Dravet’s syndrome was described first by Charlotte Dravet in 1978 and then in the publication Advances in Epileptology in 1982 [Dravet et al., 1982]. Dravet described a group of children using the name “severe myoclonic epilepsy of infancy” (SMEI). Over time, it became recognized that some children have an incomplete form of the disease, leading to the terminology of “severe myoclonic epilepsy of infancy – borderline.”

These children classically begin to have seizures in the first year of life, typically in the setting of fever and usually characterized by prolonged seizures with hemiconvulsions. The laterality of seizures can alternate with each individual seizure and often evolve into status epilepticus. In the second year of life, other seizure types may begin to emerge, including absence, myoclonic, and generalized tonic–clonic seizures, as well as partial seizures typically occurring without fever. Tonic seizures are rare and, if they do occur, tend to be brief and nocturnal. Myoclonus can be either generalized, focal, or both. Photo-induced seizures occur in some of these children and self-induced seizures have been reported. Throughout childhood, fever continues to be a common provoker of seizures and these seizures are often very difficult to control.

An interesting feature of Dravet’s syndrome is the presence of “obtundation status.” This involves episodes of nonconvulsive status with intermixed myoclonus, at times building up to rhythmic bilateral jerking resembling a generalized clonic seizure. The duration can be hours to days, with slowed responsiveness or waxing and waning alertness. The electroencephalogram (EEG) will often demonstrate diffuse delta activity with intermixed focal and diffuse spikes. Myoclonus may not correlate with spike discharges, except with larger more generalized rhythmic myoclonic jerks. Hospitalization may be required for effective treatment. Some children may have several characteristics of localization-related epilepsy and occasionally have undergone surgical treatment of seizures before the syndrome has been identified.

Development is universally normal in the first year of life. As seizure types become more varied and more frequent, there is often developmental regression or cessation of developmental progress. Severe mental retardation is present in many children with Dravet’s syndrome, but the degree of cognitive impairment is associated with seizure control in many patients [Wolff et al., 2006]. Behavioral issues seem to become more of a concern after age 2. Hyperactivity and autistic traits can be present and very prominent. As children enter into adolescence, hyperkinetic behavior tends to improve and is replaced with overall slowed behavior. Ataxia may also become prominent.

Not all children with Dravet’s syndrome present with what are now considered the classical features, as described above. Some children may not have all of the varied seizure types and have little developmental regression. Myoclonic seizures need not be present for a diagnosis to be made. These seemingly less affected children continue to be exquisitely sensitive to seizure exacerbation due to elevated body temperature, as well as to anticonvulsants that are sodium channel blockers (e.g., carbamazepine, phenytoin, fosphenytoin, oxcarbazepine, lamotrigine, and zonisamide). In some cases these features may suggest the diagnosis. Recently, this syndrome was recognized in a large percentage of children (11 of 14) presenting with seizures and encephalopathy after receiving vaccines (vaccine encephalopathy) [Berkovic et al., 2006]. Logically, it would seem that, for many children, their first fever likely occurs with the first or second set of immunizations. A child was reported to have “hemiconvulsion-hemiplegia syndrome” after a prolonged episode of hemiconvulsion, and subsequently was identified to have the genetic mutation associated with Dravet’s syndrome [Sakakibara et al., 2009].

Since gene testing has become available for this syndrome, it appears that the phenotype is broader than initially appreciated. The diagnosis of severe myoclonic epilepsy of infancy no longer seems to be an appropriate label; therefore the eponym “Dravet’s syndrome” is now the preferred name, encompassing both groups of children. As more children are found to have a similar gene mutation, the true phenotype of this syndrome will likely evolve.

Genetics/Pathophysiology

Mutations in a sodium channel, SCN1A, were initially identified in 7 of 7 children with severe myoclonic infantile epilepsy [Claes et al., 2001]. Approximately 80 percent of children with a clinical diagnosis of Dravet’s syndrome have a mutation in this gene. This channel was initially implicated in generalized epilepsy with febrile seizures plus (GEFS+; see below). The sensitivity to body temperature in both of these syndromes led investigators to evaluate for mutations in the SMEI population. The majority of the children with Dravet’s syndrome have a de novo mutation, although some of the families have a higher than expected history of febrile seizures. The phenotype of patients can be predicted by mutation in most cases, as the majority of patients have a truncation mutation or a mutation that affects the function of the channel pore. Patients with less severe phenotypes often have point mutations that do not result in as severe an effect on the function of the sodium channel, although the correlation of specific SCN1A mutation to phenotype is not a tight one.

Recent discoveries related to the cell type-specific localization of SCN1A added to our understanding of how loss of function of a sodium channel, logically a cause of hypoexcitablity of individual neurons, could lead to network hyperexcitabilty and, consequently, seizures. This seeming contradiction can be explained by the finding that the loss of SCN1A function leads to selective loss of sodium channel function in inhibitory interneurons [Yu et al., 2006], causing inhibitory dysfunction and secondary hyperexcitability.

Clinical Laboratory Tests

EEG findings are typically normal in the first year of life, but evolve to demonstrate generalized and multifocal abnormalities. A photoconvulsive response can be seen, and diffuse background slowing can become more prominent as children age. No characteristic pattern is diagnostic of Dravet’s syndrome, as is seen in Lennox–Gastaut or Doose’s syndrome; in fact, there can be some overlap between these syndromes and Dravet’s syndrome, making accurate diagnosis challenging. EEG findings can fluctuate, and a small percentage of patients may continue to have normal EEGs; over time, a decrease in epileptiform abnormalities has been reported in older patients.

Magnetic resonance imaging (MRI) in patients with Dravet’s syndrome is usually without any focal abnormalities. In one study that evaluated 58 children with Dravet’s syndrome, 60 percent had SCN1a mutations and 22 percent had abnormal MRI findings, the majority with cortical atrophy and others with cerebellar atrophy, white matter hyperintensity, mesial temporal sclerosis, and focal cortical dysplasia. Abnormal findings were more likely in patients without a genetic mutation [Striano et al., 2007]. Other studies have suggested that mild, diffuse atrophy and ventriculomegaly may develop over time.

Genetic testing is appropriate in patients suspected to have Dravet’s syndrome. Early diagnosis may avoid extensive and expensive metabolic testing and inadvertent exacerbation of seizures by certain medications, as well as providing prognostic information for the family. However, as the phenotype expands, using genotype to provide an accurate prognosis may become more problematic.

Treatment

Seizure control is the primary treatment goal in this disorder. Medications that are known to block the sodium channel often will exacerbate seizures and should be avoided [Guerrini et al., 1998]. Prior to clinical diagnosis, a worsening of seizures while being treated with one of these medications should raise suspicion of Dravet’s syndrome. Topiramate, valproic acid, benzodiazepines, and levetiracetam have been helpful. Nonpharmacologic treatments, such as vagal nerve stimulation or the ketogenic diet [Caraballo and Fejeman, 2006], have been useful in some patients. Combination therapy with stiripentol, clobazam, and either depakote or topiramate has been reported to be more effective than other combinations of medication. In an initial report by Chiron et al., 15 of 21 patients responded to stiripentol [Chiron et al., 2000]. Acetazolamide has not been shown to be beneficial. A recent report with the calcium channel blocker, verapamil, has suggested that this may be helpful, but more research is required [Iannetti et al., 2009].

Avoidance of hot temperatures, both environmental and elevated body temperature, has been used by many families to reduce seizures. Antipyretics, such as acetaminophen, have been helpful, although there is a recent report of four children with transient liver abnormalities that may be associated with use of this medication [Nicolai et al., 2008]. Helmets may be indicated in some patients. Due to the severity of the cognitive impairment, appropriate support must be initiated for the family [Nolan et al., 2008]. Medications for behavioral issues may also be necessary (see Chapter 49).

Generalized Epilepsy with Febrile Seizures Plus (GEFS+)

Clinical Features

This is a familial epilepsy syndrome characterized by febrile seizures in childhood in several generations of family members, often with continuation of febrile seizures into adulthood. Some seizures related to fever may be prolonged. Some family members may also have generalized epilepsies, such as absence epilepsy, myoclonic astatic epilepsy, or, rarely, Dravet’s syndrome. Seizure types include generalized tonic clonic, myoclonic, absence, and atonic seizures. There is variable penetrance of seizures in these familial cohorts. Phenotype also varies among family members. Many family members may have resolution of seizures by age 12. The majority of these patients have normal development and intelligence. There has also been a report of temporal lobe epilepsy with mesial temporal sclerosis associated with the SCN1A mutation [Mantegazza et al., 2005].

Genetics/Pathophysiology

SCN1B was a mutation first reported in a large family with this syndrome [Wallace et al., 1998]. Mutations in other sodium channels – SCN1A [Escayg et al., 2000a] and SCN2A [Sugawara et al., 2001] – have been found subsequently. The majority of these mutations have been point mutations. In patients with SCN1A mutations, a difference in phenotype from GEFS+ and Dravet’s syndrome can often be predicted, given the location of the mutation (distance from the pore), as well as alteration in transcription of the gene. Nonsense and truncation mutations are more likely to be associated with Dravet’s syndrome. Sodium channel mutations do not account for all of the mutations in GEFS+; there also have been reports of mutations identified in GABA_A receptor subunit genes,GABRG2 and GABRD (gamma 2 and delta subunits) [Harkin et al., 2002]. GABA_A receptors are ligand-gated chloride channels that provide the majority of inhibition in brain beyond the neonatal period, and mutations resulting in GABA_A receptor dysfunction result in increased central nervous system excitability that has been associated with a number of genetic epilepsies.

Treatment

There has been little published discussion of the treatment of these syndromes. For patients with sodium channel mutations, avoidance of sodium channel blockers is wise. Treatment when necessary with broad-spectrum anticonvulsants is thought to be useful. Avoidance of temperature changes and routine use of fever control measures may be of some benefit.

Benign Familial Neonatal Seizures

Clinical Features

Benign familial neonatal seizures are an autosomal-dominant epilepsy presenting with seizures in the first or second week of life, most commonly starting on day of life 2 or 3, resolving within weeks to months. Most seizures have stopped at 4–5 months of life. Seizures are usually multifocal clonic seizures or focal seizures. The feature suggesting this entity is the presence of similar seizures in parents and first-degree relatives, occurring at the same age. Development is characteristically normal during this time period, as well as after seizures stop. Fifteen percent of children will develop epilepsy later in life, usually in childhood or as a young adult. There are some children who progress to medically refractory epilepsy with encephalopathy [Steinlein et al., 2007].

Genetics/Pathophysiology

Mutations in potassium channels KCNQ2 [Singh et al., 1998; Biervert et al., 1998] and KCNQ3 [Charlier et al., 1998] (found on chromosomes 20 and 8 respectively) have been reported in families with benign neonatal seizures. These mutations also have been reported in some families with benign rolandic epilepsy [Hahn and Neubauer, 2009]. Recently, mutations in these genes also have been reported in a small percentage of patients with idiopathic generalized epilepsy, suggesting it may play some role in the etiology of these epilepsies. Mutations can cause alteration in function or complete loss of function of the potassium channel. Approximately 50 percent of mutations lead to shortening of expressed protein [Heron et al., 2007]. The age specificity of the seizures in this disorder is thought to emanate from brain developmental changes during the neonatal period. GABA, which acts as an inhibitory neurotransmitter later in life, can be excitatory in the early neonatal period due to developmental changes in the chloride gradient that result in opening of GABA_A receptor chloride channels, producing membrane depolarization in early development rather than membrane hyperpolarization, as it does in mature neurons. In contrast, opening of potassium channels is hyperpolarizing throughout development, and due to the paucity of GABAergic inhibition, potassium channel-mediated inhibition is uniquely critical in the newborn. This may explain why impairment or absence of potassium channel inhibition results in seizures specifically at this time and why only a small fraction of patients with KCNQ2/3 mutations have seizures later in life.

Clinical Laboratory Tests

EEG generally demonstrates normal interictal features, although at the time of seizure there is an electrographic correlate. MRI is expected to be normal. Other causes of seizures, such as neonatal infection and metabolic abnormalities, should be excluded.

Developmental Delay, Epilepsy and Neonatal Diabetes (DEND)

This is a rare syndrome, presenting with neonatal diabetes, developmental delay, seizures and mild dysmorphic features, which has been associated with a mutation in the KCNJ11 gene that encodes for a subunit of the adenosine triphosphate (ATP)-sensitive potassium channel. This channel is found on pancreatic islet cells, as well as neurons, and neonates with this disorder usually present with diabetes and subsequently develop seizures and global developmental delay [Gloyn et al., 2004]. Dysmorphic features, including downturned mouth, bilateral ptosis, prominent metopic suture, and contractures, have also been described [Gloyn et al., 2004]. There have been reports of infantile spasms in some of these children [Bahi-Buisson et al., 2007], as well as others with tonic-clonic and myoclonic seizures. Seizures have been very refractory to traditional antiepileptic medications. In contrast, patients are very responsive to treatment with sulfonylurea medications such as glibenclamide, leading to improvement in diabetes as well as developmental outcomes and seizures.

Other “Idiopathic” Epilepsies

Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy

Autosomal-dominant nocturnal frontal lobe epilepsy is a familial epilepsy characterized by frontal lobe seizures that typically occur at night and usually present as arousal from sleep with bizarre hypermotor behaviors, such as spinning, thrashing and rocking. Seizures can occur several times per night. Nicotinic receptor mutations have been found in many of these familial cohorts [Steinlein et al., 1995], although there are several families for which no gene mutation has been identified. These ligand-gated receptors allow sodium and potassium to cross the cell membrane. Many patients are responsive to carbamazepine and phenytoin.

Benign Familial Infantile–Neonatal Seizures

Benign familial infantile–neonatal seizures is an epilepsy syndrome that has been described as being similar to benign neonatal seizures but occurs at a slightly older age. Mutations have been found in a sodium channel, SCN2A1, in some cohorts [Herlenius et al., 2007].

Childhood Absence Epilepsy

Childhood absence epilepsy has been linked to mutations in GABA receptors (GABRA1 and GABRG2) [Baulac et al., 2001; Wallace et al., 2001] and chloride channels (CLCN2). Mutations have also been described in a calcium channel, CACNA1H, but this mutation may represent an ethnic variant present in Chinese Han patients, as these findings were not present in a large European cohort [Chen et al., 2003]. The families with CLCN2 also had members with generalized tonic-clonic seizures on awakening and juvenile myoclonic epilepsy [Baykan et al., 2004].

Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy is a seizure disorder that usually presents in adolescents with myoclonic seizures that are more likely to occur in the early morning after awakening, as well as generalized tonic-clonic seizures that also tend to occur in the morning hours. Several gene mutations have been found in these patients, although the majority of patients have yet to have an underlying etiology determined. It appears that, similar to childhood absence epilepsy, this is likely a polygenic disorder. Channels that have been identified include GABA receptors (GABRA1 and GABRD) [Cossette et al., 2002], calcium channels (CACNB4) [Escayg et al., 2000b], and chloride channels (CLCN2) [Baykan et al., 2004]. In addition, a gene that is not a direct channel gene but enhances calcium influx into the cell and can stimulate programmed cell death (EFHC1) [Suzuki et al., 2004] has also been identified as being involved in this epilepsy syndrome.

Familial Pain Syndromes

Several pain syndromes have been associated with sodium channel mutations. This is not surprising, as sodium channels are located on spinal sensory neurons in the dorsal root ganglion.

Clinical Features

Genetics/Pathophysiology

Mutations in SCN9A, a sodium channel, have been associated with IEM and PEPD. Mutations are thought to lead to hyperexcitability of the sodium channel. Mutations in IEM allow the channel to be activated by smaller than normal depolarizations and the channel remains open longer, once activated. Familial cohorts with IEM have demonstrated mutations in this channel [Drenth et al., 2005], although a study looking at a more heterogeneous population with IEM only found 1 of 15 patients with a mutation [Drenth et al., 2005], suggesting that other factors might also be involved in this disease. Mutations in PEPD lead to prolonged action potentials and repetitive neuronal firing when stimulated [Jarecki et al., 2008]. Mutations in this same channel that lead to loss of function are associated with congenital indifference to pain [Goldberg et al., 2007; Nilsen et al., 2009]. It remains unclear why different mutations lead to different phenotypes and different pain syndromes.

Treatment

Treatment for IEM, including use of sodium channel blockers, has not been very effective, although there have been reports of some relief with lidocaine, mexiletine [Choi et al., 2009], and carbamazepine [Fischer et al., 2009]. Response to medications may vary with different mutations. Carbamazepine has been helpful in treating PEPD, but topiramate and gabapentin have not.

Congenital indifference to pain does not have a specific treatment, but patients need to be observed carefully for occult injuries, including fracture, joint injuries, and burns, as well as mouth and hand injuries. Establishing a daily routine to monitor for injuries is important.

Migraine and Ataxia Syndromes

Familial Hemiplegic Migraines

Clinical Features

Familial hemiplegic migraine often presents in the first or second decade of life with severe headache, often unilateral, and is associated with unilateral weakness that can last up to 24 hours, or rarely several days. Coma has been reported in a small number of patients. Some patients can have a less impressive clinical presentation with unilateral paresthesias and hemianopsia. Rarely, seizures can occur during hemiplegia. In some patients, ataxia and dysarthria can be seen between attacks, or for a short duration while recovering from an attack. Family members also have been reported with benign paroxysmal torticollis of infancy [Giffin et al., 2002], although this is rare and it is unclear whether this is or is not related to the gene mutation.

Headaches can at times have features of basilar migraine, including vertigo, visual symptoms, tinnitus, dysarthria, and ataxia. Some patients have been reported to have progressive ataxia later in life [Terwindt et al., 1998]. In addition, cognitive impairment has been noted in affected patients [Marchioni et al., 1995].

At times, hemiplegic migraines have been reported after minor head trauma and can be associated with the occurrence of delayed cerebral edema. There may initially be a lucid period that is followed by the development of focal or diffuse cerebral edema, observed with neuroimaging, along with symptoms of encephalopathy, coma, and occasionally seizures. Rarely, this syndrome can result in death.

Genetics/Pathophysiology

Many patients with familial hemiplegic migraine have a calcium channel mutation (CACNA1A) [Stam et al., 2008]; if this is present, patients seem to be more likely to have ataxia and coma, and to be more prone to delayed cerebral edema after minor head injury [Terwindt et al., 1998; Kors et al., 2001; Stam et al., 2009]. Mutations in CACNA1A also have been reported in patients with alternating hemiplegia of childhood, which phenotypically has some overlap with hemiplegic migraine [de Vries et al., 2008], as well as in patients with episodic ataxia type 2 (see below) and spinocerebellar ataxia type 6. Mutations in SCN1A and in ATP1A2 also have been found in some patients with this clinical syndrome [De Fusco et al., 2003; Dichgans et al., 2005a]. Interestingly, febrile seizures also have been reported in patients with mutations in either SCN1A or ATP1A2 [de Vries et al., 2009; De Fusco et al., 2003].

Clinical Laboratory Tests

MRI findings are not pathognomonic, but cerebellar atrophy [Terwindt et al., 1998], particularly in the superior cerebellar vermis, has occasionally been reported. MR spectroscopy of this region demonstrated metabolic abnormalities consistent with neuron loss [Dichgans et al., 2005b]. EEG during events can demonstrate slowing in the affected hemisphere, and mild asymmetries with minimal unilateral slowing have been noted on EEGs performed between episodes [Marchioni et al., 1995].

Treatment

Most commonly, patients are treated with acetazolamide, calcium channel blockers, such as verapamil, or a trial of other standard migraine prophylactic drugs (tricyclic antidepressants, beta blockers). Limited correlation exists between drug response and hemiplegic migraine type.

Episodic Ataxia

Clinical Features

This disorder is characterized by intermittent periods of ataxia, (also see Chapter 67). There are two commonly described disorders: episodic ataxia type 1 and type 2. They differ slightly from one another in clinical presentation, allowing clinical separation.

Type 1 has frequent, brief episodes of ataxia, involving ataxic gait and slurred speech, that can be precipitated by strong emotional outbursts, sudden movements, and exercise. Episodes can last several seconds to minutes in duration and typically occur several times a day. In addition, there usually is evidence of muscle hyperexcitability manifested by the presence of myokymia clinically and electrographically. Some family members have reported seizures and isolated myotonia.

Episodic ataxia type 2 involves primarily truncal ataxia, with more prolonged periods of ataxia lasting hours to days. Eye movement abnormalities are sometimes present. Episodes can be induced by stress or exercise. Myokymia is not often present. Some patients can have slowly progressive cerebellar features that are often very subtle. Cerebellar atrophy also has been reported. Migraine symptoms can be present in both types of episodic ataxia but are more common in type 2; they may have many features consistent with basilar migraine, including vertigo, nausea, and occipital pain.

Genetics/Pathophysiology

Both disorders are inherited in an autosomal-dominant fashion, although penetrance is not always complete. Ion channel abnormalities also have been found in both disorders. Type 1 has been associated with point mutations in KCNA1, located on chromosome 12 [Browne et al., 1994]. This is a potassium channel that has no intervening introns. Episodic ataxia type 2 has been linked to mutations in CACNA1A (a calcium channel). Mutations that interfere with splicing or lead to a premature stop have been linked to the episodic ataxia type 2 phenotype [van den Maagdenberg et al., 2002]. This appears to lead to loss of function of the calcium channel. Familial hemiplegic migraine (see above) and spinocerebellar ataxia type 6 (see below) also have been reported to have mutations in this gene.

Clinical Laboratory Tests

Electromyography (EMG) is helpful with episodic ataxia type 1 in identifying and/or confirming myokymia. MRI also maybe useful, especially in episodic ataxia type 2, and should be performed to rule out other underlying etiologies of ataxia.

Treatment

Acetazolamide and carbamazepine have both been reported to lead to reduction and severity of events.

Spinocerebellar Ataxia

Clinical Features

Several progressive ataxias have been described and reported as due to a variety of etiologies (see Chapter 67). Channelopathies are responsible for one subtype, now called spinocerebellar ataxia type 6. This presents as a slowly progressive cerebellar degeneration with ataxia, dysmetria, and other cerebellar signs as a prominent clinical feature. Spasticity and cranial neuropathies are not prominent. There can be some overlap with episodic ataxia type 2, with episodes of truncal ataxia lasting for several hours to days and often precipitated by stress or exertion. There also may be some features associated with basilar migraine or familial hemiplegic migraine.

Genetics/Pathophysiology

Spinocerebellar ataxia type 6 has been reported to be associated with triplet repeats in the CACNA1A gene [Zhuchenko et al., 1997]. Unlike the gene changes associated with other triplet repeat disorders, this one seems relatively stable and is a smaller expansion than that typically seen in association with an abnormal phenotype. It is unclear if symptoms are related to channel dysfunction or the cytotoxic effects of the repeat, as is seen in other diseases. The overlap between these phenotypes suggests that there is a pathological role in the abnormal function of the calcium channel. Mutations in this gene also have been reported in cohorts with familial hemiplegic migraine – which usually have point mutations. Cohorts with episodic ataxia type 2 also have been reported to have mutations in this gene that often lead to splicing errors or premature stops.

Clinical Laboratory Tests

MRI is helpful, as many symptomatic episodic ataxia patients will have cerebellar atrophy.

Treatment

Supportive treatment is recommended. Patients with episodes of headaches may be helped by the treatments outlined for the episodic ataxias and familial migraine syndromes.

Muscle Channelopathies

Contraction in skeletal muscle occurs by generating and propagating action potentials. The release of intracellular calcium stores triggers mechanical contraction. This process is dependent on proper functioning of ion channels. Mutations in muscle ion channel genes have been identified, which cause a variety of diseases collectively called muscle channelopathies. Voltage-gated ion channels share similar structural features. The ion-conducting pores are selective for a specific ion. Mutations in muscle channel genes cause changes in channel function that alter membrane excitability and cause neuromuscular symptoms. Understanding the pathophysiological mechanisms involved in these diseases is an on-going focus of many studies. Clinical symptoms and their underlying neurophysiology are being linked with abnormal muscle membrane function. The overall incidence of muscle channelopathies is estimated at 1 in 100,000 [Meola et al., 2009].

Skeletal muscle disorders associated with ion channelopathies produce symptoms of myotonia, weakness, or both [Hudson et al., 1995]. Table 42-1 summarizes the various disorders (see also Chapter 96).

Table 42-1 Muscle Channelopathies

Myotonia Congenita

Myotonia congenita is a chloride channel disorder. Both dominant and recessive forms of this channelopathy exist. Thomsen’s disease is autosomal-dominant, while Becker’s disease is autosomal-recessive. Both have myotonia as the primary symptom.

Clinical Features

Symptoms of painless generalized myotonia develop in the first or second decade of life in myotonia congenita. Characteristics of this disorder include a “warm-up phenomenon” in which repeated muscle movements relieve the myotonia and stiffness that occur with sudden physical exercise after a period of rest. A similar response is seen in individuals with myotonic dystrophy. In contrast, some sodium channel myotonias demonstrate increasing stiffness with repetitive movement, which is a paramyotonic response.

In both dominant and recessive forms of myotonia congenita, prominent muscle hypertrophy occurs and is most notable in the legs. Grip and eyelid closure myotonia is noted. Lid lag may be present. Strength, muscle stretch reflexes, and cerebellar and sensory testing are normal. The warm-up phenomenon can be demonstrated during the examination by having the patient sit or recline for 10 minutes, then attempt to stand, run, or walk suddenly.

Patients with Becker’s or autosomal-recessive myotonia congenita may have transient muscle weakness on initiation of movement after a period of rest or quiescence. Muscle strength normalizes after several muscle contractions. Both forms of myotonia congenita are more severe in men than women [Platt and Griggs, 2009].

Genetics

The point mutation for the skeletal muscle chloride channel is located on chromosome 7q35 [Koch et al., 1992]. Both recessive and dominant forms are due to mutations in the voltage-gated chloride channel gene (CLCN1).

Pathophysiology

In normal skeletal muscle, a nerve stimulus causes depolarization of the sarcolemma, propagating an action potential that results in muscle contraction, followed by relaxation. Increased excitability of the muscle fibers in myotonia results in a single nerve stimulus causing repetitive action potentials. Skeletal muscle has a high chloride conductance, which accounts for up to 85 percent of resting membrane conductance [Bryant and Morales-Aguilera, 1971]. In myotonia congenita, reduced sarcolemmal chloride conductance causes enhanced excitability of the muscle cells, resulting in myotonic discharges [Lipicky et al., 1971].

Clinical Laboratory Tests

Myotonia congenita is usually diagnosed clinically. The presence of repetitive discharges on EMG, both on insertion as well as with voluntary contraction, can be used for conformation. Muscle biopsy is unnecessary.

In patients suspected of having myotonia congenita, other myotonic disorders should be considered, including myotonic dystrophy, paramyotonia congenita, and periodic paralyses.

Treatment

Medications used to treat myotonia are acetazolamide, mexiletine, procainamide, quinine, phenytoin, carbamazepine, and dantrolene. Exercise may temporarily relieve the muscle stiffness.

Sodium Channel Disorders

Paramyotonia Congenita (Eulenberg’s Disease)

Paramyotonia congenita is a syndrome consisting of episodic paralysis and myotonia that is triggered by cold and exercise. As opposed to the warm-up phenomenon seen in patients with myotonia congenita, paradoxical myotonia that quickly worsens with exercise can be demonstrated. Facial muscles (particularly eyelids), pharyngeal muscles, and hand muscles are particularly involved. The legs are more mildly affected [Miller et al., 2004]. Myotonia may be present for a brief time, but weakness may persist for hours. Muscle hypertrophy is present in about 30 percent of patients [Matthews et al., 2008]. Paramyotonia congenita is present from infancy and symptoms manifest within the first decade of life.

Genetics

Paramyotonia congenita is caused by a mutation of the SCN4A gene, with exons 22 and 24 being active areas of interest [Matthews et al., 2008].

Pathophysiology

Episodes of weakness experienced by individuals with paramyotonia congenita are caused by intermittent loss of fiber excitability. This is due to persistent depolarization of the membrane resting potential, as sodium channels do not inactivate completely, resulting in a persistent influx of sodium current [Cannon, 2006].

Clinical laboratory tests

Muscle biopsy is rarely necessary, but shows an absence of type 2B fibers. Clinical electrophysiology may be useful as the compound muscle action potential (CMAP) will show a gradual and prolonged decrement after exercise. With repeated exercise testing and muscle cooling, the decrement is exacerbated [Fournier et al., 2006].

Treatment

Counseling regarding decreased exposure to cold and strenuous exercise as precipitants for myotonia is recommended. If symptoms are mild, no further treatment may be necessary. In patients with more severe disease, the medications previously listed for myotonia may be used.

Hyperkalemic Periodic Paralysis

Hyperkalemic periodic paralysis shares features with paramyotonia congenita. The disorder can occur at any age, but may appear in infancy. The frequency of attacks increases during adolescence, and decreases after the fourth decade [Miller et al., 2004]. Mild myotonia of the eyelids and finger extensors may be noted on examination between attacks. Myotonia may be cold-induced but is not exacerbated by exercise [Subramony et al., 1986], which distinguishes it from paramyotonia congenita. Moderate exercise may trigger attacks of flaccid muscle weakness, which may be brief or last for several hours. Attacks also may be precipitated or made worse by eating foods containing high potassium, exposure to cold, rest after moderate exercise, glucocorticoids, or emotional stress [Lehmann-Horn et al., 2004]. Permanent weakness may develop in older individuals [Bradley et al., 1990]. Before confirming a diagnosis of hyperkalemic periodic paralysis, other causes of potassium elevation should be excluded. Adrenal insufficiency, rhabdomyolysis, hypoaldosteronism, or medications such as angiotensin-converting enzyme inhibitors should be ruled out.

Genetics

Between 60 and 70 percent of patients have a mutation in the SCN4A gene on chromosome 17, which encodes skeletal muscle voltage-gated sodium channels [Fontaine et al., 1990]. Genetic testing should focus on the common sites of mutations (T704M and M1592V) in the SCN4A gene. It has also been confirmed that hyperkalemic periodic paralysis and paramyotonia congenita are allelic disorders [Ptacek et al., 1991]. These are inherited in autosomal-dominant fashion.

Pathophysiology

Abnormal inactivation of voltage-gated sodium channels causes membrane depolarization. The abnormal sodium channel gating creates a gain of function, resulting in increased sodium current that depolarizes affected muscle and leads to weakness [Venance et al., 2006].

Clinical Laboratory Tests

Serum potassium elevation by 1.5–3 mmol/L during an attack and electrocardiogram changes (peaked T waves) confirm the diagnosis. Myotonia is detectable on EMG in approximately 50 percent of patients [Lehmann-Horn et al., 2004] and supports the diagnosis. Muscle biopsy in patients with periodic paralysis may exhibit vacuoles and tubular aggregates.

Treatment

Carbohydrate-rich meals, ongoing mild exercise, avoidance of potassium-rich foods, and exposure to cold may prevent or mitigate attacks. For frequent attacks, use of acetazolamide or thiazide diuretics may be beneficial. Glucose and insulin therapy may be required to treat an acute attack.

Potassium-Aggravated Myotonias

There are several other myotonic disorders, all associated with allelic point mutations in the gene encoding SCN4A. All are characterized by stiffness following ingestion of potassium or strenuous exercise. All share the absence of sensitivity to cold. Myotonia fluctuans is a mild form of myotonia precipitated by rest and resolved with continued exercise. The onset of myotonia is delayed for 10 or more minutes after exercise. Pain sometimes accompanies the myotonia, but muscle weakness is not a feature [Heine et al., 1993]. Acetazolamide-responsive myotonia (atypical myotonia congenita) is a painful myotonia precipitated by exercise and is insensitive to cold [Ptacek et al., 1994a]. Myotonia permanens is a very severe disorder, with EMG showing continuous myotonic activity. As a result, generalized muscle hypertrophy is noted, as well as serum creatine kinase elevation.

Calcium Channel Disorders

Hypokalemic periodic paralysis, the most frequent cause of periodic paralysis, is an autosomal-dominant disorder. Two different forms exist: a myopathic form and a paralytic form. The pure paralytic form is the most common and is present in 60 percent of cases. The onset of symptoms is between 5 and 16 years of age. Attacks are often precipitated by carbohydrate-rich meals or by exercise followed by a period of rest. As a consequence, many patients have attacks early in the morning. Exposure to cold may also be an inciting event. Most attacks last between 4 and 6 hours, but may be longer. Some patients will experience proximal weakness; some have a more diffuse paralysis. Extraocular and respiratory muscles are not involved. Recurrent attacks typically wane over 30 years. The myopathic form is seen in approximately 25 percent of cases. Progressive fixed weakness develops in the legs. This weakness may occur in the absence of paralytic symptoms.

A positive family history and the characteristics of paralysis render a clinical diagnosis. During an attack, potassium concentrations may be as low as 1.5 mmol/L, but may also be only slightly below normal values. Electrocardiogram changes of bradycardia, prolonged PR and QT intervals, and flattened T waves are present. Secondary causes of hypokalemia, such as renal or gastrointestinal potassium wasting, or use of medications such as thiazide, should be excluded prior to diagnosing this condition.

Genetics

Mutations in the CACNA1S gene account for about 70 percent of cases of hypokalemic periodic paralysis [Ptacek et al., 1994b]. CACNA1S codes for the dihydropyridine receptor. The gene maps to chromosome 1q31–32. About 12 percent of patients have a mutation in the SCN4A gene [Jurkat-Rott et al., 2000]. There may be further gene heterogeneity to account for other patients who do not test positive for either of these mutations.

Pathophysiology

In hypokalemic periodic paralysis, the mechanism for depolarization-induced attacks of weakness is not well characterized. A loss of function leading to reduced current density and slower activation is a result of calcium channel mutations. There are also sodium channel mutations that enhance inactivation, producing a net loss of function defect as well [Venance et al., 2006].

Clinical Laboratory Tests

Vacuolar myopathy, centralization of nuclei, and fiber type disproportion are noted on histopathology in biopsies from patients with the myopathic form of hypokalemic periodic paralysis. EMG does not show evidence of myotonia.

Treatment

In patients with normal renal function, oral potassium chloride is the treatment of choice. A low-sodium diet and chronic potassium supplementation may help to prevent attacks. Acetazolamide may also be beneficial [Links et al., 1988].

Andersen–Tawil Syndrome

Andersen–Tawil syndrome is characterized by periodic paralysis, cardiac ventricular ectopy, and skeletal abnormalities [Tawil et al., 1994]. It was first described in 1971 [Andersen et al., 1971]. Clinical symptoms of intermittent weakness begin in the first or second decade. Episodes can be triggered by prolonged rest or rest following exertion. Proximal weakness may develop and be permanent. Potassium may be elevated, normal, or reduced during attacks, and levels do not correlate well with the frequency or severity of weakness. ECG abnormalities include prolonged QT interval, prominent U waves, premature ventricular contractions, ventricular bigeminy, and polymorphic ventricular tachycardia. Patients with ventricular ectopy may be asymptomatic, or may present with palpitations, syncope, or cardiac arrest [Tristani-Firouzi et al., 2002]. The physical phenotype includes small mandible, hypertelorism, low-set ears, clinodactyly, syndactyly, and a broad nasal bridge [Donaldson et al., 2004]. The disorder is autosomal-dominant and maps to chromosome 17q23, which includes the KCNJ2 gene that encodes the kir2.1 potassium channel receptor.