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Hypokalemic periodic paralysis (Hypokalemic PP)
EPIDEMIOLOGY —
prevalence : 1 in 100,000
familial with autosomal dominant inheritance
acquired in patients with thyrotoxicosis
disorder is 3-4 times more common in men.
one-third of cases represent new mutations .
PATHOGENESIS —
mutation in the gene :
1- dihydropyridine-sensitive Ca channel in skeletal muscle is the most common genetic abnormality in hypokalemic PP (70 %) .
2- sodium channel, SCN4A, in other families .

CLINICAL FEATURES —

attacks occur suddenly with generalized weakness.

Consciousness is preserved and bulbar and respiratory muscles are only mildly affected, if at all.

attacks begin in late childhood or teenage years. These attacks vary in frequency and duration.
Intervals of attacks : weeks to months are common, but some patients experience several attacks per week.
duration of Attacks : several hours, but the can range from minutes to days.
trigging of Attacks : rest after vigorous exercise, stress, or a high-carbohydrate meal, 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 .
Neurologic examination during an attack demonstrates weakness, usually affecting proximal more than distal muscles, and the legs more than the arms; hyporeflexia or areflexia is typical.

Some patients experience a milder degree of weakness between attacks that fluctuates and improves with mild exercise.

The mean plasma K during the attack in one series was 2.4 meq/L.

Levels can be as low as 1.5; however, K < 2 meq/L should suggest a secondary cause of hypokalemic paralysis, such as that seen in some cases of severe hypokalemia due to distal renal tubular acidosis.

Cardiac arrhythmias, such as tachycardia, AF , PSVT , or VF are not common but have been reported during attacks
During attacks: ECG may show findings OF hypokalemia, including depression of the ST segment, decrease in the amplitude of the T wave, and an increase in the amplitude of U waves.
A progressive proximal myopathy ultimately develops in most patients with hypokalemic PP . This becomes clinically manifest in most individuals after the age of 50 years, as attacks of paralysis wane.

DIFFERENTIAL DIAGNOSIS —
thyrotoxicosis and Andersen syndrome can be associated with hypokalemia.
Other disorders :
• Myasthenia gravis. Weakness in myasthenia gravis typically occurs predictably in the setting of milder degrees of exertion, does not occur in “attacks” as does periodic paralysis, and often involves bulbar and extraocular muscles, which are rarely if ever affected in hypokalemic PP. In contrast to periodic paralysis, when profound weakness occurs in a myasthenic crisis, respiratory muscle involvement is common.
• Metabolic myopathies. Patients with a metabolic myopathy typically complain of exercise intolerance, with myalgias and muscle fatiguability, rather than attacks of weakness. Myoglobinuria may accompany or follow more severe symptoms
• Secondary hypokalemia. Episodic weakness may be seen in association with severe hypokalemia due to renal, GI , or other causes .
• Guillain Barré syndrome, acute myelopathy (eg, transverse myelitis), myasthenic crisis, tick paralysis, and botulism may be considered initially.

DIAGNOSIS — When there is an established family history of hypokalemic PP, episodes of periodic paralysis often require no further diagnostic evaluation.
Otherwise, the diagnosis of hypokalemic PP is suggested by documentation of hypokalemia during a typical attack of weakness. Even when this is demonstrated, other testing is required to rule out alternative diagnoses.
Further diagnostic options include genetic tests, provocative testing and EMG .

Initial lab evaluation —
serum K ,
T3, T4, and TSH : In the acute setting, findings of tachycardia and hypophosphatemia can raise suspicion of this disorder .
• ECG : prolonged QT or QU interval suggestive of Andersen syndrome .
During an attack of hypokalemic PP: ST depression, decrease in T, increase in U.
ABG , BUN , cr, and other electrolytes (p , ca , Mg ) should be measured during an acute attack.
• metabolic acidosis or alkalosis was found in all cases with secondary hypokalemia and in none of the patients with periodic paralysis .
• Hypophosphatemia can cause acute paralysis in patients with DKA who may also have hypokalemia .
• reliable tests to distinguish hypokalemic PP from secondary hypokalemic paralysis :
– low urine K/Cr ratio (<22 meq/g or <2.5 meq/mmol);
– low TTKG (<3.0) as calculated from :
(urine K/plasma K) ÷ (urineosmolality/plasma osmolality)
• Normal plasma K between attacks help distinguish primary hypokalemic PP from other secondary causes of hypokalemic paralysis, such as distal RTA .

Genetic testing —
It is possible to test for many but not all of the mutations that underlie hypokalemic PP. When genetic testing is negative, further testing with provocative testingand/or electromyography may help establish the diagnosis of hypokalemic PP.
Provocative testing —
Provocative testing can be employed, when genetic testing fails to identify an underlying mutation. Careful monitoring, usually in an inpatient setting, is recommended for all forms of provocative testing:
• Precipitating an attack of hypokalemic PP with an oral glucose load (2 gm/kg) and/or insulin administration (10 units subcutaneously) can be risky .
Exercise, such as 30 minutes of running on the treadmill, may provide a safer alternative to glucose or insulin administration.
• Both hypokalemic PP and hyperkalemic PP can be induced with ACTH.
EMG —
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 .

Muscle biopsy — A muscle biopsy is not usually performed in the diagnosis of periodic paralysis. Vacuolar changes, representing reduplication of the sarcoplasmic reticulum and transverse tubules, are nonspecific findings common to all periodic paralyses . Tubular aggregates are less often seen, but may be more common in the sodium channel mutation variant of hypokalemic PP and in the Andersen syndrome.

ACUTE TREATMENT —
oral administration of 60 to 120 meq of KCL .
Recovery may take minutes to hours.
Important caveats of acute treatment include the following:
• The presence of hypokalemia must be confirmed prior to therapy.
• K administration during an acute episode may lead to posttreatment hyperkalemia . Treatment should therefore be administered incrementally and posttreatment potassium levels should be monitored for 24 hours.
• K should not be administered in solutions containing dextrose.
• Cardiac monitoring is recommended during treatment and posttreatment monitoring.
A suggested protocol is KCL 30 meq orally every 30 minutes until serum potassium normalizes .
some recommend slower rates of administration (10 mEq per hour), to minimize rebound hyperkalemia .
Milder attacks can be aborted by low level exercise .

PREVENTIVE TREATMENT —
Nonpharmacologic interventions :
low-carbohydrate diet and refraining from vigorous exercise. When attacks continue to be disabling, prophylactic treatment is indicated to avoid morbidity, even mortality, which can be associated with hospitalization and acute treatment .
Medications, symptomatic K supplementation, K-sparing diuretics, and carbonic anhydrase inhibitors are used when lifestyle changes are not sufficiently effective :
• The carbonic anhydrase inhibitor : dichlorphenamide (50 mg twice daily) : reducing attack frequency

Acetazolamide (250 mg twice daily) is also effective in reducing attacks .
combined acetazolamide + spironolactone ,
topiramate 75 to 100 mg twice daily . While attack frequency increased, the severity of individual attacks was decreased, resulting in fewer emergency room visits and an overall improved quality of life.

Side effects OF carbonic anhydrase inhibitors : malaise and fatigue , Kidney stones.
• A K-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 . K supplementation should be avoided in these patients.
• The efficacy of verapamil 240 mg daily : was not associated with a reduced frequency of events in the group as a whole, significant reduction of events .
• Pinacidil, a K channel opener,
• those with mutations in CACNA1S were more likely to respond to treatment with acetazolamide compared to those with SCN4A mutation .
• specific mutation in the Ca channel had marked improvement with treatment with K-sparing diuretics after failing to respond to acetazolamide . Acetazolamide has been reported to exacerbate symptoms in some families with mutations in the Na channel, but not in others .
There is no known treatment for the late-onset myopathy in hypokalemic PP. While some believe that limiting attacks of periodic paralysis ameliorates the subsequent myopathy, this is unproven.
The association between malignant hyperthermia and hypokalemia has been described , suggesting caution be used when certain inhalational anesthetic agents orsuccinylcholine are used.
ANDERSEN SYNDROME —
one-tenth the prevalence of hypokalemic PP . It is manifest by a triad of PP , ventricular dysrhythmias, and dysmorphic features (short stature, hypertelorism, clinodactyly, micrognathia) . A prolonged QT interval on ECG is also a feature of this disorder .
K may be low, normal, or high during paralytic attacks, which first manifest during the first or second decade of life .
paralytic attacks are commonly precipitated by rest after exercise. a dietary trigger is rarely identified. Provocative challenges to induce hypokalemia or hyperkalemia should not be performed in these patients because of the risk of cardiac arrhythmias.
There is little information on the treatment or prognosis of periodic paralysis in this setting.
diuretics are contraindicated in patients with the long QT syndrome. Carbonic anhydrase inhibitors, acetazolamide and dichlorphenamide, are reportedly useful .

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