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.
Autosomal dominant but 1/3 of cases are sporadic.
Prevalence: 1 in 200,000.
Most frequent periodic paralysis disorder.
Poor penetrance in females, resulting in male to female ratio of 4:1
Onset is usually in the 2nd decade (peak freq: 15-35 yrs).
The majority (70%) of cases are of HypoKPP1 result from mutations on 1q31-32 in the gene that encodes the alpha-1 subunit of dihydropyridine-sensitive calcium channel, CACNA1S (Cav.1).
Most patients have mutations in the skeletal muscle calcium channel gene
HypoKPP1 is allelic with malignant hyperthermia (CACNA1S). All patients with HypoKPP1 undergoing surgery must take the anesthetic risk in consideration and monitored for malignant hyperthermia (rigidity, elevated CK). Often these groups of patients may experience postoperative paralysis likely related to stress of surgery.
In ~10% of cases affected individuals have HypoKPP2, SCN4A mutation, and no identifiable mutation can be found in the remaining 20% of cases. Rare cases due ot mutations in potassium channel gene (KCNE3). Giltelman syndrome, caused by mutations affecting the thiazide-sensitive sodium chloride co-transporter, may also cause hypokalemic paralysis.
Attacks are usually longer than those seen with hyperkPP and last between hours to days.
HypoKPP1 has age of onset earlier (10 years) and the duration of episodes are longer (20 hours) compared to HypoKPP2 (16 yrs and 1 hr).
Frequency of attacks: 7 - 9 per month, each lasting hours to days.
Between 15 - 35 years the frequency of attacks peaks and may occur at daily, weekly, or monthly intervals.
The first attack most commonly occurs in the first 2 decades of life, and rarely after 30 years of age.
After age 30 years the frequency of attacks diminish and by 40s-50s become attack free. Some developed fixed permanent weakness or slowly progressive weakness over time especially involving the proximal leg muscles.
Clinical features:
Attacks are provoked by alcohol, carbohydrates, stress, and rest after exercise.
Although symptoms can be associated with rest after exercise these patients are also sensitive to other provoking factors that lower serum potassium, including exercise, large carbohydrate meals, ethanol, cold, and certain medications (steroids, beta agonists, or insulin).
Usually occurs in the morning but can occur at any time of day.
The attack of weakness begins with a sensation of heaviness or aching in the legs or lower back. This sensation gradually increases and is associated with weakness in proximal muscles. Distal weakness may occur as the attack develops. The paralysis may be severe enough that the patient cannot get up from bed or raise the head from the pillow. However, if the patient performs mild exercise, a full blown attack may be staved off, although not always successfully.
Ocular, bulbar and respiratory and sphincter muscles are usually spared
The severity of an attack varies from mild focal weakness of an isolated muscle group to severe generalized paralysis.
DTR are absent during the attack
Muscle feel swollen and firm to palpation and a variable myopathy develops in many affected individuals. This may result in progressive weakness predominantly in proximal muscle groups of the lower limbs.
Symptoms often resolve in later life, although patients may be left with some fixed residual weakness especially in legs, which may be progressive in HypoKPP1.
Recovery is abrupt.
Consensus diagnostic criteria for primary hypokalemic periodic paralysis:
Two or more attacks of muscle weakness with documented serum K <3.5 mEq/L
OR
One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum K <3.5 mEq/L
OR
Three of the following six clinical/laboratory features:
Onset in the first or second decade
Duration of attack (muscle weakness involving one or more limbs) > 2 hours
The presence of triggers (previous carbohydrate rich meal, high sodium, alcohol consumption, emotional stress, concurrent viral illness, lack of sleep, menstruation. Symptom onset during rest after exercise, stress)
Improvement with potassium intake
A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation.
Positive long exercise test (McManis) on EMG/NCS
AND
Exclusion of other causes of hypokalaemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse)
Absence of myotonia (clinically or electrically), except eyelids.
For individuals who do not meet the diagnostic criteria above, a diagnosis of primary HypoKPP may be suspected if an individual has the following symptoms and signs:
Decreased muscle tone (flaccidity)
Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles
Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes)
Concomitant hypokalemia that is usually pronounced (0.9-3.0 mmol/L)
The typical evolution of symptoms is as follows:
Rapid (over minutes or over hours)
Duration of several minutes to several days
Spontaneous recovery
Symptoms tend to occur under the following circumstances:
At rest after strong physical exertion
On awakening after a carbohydrate-rich meal the previous evening
After prolonged immobility (e.g., with long-distance travel)
Primary HypoKPP may also be considered in individuals who have
A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs
A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics.
Electrically and mechanically inexcitable and silent muscles (no myotonia) during the attack.
Individuals with HypoKPP1 do not have clinical or electrophysiological myotonia or paramyotonia unlike paramyotonia congenita and hyperKPP.
The episode is associated with transiently elevated CK and low serum potassium which can drop to 3 mEq/L.
ECG changes include bradycardia, flattened T waves, prolonged PR and QT intervals, and notable U waves secondary to hypokalemia.
Neurophysiology:
Sensory and motor NCS are normal between attacks of weakness. During attacks sensory NCS are normal, but CMAP amplitudes are reduced due to muscle membrane inexcitability. Needle EMG shows increased insertional and spontaneous activity which are not due to denervation but due to muscle membrane irritability. As the attack progresses, there is a decrease in amplitude and duration of voluntary MUAPs as well as an overall reduction in the number of voluntary MUAPs contributing to the reduced interference pattern. In severe attacks, there may be a complete absence of insertional activity, and there are minimal if any, voluntary MUAPs. In patients with weak muscles, myopathic motor units may be seen in those muscles.
RNS of mildly affected muscles demonstrates preservation of CMAP amplitudes to some extent, supporting the clinical impression that mild exercise can stave off an attack.
SET: There are minimal or no changes in CMAP amplitudes immediately after exercise as compared with HyperKPP.
LET: There is a delayed decline in CMAP amplitudes.
Bx:
HypoKPP1 shows vacuolar dilatation of sarcoplasmic reticulum of muscle only during the attack.
HypoKPP2 reveals muscle fibers with tubular aggregates.
Muscle fiber size variation, splitting fibers, hypertrophic, and some atrophic fibers can also be present. Rarely, necrotic and degenerating muscle fibers are noted.
Treatment:
Acute management:
Mild exercise (walking, shaking and flailing arms) at the onset of attack
Oral supplementation of potassium (10-20 mEq q15-30 min) 0.2-0.4 mEq/kg every 30 minutes, not to exceed 200-250 mEq in a 24-h period.
If patient cannot take oral, give potassium 20-40 mEq in 1 L of 5% mannitol; run at 20 mEq/hour, and not to exceed 200 mEq in 24 hours).
Cardiac monitoring is essential.
Prevention:
To prevent the occurrence of attacks, a diet low in sodium and carbohydrates, but rich in potassium (10-20 mEq tid, with a goal of maintaining Sr K: 4 mEq/L) is recommended. In acute attacks oral potassium salts (0.25 mEq/kg) q30 minutes until strength improves. In severe cases IV KCL, bolus 0.05-0.1 mEq/kg or 20-40 mEq/L in 5% mannitol may be administered. Cardiac monitoring is essential throughout treatment.
Carbonic anhydrase inhibitors, and potassium sparing diuretics are used. HypoPP caused by an SCN4A mutation are less responsive to carbonic anhydrase inhibitors or may even experience worsening of symptoms; responses is around 16%. Among those with the CACNA1S mutation, the response was 56%. Overall response to acetazolamide was 46% - 50%.
Acetazolamide, 125 - 1500 mg/d in adults and in children 5 - 10 mg/kg/d, and potassium salts (0.25 - 0.5 mEq/kg) are often prescribed prophylactically. However a large retrospective study found that only ~50% of patients with HypoKPP1 responded to acetazolamide and even fewer with HypoKPP2.
Acetazolamide may sometimes worsen attack in case of HypoKPP2 caused by SCN4A mutations R672G or R672S and in one patient with the CACNA1S mutation R1239H.
In particular, dichlorphenamide or acetazolamide have been repeatedly shown to be effective in HypoKPP1.
Dichlorphenamide: 50 - 200 mg/daily.
Triamterene 25-100 mg/d or spironolactone 25-100 mg/d or Eplerenone 50 - 100 mg/d may be tried to prevent attacks.
Other pharmacological treatments for periodic paralyses depend on serum potassium levels and the specific diagnosis but include potassium supplementation, thiazide or potassium-sparing diuretics or beta-adrenergic agents.
For patients receiving chronic potassium supplementation for HypoPP, providers can consider adding magnesium, which can be helpful to promote renal retention of K+ and, therefore, reduce the potassium dose.
Patients with HypoKPP are at increased risk for pre- or postanesthetic weakness.
Autosomal dominant disorder with a high degree of penetrance, which manifests as episodic weakness usually during the first decade.
Sodium channel gene SCN4A (Nav 1.4), on 17q23-25. These mutations are associated with gain of function changes, usually from an impaired channel inactivation or occasionally from enhanced activation.
Allelic to Paramyotonia congenita.
Prevalence is 1:100,000
HyperKPP manifests in 3 forms:
Without myotonia
With clinical and electrical myotonia
Associated with paramyotonia.
Attacks usually last 15 minutes to 2 hours (shorter than HypoKPP), are generalized, and triggered by rest after exercise, fasting, exposure to cold, emotional stress, pregnancy, or triggered by potassium-rich food; frequency around 16 per month to less than once a year. Mild weakness can persist for days, however, most likely due to myotonia or paramyotonia.
Not provoked by taking carbohydrates.
Often begin in the morning lasting upto 2 h.
Symmetrical proximal muscle weakness lasting shorter than weakness seen in hypoKPP.
In contrast to HypoKPP, generalized flaccid paralysis is uncommon.
People may get paresthesiae and achiness in the muscles prior to development of weakness. Facial and respiratory muscles are usually spared; lid lag (lagging of upper eyelid on downward gaze) may be seen is some cases.
The thigh and calf muscles are often affected and weakness usually progresses to other muscle groups. However weakness can be focal.
During attacks patients are areflexic with normal sensation.
Strength is normal between the attacks. Mild clinical myotonia can be elicited in the face (eyelids), tongue, forearms (finger extensors) and the thenar eminence with percussion or activity.
Some patients develop a fixed proximal muscle weakness (limb-girdle type).
Rarely, bulbar and respiratory muscles are affected.
Sphincter muscles are well preserved during attacks.
Electrical myotonia is found in up to 75% of affected individuals.
It is typically associated with elevated serum K levels, however many individuals may be normokalemic during an attack. Therefore, it is appropriately termed potassium sensitive periodic paralysis.
Although there can be significant overlap in presentation and associated triggers between hyperKPP and hypoKPP, association with fasting and presence of interictal lid lag and eyelid myotonia is specific for hyperKPP.
Diagnostic criteria. The diagnosis of hyperkalemic periodic paralysis type 1 (hyperKPP1) is based on the following findings:
A history of at two or more attacks of flaccid limb weakness (which may also include weakness of the muscles of the eyes, throat, and trunk) and serum K > 4.5 mEq/L
One attack of muscle weakness in the proband, and 1 attack of weakness in first-degree relative with documented serum K >4.5 mEq/L in at least 1 attack.
3 of 6 clinical or laboratory features:
Onset before 3rd decade
Attack duration (muscle weakness involving 1 or more limbs) <2 hours
Positive triggers (exercise, stress)
Myotonia
Positive family history or genetically confirmed skeletal sodium channel mutation
Positive McManis long exercise test.
Exclusion of other causes of hyperkalemia (renal, adrenal, thyroid dysfunction; potassium-sparing diuretics use).
Lab: serum CK are mildly elevated. Sr, K, Na, ECG. During attack there is increased urinary excretion of potassium that can actually result in transient hyperkalemia at the end of an attack.
Genetic test for SCN4A mutation.
Neurophysiology: Routine motor and sensory NCS are normal between attacks of weakness. However, during an attack, the CMAP amplitudes may be reduced in affected muscles. in SET some patients with HyperKPP, depending upon the exact mutation (e.g. T704M) have abnormal increased CMAP amplitudes that persist for a longer period of time than normal individuals. Further, repetition of SET amplifies the increase in CMAP amplitudes. With LET, during the exercise period and immediately afterwards, there is an initial increase in CMAP amplitudes from baseline that is followed by a progressive decline in the amplitudes over the next 40-50 minutes. This is Fournier pattern IV. Needle EMG reveals variable findings. Myotonic discharges are seen in 50-75% of affected individuals, though clinical myotonia is apparent in less than 20% of cases. Examination of the muscles in-between the attacks of weakness reveal an increase in insertional and spontaneous activity, in addition to myotonic discharges. These are not due to denervation but due to hyperexcitability or instability of muscle membrane. Cooling the limb increases the myotonic discharges. Voluntary motor unit potentials may appear myopathic. Motor units may disappear altogether in plegic muscles.
Muscle biopsy may show non-rimmed vacuoles during an attack.
Management of the periodic paralyses is symptomatic and behavioral.
Acute attack:
Inhaled beta agonist 2 puff 0.1 mg have been shown to ameliorate attacks.
During an attack, a patient can be given IV glucose or insulin, inhaled beta agonist, or oral carbohydrates in the ER setting.
Affected individuals learn to avoid precipitating triggers (avoid fasting, strenuous activity and cold).
Avoid fruit juices with high potassium content.
Hyperkalemic periodic paralysis patients should stay away from K rich foods, medications that increase serum K levels, and fasting.
Prophylactic treatment is a chlorothiazide (250-1000 mg/day) diuretic or acetazolamide (125 to 1000 mg/day) to reduce frequency of attacks.
Acetazolamide in adults 125 - 1000 mg/d, and in children 5 - 10 mg/kg/d
Mexiletine may be tried for myotonia. ECG for prolonged QT interval must be performed first.
Notably, episodes can improve with glucose, which is not the case in hypokalemic periodic paralysis, in which glucose loads can provoke an attack.
ATS is a rare ion channel disorder characterized by the clinical triad of periodic paralysis, ventricular arrhythmia and prolonged QT interval and U waves; and skeletal dysmorphic features. Only about 60% of affected individuals have the complete triad, while 80% express two of the three cardinal features. A diagnosis of ATS can be made when an individual exhibits two of these three cardinal features.
It is genetically heterogenous, inherited as an autosomal dominant mutation in potassium inward rectifier gene, KCNJ2, which encodes Kir 2.1 on 17q23 which is responsible for stabilizing the resting membrane potential of skeletal and cardiac muscles. Approximately 60% of all cases have an identified genetic mutation, while the remaining 40% of cases may be denovo and where the cause is unknown. Clinical expression is variable.
Prevalence: 1 in 1,000,000
Mutations in the KCNJ2 gene are identified in approximately 60% of all individuals with the disorder; a genetic mutation is not identified in the remaining 40% of cases where the cause is unknown.
In those with KCNJ2 mutations, hyperkalemic episodes occur in approximately 15% of patients, normokalemic episodes in approximately 20% of patients, and the remainder have hypokalemic episodes of paralysis that are similar to those seen in HypoPP
Attacks can occur in childhood or later (10-20 years of age). A diagnosis of AT can be made if there are 2/3 cardinal features present.
Periodic paralysis
Symptomatic cardiac arrhythmias or ECG evidence of enlarged U-waves, ventricular ectopy or a prolonged QTc or QUc interval in the absence of hypokalemia.
Characteristic facies, dental anomalies, small hands and feet, and at least 2 of the following:
Low-set ears
Widely spaced eyes
Small mandible
Fifth-digit clinodactyly
Syndactyly of toes 2 and 3
One of the above 3 in addition to at least 1 other family member who meets 2 of the 3 criteria.
Typical dysmorphic features include short stature, low-set ears, ocular hypertelorism, broad nasal root and forehead, micrognathia, fifth-digit clinodactyly (abnormally bent or curved finger), and syndactyly (joining) of the second and third toes and scoliosis. Other features less commonly associated are broad forehead, cleft or high-arched palate, short digits, vaginal atresia, cardiac valve abnormalities, and hypoplastic kidney.
Neurocognitive abnormalities may occur characterized by deficits in executive fundtion and abstract reasoning.
Attacks can occur spontaneously, or be triggered by rest following exertion. They vary in durations (hours to days), severity, and frequency ranging from a single lifetime event to daily attacks.
Periodic paralysis in this condition is usually seen in first or second decade of life and can be associated with normal, high, or most commonly low serum potassium levels.
There is no evidence of myotonia or paramyotonia.
LET protocol may help support the diagnosis.
Cardiac arrhythmias consists of bidirectional, polymorphic, and multifocal ventricular tachyarrhythmias, Torsades de Pointes, and PVCs; however SCD is rare.
Muscle bx shows chronic myopathic changes and tubular aggregates.
Evaluations recommended to establish the diagnosis of Andersen-Tawil syndrome
Baseline assessments by a neurologist familiar with PP and a cardiologist familiar with long QTc syndrome.
Syncope in ATS requires cardiology assessment and implantation of PPM or AICD. ATS must be a consideration in all individuals who present with long QT syndrome and episodic weakness.
Assess serum potassium concentrations at baseline and during attacks of weakness.
Obtain 12 lead ECG and perform 24 - hour Holter monitoring.
Check TSH level to ensure no thyroid disease.
Obtain a medical genetics consultation.
Acute attack:
Mild exercise, carbohydrates (if attack is associated with hyperkalemia)
If attacks are associated with hypokalemia, give oral K+ 1 mEq/kg upto 200 mEq/12h+ to normalize
Prophylaxis:
Acetazolamide 125 - 1000 mg/d in adults; 50 - 200 mg/d in children is of therapeutic benefit in reducing and decreasing the severity of the attacks.
Antiarrhyhthmics: Flecainide, beta-blockers or calcium channel blockers.
Yearly ECG and Holter monitor are recommended, as well as consideration for implantable AICD for unexplained syncopal episodes associated with cardiac arrhythmias.
It is a potentially fatal condition.
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:
Baseline assessments by a neurologist familiar with periodic paralyses and a cardiologist familiar with long QT syndrome.
Syncope in patients with Andersen-Tawil syndrome requires a cardiology assessment
Assess serum potassium concentrations at baseline and during attacks of weakness.
Obtain 12-lead ECG and perform 24-hour Holter monitoring
Confirm that serum thyroid stimulating hormone concentration is within normal limits
Obtain a medical genetics consultation.
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.
When interpreting genetic testing it is important to put the results in the clinical context. A known pathological mutation in the typical clinical context is confirmatory
In the absence of an identified genetic mutation in approximately 30% of patients, periodic paralysis subtypes can be distinguished on the basis of clinical presentation, serum potassium levels during attacks, and pattern of abnormalities on long exercise testing.
If primary PP is suspected but cannot be confirmed by genetic testing, further examination should be undertaken to confirm that the symptoms are not secondary to other conditions such as thyrotoxicosis or secondary causes of blood potassium deficiency or excess.
Variants of unknown significance may require testing of additional family members, or further functional testing of the mutation in vitro to fully resolve its significance.
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 K1 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.
Secondary causes of periodic paralysis
Hypokalemic
Thyrotoxic periodic paralysis (KCNJ18) (KCNJ2)
Primary hyperaldosteronism (Conn's syndrome)
RTA (Fanconi syndrome)
Juxtaglomerular apparatus hyperplasia (Bartter syndrome)
Gitleman syndrome
Bartter syndrome
Gastrointestinal potassium wastage
Villous adenoma
Laxative abuse
Pancreatic non-insulin secreting tumors with diarrhea
Nontropical sprue
Barium intoxication
Potassium-depleting diuretics
Amphotericin B
Licorice
Toulene toxicity
Corticosteroids
p-Aminosalicylic acid
Hyperkalemic
Addison disease
Hypoaldosteronism
Excessive potassium supplementation
Potassium sparing diuretics
CKD
Rhabdomyolysis