Myasthenia Gravis , Etiology of Myasthenia Gravis, Managment of Myasthenia Gravis

1. Acute non traumatic neuromuscular weakness
Dr Anand Naik
23/03/2023

2. History
46 year old female
RVHD - severe MS -2012
S/P BMV -2013, 2018
IHD -CAG -DVD non critical ds
Severe LV dysfunction
Advised - medical management and MvR
Now came with ℅
Breathlessness - NYHA class 2—4
Palpitation since 4 days
ECG -AF FVR
RHD with severe Ms with severeLV
dysfunction with AKI (145/4.5)
Received 2 cycle of HD
Developed shock
Transferred to ssh for further
management
Case 1

3. SSH
13/01/2023
ER - unresponsive ,bradycardia
,hypoglycaemia
Inj. Adrenaline
No CPR
IMV - prvc mode
Admitted in IcU
Icu
Cardiogenic shock
Ischemic hepatitis
AKI
Coagulopathy
Metabolic encephalopathy

4. O/E -
Comatose
Hypotonia all 4 limb
Reflexes absent
Pupil - BERTL
? Metabolic enceph ? HIE ?
After 4 days
Eye opening +
Quadriparesis persist
MRI brain -
Normal
Small vessel ischemic changes
Neuro ref -
Hypotonia disproportionate to mri
finding
Adv -
NCV

5. NCV
NCV - reduced amplitude of CAMPs without conduction slowing or prolongation of
distal latencies. axonal neuropathy
Diagnosis of CIMN was made.
Later course in the hopsital- Patient had fever spikes, blood culture grew candida
tropicalis, ETT culture grew Acenatobacter , neurology refrence i/v/o
encephalopathy done, MRI brain with Angiography was done s/o vertebral aretry
occlusion and cortical edema. Hyperammonemia was also observed, develooped
anuria , aki needed 2 sessions of HD, persitant shock- inotropes and vasopressors
were continued. Blood produts given as needed, antibiotics and antifungals
optimised. Bradycardia 2 time CP arrest and CPR given twice ROSC achieved, was
being planned for Definative BMV but patient went into arrest again and could not
be revived.

6. Critical Illness Myopathy
&
Critical Illness Polyneuropathy

7. • Muscular weakness is not a new phenomenon in ICU, 1st described by
Aster in 1892
• Weakness is partly a consequence of improved survival in patients with
multiorgan failure and sepsis, but may be associated with treatments
administered in the intensive care unit (ICU).
• Neuromuscular weakness in the ICU is most often due to critical illness
myopathy (CIM), critical illness polyneuropathy (CIP), or a combination of
the two.
• Over the past two decades, improvements in survival after discharge
from the ICU probably have led to increased awareness of ICU-acquired
weakness. The magnitude of neuromuscular impairment in the increasing
population of patients undergoing post-ICU rehabilitation has come to the
attention of health care providers, patients, and families.

8. Risk Factors:
• Sepsis
• SIRS
• Multiorgan Failure (Renal, Hepatic)
• Long duration of Mechanical Ventilation
• Hyperosmalarity
• Low Serum Albumin
• Vasopressor Support
• Hyperglycemia
• Parenteral Nutrition
• Long term neuromuscular Blockade
• Corticosteroids ?
1)Schweickert, w. D. & Hall, J. iCU-acquired weakness. Chest 131, 1541–1549 (2007)
2) Lacomis, D. & Campellone, J. v. Critical illness neuromyopathies. Adv. Neurol. 88, 325–335 (2002)
3) Hermans, G., De Jonghe, B., Bruyninckx, F. & van den Berghe, G. interventions for preventing critical illness
polyneuropathy and critical illness myopathy. Cochrane Database of Systematic Reviews, issue 1. Art. No.:
CD006832. doi:10.1002/14651858.CD006832.pub2 (2009).

9. Wolfgang Et all, Nature Reviews Neurology
2009
Pathophysiology

10. Critical illness myopathy
• The most common form of ICU-acquired myopathy is CIM. (UpToDate)
• Also known as Acute quadriplegic myopathy and thick filament
myopathy.
• The major histopathologic finding in CIM is relatively selective loss of
myosin, which can be identified as a lack of reactivity to myosin
ATPase in non-necrotic fibers
• There is usually atrophy of myofibers, type 2 more than type 1.

11. - Myosin ATPase (pH 9.4)-reacted frozen muscle section reveals atrophic, type 2 (dark) fibers,
patchy regions of reduced reactivity (arrows) in some type 1 (light) and type 2 fibers, and
absent staining (asterisks) in other fibers. Normal muscle is seen in the inset.

12. Critical Care Polyneuropathy
• The second neuromuscular condition that is commonly acquired in
the ICU is CIP
• CIP appears to be a common complication of severe sepsis and is
thought to represent a neurologic manifestation of the systemic
inflammatory response syndrome (SIRS).
• The mechanism of axonal injury in CIP is unknown.
• However, speculation focuses on injury to the microcirculation of
distal nerves, causing ischemia and axonal degeneration

13. Clinical Features:
• CIM – Several days, CIP- 2-3 Weeks
• Failure to wean a patient off ventilator is the weakness in absence of
an explainable pulmonary pathology is a common presentation.
• Distal and proximal flaccid muscle weakness, symmetrical, although
isolated limb weakness has been described
• Deep Tendon Reflexes can be absent.
• Unlike CIM, CIP can have distal sensory involvement (Often Difficult to
test since many patients are encephalopathic or under sedation)
• Facial and Opthalmic muscles spared most of the times
• If cranial nerve involvement occurs, GBS should be ruled out.
Lacomis D et al, Acute myopathy of intensive care: clinical,
electromyographic, and pathological aspects.

14. • For patients with CIM, sensation should be normal if it can be tested
reliably. Patients should at least grimace to pain stimuli even when
they are encephalopathic
• Combined CIM/CIP has clinical features that overlap the individual
but closely corresponding features of CIM and CIP

15. • The basic steps in the initial evaluation include:
• Identifying generalized weakness and assessing muscle strength
• Reviewing prehospital functional status and patient and family history of
conditions that might be causing or contributing to weakness
• Searching for factors associated with neuromuscular weakness related to
critical illness, including:
•Sepsis
•Multiorgan failure
•Mechanical ventilation
•Hyperglycemia
•Exposure to glucocorticoids and/or neuromuscular blocking agents
Evaluation & Diagnosis

16. Examination
• In an awake and cooperative patient with unfettered ability to voluntarily move
the limbs, muscle strength can be tested manually in each limb and graded on
the Medical Research Council (MRC) scale
• CIM can be distinguished from CIP if preservation of sensory function (indicative
of the former) can be demonstrated. (Difficult in ICU)

17. Neuroimaging
• Neuroimaging is indicated if the neurologic assessment of weakness is
unreliable, or if the evaluation reveals evidence that raises suspicion
for a CNS lesion. (MR preffered over CT)
Laboratory Evaluation
-It is reasonable to obtain a serum creatine kinase (CK) level in all patients
who have critical illness associated with weakness.
-An elevation in serum CK is usually present with CIM and supports the
diagnosis but can occur in the absence of CIM among patients treated with
intravenous glucocorticoids

18. • Lumar Puncture and CSF analysis to rule out - encephalitides, myelopathies,
and the acute motor axonal neuropathy form of Guillain-Barré syndrome (GBS)
(IF SUSPECTED)
• Electroencephalography (EEG) is appropriate in patients with altered
consciousness to evaluate for seizures.
• Muscle biopsy is rarely performed unless another treatable condition, such as
an inflammatory myopathy, is in the differential diagnosis.
• For patients with CIM or combined CIM and CIP, muscle biopsy and
histopathology can confirm the presence of myopathy. In CIP, muscle biopsy
findings are those of neurogenic atrophy.

19. Electrodiagnostics
Electroneuronography
Electromyography
Direct Muscle
Stimulation

20. Electroneuronography
• A motor response is induced by transcutaneous stimulation of a
peripheral nerve, and compound muscle action potentials (CMAPs)
from the corresponding distal muscle are recorded.
• To calculate motor nerve conduction velocity, stimulation at two
points along the nerve is required.
• Sensory or mixed nerve action potentials are obtained by stimulation
of a sensory or mixed nerve, respectively, with recording electrodes
being placed distal or proximal to the stimulating electrode.
• Abnormalities in motor and sensory nerve conduction point to a
neuropathic process.

21. Myasthenia Gravis

22. Myasthenia Gravis & Other NMJ Diseases
• Disorder of Neuromuscular Junction(NMJ) characterized by weakness
and fatigability of skeletal muscles.
• Underlying defect in the disease is a decrease in number of available
Acetyl Choline Receptors at NMJ due to an antibody mediated
autoimmune attack.
“ a woman who spoke freely and readily enough
for a while, but after a long period of speech was
not able to speak a word for one or two hours”
1st description of diseases in 17th century by Oxford Physician Dr. Thomas
Willis, M.D.
Many scientist were later involved in studying the disease and
understanding the pathophysiology

23. Normal Physiology of Neuro-muscular Junction
• At the neuromuscular junction, acetyl choline(Ach) is synthesised in the
motor nerve terminal and stored in vesicles.
• When action potential reaches nerve terminal , Ach released and it
combines with post synaptic Ach Receptors.
• Ach Receptor consist of 5 subunits which are arranged around a central
pore. Ach R after combining with Ach -> permits rapid entry of Sodium
ions which depolarize the post synaptic membrane-> propogation of
action potential along muscle fibre -> muscle contraction.

24. Normal Neuromusclar Junction Activity

25. Pathogenesis of MG
• In Myaesthenia gravis, the fundamental defect is a decrease in the
number of AVAILABLE Ach-R at post synaptic muscle membrane.In
addition, post synaptic folds are flattened.
• Both changes cause decrease in efficiency of neuromuscular junction
transmission.
• As the successive nerve impulses depolarize the presynaptic
membrane, the Ach released per impulse declines with every
impulse( termed as PRESYNAPTIC RUNDOWN).
• So on repeated and successive muscle stimulation , fewer and fewer
muscle fibres are activated increasing weakness.
• This mechanism also accounts for the decremental response to
repetitive nerve stimulation seen on electrodiagnostic testing.

26. Neuromuscular transmission involves
release of presynaptic acetylcholine,
which binds to acetylcholine receptors
in the postsynaptic membrane. The
receptors interact with several other
proteins in the membrane, including
Dok7 and rapsyn. Mutant Dok7 and
rapsyn are important in the
development of congenital
myasthenia. Antibodies against
acetylcholine receptors, as well as
antibodies against muscle-specific
kinase (MuSK) and lipoprotein
receptor–related peptide 4 (LRP4),
induce myasthenic weakness.
Antibodies against the intramuscular
proteins titin and ryanodine receptor
are relevant biomarkers in some
subgroups of myasthenia gravis.
Acetylcholine is degraded by local
acetylcholinesterase, and
acetylcholinesterase inhibition leads
to symptomatic improvement in
patients with myasthenia gravis.

27. • MG is an autoaimmune disorder most commonly caused by Anti-AchRs
Antibodies.
• These Antibodies reduce number of available AchRs at NMJs by three
distinct mechanisms:
• MuSK protein(Muscle specific Kinase), LRP4 (Low density lipoprotein
receptor 4), are some other proteins involved in Ach-Recptor clustering.
• Anti- MuSK Ab occurs in 10% of patients, Anti LRP4 antibody occurs in 1-
3% patients.
BLOCKADE OF ACTIVE SITE OF THE
AChR(Site that normally binds Ach)
Damage to post synaptic muscle
membrane by the antibody in
collaboration with compliment
Accelerated turnover of AchRs by
crosslinking and endocytosis of
receptors

28. Role of thymus in Pathogenesis of MG?
• The pathogenic antibodies are IgG and are T-cell dependant suggests
that thymus might play a role in this process. However how the
autoimmune response is initiated and maintained in MG is not
completely understood.
• Muscle like cells within Thymus (myoid cells), which express AchRs on
their surface, may serve as a source of autoantigen and trigger
autoimmune response
• Thymus is abnormal in 75% of patients with Ach-R Antibody positive
patients .
65%
Thymic Hyperplasia
10%
Thymoma

29. Clinical Features
• Incidence 200 in 100,000.
• Women in 20-30s
• Men 50-60s
• M:W 2:3 overall.
• Cardinal features are WEAKNESS and FATIGABILITY
• Weakness increases during repeated use(fatigue) or late in the day,
may improve following rest or sleep.
• Course is variable , exacerbations and remissions are part of illness.
• Unrelated infections or systemic disorders can lead to precipitation of
crisis.
• Despite of weakness, DTRs are preserved till late.

30. • Distribution of weakness has characteristic patterns:
Extraoccular muscles-
Ptosis, Diplopia
(Affected early in course)
Bulbar muscle weakness-
Nasal twang to voice,
difficulty in swallowing
Facial muscle weakness-
Snarling expression when
patient attempts to smile.
Generalised weakness
(85%)-
Affects limbs (symmetric)
Weakness in jaw muscles:
Appreciated after
chewing
When respiratory muscle
weakness devoploes and
patient needs support:
CRISIS

31. Diagnostic Evaluation
• Suspected on the basis of weakness and fatigability in typical
distribution described above, without loss of reflexes or impairment
of sensation or other neurological function.
1)Ice pack Test: Application of ice pack over ptosis-> improvement
Quick and easy bedside test , Hypothesis-> decreased activity of
AChE at NMJ.

32. •Auto-antibodies associated with MG:
- Presence of Antibodies is virtually diagnostic but absence does not rule out
the disease.
-Measured level of Antibodies doesn’t correlate with severity of MG.
1) Anti Ach Receptor Ab-
85% of patients with Generalised MG
50% patients with Occular MG.
2)Anti MuSK Ab- 40% of AchR Ab negative Generalised Myesthenia Gravis
3) Anti LRP4 Ab- Small proportion of patients not having above 2 antibodies
have this.

33. Electrodiagnostics:
• Repetitive nerve stimulation test-
- Stop Anti-Ach E medications 6-12 hours
before test.
- Best to test the weak muscles or proximal
muscles.
- Stimulation is delivered at rate of 2-3
/seconds to appropriate nerve and action
potentials are measured at muscles.
-In Normal Individuals, amplitude of muscle
potentials does not change >10% at these
rate of stimulation.
- In MG Patients , rapid reduction in >10%
of amplitude of evoked action potenstials.

34. Anticholinesterase Tests
• Drugs that inhibit the enzyme AchE allow Ach to interact repeatedly
with limited number of AchR, producing muscle strength .
• Edrophonium used commonly
• Onset of Action- 30s
• Duration of Action 5 min
• What is tested?
-EOM, Impairment of speech
-Time for which patient can hold
arms forwards
Side effects-
Nausea, diarrhea, salivation,fasciculations,
RARELY BRADY SYNCOPE – KEEP ATROPINE
0.6MG ReADY

35. • Edrophonium test reserved for Antibody Negative, RNS Negative and
Ice pack test negative.
• False positive in ALS and Placebo. False negative or equivocal tests can
occur.
• Pulmonary function test – Measurements of ventilatory functions are
valuable because of frequency and seriousness of respiratory
impairment in myasthenic patients.

36. Differential Diagnosis
• Non auto immune congenital myasthenia
• Lambert eaton myaesthenic syndrome(LEMS)
• Hyperthyroidism (Graves disease)
• Botulism
• Intracranial mass lesion
• Oculopharyngeal dystrophy
• Mitocondrial myopathy

37. LEMS
• NMJ weakness similar to MG
• Proximal muscles of lower limb are most commonly involved.
• Cranial nerve involvement, ptosis may occur in 70% patients like MG
• DISTINGUISHED BY DECREASED OR ABSENT REFELXES AND AUTONOMIC CHANGES
such as DRY MOUTH and IMPOTENCE
• RNS- At 2-3Hz decremental response, at 20-30Hz Incremental response
• Antibodies against P/Q-type calcium channels at motor nerve terminals.
• These antibodies impair release of Ach from motor nerve terminals.
• Underlying cancer association in young patients. Small CC Lung (m/c)
• Tumor cells express a calcium channel that induces autoimmune response
• Rx same as MG Immunotherapy, Pyridostigmine.
• 3,4-DAP acts by blocking potassium channels, which result in prolongs depolarisation
of motor nerve terminals and thus enhances Ach release.

39. Amifampridine (3-4 diafampridine derivative) Starting dose - 15 to 30 mg daily divided in TDS/QID -> Titrate
max dose-80mg/day [FIRDAPASE brand name- Available in India]

41. Congenital Myasthenia Gravis
• Rare heterogenous group of disorders of NMJ that are not AUTOIMMUNE
but rather due to genetic mutations in which virtually any compoment of
NMJ may be affected.
• Share Clinical features of autoimmune MG , including weakness and
fatigablity of proximal and distal weakness and also EOMs.
• Should be suspected when symptoms begin in infancy or childhood but they
can also present late till early adulthood.
• RNS- Decremental response
• Double sero negative
• Molecular analysis required.
• Some only froms improve with AchE Inhibitors.

42. Botulism
• Due to potent bacterial toxins produced clostrodium bolulinum
• Toxins enzymatically cleave proteins essential for the release of Ach from motor
nerve terminal.
• Food poisoning, improperly packed
• Myasthenia like bulbar weakness and lack sensory signs
• Weakness may generalize and to the limbs and involve respiration.
• Autonomic findings include paralytic ileus, urinary retention, pupillary
abnormality and dry mouth.
• Demonstration of toxins by bioassay
• Antitoxins is the mainstay of treament

43. Associated Conditions
• Myasthenic patients have a increased incidence of several associated disorders.

44. Treatment
• 1) Anti Cholinesterase Inhibitors
• 2) Glucocorticoids
• 3) Immunosuppression
• 4)Thymectomy
• 5)Plasmapheresis
• 6)IVIg
• 7)Rituximab
• 8)Compliment inhibitors(Eculizumab)

45. Anticholinesterase Inhibitors
• Anti ChR Ab +ve patients respond better than Anti MuSK Ab +ve
• Pyridostigmine 30-60mg TDS/QID
• Onset of action- 15-30mins, last for 3-4 hours
• Those who have chewing difficult should take tablet before meals
• Long acting pyridostigmine useful in night time
• Max dose 300mg/day
• Muscarinic side effects (diarrhea, cramps, salivation, nausea)

46. Thymectomy
• Thymectomy should never be carried out as an emergency procedure.
• IVIG or plasmapheresis may be used before surgery to maximize strength in
weak patients.
• Patients which repond to thymectomy:
1) AchR antibody positive
2) Generalised MG
• Post procedure less dose of glucocorticoids and fewer additions of second
line agents , fewer hospitalisations for exacerbations lasting at least 5 years
• Role in Ocular myasthenia, MuSK-positive, and seronegative MG is not well
studied.

48. Glucocorticoids
• When used properly , produce improvement in myasthenic weakness
in majority of patients.
• Initial dose (15-25mg/day), preferably single dose
• Increments in dose 5mg/day at 2-3 days interval)
• Untill there is marked clinical improvement or a dose of 50-60mg/day
is reached.
• Maintained on this dose for a month then tapered slowly
• Meanwhile other immunotherapies can be initiated
• Bridging therapy
• After tapering, some patients may not even require secondary
immunotherapy.

49. Immunotherapy
• Mycophenolate mofetil- 1-1.5gm bid is recommended dose
• MOA- Inhibition of purine synthesis by de novo pathway, since
lymphocytes have only this pathway, selectively depleted, other cells have
alternate pathway
• It doesn’t kill or eliminate already existing cells therefore few months-
year is needed for its action.
• Minimal side effects like GI upset, leukopenia
• Azathioprine-
• Effective in reducing dosage of prednisone necessary to control
symptoms
• Needs year or more to have evident action
• 50mg/d -> increase gradually till 2-3mg/kg of total body weight or until
white blood count falls to 3000-4000/mcg l

50. • Tacrolimus and Cyclosporine effective and work more rapidly than
azathioprine and MMF.
• More frequent side effects Hypertension, Nephro toxicity
• Cyclosporine usual dose- 4-5mg/kg , Tacrolimus- 0.07-o.1mg/kg
• Therapeutic drug monitering needed, 12 hours after evening dose
• Cyclosporine- 150-200ng/l , Tacrolimus-5-15ng/l
• Rituximab is a monoclonal antibody CD20 on lymphocytes.
• Used in difficult to treat ACH R ab Negative MG , Anti MuSK Ab +ve MG
• 1gm on two occasions 2 weeks apart, repeat course may be needed

51. • Eculizumab antibody that binds to the terminal complement
component 5(C5). Passed phase 3 trial in MG.
• r/o meningococcal infection, vaccines in the beginning and penicillin
prophylaxis while treatment ongoing
• High dose Cyclophosphamide in refractory cases.

52. Plasmapheresis and IVIG
• Course of five exchanges (3-4 L per exchange) is generally admistered over 10-
14 days
• Removes pathogenic Antibodies
• Used in crisis, prior to themectomy
• Used when rapid improvement of the patient is required.
• Indications for IVIG are same as plasmapheresis
• 2gm/kg given over 2-5 days

53. Myasthenic crisis Management
• Acute exacerbation of weakness sufficient to endanger life, ventilator
failure
• ICU management, Mechanical ventilation
• Anticholinestrases should be stopped, since it can cause cholinergic crisis
• Plasma pheresis, IVIG is mainstay of treatment
• Most common cause is intercurrent infection

54. • Assessment of Respiratory Dysfunction in Myasthenic Crisis:
Inspiratory muscle Assessment
1)Vital Capacity <1 Ltr (10-15ml/kg)
2)Negative Inspiratory Force <20cm
of H2o (NIF)
Expiratory muscle Assessment
1) Positive Expiratory Force (PEF)
<40cm
Regardless of ventilatory function- need of mechanical ventilation defines myasthenic crisis
Beside assessment-
1) Active accessory muscles of respiration
2) Difficulty counting to 20 in a single breath signifies weakness of the expiratory muscles

55. • Intubation and Mechanical Ventilation
- Elective Intubation – Vt 8-10ml/kg , Ps -8-10 cm H20 to avoid
development of basal atelectasis.
- Succinylcholine is less effective since post synaptic nerve receptors are
unavailable
- Minimum NM Bloakcade for paralysis should be used if needed at all.
- Weaning whenever – Vital capacity >15ml/kg , improvement in neck
flexors, bulbar muscle improvement
- Fluctuating weakness and pulmonary complications often confound the
decision to extubate.
- Older age, atelectasis, and pneumonia are also associated with
extubation failure.

56. - To prevent atelectasis, early intubation, aggressive chest
physiotherapy, and frequent suctioning should be implemented and
high positive end-expiratory pressure given while the patient is
mechanically ventilated.
- Role of NIV?
1) Noninvasive ventilation (NIV) may be used to prevent intubation or
reintubation of patients in myasthenic crisis.
2) Independent predictors of NIV success are a serum bicarbonate
<30 mmol/L and an APACHE II score <6.
3) An independent predictor of NIV failure is hypercapnia (PCO2
>45mm Hg)

57. Precipitors of Myasthenic Crisis

58. Drugs to be avoided in MG

59. Myasthenic crisis Vs Cholinergic Crisis
• Cholinergic crisis is secondary to excess cholinesterase inhibitor
medication.
• In these cases, excessive Ach stimulation of striated muscles at the
neuromuscular junction produces flaccid muscle paralysis that can be
clinically indistinguishable from weakness due to myasthenia crisis.

60. • Etiology of Cholinergic crisis
1) Over Medication in MG
2) OP poisoning
3) NM blockade reversal (if neostigmine/priridostigmine is used to
reverse effects of NM blockers like vecuronium,rocuronium)
Rx-
1) Atropine-
Atropine dose is about 0.03- 0.05 mg/kg for pediatric and about 2 mg
for adult patients. It is recommended to give atropine until signs of
atropinization is present –
Tachycardia
Warm, dry, and flushed skin
Mydriasis
2) Oximes-

61. Hypokalemic Periodic Paralyses

62. • -Periodic paralysis (PP) is a rare neuromuscular disorder related to a
defect in muscle ion channels, characterized by episodes of painless
muscle weakness, which may be precipitated by heavy exercise,
fasting, or high-carbohydrate meals.
• PP is classified as hypokalemic when episodes occur in association
with low potassium blood levels or as hyperkalemic when episodes
can be induced by elevated potassium.
• Most cases of PP are hereditary, usually with an autosomal dominant
inheritance pattern.

63. HYPOKALEMIC
PERIODIC
PARALYSIS
THYROTOXIC
PERIODIC
PARALYSIS
HYPERKALEMIC
PERIODIC
PARALYSIS
ANDERSON TAWIL
SYNDROME

64. HYPOKALEMIC PERIODIC PARALYSIS
• In this type of PP, ictal potassium level is low.
• Most common type of PP
• Autosomal dominant with incomplete penetrance especially in women
• 1:3 F:M ratio

65. Pathogenesis
• 1)Calcium channel mutation -
->A mutation in the gene that codes for the alpha-1 subunit of the dihydropyridine-
sensitive calcium channel in skeletal muscle is the most common genetic
abnormality.
-However, calcium movement is not clearly responsible for either altered
potassium fluxes or clinical symptoms
• 2) Sodium channel Mutation -
-A mutation in the skeletal muscle sodium channel, SCN4A, is responsible for this
syndrome in other families.
-Mutant sodium channels produce an anomalous gating pore current that may
cause aberrant depolarization during attacks of weakness.

66. Sodium channel Mutation -
- Increased permeability of Na+ inside cell membrane
- Depolarisation
- Excess sodium is pumped out by NaKATPAse but potassium is shifted
inwards
- Resultant Hypokalemia
- Weakness

67. Clinical features
• Attacks —
• Occur suddenly with generalized weakness.
• Consciousness is preserved and bulbar and respiratory muscles are only mildly
affected, if at all.
• In hypokalemic PP, attacks begin in late childhood or teenage years.
• Intervals of weeks to months are common, but some patients experience several
attacks per week. Attacks typically last several hours, but the duration can range
from minutes to days.
• Attacks may be triggered by rest after vigorous exercise, stress, or a high-
carbohydrate meal, often after a delay of several hours. These events are often
associated with an increased release of epinephrine or insulin, both of which cause
movement of potassium into cells and low potassium blood levels
• Cardiac arrhythmias, such as tachycardia, atrial fibrillation, paroxysmal
supraventricular tachycardia, or ventricular fibrillation, are not common but have
been reported during attacks

68. • Myopathy — A progressive proximal myopathy ultimately develops in most patients
with hypokalemic PP [28]. This becomes clinically manifest in most individuals after
the age of 50 years, as attacks of paralysis wane. Evidence of muscle disease may be
evident on muscle biopsy, computed tomography scans, or magnetic resonance.

69. Investigations
• Sr. Electrolytes, ECG – Prolonged PR interval , Qt prolongation , u
waves, ST depression.
• Hyperthyroidism should be excluded with laboratory testing: T3, T4,
and thyroid-stimulating hormone (TSH) levels.
• Genetic testing — It is possible to test for many but not all of the
mutations that underlie hypokalemic PP.
• Electromyography — During an attack, EMG may show decreased
amplitude of the compound muscle action potential (CMAP), with
reduced motor unit recruitment or electrical silence, depending on
the severity of weakness.
• The presence of myotonia on EMG strongly suggests the alternative
diagnosis of hyperkalemic PP.

70. Treatment
• Acute treatment
• The oral administration of 60 to 120 mEq of potassium chloride, given
incrementally, usually aborts acute attacks of hypokalemic PP. Recovery may
take minutes to hours.
• Potassium administration during an acute episode may lead to posttreatment
hyperkalemia as potassium moves back out of the cells. Treatment should
therefore be administered incrementally, and post treatment potassium
levels should be monitored for 24 hours.
• Potassium should not be administered in solutions containing dextrose, as
patients have an exaggerated insulin response to carbohydrate loads .
• Cardiac monitoring is recommended during treatment and post treatment
monitoring.
• A suggested protocol is potassium chloride 30 mEq orally every 30 minutes
until serum potassium normalizes. However, some recommend slower rates
of administration (10 mEq per hour), to minimize rebound hyperkalemia

71. • Preventive treatment:
• Non pharmacologic interventions that may be effective for preventing
attacks include a low-carbohydrate diet and refraining from vigorous
exercise.
• Carbonic anhydrase inhibitors appear to be effective in reducing attacks
of PP. Acetazolamide (250 mg twice daily) is commonly reported to be
effective in reducing attacks (exact mechanism unclear)
• A potassium-sparing diuretic, either spironolactone (100 mg daily) or
triamterene (150 mg daily), can be effective as monotherapy or as a
supplement to carbonic anhydrase inhibitor
• Pinacidil, a potassium channel opener, appeared to improve strength
during episodes of induced hyperglycemia compared with placebo in
four patients with hypokalemic PP