A case of Hypokalemic periodic

paralysis

Preceptors: Dr. Srikanth Gundlapalli

Dr. Sujeeth Reddy
Dr. Yogesh Gaur

Presented by:
Varun Vankeshwaram
A 29 year-old male with no significant past medical history presented to the emergency room with sudden onset
paralysis for 1 day .The patient had gone to bed at 10 pm with no weakness and awoke at midnight unable to
move his upper or lower extremities. The weakness was bilateral and involved both the proximal muscles of the
shoulders and hips as well as the distal extremities. He had no respiratory or swallowing difficulty and was able
to move his neck and facial muscles. He denied any pain or paresthesia. Prior to this episode, the patient had
been healthy and denied any recent diarrhea, chest pain, shortness of breath, or weight change. He did report
several episodes of waking from sleep with a "racing heart." He did not take any medications and denied use of
alcohol or drugs, or significant changes in diet or activity levels. His mother had been diagnosed with
hypothyroidism but his parents and brother had no history of similar episodes and no other significant illnesses.

On physical exam:

He was mildly obese, but otherwise normal in overall appearance. His skin was cool and dry, and the oral
mucosa was moist. No jugular venous distension, goiter or lymphadenopathy were appreciated. Cardiac exam
revealed tachycardia with a regular rhythm and no murmurs. Examination of the lungs and abdomen were
unremarkable. There were no deformities or edema of the extremities and distal pulses were present and equal
bilaterally. Neurologic exam revealed flaccid paralysis of all extremities which involved the proximal and distal
muscles and included the hips and shoulders. Sensation was intact but deep tendon reflexes were slightly
diminished to 3 out of 4 throughout. Cranial nerve function was grossly intact.

Heart rate:124,
Blood pressure was 150/80.

Lab values: Sr. K: 2.5Meq/L

ECG: U waves, short QT intervals
Channelopathies:

These are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all
cells and many cellular organelles.

These diseases involve various organs:

Nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and
hyperkalemic and hypokalemic periodic paralysis),

Cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic
polymorphic ventricular tachycardia),

Respiratory system (e.g., cystic fibrosis),

Endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic
periodic paralysis, and familial hyperaldosteronism),

Renal system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and
hypomagnesemia with secondary hypocalcemia)

Immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate]
receptor encephalitis).
Hypokalemic Periodic Paralysis:

Definition

Causes

Pathophysiology

Symptoms

Diagnostic Approach

Treatment
Definition:
Hypokalemic periodic paralysis is a condition that causes episodes of extreme muscle weakness typically
beginning in childhood or adolescence.

Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Attacks cause
severe weakness or paralysis that usually lasts from hours to days. Some people may have episodes almost
every day, while others experience them weekly, monthly, or only rarely.

Attacks can occur without warning or can be triggered by factors such as rest after exercise, a viral illness, or
certain medications. Often, a large, carbohydrate-rich meal or vigorous exercise in the evening can trigger an
attack upon waking the following morning. Although affected individuals usually regain their muscle strength
between attacks, some develop persistent muscle weakness later in life.

People with hypokalemic periodic paralysis typically have reduced levels of potassium in their blood
(hypokalemia) during episodes of muscle weakness.
Causes:
Periodic paralysis due to hypokalemia may occur in two settings.
1. Inherited channelopathy causing hypokalemia and paralysis.
2. Hypokalaemia by other mechanisms causing paralysis (secondary hypoKPP).

Two inherited channelopathies have been identified to cause hypoKPP,

Calcium channel mutation (CACNA1S).-HypoKpp1
Sodium channel mutation (SCN4A)-HypoKpp2
Those two in general, have similar pathogenic mechanisms, clinical profiles and treatment options.
However subtle differences in the phenotypes of the two types have also been recognized
Both are Autosomal dominant disorders
Pathophysiology:
1.The physiologic basis of flaccid weakness is inexcitability of the muscle membrane (ie, sarcolemma).

2.Alteration of serum potassium level is not the principal defect in primary PP. In primary and thyrotoxic PP, flaccid
paralysis occurs with relatively small changes in the serum potassium level, whereas in secondary PP, serum
potassium levels are markedly abnormal.

3.No single mechanism is responsible for this group of disorders. Thus, they are heterogeneous but share some
common traits. The weakness usually is generalized but may be localized.

4.Cranial musculature and respiratory muscles usually are spared. Stretch reflexes are either absent or diminished
during the attacks.

The muscle fibers are electrically inexcitable during the attacks. Muscle strength is normal between attacks but,
after a few years, some degree of fixed weakness develops in certain types of PP (especially primary PP).
Pathophysiology:
Pathophysiology:
SYMTPOMS:

● Mild attacks are frequent and involve only a particular group of muscles, and may be unilateral,
partial. This may affect predominantly legs; sometimes, extensor muscles are affected more than
flexors. Duration varies from a few hours to almost 8 days but seldom exceeds 72 hours. The attacks
are intermittent and infrequent in the beginning but may increase in frequency until attacks occur
almost daily. The frequency starts diminishing by age 30 years; it rarely occurs after age 50 years.

● Severe cases usually present in early childhood and mild cases may present as late as the third
decade. A majority of cases present before age 16 years. Weakness may range from slight transient
weakness of an isolated muscle group to severe generalized weakness. Severe attacks begin in the
morning, often with strenuous exercise or a high carbohydrate meal on the preceding day.

● Attacks may also be provoked by stress, including infections, menstruation, lack of sleep, and certain
medications (eg, beta-agonists, insulin, corticosteroids). Patients wake up with severe symmetrical
weakness, often with truncal involvement.
SYMTPOMS (Continue..)

● Urinary output is decreased during the attack because water accumulates intracellularly in muscles. In
HypoPP1 patients, the age of onset is earlier (10 y), the symptoms lasts longer (20 h), and the fixed
proximal weakness is more frequent (about 70%), compared with HypoPP2 patients (16 y, 1 h, none).
● Permanent muscle weakness may be seen later in the course of the disease and may become severe.
Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may
be seen in patients with permanent weakness.
● HypoPP2 differs from HypoPP1 by (1) late onset, (2) tubular aggregates in muscle biopsy (vacuolar
myopathy in HypoPP1), (3) aggravation by acetazolamide in HypoPP2.
Complications
Rhabdomyolysis

Rhabdomyolysis is rare but well recognized and potentially life threatening complication of PP. This has been reported in several
patients with hypoKPP. Exact mechanism is uncertain, but is thought to be due to ischaemia of skeletal muscles.24 Potassium causes
vasodilation increasing skeletal muscle perfusion, particularly during exercise. Absence of this protective mechanism in hypoKPP
leads to muscle ischaemia. Interestingly, rhabdomyolysis has not been reported with hyperKPP and is commoner in secondary
hypoKPP where hypokalaemia is worse, further supporting the above hypothesis.

Cardiac arrhythmia

hypoKPP is associated with hypokalaemia related ECG changes including U waves, atrial fibrillation, supraventricular tachycardia,
ventricular ectopics, ventricular tachyarrhythmias and rarely bradycardia. Tachyarrhythmias are more in TPP20 probably due to effects
of thyrotoxicosis itself. These are potentially fatal and need close monitoring and early treatment.

Progressive myopathy

Slowly progressive degenerative myopathy is known to affect patients with periodic paralysis. This is more common with hypoKPP
than with hyperKPP, and clinically manifests in the fifth decade of life. Lower limb muscles are predominantly affected. With the onset
of myopathy, episodes of paralytic attacks become infrequent. Histological characteristics are vacuoles in the centre of myofibres and
absence of inflammatory cell infiltrates.Degenerating muscles will be replaced by fatty tissue which is detectable in MRI scan.
Electron microcopy will demonstrate dilatation and proliferation of T tubules.
Diagnostic evaluation:
Diagnostic evaluation:
Clinical diagnosis: Demonstration of hypokalemia during an episode of weakness and history of recurrent episodes of paralysis
and family history of similar events are often adequate for the diagnosis. Further studies are rarely required.

However, it may not be feasible with all patients, particularly if presentation is delayed, since potassium rapidly corrects by itself with
recovery. Patients should be advised on early presentation and attempts should be made to assess serum electrolytes soon after
symptom onset. In cases of uncertainty, genetic studies, electromyogram (EMG) and provocative testing may be useful.

Genetic studies to detect specific mutations are useful for confirmation. However, variety of mutations account for the diseases,
and it is likely that not all mutations are recognized thus far. Furthermore, genetic testing is not widely available.

EMG during an attack will show myopathic changes (low compound muscle action potential). These features are common to all types
of PP. Nerve conduction studies are essentially normal. EMG in between episodes is particularly useful in hyperKPP where
electrodiagnosis of subclinical myotonia is found in 50-75%, a feature not seen with hyperkalemia associated periodic paralysis.

Provocative tests induce precipitating factors in controlled environment. This can be achieved by administration of a
glucose load (increasing endogenous insulin), insulin, ACTH (permissive effect on beta adrenoceptors) or by exercise. Evidence for
these methods is limited to observations from case series, but they may be useful when diagnosis is in doubt. Exercise provocation
test is probably the safest out of provocation methods. However, no studies have compared sensitivity, specificity and relative safety
of any of the diagnostic methods.
Treatment:
Acute management:

Initial aim should be to prevent life threatening arrhythmias by continuous monitoring of electrocardiogram and correction of potassium.

Aetiology for potassium disturbance should be explored simultaneously. Development of rhabdomyolysis should be actively observed for and
preventive measures should be implemented by regular monitoring and maintaining adequate hydration. Correction of hypokalemia should
promptly reverse the paralysis, thus limiting the complications of prolonged immobilization. Sustained weakness despite correction of serum
potassium should raise the suspicion of an alternative diagnosis.

Correction of potassium should be achieved with caution. In hypoKPP, correction of hypokalemia restores cell membrane polarization, resulting in
release of potassium stored in intracellular compartment causing a rebound hyperkalemia. Therefore, it is preferable to correct serum
potassium with oral (rather than intravenous) potassium supplementation and serum potassium level should be monitored up to 24 hours after
correction of potassium. If intravenous administration is required, KCl should be infused at a slow rate not exceeding 10 mmol/h. higher rates are
associated with 40% risk of rebound hyperkalemia. It is important not to administer glucose containing solutions or carbohydrate rich food since
those trigger endogenous insulin release, further promoting potassium influx in to skeletal muscles. Physical exercise may help mild cases of
hypoKPP since exercise causes release of potassium from skeletal muscles.

In patient with TPP, non-selective beta blockade with oral or intravenous propranolol may also rapidly reverse the paralysis without causing
rebound hyperkalemia according to several case reports. Its role in non thyrotoxic hypoKPP is not known.
Long term management
Identification of triggers and their avoidance is important. Patients with hypoKPP1 respond to acetozolamide. Its mechanism of
action is not well understood, but appears to be independent of carbonic anhydrase inhibition. Potassium sparing diuretics
(spironolactone 100 mg daily) are the other option, either alone or in combination with acetozolamide. Potassium should be monitored
for hyperkalemia. Painful gynaecomastia is a disturbing side effect.

Regular potassium supplementation is not required. Patient can be advised to take oral potassium supplements if paralytic
symptoms develop. Acetazolamide and spironolactone are effective for hypoKPP due to CACNA1S mutations. SCN4A mutant
hypoKPP responds less well to above measures. In fact some of the patients with SCN4A may deteriorate with those. Reasons for
this discrepancy are not clear.

Best method of preventing TPP recurrence is by treating the thyrotoxicosis. Long term beta antagonism with propranolol has
also shown to prevent attacks of PP in these patients, but evidence is limited to several old case reports and series.Few case reports
have indicated that acetazolamide and potassium sparing diuretics are thought to worsen TPP and should be avoided.Clearly,
evidence for optimum management of TPP is lacking.

Although familial periodic paralysis syndromes are inherited in autosomal dominant pattern, role of screening family members for the
disease is not clear. It may be useful if the index patient’s mutation is known. Lack of wide availability, high rate of sporadic cases
due to acquired mutations, variable penetrance, unavailability of an established preventive method or prophylactic therapy
are the potential limitations in genetic screening for the management of periodic paralysis.
Summary
Periodic paralysis syndromes are important diagnostic consideration in patients presenting with acute flaccid paralysis.
Serum potassium should be tested in all, and if abnormal, should be investigated for a cause. Primary periodic paralysis
syndromes are inherited and family history, onset at young age and recurrent nature along with abnormal potassium levels
during episodes confirm diagnosis. Thyrotoxic periodic paralysis occurs only when the patient is thyrotoxic (at least
biochemically, may be clinically silent) and is associated with hypokalemia. All patients with hypokalemic periodic paralysis
should be tested for thyrotoxicosis. Treatment of thyrotoxicosis is adequate to prevent recurrent episodes.
References
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THANK YOU.