Paroxysmal movement disorders are defined as abnormal involuntary movements that are intermittent or episodic in nature, with sudden onset and variable duration, and with no change in consciousness (1). The episodic involuntary movements may be dystonia, chorea, ballismus, or a complex combination of these, hence referred to as paroxysmal dyskinesias (PxDs) (1). Although prevalence estimates are unclear, these are deemed to be rare disorders (1). For example, Blakeley and Jankovic identified only 92 cases among 12,063 patients (0.76%) seen over 19 years (2). PxDs can be inherited or acquired, and can also be a feature of more complex chronic neurologic disorders (1,2). However, PxDs manifesting as isolated symptoms in patients, whose neurologic examination between episodes is typically normal, has always constituted the core of this group of conditions.
The current widely accepted clinical classification of PxDs is by Demirkiran and Jankovic (3). Following earlier allocations focusing on the duration of attacks (4), the classification of PxDs by Demirkiran and Jankovic is mainly based on the difference of precipitating factors and recognizes three subtypes comprising paroxysmal kinesigenic (PKD), nonkinesigenic (PNKD), and exercise-induced (PED) dyskinesias (3). A fourth form of paroxysmal disorder, referred to as hypnogenic paroxysmal dyskinesia (HPD), was initially included into the PxDs classification (3). However, it has become clear that HPD was a form of frontal lobe epilepsy termed “Autosomal Dominant Nocturnal Frontal lobe Epilepsy” (ADNFE) (5), and as such, this condition should not be any more classified into the PxDs and will not be discussed further.
Each of the three major types of PxDs was to be further classified as either idiopathic or symptomatic, depending on the etiology (3). As to the symptomatic forms, with the exception of PED that will be therefore discussed separately, clear anatomic–functional correlations are missing (2,3) and evidence is largely anecdotal. Hence, a list of reported secondary causes of PxDs is provided in Table 37.1 and these, as well as the psychogenic forms (6), will not be covered anymore.
Great advances in the field have followed the discovery of the major genes responsible for the “idiopathic” forms of PxDs (Table 37.2) (7–9). Genotype–phenotype correlations for the three major forms of PxDs, namely PKD, PNKD, and PED, have been found reasonably robust, and therefore, these will be described separately, accordingly.
Moreover, nonepileptic paroxysmal involuntary movements, which classically escape the aforementioned clinical classification, can be also embedded in chronic neurologic conditions, namely Alternating Hemiplegia of Childhood (AHC) and Allan–Herndon–Dudley syndrome (monocarboxylate transporter 8 deficiency), the genetic bases of which have been recently elucidated (10–13). These will be therefore also covered here.
Finally, we will briefly mention paroxysmal attacks characterized by ataxia, also referred as to Episodic Ataxias (EAs), while other nonepileptic attacks such as periodic paralyses will not be covered here, since these conditions do not technically manifest with a movement disorder.
• Demyelination, such as multiple sclerosis
• Vasculopathy, such as ischemia, hemorrhage
• Infectious disease, such as encephalitis, HIV, CMV, after streptococcal pharyngitis
• Cerebral and peripheral trauma
• Neurodegenerative disease, such as Huntington’s disease
• Hormonal and metabolic dysfunction, such as diabetes mellitus, hyperthyroidism, hypoparathyroidism, Albright pseudohypoparathyroidism, antiphospholipid syndrome, kernicterus
• Neoplasm (parsagittal meningioma)
• Chiari malformation, cervical syringomyelia
• Cerebral palsy after perinatal hypoxy
• Drug-induced (methylphenidate therapy)
• Faciobrachial dystonic seizures (LG1 antibodies)
PAROXYSMAL KINESIGENIC DYSKINESIA
PKD was first described by Kertesz in 1967 as “paroxysmal kinesigenic choreoathetosis” (14). By definition, PKD episodes are triggered by sudden movements like initiation of standing, walking, or running (3). Intention to move and acceleration have also been reported as triggers for PKD. Although age of onset is variable between the first year of life and 40 years, PKD usually occurs during childhood or early adolescence, being onset after 18 years of age very rare (1,3,15). There is a higher prevalence in men than in women (about 2:1) (1,3,15). As stated before, virtually in all patients with PKD attacks are brought on by a sudden movement or increase in speed, amplitude, force strength, or sudden addition of new actions during ongoing steady movements (15). However, startle, sound and photo-stimulation, stress/anxiety, coffee intake, and sleep deprivation can also induce attacks. An aura, either paresthesias or sensations of muscular tension, preceding the attack is frequently reported (16), and a number of these patients can use the aura as warning sign to prevent the attacks by slowing down or “holding tight” of the affected limb (1,15,16).
The clinical manifestation of PKD is variable, but most patients present with dystonia, although chorea, ballismus, or a combination may also occur. Limb dyskinesias (often hemibody) are most common, but the face can be involved, and the attack may be generalized in some. Speech disturbance (dysarthria or anarthria, possibly from face involvement) has been reported in some patients (16). Attacks are brief, lasting only seconds in most cases (16). Frequency of PKD episodes is variable. Climax of frequency is reached during puberty with up to 100 attacks per day. After the age of 20 years, the attack frequency may diminish and remissions can occur. PKD attacks usually respond dramatically to anticonvulsants, primarily carbamazepine, which is the drug of choice (1,16). Usually, carbamazepine is effective on attacks at low dosage (50–200 mg daily), but higher dosage is required in some patients. Oxcarbazepine, phenytoin, hydantoin, and topiramate, as well as barbiturates, have been also reported to be beneficial.
PKD can run in families with an autosomal dominant fashion. Moreover, a long-standing observation is the association of familial PKD with benign familial infantile convulsions (BFIS) (17) within families or even in the same patient. In fact, identification of a common locus in the pericentric region of chromosome 16 (18–20) suggested allelism of these two disorders. Several independent studies using whole exome-sequencing approaches on such families have subsequently identified heterozygous mutations in PRRT2, a gene encoding the proline-rich transmembrane protein 2, as the cause of PKD (7,21–23). After this discovery, an increasing number of reports confirmed that PRRT2 mutations are the major cause of both familial and sporadic cases of PKD as well as of BFIS (24–29).
PRRT2: GENETIC AND PATHOPHYSIOLOGIC OUTLINES
The majority of the PRRT2 patients are of far-east ancestry. Caucasian patients represented the second most common ancestry. By far, the most common mutation accounting for approximately half of these patients is the c.649dupC mutation, but other truncating mutations (7) have been described and are predicted to result in haploinsufficiency (22). Phenotypic missense variants (possibly with reduced penetrance) (29–31) and microdeletions (27,30,32,33) have also been reported. The PRRT2 gene encodes a protein that is highly expressed throughout the nervous system. To date, the function of PRRT2 is poorly understood. There is evidence for an interaction with synaptosomal-associated protein 25 (SNAP-25), suggesting disrupted neurotransmission from synaptic vesicles at the presynaptic membrane (34). An imbalance in the release of excitatory and inhibitory transmitters may lead to intermittent neurologic symptoms like seizures and PKD.
PHENOTYPIC SPECTRUM OF PRRT2-RELATED DISORDERS
The discovery of PRRT2 mutations in PKD and BFIS prompted further research on this gene in related “paroxysmal” conditions. The phenotypic spectrum of PRRT2-related disorders is still expanding. PRRT2 mutations have been detected in migraine, hemiplegic migraine, EA, febrile seizures, sporadic infantile convulsions, and paroxysmal torticollis of the infancy—alone or in various combinations (32,33,35–37).
CLINICAL DIFFERENCE BETWEEN PRRT2 POSITIVE AND NEGATIVE CASES
Although there is now evidence that PRRT2 mutations are the major cause of PKD, several studies reported prevalence estimates of PRRT2 mutations in patients with a clinical diagnosis of PKD between 30% and 80% (40), suggesting genetic heterogeneity of PKD.
Comparison of patients with and without PRRT2 mutations shows that PRRT2-positive cases are younger at symptom onset, have more frequently presence of premonitory sensation, and can also have additional features including seizure, writer’s cramp, and migraine than patients without PRRT2 mutation (41,42). As to the phenomenology of PKD attacks, they tend to be more “dyskinetic,” usually bilateral, and longer in patients with PRRT2 mutations than in those without, who generally manifest unilateral dystonic attacks (43). Virtually, all PRRT2 mutation carriers respond completely to low-dose carbamazepine (50–200 mg daily), while the majority of the negative PRRT2 cases do not have a full response to carbamazepine, even at higher dosage (43).
PAROXYSMAL NONKINESIGENIC DYSKINESIA
PNKD is characterized by attacks of longer duration (usually hours) compared to PKD that are not induced by sudden movement (3). Mount and Reback gave the first clear description, which they named “familial paroxysmal choreoathetosis” in a large family with 28 affected members in five generations (44). Typically, attacks were precipitated by alcohol, coffee, fatigue, emotional stress, and with improvement after rest and sleep (44).
Age at onset is usually in childhood, and only a few patients have onset after 18 years of age (1,3,44). Attacks are often characterized by a combination of dystonia and chorea, but in a number of patients, episodes became heterogeneous during the course of the disease, being more dystonic in the early phase, while more choreic components can be observed thereafter (1). Attacks can be either unilateral or generalized (4), and speech impairment is reported in approximately one-third of patients, most likely due to involvement of the face (oral dyskinesia and\or tongue dystonia) (44). Additional features during the attacks are less commonly seen and include oculogyric crises, blepharospasm, risus sardonicus, inability to move, and pain, but usually there are no interepisodic neurologic signs (1,3). A number of patients can have premonitory feeling, including weakness, shortness of breath, and migraine, before the attacks (1,3). Frequency of attacks ranges from several per day to one attack over a lifetime, but is variable even within families (45). Many patients do not require treatment, being able to control their attacks by avoiding precipitants. Clonazepam or diazepam, taken both as a prophylactic and as an abortive agent, usually produce a reasonable benefit, but the initial good response can be then lost over the years (1,3). There is general tendency to decreasing attacks frequency with aging (1,3,4,44,45).
In 2004, two independent studies detected heterozygous mutations in the myofibrillogenesis regulator gene (MR-1) in several families with PNKD (8,46). Several subsequent reports have confirmed MR-1 mutations as the most common cause of PNKD. However, in 2005 a missense mutation of the KCNMA1 gene was detected in a large family with 16 affected individuals who developed PNKD, generalized epileptic seizures (absence, generalized tonic clonic), or both (47). To date, no further patients with KCNMA1 gene defect have been reported.
MR-1 AND KCNMA1: GENETIC AND PATHOPHYSIOLOGIC OUTLINES
Missense mutations in the MR-1 gene with substitution of valine for alanine at either amino position 7 or 9 have been found in all but one patient carrying a p.Ala33Pro mutation. Exon 1 appears to be a mutational hotspot as evidenced by the recurrence mutations on different haplotypes in several unrelated families from different ethnicities. Four asymptomatic carriers have been also identified (35,48,49), and thus, penetrance of MR-1 mutations may be estimated around 95%. The MR-1 gene on chromosome 2q35 encodes for a protein with three isoforms with different cellular distribution and presumably distinct biologic functions (8). However, details of its function are not yet known. MR-1 is a homologue of the hydroxyacylglutathione hydrolase (HAGH) gene, which plays a role in the pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic drinks and produced as a by-product of oxidative stress (8), therefore suggesting a possible mechanism whereby alcohol, coffee, and stress may induce attacks in these patients.
The KCNMA1 gene encodes for the pore-forming α-subunit of the BK channel, a calcium-sensitive potassium channel (47). The mutant BK channel in vivo leads to increased excitability by inducing rapid repolarization of action potentials, resulting in generalized epilepsy and PxDs by allowing neurons to fire at a faster rate (47). However, the exact function of such channel is not yet totally clear.
CLINICAL DIFFERENCE BETWEEN MR-1-POSITIVE AND -NEGATIVE CASES
Prevalence estimates of MR-1 mutation in PNKD are around 70%, suggesting genetic heterogeneity of this disorder. In one study, Bruno and colleagues compared 49 patients with PNKD from 8 families carrying MR-1 mutations and 22 patients from 6 kindreds without MR-1 mutations (48). Patients with MR-1 mutations had three distinguish features: (1) onset of attacks in infancy or early childhood, (2) precipitation of attacks by caffeine and alcohol, and (3) very favorable response to benzodiazepines and sleep (48). In contrast, patients with PNKD who did not carry a MR-1 mutation were more variable in their age of onset, provoking factors, and response to medication (48). Moreover, the kindreds without MR-1 mutations had more intrafamily and interfamily heterogeneity as to the paroxysmal features compared with the kindreds with MR-1 mutations (48).
Finally, PNKD has been described in one family with mutations in KCNMA1 gene (47). Clinical characteristics were deemed to be classical for PNKD and are apparently indistinguishable from those seen in MR-1 patients. The only additional feature in patients with KCNMA1 mutations is the possible presence of a personal/familial history of epilepsy (47), which instead is never seen in patients with MR-1 mutations.
PAROXYSMAL EXERCISE-INDUCED DYSKINESIA
In 1977, Lance newly classified and delineated PED as an “intermediate type” of paroxysmal dystonic choreoathetosis distinct from both PKD and PNKD (4). In fact, attacks were longer in duration compared to PKD but shorter than PNKD. Moreover, they were not precipitated by alcohol, stress, or anxiety, and were never induced by sudden movements (4). In the original family described, attacks lasted 5 to 30 minutes, and were distinguishably triggered by continuous exertion and physical exhaustion (4). An autosomal dominant inheritance was noted in the familial cases, but sporadic cases have also been reported (3,50).
Recently, mutations in the SLC2A1 gene encoding for glucose transport protein type 1 (GLUT1) were detected in several families and sporadic patients with PED (9,51,52). PED may present the sole clinical feature without any accompanying interepisodic clinical signs or be part of the complex phenotypic spectrum of GLUT1 deficiency syndrome (53). However, PED may be also part or even the presenting symptom of other chronic neurologic disorders (54). As such, we will discuss separately PED in the context of GLUT1 and PED associated with other neurologic disorders.
PED AND GLUT1 DEFICIENCY SYNDROME
Phenotype–genotype correlations exist for SLC2A1 gene defects, with splice site, nonsense, insertions, deletions (i.e., loss-of-function mutations) being associated with younger age at onset and a more severe clinical phenotype of GLUT1 deficiency syndrome, including epilepsy, hypotonia, spasticity, ataxia, and developmental delay, compared with missense mutations, which more commonly present with PED in older patients (52,55,56) (Fig. 37.1). Despite these trends, there remains considerable clinical heterogeneity that is not explained by mutation type alone. The majority of reported patients with PED carry a de novo heterozygous mutation in SLC2A1. About 10% of affected individuals have a clinically affected parent (51,57). Although autosomal recessive transmission has been described in rare cases of GLUT1 deficiency syndrome (58), this has not been reported in patients with PED.
As far as PED is concerned, age at onset is variable and ranges from 1 to 50 years, but is usually in childhood (9,51–53). Attacks are choreodystonic in nearly all patients and present predominantly focal/unilateral involvement (leg > arm > face), being generalization of attacks rather unusual (9). Additional features reported during the attacks can be occasionally seen and include oculogyric crises, gait disturbances, clumsiness, weakness, and migraine. Isolated PED can be seen in up to one-third of cases with SLC2A1 mutations. Frequency of attacks ranges from several per day to one per month. PED can have a positive but partial response to a ketogenic diet (59), which should anyway be pursued to treat the underlying neuroglycopenia.