Periodic paralysis

 Primary Periodic paralysis (PPP are rare and include hypokalemic paralysis (HypoPP), hyperkalemic paralysis (HyperPP), and Andersen-Tawil syndrome.  There are also closely related diseases whose features overlap with HypoPP and HyperPP, including paramyotonia congenita (PMC) and normokalemic PP.

Calcium (CACNA1S):  HypoKPP1 - 60%

Chloride:  Myotonia congenita

Potassium:  HypoKPP, Andersen-Tawil syndrome

Sodium (SCN4A):  HypoKPP2 (20%), HyperKPP1, paramyotonia congentia, potassium aggravated myotonia (acetazolamide responsive myotonia, myotonia fluctuans, myotonia permanens).  They are all caused by a missense mutation in the pore forming subunit of voltage-gated skeletal muscle sodium channel Nav1.4 encoded by SCN4A gene on 17q23-25.

For HypoKPP (CACNA1S).   SCN4A (associated with HypoKPP2),  KCNJ2 (Andersen-Tawil syndrome), RYR1 (central core and multi-minicore disease and atypical periodic paralysis),  MCM3AP (a novel gene hypoKPP), ATP1A2 (associated with familial hypokalemic periodic paralysis and hemiplegic migraine). KCNJ18 associated with thyrotoxic HypoKPP.

Primary Periodic paralysis

These are a group of very rare, genetic ion channel disorders characterized by transient attacks of severe flaccid weakness accompanied by serum potassium levels that are high, low, or normal. The episodic partial or general weakness is associated with abnormal ion channel conductance. There is depolarization of the muscle membrane, which in turn causes sodium channel inactivation and reduced muscle fiber excitability.  Common features of PPP include autosomal dominant inheritance, onset typically in first or second decades of life, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise.  Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing.  In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis.  The treatment approach should include both management of acute attacks and prevention of attacks.  Treatment include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and use of carbonic anhydrase inhibitors. 

The clinical presentation is identical for patients with HypoPP caused by calcium or sodium channel mutations because homologous gene defects of either channel cause an anomalous leakage current, which is active at the resting potential and produces susceptibility to paradoxical depolarization of the fiber and inexcitability in the setting of low extracellular K1 (2.5 to 3.5 Meq/L).

The diagnosis of an episodic muscle disorder is primarily clinical.  Muscle strength is usually normal in these patients. Patients with periodic paralysis or nondystrophic myotonia will have episodic weakness involving one or more limbs and usually also loss of deep tendon reflexes during an attack. Patients with nondystrophic myotonia differ from those with periodic paralysis because myotonia is always present in the nondystrophic myotonias involving sodium and chloride channels, while it is absent in the calcium channelopathies resulting in hypokalemic periodic paralysis and in patients with Andersen-Tawil syndrome.

Hyperkalemic periodic paralysis (hyperkPP) or potassium-sensitive periodic paralysis 

Autosomal dominant disorder with a high degree of penetrance, which manifests as episodic weakness usually during the first decade. 

Acute Management of HypoPP

Mild exercise (e.g., nonresistance activities such as walking around a room or shaking the arms) at the onset of the attack may be of benefit.  

Low serum potassium is not due to low total body potassium but rather shifts of potassium from the blood compartment into the intracellular muscle compartment.  Therefore, correction of serum potassium should not be undertaken with the goal of correcting low total body potassium.  

Treatment options include oral or intravenous (IV) potassium administration.  Oral potassium is recommended for outpatient treatment.  Slow-release formulations usually should be avoided for acute management.  The dose of oral potassium is 0.2–0.4 mEq/kg every 30min not to exceed 200–250 mEq/day.   

Administering potassium by IV infusion usually requires hospitalization for ECG monitoring but is only necessary if the patient cannot take oral potassium.  The dose of IV potassium is 40 mEq/L in 5% mannitol solution infused at a maximum of 20 mEq/h, not to exceed 200 mEq/day.   A potassium chloride IV bolus of 5 mEq can be used as an alternative.  Use of glucose- and saline-containing IV solutions for administering potassium should be avoided, as this may worsen muscle weakness.

Prevention of HypoPP

The patient should be advised to avoid triggers such as high-carbohydrate and/or high-salt meals, alcohol, and stress.  Although no randomized controlled studies are available to inform dosing, a daily slow-release potassium salt formulation may be considered the standard of care for chronic therapy.

Dichlorphenamide is approved for HypoPP, and has been associated with reductions in attack frequency, severity, and duration during chronic treatment.  Based on anecdotal reports, acetazolamide 125–1000mg/day may be effective chronic treatment of HypoPP.   

Potassium-sparing diuretics are a potential option for chronic treatment of HypoPP.  Recommended doses are triamterene 50–150 mg/day, spironolactone 25–100 mg/day or eplerenone 50–100mg daily.  Spironolactone may be poorly tolerated because of androgenic side effects, and epleronone may be substituted because it causes fewer hormonal issues.  For patients with HypoPP, potassium supplementation and a potassium-sparing diuretic may be used concomitantly, but potassium levels should be routinely monitored.

Recent studies in mouse models of HypoPP with both SCN4A mutations and CACNA1S mutations show that maneuvers to reduce the activity of the Na-K-2Cl (NKCC) co-transporter can reverse an acute attack of HypoPP and protect against an attack triggered by low K+ exposure.  The beneficial effect is the result of biasing intracellular chloride to be low, which promotes hyperpolarization of the resting potential.  The NKCC co-transporter is activated by hyperosmolarity (hence the importance of avoiding high sodium diet, dehydration or hyperglycemia) and is inhibited by loop diuretics such as bumetanide.  Pharmacologic inhibition of NKCC as an acute therapy for HypoPP is under study.

Acute Management of HyperPP

Acute Management management may include mild exercise at attack onset and a carbohydrate snack.  Beta agonists can be an effective acute potassium-lowering therapy for HyperPP.  In case reports, salbutamol 1–2 puffs (0.1mg) and other beta-agonists have shown benefits.  While severe hyperkalemia during attacks is typically not seen, the treatment for acute hyperkalemia which is severe or life-threatening should match institutions’ established protocols.

Prevention of HyperPP

 In individuals with HyperPP, consider recommending consumption of multiple small carbohydrate snacks and avoid potassium rich foods.  

Dichlorphenamide can be effective for chronic treatment and is approved for HyperPP.22,  In randomized, placebo-controlled studies, dichlorphenamide reduced attack frequency and severity among patients.  The initial dose is 50 mg twice daily, which may be increased or decreased at weekly intervals based on individual response or the occurrence of adverse events.  The maximum recommended dose is 200 mg daily.  

Acetazolamide 125–1000 mg/day may be effective for chronic treatment of HyperPP.  Thiazide diuretics are an option for chronic treatment of HyperPP.  The drug of choice is hydrochlorothiazide 25mg to 75mg daily.  

Potassium-sparing diuretics should be avoided.  There are no rigorously controlled data on the treatment of PMC, normokalemic PP, and other atypical PPs, but in general, the same treatment strategies used for HyperPP are appropriate.

Management of Andersen-Tawil Syndrome

Management of individuals with Andersen-Tawil syndrome requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias.  Treatment for acute attacks of weakness or for chronic suppression of attacks of weakness in individuals with Andersen-Tawil syndrome depends on whether the attack is associated with high or low levels of potassium, and treatment needs to be individualized for each patient above for HypoPP and HyperPP for specific recommendations).  Evaluations recommended to establish the extent of disease and needs in a patient diagnosed with Andersen-Tawil syndrome.  For asymptomatic patients with a KCNJ2 mutation, annual screening should include a 12-lead ECG and 24-h Holter monitoring.

Treatment of Manifestations.  

Cardiac considerations.  Empiric treatment with an antiarrhythmic agent should be considered for significant, frequent ventricular arrhythmias in the setting of reduced left ventricular function.

Evaluations recommended to establish the diagnosis of Andersen-Tawil syndrome:

Flecainide, a type 1c antiarrhythmic, for the prevention of cardiac arrhythmias.  Assessments included 24-h Holter monitoring before and after treatment, and a treadmill exercise test.  Flecainide significantly reduced the number of ventricular arrhythmias observed on Holter monitor and suppressed exercise induced ventricular arrhythmias.  After a mean follow-up of 23 months, no syncope or cardiac arrest was documented.  Thus, flecainide may reduce cardiac arrhythmias in Andersen-Tawil syndrome, although further evaluation is needed.  Others have reported beneficial effects with flecainide.  Others report beneficial effects for suppressing ventricular arrhythmias with the use of beta-blockers, calcium channel blockers, or amiodarone.

Prevention of secondary complications. 

Some antiarrhythmic drugs (e.g., lidocaine, mexiletine, propafenone, quinidine) may paradoxically exacerbate neuromuscular symptoms and should be used cautiously in individuals with Andersen-Tawil syndrome.  Although malignant hyperthermia has not been reported in Andersen-Tawil syndrome, appropriate precautions should be undertaken when using anesthesia for surgical procedures.  Patients should be instructed about medications known to prolong QT intervals and avoid their use.  Inhaled salbutamol, which may be used for the treatment of HyperPP, should be avoided because of the potential to exacerbate cardiac arrhythmias.  Thiazide diuretics should be avoided, because they may induce drug-induced hypokalemia and could aggravate the QT interval.

Differentiating features HypoKPP,  HyperKPP, Anderson-Tawil syndrome

Carbonic anhydrase inhibitors side-effects:

 Include paresthesia, fatigue, and mild, reversible cognitive disturbances.  An additional concern with carbonic anhydrase inhibitors is an increased risk of nephrolithiasis.  In patients receiving long-term treatment with acetazolamide for myotonia experienced nephrolithiasis.  Nephrolithiasis has been widely reported with acetazolamide when used for other conditions and may be managed by removal of renal calculi without necessitating discontinuation of carbonic anhydrase inhibitor treatment.

Dichlorphenamide 

This drug was recently approved by the FDA for the treatment of PP. Dichlorphenamide has been evaluated in four randomized, placebo  controlled studies, two each in patients with HypoPP and HyperPP.   It is given 50mg twice daily for treatment-naıve patients.  Patients already on dichlorphenamide before the study continued on the same dose during the study.  In patients taking acetazolamide before the study, the dose of dichlorphenamide was set at 20% of the acetazolamide dose.  Dose reduction for tolerability was permitted.  The most common side effects with dichlorphenamide were paresthesias, cognitive disorder, dysgeusia, headache, fatigue, hypoesthesia, and muscle spasms, generally not requiring discontinuation of dichlorphenamide, and reversible with drug discontinuation.

Secondary causes of periodic paralysis