Clinical manifestations

Presentation and course

The clinical manifestations are variable. The attacks are often not witnessed because of their brief duration. The earlier classifications were inaccurate because they used terms like "paroxysmal choreoathetosis" or "paroxysmal dystonic choreoathetosis," implying that in all attacks movements are easily characterized. However, the type of dyskinesia observed is extremely variable. Furthermore, the duration of episodes is not a reliable characteristic for differentiating between paroxysmal kinesigenic choreoathetosis and paroxysmal dystonic choreoathetosis of Mount and Reback. Demirkiran and Jankovic proposed that a classification scheme should be based primarily on the precipitating events, arguing that the precipitant is the best predictor of clinical course and response to specific medications (46; 134; 52; 71; 208). For example, kinesigenic dyskinesias are far more responsive to nonbenzodiazepine anticonvulsants than are nonkinesigenic, regardless of duration of spell or etiology. They proposed the following classification of paroxysmal dyskinesias: kinesigenic, nonkinesigenic, exertion induced, and hypnogenic (aka, paroxysmal nocturnal dystonia of sleep). Paroxysmal hypnogenic dyskinesia, however, may in fact be a form of nocturnal frontal lobe epilepsy (198) and, thus, is outside the scope of this discussion. Secondary categorization is based on duration; short is less than or equal to 5 minutes, and long is greater than 5 minutes. The tertiary classification is based on etiology: idiopathic (familial vs. sporadic) and secondary.

Table 1. Classification According to Clinical (Axis I) and Genetic (Axis II) Characteristics

Paroxysmal kinesigenic dyskinesia. This condition is often inherited in an autosomal dominant fashion, but a quarter of the cases are sporadic.

Males are affected more often than females (male:female=4:1) (77; 124; 193). In a review of confirmed PRRT gene-positive cases, the majority had an age of onset before 18 years (range 1 to 40 years) (53). The attacks are typically precipitated by the patient being startled or making a sudden movement after a period of rest. They may occur when running. Other less commonly reported triggers include anxiety, startle, intention to move, acceleration, coffee intake, and sleep deprivation (53). A sensory aura may precede the attack, and in some cases, it may be used as a warning sign to prevent the attack (32; 53). Dystonia and chorea are the most common phenomenologies (190). The extremities are most often affected (171; 124). During a refractory period after an attack, sudden movement may not provoke an attack. The attacks occur frequently—up to 100 per day. The duration is short, usually a few seconds to a few minutes. However, longer-lasting attacks may occur rarely (46). In an analysis of 121 patients referred for genetic study of paroxysmal kinesigenic dyskinesia, 79% were found to have a homogeneous phenotype (23). The phenotype consisted of (1) identified trigger for the attacks (sudden movements), (2) short duration of attacks (less than 1 minute), (3) lack of loss of consciousness or pain during attacks, (4) antiepileptic drug responsiveness, and (5) age at onset between 1 and 20 years. Patients may only have an abnormal sensation in the limbs involved, or the sensation may precede motor manifestation. The attacks may be limited to one side of the body or even one limb, although more often there is a tendency for generalization (53). The attacks decrease in frequency during adulthood (97; 124). The patients typically respond well to anticonvulsants. Patients may manifest co-existent epilepsy, infantile convulsions, migraine, or other neurologic symptoms, which is also noted in overlap syndromes.

Two sporadic patients with interictal myoclonus and paroxysmal kinesigenic dyskinesia have been reported, with both cases responding to antiepileptic medication (39). Two further cases of myoclonus and paroxysmal dyskinesias have been described, with myoclonus and dystonia occurring between attacks (44). One individual displayed paroxysmal kinesigenic dyskinesia, whilst the other had paroxysmal exercise-induced dystonia. A patient with features of both paroxysmal kinesigenic dyskinesia and paroxysmal exertion-induced dyskinesia has also been described (155). Focal laryngopharyngeal paroxysmal kinesigenic dyskinesia presenting as dysphagia and chronic cough has been described, with good response to carbamazepine (105).

Paroxysmal nonkinesigenic dyskinesia. This is usually inherited as an autosomal dominant trait. Incomplete penetrance and intrafamilial variability have been described (154). The attacks occur more often in males (male:female=2:1). The mean age of onset is 5 years, but attacks may not start until the early 20s. The frequency varies from three per day to two per year, although the majority of patients experience at least one attack per week. The usual precipitating factors are fatigue, alcohol, caffeine, and emotional excitement. Other less commonly reported triggers include fever, menstruation, and change in temperature. The attack may start with involuntary movements of one limb but may spread to involve all extremities and the face. The usual duration is minutes to 3 to 4 hours. During the attack, the patient may be unable to communicate due to speech impairment from oral dyskinesia or tongue dystonia. The typical phenomenology consists of chorea, dystonia, or a combination of chorea, dystonia, or ballism (53). The attacks are relieved by sleep and sometimes respond to pharmacologic intervention.

Identification of an association of paroxysmal nonkinesigenic dyskinesia with mutation in the myofibrillogenesis regulator 1 (MR-1) gene has provided more precise specification of the phenotype associated with this mutation (24). Patients with MR-1 mutations had: (1) onset in infancy or early childhood; (2) a mixture of chorea and dystonia in the limbs, face, and trunk; (3) typical attack duration between 10 minutes and 1 hour; (4) precipitation by caffeine, alcohol, or emotional stress; and (5) favorable response to benzodiazepines. Families without MR-1 mutations had more variable age at onset, precipitants, clinical features, and response to medications.

In a large Polish family with confirmed mutation in the MR-1 gene, the frequency and severity of the paroxysmal nonkinesigenic dyskinesia attacks increased with age in all male subjects (64). In addition, the female family member experienced complete disappearance of the attacks during pregnancy and a decrease in severity and frequency of the attacks after menopause. In a large MR-1 gene-positive Chinese family, symptom severity was variable across family members, ranging from mild clinical signs in some subjects to severe involvement affecting normal daily functioning (114). Response to benzodiazepines was also variable, with more than 20% of subjects exhibiting a poor response to medication.

Paroxysmal nonkinesigenic dyskinesia has been reported in a patient with familial ataxia (132), and in one family, paroxysmal nonkinesigenic dyskinesia was accompanied by myokymia (26). Some families also have exertional cramping, which may be a forme fruste of paroxysmal nonkinesigenic dyskinesia (106; 152) or may represent paroxysmal exertion-induced dyskinesia.

Paroxysmal exertion-induced dyskinesia. This is usually inherited in an autosomal dominant fashion although sporadic cases have been described (13). The attacks are triggered by prolonged exercise (109; 153). The frequency varies from one per day to two per month. The usual duration is 5 to 30 minutes. The clinical features may be indistinguishable from paroxysmal nonkinesigenic dyskinesia of long-lasting type, but legs are usually more affected. However, exercise limited to the upper extremities may provoke an attack in the upper extremities alone (153). The disorder may occur sporadically, and one reported patient had paroxysmal hemidystonia precipitated by prolonged running and cold (207). Another variant of paroxysmal exertion-induced dyskinesia is “runner’s dystonia” (218). This usually affects proximal lower limbs, although it may start in the feet, in long-distance runners and overlaps with other forms of focal dystonia, including relief with sensory or motor “tricks.” In some cases, it also overlaps with paroxysmal kinesigenic dyskinesia in that carbamazepine may markedly ameliorate the symptoms, although most patients require other forms of treatment, including repeat botulinum toxin injections. There is usually no family history of dystonia, and the leg dystonia tends to remain focal without spreading to other body parts. Some patients report prior injury to the affected leg, raising the possibility of peripherally induced dystonia.

Prognosis and complications

Prognosis depends on the type of paroxysmal dyskinesia. Paroxysmal kinesigenic dyskinesia, even of prolonged duration, responds well to standard anticonvulsants, and the attacks tend to diminish during adulthood. Paroxysmal nonkinesigenic dyskinesia and paroxysmal exertion-induced dyskinesia have a variable prognosis. Even with repeated attacks, the neurologic function between the attacks is normal. In symptomatic dyskinesias, the prognosis depends on the underlying disease. In multiple sclerosis, the attacks tend to run a self-limited course even with continued disease activity.

Clinical vignette

A 16-year-old right-handed female complained of intermittent abnormal muscle contraction on her left side beginning about 8 months earlier. Typical episodes occurred after standing suddenly from a seated position. She experienced a sensation, lasting several seconds, of pulling in the left side of her face during which her mother noted facial distortion. Initially, the events were once daily involving the face with increasing intensity over several weeks. She then began to have episodes involving the entire left side with flexion of the elbow, wrist, and fingers, adduction of the shoulder, extension of the hip and knee, inversion of the ankle, and flexion and leftward rotation of the neck. The episodes typically lasted 5 to 10 seconds but occasionally persisted for a few minutes, occurring up to 60 times per day. The episodes were consistently triggered by volitional movements, particularly those with abrupt onset. Not all movements triggered episodes of involuntary movements. She could not elicit an episode on command or abort an episode once it began. There was no alteration of consciousness. There was no family history of movement disorders or seizures.

The general physical and neurologic exams were normal between spells. A 24-hour video EEG captured several spells. None of the spells had electrographic correlates, and the EEG was completely normal between spells. Treatment was begun with carbamazepine 100 mg twice daily (2.5 mg/kg per day). On that dose of carbamazepine, the spells decreased in frequency and duration by about 50%. The dose was eventually increased to 300 mg three times daily (10.75 mg/kg per day), with nearly complete resolution of the spells.

Biological basis

Etiology and pathogenesis

Paroxysmal kinesigenic dyskinesia, paroxysmal nonkinesigenic dyskinesia, and paroxysmal exertion-induced dyskinesia are genetic disorders that are usually inherited in an autosomal dominant fashion, or they may arise from a sporadic mutation. Autosomal recessive inheritance has also been described (119).

Genetics. Substantial progress has been made in genomic mapping of several of the paroxysmal dyskinesias.

Paroxysmal kinesigenic dyskinesia. The first gene to be associated with paroxysmal kinesigenic dyskinesia, proline-rich transmembrane protein 2 (PRRT2), is a primarily presynaptic protein involved in calcium-mediated neurotransmitter release through interaction with SNARE proteins synaptosomal-associated protein 25 kDa (SNAP25) and synaptotagmin 1/2 (202; 40). Thus, mutated PRRT2 results in loss of function of the protein, disrupting the SNARE function, which is manifested as a variety of paroxysmal neurologic disorders.

Previous linkage studies mapped the locus for paroxysmal kinesigenic dyskinesia, EKD1, to chromosome 16p11.2-q12.1 (99), where the PRRT2 gene was subsequently identified by whole exome sequencing and linkage analysis methods. A second locus, termed EKD2 has been mapped to chromosome 16q13-q22.1 in a large Indian family with paroxysmal kinesigenic dyskinesia (203). A third EKD locus has also been described (184). Linkage to the paroxysmal kinesigenic dyskinesia loci on chromosome 16 was excluded in a British family with paroxysmal kinesigenic dyskinesia without epilepsy.

Over 70 mutations have been described in PRRT2 (136; 119; 52; 89). Most are believed to be truncating mutations and are predicted to cause haploinsufficiency (81). The recurrent frameshift and disease-causing mutation c.649_650insC, p.R217Pfs*8 is the most common mutation found in most well-characterized paroxysmal kinesigenic dyskinesia or infantile convulsion families from diverse ethnic backgrounds (38; 70; 80; 112; 136; Steinlein and Korenke 2012). The mutation rate is higher in familial cases than in sporadic cases, with approximately 80 to 100% of familial cases being gene-positive, in contrast to 33 to 46% of sporadic cases (09; 78). In one study, penetrance was estimated to be 61% if only paroxysmal kinesigenic dyskinesia was considered but was almost complete when infantile convulsions were taken into account (see Overlap Syndromes) (204). Estimations of penetrance may be difficult due to the transient or very mild phenotype in some individuals (63; 204).

Studies on genotype-phenotype correlations suggest that a younger age of onset (224), longer duration of paroxysmal kinesigenic dyskinesia attacks, complicated paroxysmal kinesigenic dyskinesia, combined phenotypes of dystonia and chorea, a positive family history (89), bilateral involvement, a complete response to low-dose carbamazepine (113), and the presence of premonitory sensation (194) are correlated with the PRRT2 mutation.

Overlap syndromes. Benign familial infantile epilepsy is an autosomal-dominant self-limiting epilepsy syndrome, with onset at 3 to 12 months of age. The seizures are usually comprised of clusters of focal or convulsive attacks, with good response to antiepileptic therapy. Spontaneous resolution occurs by around 2 to 3 years of age. Mutations in PRRT2 have been identified in approximately 80% of benign familial infantile epilepsy families, indicating that they are the most common cause of this disorder (47; 82; 166; 169; 148). Benign familial infantile epilepsy mutations have also been identified in sporadic cases (185).

Febrile seizures, with or without afebrile seizures, have been observed in a few families with PRRT2 mutations, making the distinction between benign familial infantile epilepsy and febrile seizures, or febrile seizures plus, difficult. The co-occurrence of benign familial infantile epilepsy and childhood absence epilepsy has also been observed in one PRRT2-positive family (131). Infantile nonconvulsive seizures and nocturnal convulsions have also been reported rarely (119). Mutations in PRRT2 are not classically associated with other types of infantile epilepsy (166), although one case of infantile focal epilepsy with bilateral spikes has been described (199). Familial seizures with a more severe seizure course than that which is expected in benign familial infantile epilepsy, such as seizures continuing into childhood, episodes of status epilepticus, later onset seizures, and infantile epileptic encephalopathies, are not generally associated with PRRT2 mutations (83).

The syndrome of paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), otherwise known as infantile convulsions and paroxysmal choreoathetosis (ICCA syndrome), is an overlapping disorder consisting of features of paroxysmal kinesigenic dyskinesia in addition to the syndrome of benign familial infantile epilepsy (215; 161; 54). Paroxysmal kinesigenic dyskinesia often appears by early childhood, after the seizures have resolved. Both intrafamilial and interfamilial variability exists, and members of a PKD/IC family may manifest paroxysmal kinesigenic dyskinesia, infantile convulsions, or both (38). Mutations in PRRT2 have also been identified in more than 80% of families with PKD/IC (209; 82; 166) as well as apparently sporadic cases (112). Unaffected carriers are also observed.

The phenotypic spectrum of PRRT2 mutations also includes the association of hemiplegic migraine and other migraine types in PKD/IC families (38; 41; 70; 29), as well as pure hemiplegic migraine without paroxysmal kinesigenic dyskinesia (159), in cases that are negative for the migraine genes CACN1A, ATP1A2, SCN1A. A PRRT2 mutation was also found in a family with hemiplegic migraine and episodic ataxia (70) and another paroxysmal kinesigenic dyskinesia family where migraine with aura was the predominant phenotype (175). Other syndromes reportedly associated with PRRT2 mutations include paroxysmal torticollis (41), paroxysmal exertion-induced dyskinesia (118; 204), a nonkinesigenic paroxysmal dyskinesia-like phenotype (118; 180), and a family manifesting overlapping features of paroxysmal kinesigenic dyskinesia, paroxysmal exertion-induced dyskinesia, and nonkinesigenic paroxysmal dyskinesia (211). A more severe phenotype of benign familial infantile seizures/paroxysmal kinesigenic dyskinesia, with associated mental retardation, episodic ataxia, and absences, has been described in homozygous c.649dupC mutations in a consanguineous family (107). Intellectual delay was observed in a patient harboring a double mutation in PRRT2 (194).

Thus, PRRT2 mutations may manifest as several childhood-onset episodic syndromes, including pure paroxysmal kinesigenic dyskinesia, pure infantile convulsions, paroxysmal kinesigenic dyskinesia/infantile convulsions, and mixed paroxysmal kinesigenic dyskinesia/hemiplegic migraine (135). The same mutation may vary in age of onset (27). The mechanisms underlying the phenotypic heterogeneity of PRRT2 mutations are yet to be defined, although gene pleiotropy is a possibility (210).

A large sample study evaluating genetic etiologies of PRRT2-negative cases of paroxysmal kinesigenic dyskinesia identified 29 patients with variants in transmembrane protein 151 (TMEM151A). Patients with TMEM151A causing paroxysmal kinesigenic dyskinesia were more commonly sporadic in nature and were often later onset but otherwise shared the same clinical features (195).

Mutations in SCN8A have also been described in three unrelated families with benign familial infantile epilepsy or infantile convulsions and paroxysmal choreoathetosis (68; 69). A minority of the affected individuals also developed clinical features of paroxysmal kinesigenic dyskinesia, although these were associated with an ictal EEG correlate suggestive of cortical impairment.

Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer’s cramp has been described in three individuals from one consanguineous Sardinian family who experienced paroxysmal exertion-induced dyskinesia and partial seizures from 1 to 3 years of age. The patients developed writer’s cramp in late adolescence (79). Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer’s cramp has been found to share a locus on chromosome 16p12-q12 with paroxysmal kinesigenic dyskinesia, infantile convulsions and paroxysmal choreoathetosis, and benign familial infantile seizures/convulsions. It appears that individuals homozygous for the disease haplotype at chromosome 16p12-q12 may have earlier age of onset and higher frequency of attacks than heterozygous family members (45). A family with benign familial infantile seizures/convulsions-like phenotype without paroxysmal dyskinesia had suggestive linkage to chromosome 16 (213).

Two cases of paroxysmal kinesigenic dyskinesia have been associated with the SACS gene, which is responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) that is typically characterized by ataxia, peripheral neuropathy, and epilepsy (125).

Three cases of paroxysmal kinesigenic dyskinesia have been reported in homozygous variants in PDE2A with associated intellectual disability or developmental delay as well as epilepsy (49).

POLG is involved in DNA replication of the mitochondria, and disorders involving POLG include progressive external ophthalmoplegia, spinocerebellar ataxia, neuropathy, and epilepsy. A case of paroxysmal kinesigenic dyskinesia and associated spasmodic torticollis was reported; however, the patient also carried a missense variant in PLA2G6, which was described as unlikely to be pathogenic (227).

Other genetic causes of paroxysmal kinesigenic dyskinesia include SLC2A1, PNKD, DEPDC5, KCNMA1, and KCNA1 (88; 110).

Paroxysmal nonkinesigenic dyskinesia. Paroxysmal nonkinesigenic dyskinesia (Mount and Reback type) has been associated with missense mutations in the PNKD gene, previously referred to as the myofibrillogenesis regulator gene (MR-1), on chromosome 2q33-35 (111; 158). The most common mutation is p.Ala7Val, followed by p.Ala9Val mutation (220). Most reported families are of European ancestry, although families from other ethnicities have also been described. The gene is transcribed into three alternatively spliced forms: long (MR-1L), medium (MR-1M), and small (MR-1S). A third mutation described in the N-terminal region is common to MR-1L and MR-1S, the region that also carries the other previously reported mutations (75). Although the precise function of the gene product is unknown, it appears to share homology with the family of glyoxalases that function in the glutathione-dependent metabolic pathway (111). Further cellular and animal studies suggest a role for the protein in maintaining cellular redox status, with mutations in the gene resulting in altered protein cleavage and stability (176). In a Canadian family of European descent, a second locus for paroxysmal nonkinesigenic dyskinesia was described, which was linked to a distinct region on chromosome 2q31 (183); the underlying gene has not been identified. Caffeine and alcohol did not trigger episodes of paroxysmal nonkinesigenic dyskinesia in this family.

A case of paroxysmal nonkinesigenic dyskinesia triggered by intense crying has been described in a child with disruption in the fibroblast growth factor 14 gene (FGF14), consistent with spinocerebellar ataxia type 27 (SCA27) (178).

An autosomal dominant syndrome of generalized epilepsy and paroxysmal nonkinesigenic dyskinesia has been associated with mutations in the KCNMA1 gene, located on chromosome 10q22 in the alpha subunit of the large conductance calcium-sensitive potassium (BK) channel (50). This mutation is associated with increased neuronal excitability by causing rapid repolarization of action potentials. The onset of paroxysmal nonkinesiogenic dyskinesia in affected individuals ranges from infancy to adolescence. Developmental delay, cerebellar atrophy, and corticospinal tract atrophy have been reported in some individuals, whereas epilepsy may be absent (226; 221).

A case of paroxysmal nonkinesigenic dyskinesia was described in monozygotic twins with an ATP1A3 mutation (typically associated with rapid onset dystonia-parkinsonism and alternating hemiplegia of childhood). Episodes were characterized by painful abnormal postures, first occurring in infancy, lasting from minutes to hours, occurring up to 20 times per week, with triggers including weather changes, mood swings, caffeine intake, exercise, fever, and infections. Interestingly, these patients showed a dramatic response to levodopa (228).

Paroxysmal exertion-induced dyskinesia. Mutations in SLC2A1, which encode glucose transporter 1 (GLUT1), were identified by whole-genome linkage analysis in a 5-generation family and three unrelated nuclear families with co-occurrence of paroxysmal exertion-induced dyskinesia and epilepsy (189; 104). Among the 25 individuals carrying a SLC2A1 mutation, 19 (76%) had a history of paroxysmal exertion-induced dyskinesia, and 14 (56%) had a history of epilepsy. A history of both paroxysmal exertion-induced dyskinesia and epilepsy was present in 11 individuals (44%). In a parallel investigation, a causative deletion in the pore region of GLUT1 was identified using a candidate gene approach in a family with paroxysmal exertion-induced dyskinesia associated with epilepsy, mild developmental delay, and hemolytic anemia with echinocytosis (216). Two novel mutations have also been identified in the GLUT1 gene in sporadic paroxysmal exertion-induced dyskinesia (168). One of the patients also suffered from hemiplegic migraine and had a history of seizures during childhood. A novel missense mutation was reported in two monochorionic twins with paroxysmal exertion-induced dyskinesia, migraine, absence seizures, and writer's cramp (201). The clinical phenotype of GLUT1 deficiency may be mild in some cases. Paroxysmal exertion-induced dyskinesia associated with mild epilepsy of adolescent/adult onset has been reported (02). In this family, seizures consistent with idiopathic generalized epilepsy were observed. In addition, a case of mild paroxysmal exertion-induced dyskinesia and self-limiting partial epilepsy has been described in the setting of a novel de novo heterozygous SLC2A1 mutation (19).

GTP-cyclohydrolase 1 deficiency has also been identified as a cause of autosomal dominant paroxysmal exertion-induced dyskinesia (42). Family members had a history of restless legs syndrome, depression, and adult-onset parkinsonism. Levodopa therapy was successful in controlling the paroxysmal exertion-induced dyskinesia and restless legs syndrome. Several cases of paroxysmal exercise-induced dystonia have also been described in pyruvate dehydrogenase deficiency involving various genes in the pyruvate dehydrogenase complex. Thiamine supplementation has shown some benefit in such cases (30; 61).

Autosomal dominant paroxysmal choreoathetosis/spasticity (DYT9), an exercise-induced dyskinesia that may be associated with spastic paraplegia, has been mapped to a 12 cM region on chromosome 1p in the vicinity of the potassium channel gene cluster (06). Further clinical re-evaluation and gene sequencing of this family revealed linkage to the SLC2A1 locus (214). Affected family members had paroxysmal, predominantly exercise-induced dyskinesia, and five of 18 individuals manifested spastic paraparesis. Other clinical features included mild gait ataxia, cognitive impairment, epileptic seizures, and migraine. Different SLC2A1 mutations were also identified in a monozygotic twin pair who presented with similar symptoms of paroxysmal choreoathetosis and progressive spastic paraparesis, suggesting that paroxysmal exertion-induced dyskinesia and slowly progressive spastic paraparesis may form part of the GLUT1 phenotypic spectrum.

Paroxysmal exertion-induced dyskinesia has also been described in association with biallelic variants of TBC1D24. This gene has also been associated with several neurologic conditions, including familial infantile myoclonic epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures), hearing loss, and episodic ataxia. Paroxysmal exertion-induced dyskinesia has been reported to start in infancy with dystonic posturing triggered by exercise (115).

Munchau and colleagues described a family with paroxysmal exercise-induced dystonia and migraine that was not linked to the paroxysmal dystonic nonkinesigenic dyskinesia locus on chromosome 2, the infantile convulsions and paroxysmal choreoathetosis locus in chromosome 6, or the familial hemiplegic migraine locus on chromosome 19 (143). A family with autosomal dominant paroxysmal exercise-induced dystonia, generalized epilepsy, developmental delay, and migraines has been described by Kamm and colleagues (93). In this family, the linkages to chromosome 2 and 16 were excluded, suggesting an unidentified underlying genetic basis.

ADCY5-associated paroxysmal dyskinesia. Mutations in ADCY5, the gene for adenylyl cyclase type 5, have been recognized as a cause for autosomal dominant paroxysmal dyskinesia. Interestingly, a mix of paroxysmal kinesigenic, nonkinesigenic, exertional, and nighttime dyskinesias can be seen within the same individual with these mutations. Paroxysmal dyskinesia usually occurs on a baseline of dystonia, chorea, myoclonus, or tremor (62; 206).

Secondary causes. In addition to idiopathic or genetic paroxysmal dyskinesias, there are many other causes of dyskinesias (90). These include multiple sclerosis, central and peripheral trauma, strokes, and infections. Secondary dyskinesias should be considered in all atypical cases, such as older age at onset, prolonged duration of attacks, and when there are associated interictal neurologic deficits. Identifiable causes of a secondary paroxysmal dyskinesia were found in 22% of patients in one study (15; 16).

Demyelinating disease. The most common cause of secondary paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia is demyelinating disease. In multiple sclerosis, this has been associated with lesions of the internal capsule, basal ganglia, and posterior periventricular white matter (65), though thalamic and cerebellar peduncle lesions have also been reported (133; 35). Tonic spasms, manifested as paroxysmal hemidystonia or “tonic seizures,” may be the presenting manifestation of multiple sclerosis or may occur in established disease (11). These attacks may be kinesigenic but are most consistently precipitated by hyperventilation and can be extremely painful. Attacks typically involve one side of the body with or without the face but may occur bilaterally. Each attack lasts from a few seconds to a few minutes, and multiple attacks may occur during the day. The attacks tend to subside spontaneously over many weeks despite continuing disease activity. Short-lasting (1- to 2-minute) attacks of paroxysmal nonkinesigenic dyskinesia have been reported due to a solitary cervical cord lesion that was presumed to be demyelinating (156). Paroxysmal hypnogenic dyskinesia has also been described in the setting of multiple sclerosis (92; 11).

Metabolic disorders. Paroxysmal kinesigenic dyskinesia has been reported with idiopathic hypoparathyroidism and pseudohypoparathyroidism (192; 181; 225). A patient with features of both paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia has been reported in association with familial idiopathic hypoparathyroidism (94). Paroxysmal dyskinesia may also occur due to pseudohypoparathyroidism (Dure and Mussel 1998; 225). Paroxysmal kinesigenic dyskinesia has been reported in a family with pseudohypoparathyroidism type 1b due to a 3-kilobase deletion on chromosome 20q13.3 (130). Basal ganglia calcifications may be seen in these cases. Another case of paroxysmal kinesigenic dyskinesia due to pseudohypoparathyroidism type 1b, with complete response to calcitriol and calcium carbonate, has also been described (197). Paroxysmal kinesigenic dyskinesia has been reported along with severe global mental retardation and thyroid hormone abnormalities as an X-linked condition due to mutations in the thyroid hormone transporter gene MCT8 (21). Paroxysmal dyskinesia and titubation were also described in an adolescent with acquired hypothyroidism (86). Nonketotic hyperglycemia may cause paroxysmal kinesigenic dyskinesia (37). Paroxysmal kinesigenic dyskinesia has been described in a patient with Wilson disease, with complete remission to oxcarbazepine (140). Rarely, paroxysmal nonkinesigenic dyskinesia may occur in inherited metabolic disorders, but it is usually accompanied by other clinical problems (55). Paroxysmal nonkinesigenic dyskinesia has been reported in a child with maple syrup urine disease (196). Paroxysmal nonkinesigenic dyskinesia also has been reported in hypoglycemia (217) and thyrotoxicosis (59). A sporadic case of paroxysmal nonkinesigenic dyskinesia due to recurrent hypoglycemia caused by an insulinoma has been described (43).

Head injury. Paroxysmal kinesigenic dyskinesia may occur after head trauma (74), and there may be a lag period of several months between the head injury and the involuntary movements (157). Head injury may also cause paroxysmal nonkinesigenic dyskinesia, and the attacks have been reported to occur as early as 20 minutes after injury (150). Posttraumatic paroxysmal exertion-induced dyskinesia has also been described (46; 116). There has been a report of paroxysmal hypnogenic dyskinesia occurring after trauma (14).

Cerebrovascular disease. With advanced neuroimaging, more cases of paroxysmal kinesigenic dyskinesia are being attributed to cerebral infarcts, including putaminal infarcts (137) and thalamic infarcts (28). It has also been reported in a patient with Moyamoya disease (76; 127; 129). Stimulus-sensitive and action-induced paroxysmal dyskinesia has been described in a patient with posterior thalamic infarct (144). Paroxysmal nonkinesigenic dyskinesia has been reported following a striatal infarct (182). A case of orthostatic paroxysmal dystonia has been described in a patient with significant cerebrovascular disease. The paroxysmal dystonia precipitated by suddenly assuming an upright posture was associated with decreased perfusion of the contralateral frontoparietal cortex (173). Transient ischemic attacks may sometimes present with paroxysmal nonkinesigenic dyskinesia (84), and these attacks may herald a major stroke. Paroxysmal dyskinesia has been reported after subthalamic nucleus infarction (67). Both paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia have also been reported in Moyamoya disease (76). A case of paroxysmal nonkinesigenic dyskinesia secondary to pallidal ischemia, specifically triggered by alcohol, has been described (212). Intermittent, episodic limb shaking and other involuntary movements have been described as part of transient ischemic attack associated with carotid occlusion (151).

Infection or inflammation. Both paroxysmal kinesigenic dyskinesia and paroxysmal nonkinesigenic dyskinesia have been described in a series of six HIV-1-seropositive patients in the absence of a known opportunistic infection. Histopathological studies from one of the paroxysmal nonkinesigenic dyskinesia patients revealed evidence of severe HIV encephalitis as well as loss of calbindin-positive neurons in the basal ganglia (141). Paroxysmal dyskinesia has been reported in association with subacute sclerosing panencephalitis (149). A case of kinesigenic dyskinesia and cramp-fasciculation syndrome has also been reported in the setting of voltage-gated potassium channel–complex protein antibody encephalitis (05).

Cerebral palsy. Paroxysmal kinesigenic dyskinesia has been described as a delayed manifestation after perinatal hypoxic encephalopathy (163). The age of onset was 12 years; the attacks were precipitated by being bumped from behind and not by a sudden movement. These were short-lasting (5 to 30 seconds) and occurred five to 20 times daily.

Miscellaneous conditions. Paroxysmal kinesigenic dyskinesia has been reported to occur in progressive supranuclear palsy (01) after methylphenidate therapy (73) and in a patient with primary CNS lymphoma (162). Paroxysmal kinesigenic dyskinesia has also been observed in an individual with neuroacanthocytosis, manifesting with mild chorea, weakness of the right lower extremity, and myoclonic jerks (200). Her attacks improved with carbamazepine. Paroxysmal kinesigenic dyskinesia associated with sporadic bilateral striopallidodentate calcinosis has been described (48; 34). Paroxysmal nonkinesigenic dyskinesia has been described in the setting of Fahr disease (139; 101; 03). Symmetrical intracranial calcifications were described in a report of a 4-generation family with paroxysmal nonkinesigenic dyskinesia; linkage to 14q (described in families with Fahr disease and neurologic symptoms) was excluded (219). Paroxysmal nonkinesigenic dyskinesia has also been reported in the setting of spinal cord infiltration from low-grade B-cell non-Hodgkin lymphoma (10). There is a report of paroxysmal hypnogenic dyskinesia due to orbitofrontal cortical dysplasia (121). A case of paroxysmal kinesigenic hemidystonia following peripheral trauma has been described, raising the possibility of a sporadic peripheral trauma-induced paroxysmal kinesigenic dyskinesia (33); this case responded to carbamazepine. Cortical reflex seizures have also reportedly presented as paroxysmal dyskinesia induced by weight (95). Sporadic paroxysmal exertion-induced dyskinesia of the hands has been described (36).

Paroxysmal dyskinesia is attributed to basal ganglia dysfunction, but conclusive evidence is lacking. Some view this group of disorders as a form of subcortical epilepsy because of overlapping features, including presence of an aura for many patients, the paroxysmal nature of events, remarkable responsiveness to anticonvulsants, normalization of neurologic exam between events, and familial association (167). Some patients have abnormal baseline EEGs consistent with seizures (77; 147). In an animal model of paroxysmal dystonia, predominant EEG changes are in caudate-putamen and globus pallidus with a significant decrease in the high-frequency beta2 range; there is a tendency to increase in delta and theta activities. These changes are seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of dystonic animals. Thus, paroxysmal dyskinesias may reflect seizure-like discharge in the basal ganglia. A report with depth electrodes suggests that in some patients with paroxysmal kinesigenic dyskinesia, an electrical discharge from the medial frontal lobe spreads to the caudate nucleus (122).

Several reports support the idea of basal ganglia dysfunction in paroxysmal kinesigenic dyskinesia. Several cases of paroxysmal kinesigenic dyskinesia have been reported to respond to levodopa (123; 117). In five patients with paroxysmal kinesigenic dyskinesia, proton magnetic resonance spectroscopy revealed decreased basal ganglia choline levels in two patients and decreased myoinositol in one patient (100). In a case of paroxysmal kinesigenic dyskinesia, ictal SPECT revealed increased perfusion of the basal ganglia (103). Another report demonstrated ictal perfusion in the posterolateral thalamus in one case of paroxysmal kinesigenic dyskinesia (179), suggesting that abnormal activity is not limited to the basal ganglia. A study of 16 patients with idiopathic paroxysmal kinesigenic dyskinesia and 18 controls demonstrated significant interictal hypoperfusion in the posterior regions of the caudate nuclei bilaterally (91). A study using functional magnetic resonance imaging demonstrated increased amplitude of low-frequency fluctuation in the right postcentral gyrus in patients harboring the p.P217fsX7 mutation, compared to nonmutation carriers (126).

Several reports implicate the basal ganglia in paroxysmal nonkinesigenic dyskinesia. PET scanning revealed abnormalities in the basal ganglia metabolism of a patient with posttraumatic paroxysmal dystonia (150). One patient with paroxysmal nonkinesigenic dyskinesia showed decreased [18]FDOPA uptake and increased [11]C raclopride binding in the striatum but no metabolic abnormalities with [18]FDG PET (122). However, another family with paroxysmal nonkinesigenic dyskinesia was shown not to have abnormalities of striatal dopamine innervation (17). Invasive electrophysiology showed no cortical discharges associated with the paroxysmal nonkinesigenic dyskinesia but showed an abnormal discharge in the caudate nucleus. In a mutant hamster model of paroxysmal dystonia, pharmacological modulation of the GABAergic function affected the dystonia (60). The support for the GABAergic mechanisms also comes from an increase in the GABAA/benzodiazepine receptor-chloride ionophore complex in an animal model of paroxysmal dystonia (145).

In two patients with paroxysmal exertion-induced dyskinesia, SPECT scanning revealed decreased ictal perfusion of the frontal cortex during the motor attacks. In contrast, increased cerebellar perfusion was observed. The perfusion of the basal ganglia also decreased (102). No cortical hyperperfusion indicative of an epileptic nature was seen. Cerebellar hyperactivity in connection with prominent frontal hypoactivity has also been described in both the idiopathic and the symptomatic forms of dystonia. In contrast, a case report using subtraction SPECT imaging in a 16-year-old with paroxysmal exertion-induced dyskinesia revealed significantly increased cerebral perfusion in the medial aspect of the postcentral gyrus during an attack of foot dystonia (223). There was also mildly increased perfusion in the primary motor area and cerebellum during the episode. In a study of a number of families with co-occurrence of paroxysmal exertion-induced dyskinesia and epilepsy, there was a positive correlation between relative FDG uptake and the paroxysmal exertion-induced dyskinesia frequency score at the time of PET scanning in the left putamen (189). A negative correlation was observed in the left superior frontal cortex and left anterior cingulate cortex extending to the right side. In addition, when a patient had more frequent paroxysmal exertion-induced dyskinesias, the frontal lobe hypometabolism was more pronounced, as was the relative hypermetabolism in the putamen.

As already alluded to, paroxysmal hypnagogic dystonia, especially of short duration, represents a form of frontal lobe epilepsy in most cases.

Paroxysmal hemidystonia in demyelinating disease may reflect ephaptic transmission in the plaques. The site of the ephaptic transmission may occur at different levels of the neuraxis, including the midbrain and the thalamus (25; 170), the medulla (72), and the spinal cord (177). In one patient with paroxysmal dyskinesias in HIV-associated dementia, the autopsy showed diffused astrogliosis in the basal ganglia and the thalamus (141).

Paroxysmal nonkinesigenic dyskinesia has been reported in association with familial ataxia (132). Paroxysmal ataxias have been classified into two categories. Episodic ataxia type 1 is associated with interictal facial and hand myokymia and has been determined to be due to a missense point mutation in the potassium channel gene, KCNA1, on chromosome 12P (22). Episodic ataxia type 2 is associated with interictal nystagmus and has been assigned a gene locus on chromosome 12p (205). These observations, in addition to the linkage of paroxysmal choreoathetosis/spasticity to the vicinity of a potassium channel gene cluster on chromosome 1 (06), and the report of a family with paroxysmal dyskinesia and facial myokymia (58), suggest that at least some of the paroxysmal dyskinesias may be channelopathies (05). At least eight different types of episodic ataxias have been characterized, and most are considered forms of channelopathies (174; 164).

There are only two autopsy reports for paroxysmal kinesigenic dyskinesia. In one patient, there was only a slight asymmetry of the substantia nigra (187), and the other showed some melanin pigment in macrophages of locus coeruleus, suggestive of neuronal loss (97).

Epidemiology

The true prevalence of both inherited and symptomatic dyskinesia is not available. PRRT2 mutations are more common in males than females (ratio 52:32) (70).

Prevention

Avoidance of precipitating factors (eg, caffeine and alcohol) is important. Patients with paroxysmal exertion-induced dyskinesia should avoid prolonged exercise.

Differential diagnosis

Confusing conditions

Paroxysmal dystonias need to be differentiated from psychogenic movement disorders (20; 46). Indeed, an abrupt onset or paroxysmal component is one of the most important clinical presentations of psychogenic movement disorders (07). The distinction between psychogenic paroxysmal movement disorders and primary paroxysmal dyskinesias can be difficult. In a series of 26 patients with psychogenic paroxysmal movement disorders, red flags proposed for suspecting a psychogenic paroxysmal movement disorder included an adult age of onset, paroxysmal tremor as the predominant clinical feature, high phenomenological variability between episodes, the precipitation of an attack or an increase in symptoms severity during examination, an atypical and variable duration of attacks, the presence of multiple atypical triggers, an altered level of responsiveness, the presence of odd precipitating factors, the presence of unusual relieving maneuvers, additional psychogenic physical signs or medically unexplained somatic symptoms, and an atypical response to medication (66). A coexistent organic movement disorder was present in 19% of cases, highlighting the fact that “functional overlay” may complicate pre-existing organic symptoms. The prevalence of psychogenic paroxysmal dyskinesias is unclear.

Paroxysmal dyskinesias should also be differentiated from dopa-responsive dystonia, seizures, pseudoseizures, and tics. Complicating matters, both seizures (as described above) and tics have been described with paroxysmal dyskinesias (08; 222). Hypnogenic paroxysmal dyskinesia, owing to a seizure disorder, may be misdiagnosed as a benign nocturnal parasomnia (165; 12). Dopa-responsive dystonia usually presents in childhood and may have marked diurnal fluctuations, with the patient improving with rest and worsening with exercise (146). However, discrete paroxysms do not occur. Seizures arising from the supplemental motor area may resemble dyskinesias and sometimes may be precipitated by movement (57). The idiopathic paroxysmal dyskinesias have to be distinguished from symptomatic ones.

Diagnostic workup

A detailed history and videotape documentation are most important in the differential diagnosis of paroxysmal dyskinesias. A detailed family history should be obtained. Seizures may be confused with paroxysmal movement disorders. The possibility of frontal lobe seizures or frontal lobe pathology should be excluded in the setting of paroxysmal hypnogenic dyskinesia. Frontal lobe epilepsy has also been reported to present as paroxysmal craniocervical dyskinesia (128). An interictal EEG may be helpful in ruling out seizures in doubtful cases. Long-term EEG monitoring with video can be helpful. Invasive EEG may also be necessary in some cases. If the attacks are precipitated by hyperventilation, or there is no family history of a similar condition, an MRI of the head should be obtained to rule out structural causes, including multiple sclerosis. If the attacks begin in an elderly person, vascular disease should be looked for. In every patient, blood sugar should be obtained during the attack to look for hypoglycemia or hyperglycemia. Genetic testing should be considered, especially when there is a positive family history.

Management

Paroxysmal kinesigenic dyskinesia. This condition responds well to anticonvulsants. Response rates of up to 98.4% have been described with carbamazepine in individuals with PRRT2 mutations, with the majority achieving a complete response with low doses (50 to 100 mg daily) (89). Oxcarbazepine, in doses of 75 to 300 mg daily, has also been used with success (110). It is important to note that Stevens-Johnson syndrome and toxic epidermal necrolysis are serious side effects associated with carbamazepine and oxcarbazepine, with a higher risk in Asians, but also affecting non-Asians, with HLA-B*15:02 allele (98). Phenytoin may also be effective, and the dose required in adults is usually less than the standard anticonvulsant dosage (85). Other anticonvulsant medications have been used, including phenobarbital (77), levetiracetam (31), topiramate (87), and lacosamide (110). One case report of paroxysmal kinesigenic dyskinesia and cerebral palsy required high doses of phenytoin (400 mg/day) for symptom control (18). Improvement with caffeine has also been described in one case of paroxysmal kinesigenic dyskinesia associated with the PRRT2 mutation (108).

Paroxysmal nonkinesigenic dyskinesia. Response to treatment in paroxysmal nonkinesigenic dyskinesia is not as consistent as in paroxysmal kinesigenic dyskinesia. Avoidance of precipitating factors like alcohol, caffeine, and stress is important. Clonazepam is the mainstay of therapy for paroxysmal nonkinesigenic dyskinesia, and individuals with MR-1 mutations seem to have better responses to benzodiazepines than those without mutations in the MR-1 gene (188). Anticonvulsants appear to be ineffective in most cases. A number of other medications have also been used with inconsistent results, including haloperidol, alternate-day oxazepam, and anticholinergics (138). Improvement with levetiracetam was described in one family (191). Thalamic deep-brain stimulation has been reported to be beneficial in a patient with painful paroxysmal nonkinesigenic dystonia (120). Bilateral globus pallidus internus deep-brain stimulation was also successful in one patient with paroxysmal bilateral dystonia, who also had a background of mild mental retardation, impulse control difficulties, and bilateral choreiform movements (96).

Paroxysmal exertion-induced dyskinesia. Avoidance of prolonged exercise may help diminish the frequency of attacks. Drug therapy is often ineffective but there are isolated reports of improvement with levodopa (46; 117; 42) and acetazolamide (13; 04). Those with GLUT1 mutation may respond to ketogenic diet or a less restrictive modified Atkins diet (168). The ketogenic diet may also improve developmental delay in affected children (188).

Symptomatic paroxysmal dyskinesias. The paroxysmal dystonia associated with multiple sclerosis responds well to anticonvulsants. Acetazolamide is a useful alternative or adjunct to anticonvulsants (172). The choreoathetosis secondary to head injury may respond to anticonvulsants or a combination of anticonvulsants and trihexyphenidyl (150). The underlying abnormality needs to be addressed in metabolic cases, including treatment of hypoglycemia, hyperglycemia, and thyrotoxicosis. The paroxysmal kinesigenic dyskinesia associated with hypoparathyroidism may resolve with treatment of hypocalcemia by vitamin D. Vascular risk factors must be addressed where the paroxysmal dyskinesia is thought to be due to transient ischemic attacks.

Special considerations

Pregnancy

In a large Polish family with paroxysmal nonkinesigenic dyskinesia and confirmed mutation in the MR-1 gene, the female family member experienced a complete disappearance of the attacks during pregnancy (64). Seven out of thirteen patients with paroxysmal kinesigenic dyskinesia reported improvement of symptoms during pregnancy, whereas one of the 13 patients described worsening of the attacks (23).