MYASTHENIA GRAVIS

1. Etiologi

Myasthenia gravis, similar to other autoimmune disorders, occurs in genetically

susceptible individuals. Precipitating factors include conditions like infections,
immunization, surgeries, and drugs. 

The commonly implicated proteins in the NMJ against which autoantibodies are
produced include the nicotinic acetylcholine receptors (n-AChR's), muscle-specific
kinase (MuSK), and lipoprotein-related protein 4 (LPR4). Agrin–LRP4–MuSK
protein complex is essential for the formation and maintenance of NMJ, including the
distribution and clustering of the AChR. Approximately 10% of patients with MG
have a thymoma, and it is implicated in the production of autoantibodies.

2. Patogenesis

The pathophysiologic mechanisms in MG are dependent on the type of antibodies

present.

In n-AChR MG, the antibodies are of the IgG1 and IgG3 subtype. They bind to the n-
ACh receptor present in the postsynaptic membrane of the skeletal muscles and
activate the complement system leading to the formation of the membrane attack
complex (MAC). MAC brings about the final degradation of the receptors. They may
also act by functionally blocking the binding of ACh to its receptor or by enhancing
the endocytosis of the antibody-bound n-ACh receptor.

In MusK MG and LPR4 MG, the antibodies are of the IgG4 subtype and do not have
the complement activating property. They bind to the Agrin–LRP4–MuSK protein
complex in the NMJ, whose primary function is the maintenance of the NMJ,
including the n-ACh receptor distribution and clustering. The inhibition of the
complex leads to a reduced number of n-ACh receptors. The ACh released at the
nerve terminal, in turn, is unable to generate the postsynaptic potential required to
generate an action potential in muscle due to a reduced number of n-ACh receptors
leading to the symptoms of muscle weakness. The weakness is more pronounced with
the repeated use of a muscle group since it causes depletion of the ACh store in the
NMJ.
3. Tatalaksana

The mainstay of treatment in MG involves cholinesterase enzyme inhibitors and

immunosuppressive agents. Symptoms that are resistant to primary treatment
modalities or those requiring rapid resolution of symptoms (myasthenic crisis),
plasmapheresis or intravenous immunoglobulins can be used.

Management strategies in MG are based on the following four principles:

Symptomatic Treatment: Acetylcholinesterase inhibitors increases the level of ACh

at the NMJ by preventing its enzymatic degradation. Pyridostigmine bromide is
preferred over neostigmine because of its longer duration of action. In those with
bromide intolerance that leads to gastrointestinal effects, ambenonium chloride can be
used. Patients with MuSK MG respond poorly to these drugs and hence may require
higher dosages.

Immunosuppressive Treatment: These are indicated in patients who remain

symptomatic even after pyridostigmine treatment. Glucocorticoids (prednisone,
prednisolone, and methylprednisolone) and azathioprine are the first-line
immunosuppressive agents used in the treatment of MG. Second-line agents include
cyclosporine, methotrexate, mycophenolate, cyclophosphamide, and tacrolimus.
These are used when the patient is unresponsive to treatment, has any contraindication
to treatment, or intolerability to the use of first-line agents. Recently, various
monoclonal antibodies, including rituximab and eculizumab, have been used to treat
drug-resistant MG, but data from clinical trials about their efficacy is yet to be
documented.

Intravenous immunoglobulins (IVIG) / Plasmapheresis: This is recommended

during the perioperative period to stabilize a patient before a procedure. It is also the
treatment of choice for the myasthenic crisis due to its rapid onset of action and used
in cases that are resistant to immunosuppressive drugs.

Thymectomy: This is indicated for the following:

 Any subtypes of MG with evidence of thymoma.

  Non-thymomatous n-AChR MG, especially in patients aged 15 to 50 years,
performed 1-2 years of disease onset.

 Seronegative non-thymomatous MG. 

However, it is not recommended for the non-thymomatous MuSK MG (since thymic

pathology is rare) and non-thymomatous ocular MG without secondary
generalization.

Referensi: https://www.ncbi.nlm.nih.gov/books/NBK559331/

GUILLAIN BARRE SYNDROME

1. Etiologi
The Guillain-Barre syndrome (GBS) and its variants are considered post-
infectious, immune-mediated neuropathies. Evidence from animal models
suggests a key role of molecular mimicry. In Campylobacter jejuni
gastrointestinal infections, a lipooligosaccharide present in the outer membrane of
the bacteria is similar to gangliosides that are components of the peripheral
nerves. Therefore, an immune response triggered to fight infection can lead to a
cross-reaction on host nerves.
Many infections have been linked with GBS. The most common are
gastrointestinal or respiratory illnesses. Up to 70% of patients have reported an
antecedent illness in the 1 to 6 weeks before the presentation of GBS. During the
Zika virus outbreak, many GBS cases were described. Case reports detail many
other possible etiologies linked to GBS including medications and surgeries.
(Evidence level III)
In 1976, flu vaccination against the influenza A/H1N1 antigen led to a well-
documented, increased incidence of cases of GBS; however, further surveillance
data of flu vaccinations in subsequent years have described only one additional
case of GBS for every 1 million vaccines. Subsequent studies estimate that
developing GBS after a flu infection is up to 7 times more likely than developing
GBS after a vaccination.

2. Patogenesis
 Antecedent infections are reported in up to 70% of patients with Guillain-
Barre Syndrome (GBS). Therefore, molecular mimicry plays a substantial role in
our understanding of GBS, particularly the axonal variant. The
lipooligosaccharide of Campylobacter jejuni is similar to the gangliosides of
peripheral nerve membranes. Passive immunization of rabbits with these
ganglioside-like lipooligosaccharides have led to similar clinical syndromes of
flaccid tetraplegia, similar to the acute motor axonal neuropathy variant of
GBS. Ganglioside antibodies have been shown to have different peripheral nerve
targets. Anti-GD1a antibodies bind to paranadol myelin, nodes of Ranvier, and
neuromuscular junction.  GM1 and GQ1B antibodies bind to a peripheral nerve or
neuromuscular junction. These different peripheral nerve targets may play a role
in the heterogeneity of the clinical presentation of GBS. Additionally, complement
cascade is activated and plays a key role in the disease’s pathogenesis.
Certain gangliosides are more likely to be associated with specific presentations.
For example, Miller-Fisher syndrome is associated with the anti-GQ1B
antibody. The axonal motor neuropathy form may be associated with anti-GM1
antibodies. The pharyngeal-cervical-brachial variant of GBS may be associated
with anti-GT1A antibodies. However, besides Miller-Fisher syndrome’s
association with anti-GQ1B antibodies, sensitivity and specificity of all antibodies
for specific subtypes are low-to-moderate yield for clinical utility.
Given that not all patients test positive for anti-ganglioside antibodies, further
research is needed to elucidate the roles of anti-ganglioside antibodies in GBS, as
causal or epiphenomenon. Less is known about the pathophysiology behind the
acute inflammatory demyelinating polyneuropathy variant (AIDP) of GBS,
despite the fact that it is considered the most common variant in the United States.

3. Tatalaksana
In randomized controlled trials, there are two treatment options
currently considered the standard of care in Guillain-Barre syndrome (GBS).
These include either intravenous immunoglobulin (IVIG) or plasma exchange.
IVIG is thought to act by its immune-modulating action; however, the exact
mechanism remains to be elucidated. IVIG is given 2 grams/kilogram divided
over 5 days. Plasma exchange is thought to act by removing pathogenic
antibodies, humoral mediators, and complement proteins involved in the
 pathogenesis of GBS. Similar to IVIG, its exact mechanism of action in the
treatment of GBS has not been proven. Plasma exchange is generally given as a
volume of exchange over five sessions. Plasma exchange and IVIG have been
shown to be equally efficacious. The effect is present if either treatment is given
within 4 weeks, but the stronger effect may be present if treatment is administered
within two weeks. Surprisingly, corticosteroids (both oral prednisone and
intravenous methylprednisolone) have not shown benefit over placebo or in
combination with IVIG and plasma exchange over either modality alone. Overall,
treatment is generally considered to shorten the course of recovery of GBS.
Treated patients in one study achieved independent ambulation 32 days faster than
untreated patients. 
Overall, most patients with GBS do well, with up to 85% of patients achieving
independent ambulation with recovery; however, there is a significant proportion
of patients (20%) with morbidity. (Evidence level III) Further studies of plasma
exchange followed by IVIG and IVIG concurrent with steroids have not shown
significant improvement. An ongoing trial of 2 courses of IVIG should have
results within the next year. There are also ongoing trials of complement
inhibitors in patients with refractory GBS.

Referensi: https://www.ncbi.nlm.nih.gov/books/NBK532254/

PERIODIC PARALYSIS HIPOKALEMIA

1. Etiologi
Both hereditary or familial and acquired causes
of hypokalemic periodic paralysis have been identified.
Familial hypokalemic periodic paralysis is caused by a mutation in either of two
genes, calcium or sodium ion channel gene mutation. Over the last few decades,
various mutations have been identified as a cause of HypoKPP. The most
common familial form, type 1 HypoKPP, has a mutation in the dihydropyridine-
sensitive, skeletal muscle calcium channel gene, CACNA1S. While the other
familial form, type 2 HypoKPP, has mutations in the voltage-sensitive skeletal
muscle sodium channel gene, SCN4A. Disease-causing mutations in the gene
KCNJ2 and KCNJ18, code for inward rectifier potassium (Kir) channel, have also
been identified. Acquired HypoKPP has been associated with thyrotoxicosis. The
 familial form and thyrotoxic HypoKPP constitute the primary
HypoKPP. Periodic muscle weakness can also result from
hypokalemia secondary to renal and gastrointestinal potassium loss as in renal
tubular acidosis, gastroenteritis, or secondary to endocrine causes.
2. Patogenesis

The most common genetic abnormality in HypoKPP is the missense mutation in

the positively charged residues, i.e., arginine, in the S4 domain of the alpha
subunit (voltage sensor domain) of the skeletal muscle ion channel, most
commonly L-type calcium channel (Cav1.1) and less commonly voltage-gated
sodium channel (Nav1.4). The final common mechanism for all mutations is the
formation of anomalous gating pore current itself through the voltage sensor
domain of ion channel that makes sarcolemmal muscle inexcitable, resulting in
failure of muscle action potential and occurrence of subsequent attacks of
flaccid paralysis. Over the past few decades, several mutations in CACNA1S,
SCN4A, and KCNJ2 genes have been identified, which underlie almost 70% to
80% of cases of HypoKPP, while rest remain genetically undetermined. In 90% of
identified cases, arginine mutation in the S4 segment remains the primary cause.
The other possible HypoKPP mutations are yet to be determined.

The presence of gating pore current is mostly studied and understood in sodium
channels. Many experiments demonstrated the presence of anomalous gating pore
current in the setting of SCN4A mutation in sodium channels during the resting
phase. The anomalous gating pore current results inward nonselective cation leak
causing aberrant depolarization, which is sufficient to make the resting potential
of the muscle fibers unstable. And when serum potassium level drops below 3.0
mM, the affected fibers paradoxically undergo sustained depolarization making
muscle electrically inexcitable, whereas normal fibers undergo hyperpolarization
at this level of drop in serum potassium. Normally inward rectifying potassium
(Kir) channel and membrane Na-K-ATPase maintains the normal negative resting
membrane potential. In the presence of CACNA1S and SCN4A mutations, the
depolarization induced by the gating pore current, at the modest drop of serum
potassium level to around 3.0 mM, counterbalance the Kir current leading to
sustained depolarization.
 There are fewer experimental studies to demonstrate the evidence of gating pore
current in calcium channels. But as the phenotypic expression of HypoKPP in
sodium and calcium channel mutations are similar, it is believed that the gating
pore current does exist in calcium channel. While it is still unclear, there are
numerous observations from different experimental studies to explain the possible
underlying mechanisms behind muscle weakness with underlying calcium channel
defects:

 The calcium channel mutations manifest as loss of function.

Electrophysiologic studies have demonstrated slower activation of calcium
channels and diminished calcium current density. However, this
observation does not correlate with episodes of depolarization,
hypokalemia, and attacks of muscle weakness.

 In an experimental study, muscle biopsies taken from three HypoKPP

patients having R528H mutation of calcium channel (Cav1.1) showed the
abnormal function of sarcolemmal ATP sensitive K+ (KATP) channel,
supported by the fact that magnesium adenosine diphosphate (MgADP)
did not stimulate the channel. The KATP channel showed reduced opening
and reduced conductance state, i.e., reduced K current. The reduced K
current is more likely related to depolarization with hypokalemia. Altered
Ca2+ homeostasis resulting from the calcium channel mutation is likely
the reason behind the altered function of the KATP channel. This
observation hints toward the presence of a possible secondary
channelopathy in patients with HypoKPP.

3. Tatalaksana

The primary goal of treatment is to alleviate the symptoms of acute attacks,

prevention and management of immediate complications, and prevention of late
complications and future attacks. 

Acute Treatment 

The goal is to normalize the serum potassium level by administering oral

potassium chloride, which is believed to be more readily absorbed compared to
other oral potassium solutions, alleviates the symptoms of muscle weakness. Oral
potassium chloride is administered in incremental dose, starting initially with 0.5
to 1 mEq/kg (i.e., 60 to 120 mEq of potassium for a 60 kg individual) is
reasonable. If they do not respond to the initial dose, then 30% of the initial dose
(i.e., 0.3 mEq/kg) is repeated every 30 min. If the patient requires the addition of
more than 100 mEq of oral potassium, then close monitoring of serum potassium
is needed, and the total dose of oral potassium should not be more than 200 mEq
within the 24 hours of starting of the treatment. The starting dose of oral
potassium may vary according to the severity of hypokalemia. Patients should be
kept on ECG monitoring, and muscle strength should be examined periodically.
Serum potassium level should be monitored for 24 hours after treatment as the
posttreatment rise in serum potassium level can have an adverse effect on
patients. 

IV potassium is not preferred initially and is reserved for arrhythmias due to

hypokalemia or if the patient has swallowing difficulties or respiratory
muscle paralysis. IV potassium is preferentially administered with the mannitol,
not with dextrose or saline as both carbohydrate and salt can itself trigger the
muscle paralysis and thus may worsen the weakness. IV potassium therapy
requires inpatient, continuous ECG monitoring. 40 mEq/L in 5% of mannitol
solution of IV potassium is infused at a rate not more than 20 mEq/hour, not
exceeding 200 mEq in 24 hours.

Individuals having a milder form of attacks can also benefit from low-level
exercises.

Preventive Treatment 

Both pharmacological and nonpharmacological interventions can be used to

prevent recurrent future attacks. Nonpharmacological interventions include
educating patients about triggering factors and lifestyle modifications to avoid
these factors (discussed later). Pharmacologic interventions include medications
like chronic potassium supplementation, carbonic anhydrase inhibitors (CAIs),
potassium-sparing diuretics that are used when lifestyle modifications become
insufficient in reducing attack rates. The favored approach is to add one of the
diuretics with the chronic potassium supplementation. The initial choice of
diuretics is carbonic anhydrase inhibitor acetazolamide.

Carbonic anhydrase inhibitors seem to be potent in decreasing future attacks of

muscle weakness, though the mechanism of CAIs in HypoKPP is still unclear.
Carbonic anhydrase inhibitors promote urine potassium loss and non-anion gap
metabolic acidosis, which reduce the patient's susceptibility to muscle paralysis.
It is also suggested that CAIs increase the opening of the calcium-activated
potassium channels. Further, CAIs also reduce intracellular sodium accumulation,
thus reducing the cellular toxicity and prevent muscle degeneration, which may be
effective in the treatment of permanent weakness. 250 mg twice daily dose of
acetazolamide has been effective in lessening the frequency of attacks.

The genetic variation in response to acetazolamide treatment had been reported.

Patients with SCN4A mutations show less response compared to patients with
CACNA1S mutations. In a study of 74 identified cases of HypoKPP, 56% (31/55)
of patients with CACNA1S mutations, and only 16% (3/19) of patients with
SCN4A mutations showed a response to acetazolamide therapy. Patients with
SCN4A mutations had reported the exacerbation of the HypoKPP with
acetazolamide therapy. Overall, almost half of the HypoKPP patients respond to
treatment with acetazolamide.

FDA recently approved dichlorphenamide for the treatment of HypoKPP. 50 mg

twice daily dose of dichlorphenamide has been more effective than a placebo in
reducing the occurrence, severity, and duration of future
attacks. Dichlorphenamide can be used as the first choice or as a substitute for
patients who do not respond or are refractory to acetazolamide. Some patients also
benefitted from the addition of a potassium-sparing diuretic, either spironolactone
(100 mg daily) or triamterene (150 mg daily), to carbonic anhydrase inhibitors or
when used as monotherapy. Electrolytes need to be monitored regularly in patients
who are on diuretics therapy. 

While no definitive therapy for the late-onset myopathy has been proven to date,
but it is believed that reducing the attacks of muscle weakness helps to mitigate
the resulting myopathy.
 A study also reported the improvement in severity and frequency of attacks with
topiramate therapy in 11 years old twins with HypoKPP, thus necessitates further
study regarding the efficacy of topiramate in HypoKPP.

Special Consideration

Surgery and HypoKPP

HypoKPP patients with CACNA1S mutation are susceptible to malignant

hyperthermia, as the CACNA1S gene is allelic to the gene that increases
susceptibility to malignant hyperthermia. Surgeons and anesthesiologists must be
aware of this circumstance while using the inhalational anesthetics and muscle
relaxants like succinylcholine during surgery and be ready to deal with it. Further,
the cold environment and the use of saline and dextrose during surgery, and stress
due to surgery itself can act as a trigger and result in muscle weakness. Potassium
monitoring is important in such patients during the peri-surgical period. 

Pregnancy

During pregnancy, potassium management during the attacks should not differ
from the pre-pregnancy state. However, drugs like acetazolamide and
dichlorphenamide are FDA pregnancy category C so, their use during pregnancy
is quite challenging, and risks and benefits of drug use should be weighed in them.
Some pregnant women prefer not to take these medicines during pregnancy.

Referensi: https://www.ncbi.nlm.nih.gov/books/NBK559178/