Periodic Paralysis and Other Channelopathies

Comana M. Cioroiu

Lewis P. Rowland

INTRODUCTION

Muscle channelopathies comprise a heterogeneous group of diseases of skeletal muscle that include both syndromes of episodic weakness (periodic paralyses) and muscle fiber hyperexcitability (nondystrophic myotonias). The clinical phenotype depends on the particular channel mutation involved, and attacks can vary in severity, duration, and constellation of symptomatic triggers (Table 93.1). Most of these disorders are inherited in an autosomal dominant fashion, although sporadic mutations do exist. Changes in neuronal membrane depolarization secondary to various ion channel mutations can either lead to sustained depolarization and resultant overt muscle weakness or to a more mild constant depolarization (or reduced repolarization) leading to myotonia and stiffness. On occasion, there is overlap between the two, and some patients may have episodes of both myotonia and paralysis. There are three main types of periodic paralysis: hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and Andersen-Tawil syndrome (periodic paralysis with cardiac arrhythmia and dysmorphic features). The nondystrophic myotonic disorders are primarily composed of myotonia congenita, paramyotonia congenita, as well as a subgroup of potassium aggravated myotonic disorders. Electrodiagnostic testing is important in helping to identify particular patterns and make a correct diagnosis. Needle electromyogram (EMG) is needed to detect myotonic discharges or other abnormal spontaneous activity. In addition to routine nerve
conduction studies, short and long exercise tests are uniquely used to help characterize specific patterns. In short exercise testing, the patient is asked to exercise a muscle (typically the abductor digiti minimi), and a compound muscle action potential (CMAP) is recorded every 10 seconds thereafter and compared to a baseline. In the long exercise test, the patient is asked to exercise the muscle for an extended amount of time (usually 5 minutes), and CMAPs are recorded every 2 minutes thereafter for about 1 hour and compared to baseline. Changes in CMAP amplitude in both short and long exercise testing can be used to differentiate between the various channelopathies. For instance, CMAP amplitudes typically increase in the periodic paralyses and decrease in the myotonias. Different electrodiagnostic patterns diagnostic of each particular disease were described in 2004 by Emmanuel Fournier and are still used today and are known as Fournier patterns. Targeted confirmatory genetic testing is often done thereafter to confirm the diagnosis. Although patients with these diseases have a normal life expectancy, they may struggle with persistent pain or progressive weakness causing significant functional impairment.

TABLE 93.1 Clinical Features of Hereditary Periodic Paralysis and Nondystrophic Myotonias

	Hypokalemic Periodic Paralysis	Hyperkalemic Periodic Paralysis	Andersen-Tawil Syndrome	Paramyotonia Congenita	Myotonia Congenita
Gene	CACN1AS or SCN4A	SCN4A	KCNJ2	SCN4A	CLCN-1 (AD) or SCN4A (AR)
Age of onset	Usually second or latter part of first decade	First decade	First or second decade	First decade	First decade
Sex	Male preponderance	Equal	Equal	Equal	Male preponderance
Frequency of paralytic episodes	Daily to yearly	Hourly to daily	Daily to yearly	May not be present; otherwise, weekly to monthly	Usually not present, variable frequency in AR form
Degrees of paralysis	Tends to be severe	Tends to be mild but can be severe	Variable	Tends to be mild but can be severe	Lasting seconds to minutes in AR form, usually not present in AD form
Effect of cold	May induce an attack	May induce an attack	May induce an attack	Tends to induce an attack	No effect
Oral potassium	Relieves or prevents an attack	Precipitates an attack	May relieve or prevent an attack	May precipitate an attack	No effect
Myotonia	Absent	May be present	Absent	Present	Present
Precipitants	Carbohydrate-rich food, cold	Fasting, stress, rest after exercise, K-rich foods	Carbohydrate-rich food, rest after exercise	Fasting, stress, cold, rest after exercise	Exercise
Exercise testing	Increase in CMAP with gradual decline with long exercise testing; short exercise testing normal (Fournier V)	Increase in amplitudes with gradual decrease in both short and long exercise testing (Fournier IV)	Unknown	Prominent drop in amplitudes with cooling in both long and short exercise testing; PEMPs present (Fournier I)	AD: drop in amplitude on short exercise testing, less drop with repeated testing AR: drop in amplitude with slow recovery (Fournier II)
AD, autosomal dominant; AR, autosomal recessive; K, potassium; CMAP, compound muscle action potential; PEMP, postexercise myotonic potential. Modified from Hudson AJ. Progressive neurological disorder and myotonia congenita with paramyotonia. Brain. 1963;86:811.

HYPOKALEMIC PERIODIC PARALYSIS

EPIDEMIOLOGY AND PATHOBIOLOGY

Hypokalemic periodic paralysis (hypoKPP) is the most common of the periodic paralyses, yet it is still rare, affecting only about 1.7 per 1,000,000 people in England. Clinical onset is usually within the first 2 years of life (although it may be delayed into the sixth decade) and is more prevalent in men than women in a ratio of about 2:1. Most of these patients have mutations in either the CACN1AS gene (CaV1.1, chromosome 1q31-32) encoding an L-type calcium channel or less commonly, the SCN4A sodium channel gene (NaV1.4, chromosome 17q23). In the presence of these mutations, muscle fibers become depolarized and electrically inexcitable, leading to weakness. Just how these mutations cause persistent depolarization is unknown; however, one mouse model of such a calcium channel mutation proposed a possible explanation via a “gating pore current,” described as an anomalous inward current at the resting potential triggered by low extracellular potassium content, leading to depolarization and sodium channel inactivation. At the structural level, mutations in the calcium channel lead to a vacuolar myopathy, whereas sodium channel mutations are associated with the development of transverse tubular aggregates and less vacuolization.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Patients with hypoKPP typically note transient weakness after a period of rest after exercise. These episodes are often more prominent during sleep or on rising in the morning and are worse after a meal rich in sodium or carbohydrates. The extent of paralysis can be variable and asymmetric and can vary from slight leg weakness to complete flaccid quadriplegia. Bulbar and respiratory muscles are typically spared, but urinary or fecal retention may be seen. The duration of attacks can be variable and last anywhere from a few hours to several days. The interval between attacks may be as long as 1 year, although in some patients, attacks can occur daily. Patients have normal strength in between attacks, but some eventually develop fixed proximal weakness. Attacks may be associated with pain either preceding or following weakness. In a mild attack, tendon reflexes are diminished in proportion to the degree of weakness and are completely absent in a severe attack. Sensation remains normal.

Diagnosis can be made on the basis of the presence of similar attacks of transient weakness in family members. Confirmatory tests include the finding of low potassium content (3.0 mEq/L or less) and high sodium content in the serum during an attack and the ability to induce an attack with an IV infusion of glucose and regular insulin. Serum creatine kinase (CK) levels are typically normal or mildly elevated. Short exercise electrodiagnostic testing is usually normal, but an increase in CMAP amplitude with a delayed decline can be seen with long exercise testing (Fournier pattern V). Needle EMG does not show myotonic discharges. Prior to making a diagnosis of hypoKPP, it is of crucial importance to exclude other conditions than may also lead to periodic paresis and hypokalemia including hyperaldosteronism, diuretic use, gastrointestinal loss, and thyrotoxicosis (Table 93.2). The latter in particular must be considered (particularly in those of Asian ancestry). Also, attacks of hypoKPP have been described in patients with hyperthyroidism linked to the potassium channel β subunit gene KCNE3, which responds completely with treatment of the thyroid disorder.

TREATMENT AND OUTCOME

Acute attacks may be treated safely with oral potassium (20 to 100 mEq), and rarely, IV potassium can be used, although it comes with the risk of subsequent hyperkalemia and cardiac arrhythmias. Prophylaxis of recurrent attacks is usually accomplished with the carbonic anhydrase inhibitor acetazolamide (Diamox) in doses of 250 to 1,000 mg daily. About 50% of patients respond to acetazolamide, and there is a greater benefit in patients with the CACNA1S
calcium mutation than in those with the SCN4A sodium channel mutation. In fact, on occasion, it may worsen attacks in patients with sodium channel mutations. The mechanism whereby it helps attacks of weakness is uncertain but may be related to induction of a mild metabolic acidosis, improved chloride conductance, or activation of the KCa²⁺ channel. Dichlorphenamide, another carbonic anhydrase inhibitor, has also been shown to be efficacious in reducing attacks in both hyper- and hypoKPP. Other agents that may be beneficial include triamterene or spironolactone, which promote retention of potassium. More recently, bumetanide (an Na-K-2Cl inhibitor) has been effective in preventing recurrent attacks of weakness and restoring force in a mouse model of hypoKPP with either a NaV1.4 sodium channel or CaV1.1 calcium channel mutation. Patients are also encouraged to avoid strenuous exercise and meals rich in carbohydrates. In those cases of hypoKPP secondary to a general medical condition (i.e., thyroid disease), the underlying disorder must be treated.

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