulty in Chewing/Swallowing
• Insidious in onset and gradually progressive.
• She could start to eat food but as she continued chewing the strength of
chewing decreased and food started sticking to her mouth and she
would feel tired after chewing a few bites and felt the food sticking to
her mouth which made it difficult to swallow the food bolus.
• Swallowing difficulty was equal to both solids and liquids but it was
comparatively easier for her to swallow liquids than solids.
• No h/o retrosternal burning sensation, pain or impaction of food while
swallowing , any nasal regurgitation of food, any aspiration, chest or
abdominal pain during swallowing ,any neck swelling, masses or prior
neck surgery.
 Difficulty In Speaking
• Insidious in onset and gradually progressive.
• Which worsened with the progression of the day
• In the morning the quality of speech was better which declined
during the day producing a nasal intonation towards the later part of
the day
• She is able to understand and knows what to express but the quality
of words became poorer and unclear with progressing sentences.
• PAST HISTORY-
• No history of any
T2DM,HYPERTESNION,CAD,COPD,ASTHMA,
EPILEPSY

• SURGICAL HISTORY - • FAMILY HISTORY NOT

CHOLECYSTECTOMY,HYSTERECTOMY SIGNIFICANT

• PERSONAL HISTORY - • NO DRUG OR ALLERGY

• SLEEP- NORMAL HISTORY

• APPETITE – DECREASED( BECAUSE OF • DIETARY HABITS – MIXED

CHEWING AND SWALLOWING DIFFICULTY)

• BLADDER AND BOWEL NORMAL

• NON SMOKER , DOES NOT CONSUME

GENERAL PHYSICAL EXAMINATION
• CALM,CONSCIOUS,ORIENTED TO TIME ,PLACE AND PERSON.
• HEIGHT - 158 CM
• WEIGHT - 65 KG
• BMI - 25.3 KG/M2
• PULSE – 70/MIN REGULARLY REGULAR,NORMOVOLUMIC, NO(R-F,R-R)
DELAYS,NORMAL VESSEL WAL THICKNESS,ALL PERIPHERLA PULSES INTACT.
• BP - LYING DOWN-114/76 MMHG
-STANDING – 110/70 MMHG
• RR - 20/MIN
• TEMP - 98.4 F
• SPO2 - 94% ON ROOM AIR
• PALLOR ,ICTERUS,CLUBBING,CYANOSIS,LYMPHADENOPATHY AND EDEMA
WERE ABSENT.

• JVP NOT RAISED

• FACIAL APPEARANCE-
• DROOPING OF EYELIDS
• LEFT EYELID - 4MM
• RIGHT EYELID - 2MM
• ATTAINING AN EXTENDED NECK POSTURE TO FIXATE ON OBJECTS

• ORODENTAL HYGEINE – POOR

• SKIN, HAIR ,NAILS – NORMAL
 LOCAL EXAMINATION -
• ORAL CAVITY - NORMAL

• TONGUE - NORMAL

• PALATE- NORMAL

• VISIBLE NASOPHARNYX NORMAL

CNS SYSTEM EXAMINATION
• HMF –
• RIGHT HANDED
• OCCUPATION SWEEPER
• LANGUAGE HINDI
• EDUCATION QUALIFICATION 8TH
• MMSE 25/30

• CONSCIOUSNESS - INTACT
• ORIENTATION - INTACT
• ATTENTION - INTACT
• MEMORY - REMOTE INTACT - RECENT INTACT
• SPEECH

• FLUENCY - DECREASED
• COMPREHENSION - INTACT
• GRAMMAR - INTACT
• NAMING - INTACT
• READING AND WRITING - INTACT
• REPITITION - INTACT
• ARTICULATION - DECREASED
• CN - 1
CRANIAL NERVES • CN - 4
SMELL - INTACT • EYE MOVEMENTS (SO) - NORMAL

• CN - 2
• VISUAL ACUITY - INTACT
• COLOR VISION - NORMAL
• PUPILLARY REFLEX - NORMAL
• FUNDUS - NORMAL
• CN - 3
• PUPIL SIZE SHAPE AND REFLEX - NORMAL
• EYE MOVEMENTS - NORMAL
• PTOSIS - 4MM
• CN - 5
• MUSCLES OF MASTICATION - NORMAL
(DEC POWER ON PROLONGED ACTION)
• SENSATIONS IN ALL REGIONS OF FACE-
NORMAL
• CORNEAL REFLEX - PRESENT
• CN - 6
• EYE MOVEMENTS (LR) - NORMAL
• CN - 7

• FACILA EXPRESSIONS NORMAL

• FOREHEAD WRINKLING NORMAL
• LOSS OF NASOLABIAL FOLD ABSENT
• NO DEVIATION OF ANGLE OF MOUTH • CN - 9
• BLOWING NORMAL • Sensation of posterior 1/3rd of
• EYELID CLOSURE NORMAL tongue - Intact
• TASTE ANTERIOR 2/3RD TONGUE NORMAL • Gag reflex -Present
• BELLS PHENOMENA ABSENT
• Position of uvula – Central
• CN - 8

• HEARING NORMAL
• TINNITUS ABSENT
• VERTIGO ABSENT
• NYSTAGMUS ABSENT
• CN 10

• Soft palate - Normal

• Gag reflex - Present
• Vocal cords - Normal
• CN 11
• CN 12
• Protrusion - Normal
• Deviation - Normal
• Atrophy - Absent
• Fasciculations - Absent

• Trapezius - Normal
• Sternocleidomastoid – Normal
• MOTOR

• NUTRITION/BULK - NORMAL
• ATTITUDE - NORMAL
• TONE - NORMAL
• POWER -
• SHOULDER 4/5
• ELBOW 5/5
• HIP 5/5
• KNEE 5/5
• REFLEXES

• SUPERFICIAL Corneal Present

Abdominal Present
Plantars Both Flexor

Right Left
• DTR Biceps 2+ 2+
Triceps 2+ 2+
Supinator 2+ 2+
Knee 2+ 2+
Ankle 2+ 2+
Clonus Absent Absent
Jaw jerk Normal
• SENSORY

• CORTICAL SENSATIONS - NORMAL

• SUPERFICIAL SENSATIONS - NORMAL

• DEEP SENSATIONS - NORMAL

• CERBELLAR SIGNS - ABSENT

• POSTURE AND GAIT - NORMAL

• SKULL AND SPINE - NORMAL

 DIFFERENTIAL DIAGNOSIS
• CONSIDERING PARTIAL PTOSIS WORSENING TOWARDS EVENING
• DIFFICULTY IN CHEWING,SWALLOWING AND SPEAKING
• PROXIMAL MUSCLE WEAKNESS
• PRESERVED DTRs

• D/D
• GENRALISED MYASTHENIA GRAVIS WITH OCCULAR AND BULBAR INV
• SCLC WITH PARANEOPLASTIC MANIFESTATION OF MYASTHENIA GRAVIS /LEMS
• OCULO PHARYNGEAL MUSCULAR DYSTROPHY
INVESTIGATIONS
• ICE PACK TEST SHOWED POSITIVE RESULT A REDUCTION IN
PTOSIS BY 2MM

• NEOSTIGMINE INJECTION SHOWED IMPROVEMENT IN

PTOSIS BY 2.5MM AFTER 30 MINS
 Final diagnosis
Generalized Myasthenia
Gravis with Ocular and
Bulbar involvement
 Treatment
• ON DAY 3 • ON DAY 5

• TABLET PYRIDOSTIGMINE 30 MG BD • TABLET PYRIDOSTIGMINE 30 MG TDS

• TABLET PREDNISOLONE 40 MG OD
• TABLET PREDNISOLONE 40 MG OD

TILL DAY 5 SHE HAD STARTED EATING AND SPEAKING WELL , DIPLOPIA HAD
RESOLVED BECAUSE OF IMPROVEMENT IN PTOSIS AND WAS HAPPY WITH HER
OVERALL WELLBEING SO SHE WAS REFFERED TO PGI FOR RESECTION OF
THYMOMA AND WAS ATTACHED TO MMU FOR FOLLOW UP.
Review Of
Literature
 HISTORY OF MG
• The first description of myasthenia gravis (MG) was given by Thomas Willis in 1672.
• MG history was examined in four periods:
• In the first period (1868-1930), all the clinical characteristics of MG were defined.
Physiological/pharmacological studies on the transmission at the neuromuscular junction were
initiated, and the concept of RNS emerged. Association of MG with thymus was noticed. No
noteworthy progress was made in its treatment.
• In the second period (1930-1960), acetylcholine was discovered to be the transmitter at the
neuromuscular junction. RNS was used as a diagnostic test. The autoimmune nature of MG was
suspected and experiments to this end started to give results. The hallmark of this period was the
use of anticholinesterases and thymectomy in the treatment of MG.
• The third period (1960-1990)(revolutionary era) Important immunological mechanisms were
clarified and the autoimmune nature of MG was demonstrated. Treatment modalities which
completely changed the prognosis of MG, including positive pressure mechanic ventilation and
corticosteroids as well as plasma exchange/IVIg and azathioprine, were put to use.
• In the fourth period (1990-2020), more immunological progress, including the discovery of anti-
MuSK antibodies, was achieved. Video thoracoscopic thymectomy reduced the morbidity and
mortality rate associated with surgery. New drugs emerged and clinical trials were performed.
Valuable guidelines were published.
 INTRODUCTION
• Myasthenia gravis (MG) is a relatively rare acquired, autoimmune disorder
caused by an antibody-mediated blockade of neuromuscular transmission
resulting in skeletal muscle weakness and rapid muscle fatigue.
• The autoimmune attack occurs when autoantibodies form against the
nicotinic acetylcholine postsynaptic receptors at the neuromuscular junction
of skeletal muscles.
• Although the chief target of the autoimmune attack in most cases is the
skeletal muscle nicotinic acetylcholine receptor (nAChR), other antigenic
targets that are components of the neuromuscular junction (NMJ) have also
been implicated.
 EPIDEMIOLOGY
• MG has a prevalence as high as 200 in 100,000.

• It affects individuals in all age groups, but peak incidences occur in women in
their twenties and thirties and in men in their fifties and sixties.

• Overall, women are affected more frequently than men, in a ratio of 3:2.
 PATHOPHYSIOLOGY
• In MG, the fundamental defect is a decrease in the number of available AChRs
at the postsynaptic muscle membrane. In addition, the postsynaptic folds are
flattened, or “simplified.”
• These changes result in decreased efficiency of neuromuscular transmission.
Therefore, although ACh is released normally, it produces small endplate
potentials that may fail to trigger muscle action potentials.
• Failure of transmission results in weakness of muscle contraction. The amount
of ACh released per impulse normally declines on repeated activity (termed
presynaptic rundown). In the myasthenic patient, the decreased efficiency of
neuromuscular transmission combined with the normal presynaptic rundown
results in increasing weakness, or myasthenic fatigue.
• Decrease in AchR’s is caused by anti-AChR antibodies. The anti-AChR antibodies
reduce the number of available AChRs at NMJs by damaging the postsynaptic
muscle membrane and blockade of the active site of the AChR .
• An immune response to muscle specific kinase (MuSK), a protein involved in
AChR clustering at the NMJ, can also result in MG, with reduction of AChRs.
Anti-MuSK antibody occurs in 10% of patients (40% of AChR antibody–negative
patients)
• 1–3% patients have antibodies to another protein at the NMJ—low-density
lipoprotein receptor-related protein 4 (LRP4).
• The pathogenic antibodies are IgG and are T cell dependent. Thus,
immunotherapeutic strategies directed against either are effective in this
antibody-mediated disease.
• The thymus is abnormal in 75% of patients with AChR antibody–positive MG; in
65%, the thymus is “hyperplastic,” with the presence of active germinal centers.
An additional 10% of patients have thymic tumors (thymomas).
 Clinical features
• The cardinal features are weakness and fatigability of muscles. The weakness increases during
repeated use (fatigue) or late in the day and may improve following rest or sleep. Exacerbations and
remissions may occur.
• The cranial muscles, particularly the lids and extraocular muscles (EOMs), are typically involved early in
the course of MG; diplopia and ptosis are common initial complaints.
• Weakness in chewing is most noticeable after prolonged effort, as in chewing meat.
• Speech may have a nasal timbre caused by weakness of the palate or a dysarthric “mushy” quality due
to tongue weakness.
• Difficulty in swallowing may occur as a result of weakness of the palate, tongue, or pharynx, giving rise
to nasal regurgitation or aspiration of liquids or food.
• Bulbar weakness and more frequent episodes of respiratory depression can be especially prominent in
MuSK antibody–positive MG. In ∼85% of patients, the weakness becomes generalized, affecting the
limb muscles as well.
• If weakness remains restricted to the EOMs for 3 years, it is likely that it will not become generalized,
and these patients are said to have ocular MG.
• The limb weakness in MG is often proximal and may be asymmetric. Despite the muscle weakness,
deep tendon reflexes are preserved.
CLASSES OF MG PROGRESSION
•Class I – Isolated ocular muscle weakness
•Class II – Mild generalized weakness involving nonocular muscles
•Class III – Moderate generalized weakness involving nonocular
muscles
•Class IV – Severe generalized weakness involving nonocular muscles
•Class V – Intubation due to respiratory muscle weakness
 DIAGNOSTIC EVALUATION
• Ice-Pack Test - If a patient has ptosis, application of a pack of ice over a
ptotic eye often results in improvement if the ptosis is due to an NMJ
defect.

• Autoantibodies Associated with MG-

• Anti-AChR antibodies are detectable in the serum of 85% of all
myasthenic patients. The presence of anti-AChR antibodies is virtually
diagnostic of MG.

• Antibodies to MuSK are present in 40% of AChR antibody–negative

patients with generalized MG

• A small proportion of MG patients without antibodies to AChR or MuSK

have antibodies to LRP4.
• Electrodiagnostic Testing Repetitive nerve stimulation
• Provides helpful diagnostic evidence of MG.
• Anti-AChE medication should be stopped 6–12 h before testing. It is
best to test weak muscles or proximal muscle groups.

• Anticholinesterase Test
Drugs that inhibit the enzyme AChE allow ACh to interact repeatedly
with the limited number of AChRs in MG, producing improvement in
muscle strength.
Edrophonium is used most commonly for diagnostic testing because
of the rapid onset (30 s) and short duration (∼5 min) of its effect.
An initial IV dose of 2 mg of edrophonium is given. If definite
improvement occurs, the test is considered positive and is terminated.
If there is no change, the patient is given an additional 8 mg IV.
LAMBERT EATON MYASTHENIC SYNDROME
• LEMS is a presynaptic disorder of the NMJ that can cause weakness similar to
that of MG. The proximal muscles of the lower limbs are most commonly
affected. Cranial nerve findings, including ptosis of the eyelids and diplopia, occur
in up to 70% of patients and resemble features of MG.
• However, the two conditions are usually readily distinguished because patients
with LEMS have depressed or absent reflexes and experience autonomic
changes such as dry mouth and impotence.
• LEMS is caused by autoantibodies directed against P/Q-type calcium channels at
the motor nerve terminals detected in 85% of LEMS patients. These
autoantibodies impair the release of ACh from nerve terminals.
• In older adults, most LEMS is associated with malignancy, most commonly
small-cell lung cancer (SCLC).
APPROACH
 Management
• ANTICHOLINESTERASE MEDICATIONS – produce at least partial improvement
in most myasthenic patients, although improvement is complete in only a few.
Patients with anti-MuSK MG generally obtain less benefit from
anticholinesterase agents than those with AChR antibodies .

• Pyridostigmine is the most widely used anticholinesterase drug and is initiated

at a dosage of 30–60 mg three to four times daily. The beneficial action of oral
pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual
responses vary. The frequency and amount of the dose should be tailored to
the patient’s individual requirements.
• Glucocorticoid Therapy –

• Prednisone should be given in a single dose rather than in divided doses

throughout the day.
• In mild or moderate weakness, the initial dose should be relatively low (15–25
mg/d)
• The dose is increased stepwise, as tolerated by the patient (usually by 5 mg/d at
2- to 3-day intervals), until there is marked clinical improvement or a dose of 50–
60 mg/d is reached.
• In patients with more severe weakness and those already in the hospital,
starting at a high dose is reasonable.
• Patients are maintained on the dose that controls their symptoms for about a
month, and then the dosage is slowly tapered.
• Immunotherapies

• Azathioprine has long been used for MG, However, the beneficial effect can take
a year or more to become evident. An initial dose of 50 mg/d is given for about
a week to test for these side effects. If this dose is tolerated, it is increased
gradually to 2–3 mg/kg of total body weight .

• The calcineurin inhibitors - cyclosporine and tacrolimus seem to be effective.

However, they are associated with more frequent severe side effects including
hypertension and nephrotoxicity.

• Rituximab (Rituxan) is a monoclonal antibody that binds to the CD20 molecule

on B lymphocytes .There is a growing literature on the benefit of rituximab in
MuSK antibody– positive MG .The usual dose is 1 g IV on two occasions 2 weeks
apart.
• Plasmapheresis has been used therapeutically in MG.
• Plasma, which contains the pathogenic antibodies, is mechanically separated
from the blood cells, which are returned to the patient.
• A course of five exchanges (3–4 L per exchange) is generally administered over a
10- to 14-day period. Plasmapheresis produces a short-term reduction in anti-
AChR antibodies, with clinical improvement .
• It is useful as a temporary expedient in seriously affected patients or to improve
the patient’s condition prior to surgery (e.g., thymectomy).
• IVIg have same indications for use as those for plasma exchange: to produce
rapid improvement to help the patient through a difficult period of myasthenic
weakness or prior to surgery.
• This treatment has the advantages of not requiring special equipment or large-
bore venous access.
• The usual dose is 2 g/kg, which is typically administered over 2–5 days.
Improvement occurs in 70% of patients.
• THYMECTOMY

• Surgical removal of a thymoma is necessary because of the possibility of local

tumor spread, although most thymomas are histologically benign.

• A large international trial demonstrated that participants who underwent

thymectomy had improved strength and function, required less prednisone and
fewer additions of second-line agents (e.g., azathioprine), and fewer
hospitalizations for exacerbations lasting at least 5 years.
 Prognosis
• Approximately 20% of patients with MG achieve a sustained remission and can be tapered off all
immunotherapies.
• There does not appear to be a correlation between disease severity and likelihood of remission.
• Thymectomy may increase the chance of achieving remission in anti-AChR MG, thymectomy is
efficacious and led to less use of glucocorticoids and second-line agents.
• Mortality from MG diminished greatly during the twentieth century, changing from a “grave” illness
with mortality of nearly 70% a century ago, to 2–30% by the 1950s, with contemporary estimates in the
1–2% range.
• AntiMuSK patients generally were more difficult to treat than anti-AChR MG in the past. However,
recent series suggest that rituximab is effective in this subgroup, thereby reducing these risks and
improving the prognosis.
• Nonparaneoplastic LEMS is usually responsive to immunotherapy and symptomatic treatment with
pyridostigmine .
• In older adults, LEMS is most often paraneoplastic, and screening for an underlying tumor is indicated .
• Recent studies suggest that survival in patients with LEMS has improved.
Follow up