Th e second cardinal feature of EA1 is myokymia \200\224spontaneous skeletal muscle contrac tions \200\224which may produce clinically vis- ible rippling of the muscles or which may b e detectable only by EMG. Myokymia may be associated with neuromyotonia (muscle cramps and stiff ness). Unlike the ataxia, the myokymia is not epi- sodic in nature. When visible or p alpable, myokymia may be iden- tifi ed in the face (e.g. around the eyes and mouth) or the limbs. When present in the fi ngers, myokymia produces small-amplitude pseudo-choreiform mo vements when the hands are outstretched or in a relaxed prone position. Myokymia is detecte d by EMG even when subclinical (67, 69 \200\22373, 75). Other neuromuscular fea- tures may also be observed in EA1. For example, calf hypertro- phy and shortened Achilles tendons are described (70, 72, 76). Patients may also develop fi xed postures in the hands which can w orsen during attacks (70, 71). Sometimes abnormal hand and foot posturing is described as b eing present since birth (71, 72). Apart from these generally mild neuromuscular abnormalit ies, the neurological examination in EA1 is usually normal (70, 73), although mild interict al cerebellar features are described (74, 76). A single patient is reported to have a progr essive interictal cer- ebellar syndrome (75). Pharmacological eff ects are described in individual cases with- out formal clinical trials . Early reports describe improvement with phenytoin (69, 70, 72, 73), but worsening with ph enytoin is also described (72). Carbamazepine is variably reported as helpful or ineff ecti ve (74 \200\22376). While oft en presumed to be the treatment of choice, acetazolamide and diclofenamide, both carbonic anhydrase inhibitors, are ineff ective (69, 72, 73, 81) or onl y transiently benefi - cial (76). Sulthiame, another carbonic anhydrase inhibitor, halved a ttack frequency in one patient (73). Flunarazine was also helpful for one patient (69). Age nts reported as ineff ective include viga- batrin (76) and clonazepam (73, 76). Lamotrigine worsened attack frequency in one case (76). It is suggested that drug-resistant EA1 may be associated with certain genotypes (76), but this has yet to be confi rmed. Depending on at tack characteristics, patients and fami- lies should be counseled regarding particular care or avoidance of potentially dangerous activities \200\224one EA1 patient almost drowned du ring an attack (73). EA1is a monogenic potassium channelopathy associated with KCNA1 . It has AD inheritance and incomplete penetrance. Over CHAPTER 26 Paroxysmal Movement Disorders 275 20 pathogenic mutations of KCNA1 have been described, primarily missense mutations. Mutatio ns are identifi ed via sequence analysis (68). KCNA1 encodes the potassium channel subunit Kv1.1. It is theorized that mutations result in diff erent eff ects on channel func- tion, including changing potassium currents and aff ecting neuro- transmitter release (68, 82, 83 ). aff ecting extra-ocular movements are described in some EA2 cases (84, 92). Over half of EA2 patients have migraine and a small number have symptoms suggestive of FHM, consistent with the fact that both EA2 and FHM are due to mutations in CACNA1A (85, 86, 89 ). Extreme alcohol sensitivity is characteristic (89, 90). Epilepsy, dystonia, and learning disabilities have each been reported (sepa- rately and in combination) in EA2 families (84 , 85, 88, 91, 93, 94). A recent paper highlights psychiatric disorders in three patients wi th EA2 (91), but psychiatric disturbance is not commonly described in prior reports. Phenom enology and associated symp- toms vary widely between and within families. One family had d if- ferent individuals exhibiting EA2, FHM, and SCA6 phenotypes, despite the fact that thes e typically refl ect diff erent CACNA1A mutations (95). Episodic ataxia type 2 (EA2) Th e most common of the EAs (80), episodic ataxia type 2 (EA2) , is related to mutations in CACNA1A . Diff erent mutations in CACNA1A lead to familial hem iplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6). Additionally, families and individuals with phenotypes similar to CACNA1A -related EA2 are described without an ident ifi ed mutation. Th e clinical phenotype of EA2 related to CACNA1A mutations can vary even within families ( 84), but a general pattern is still clear. Attack onset almost always begins before age 20 (84 \200\22386), although presentations as delayed as the late sixties are described (87, 8 8). Episodes of truncal and limb ataxia usually last hours, though epi- sodes of shorter du ration (minutes) and longer duration (days) are also described (84 \200\22386, 89). Episode s may occur several times per day or only occasionally during a lifetime (84, 86). Triggers include physical exertion, emotional stress, heat, fever, alcohol, and coff ee (84, 86, 89 , 90). Episodes of ataxia may be accompanied by ver- tigo, nausea and vomiting, dysarthria, headache, and fl uctuating generalized weakness (84 \200\22386, 89, 90). During attacks, s pontaneous nystagmus may be seen (85) and patients may complain of double or blurred vision (84, 86). Rarely, dystonia is observed in addition to ataxia (80, 85). Clinical features o f classic CACNA1A -associated EA2 are summarized in Box 26.4. Abnormalities are present in some children with CACNA1A mutations prior to the EA onset. Be rtholon and colleagues (92) described early onset of episodic imbalance in one child (sugge stive of benign paroxysmal vertigo of childhood) and permanent imbal- ance, strabismus, hyp eractivity, and delayed cognitive milestones in another child, both of whom had family hist ories of EA2 and later developed EA themselves. Paroxysmal torticollis of infancy is report ed in many families with CACNA1 mutations (91). Th ree reported individuals with CACNA1 mut ations, two of whom were brothers, exhibited early childhood ataxia and mental retardation without superimposed ataxic episodes (84). MRI in EA2 may be normal or show cerebellar atrophy (84, 86, 89, 91, 95, 96). In one study, the presence of cerebellar atrophy cor- related with interictal limb ataxia and impaired t andem gait (91). Half the patients in one series had abnormal EEGs (91). Another study show ed varied EEG fi ndings among family members (95). Quantitative eye-movement testing and fo rmal posturography can reveal interictal abnormalities not detected clinically (86). A pre- liminary study investigated the use of nerve excitability studies to assist in the diagnos is of EA2 (97), but the results require further confi rmation. Unlike most other paroxysmal movement disorders, the inter- ictal neurological examination in EA2 patients is usually abnor- mal. Most patients have gaze-evoked nystagmus. Primary po sition downbeat nystagmus may also be present. Additionally, over half of EA2 patients disp lay gradually progressive ataxia on interictal neu- rological examination. Rare EA2 family members may have pro- gressive ataxia without superimposed attacks. Interictal dysarthria c an be present (84 \200\22386, 89 \200\22391). Strabismus and cranial nerve palsies Th e majority of EA2 patients describe decreased severity and frequency of ataxic episodes with acetazolamide (84, 85, 89), and abnormal interictal oculomotor fi ndings respond to ac eta- zolamide in some patients (98). In a series of EA2 patients, 71% (15/21) improved with acetazolamide at doses of 250 \200\2231000 mg daily (85). Response can diff er across fami ly members carrying the same mutation. Given that over a fourth of EA2 patients will not re spond to acetazolamide, lack of treatment eff ect should not exclude the possibility of CAC NA1A mutations (85). One patient with late-onset EA2 and a confi rmed CACNA1A mutation expe ri- enced a dramatic dose-dependent worsening with acetazolamide, but subsequently responde d to therapy with 4-aminopyridine (96). Th e potassium-channel blocker 4-aminopyridine is a nother therapeutic option for EA2, with complete resolution of episodes described in three patients at a dose of 5 mg three times daily (99). Improvement in interictal ataxia with 4- aminopyridine in a patient with clinically diagnosed late-onset EA2 is also described (100) . Treatment with 4-aminopyridine is generally considered if aceta- zolamide therapy has bee n ineff ective, or has lost eff ectiveness, or is associated with adverse eff ects. One pat ient who experienced side eff ects with acetazolamide benefi ted from topiramate (92) and a nother patient with an incomplete response to acetazolamide ben- efi ted from the addition of valproic acid (94). Box 26.4 Clinical features of CACNA1A mutation episodic ataxia type 2 (EA2) 1. Onset before age 20. 2. Episodes of ataxia lasting hours to days, oft en triggered by emotional stress and physi cal exertion. Ataxia may be accom- panied by vertigo, generalized weakness, and dystonia. 3. Associated symptoms may include migraine or hemiplegic migraine and seizures. 4. Interictal neurological examination demonstrates gaze-evoked and rebound nystagmus. Inte rictal ataxia and dysarthria may also be seen. 5. Family history of a similar movement disorder is supportive but not required. Adapted from Jen J, Kim GW, Baloh RW. Clinical spectrum of episodic ataxia type 2. Neurolog y 2004; 62: 17 \200\22322. Oxford Textbook of Movement Disorders 276 EA2 related to CACNA1A mutations is inherited in an AD man- ner with incomplete penetrance, but de novo mutations are also described. Th us patients with an EA2-like presentation sho uld be screened for CACNA1A mutations regardless of family history (84, 85). Over 50 diff e rent CACNA1A mutations producing an EA2 phenotype are identifi ed throughout the gene, so a full sequence analysis must be performed in patients in whom a mutation is suspected (80, 85). Families linking to 19p but without identifi - able mutations in CACNA1A , and patient s and families with an EA2-like picture but without identifi able linkages, are described ( 84, 85). In recent years, large deletions in CACNA1A have been identifi ed in EA2 patients in whom point mutation screening was negative (101 \200\223103). A genetic study in 2010 fo und deletions in CACNA1A in 4/27 patients (14%) with an EA2-like clinical pic- ture but no point mutation in CACNA1A (101). One family with a duplication in CACNA1A is also described (103). Th ese reports suggest that CACNA1A deletion and duplication analysis should be con sidered in EA2 patients, particularly if routine sequence analysis is negative. Caution sho uld be used in assigning a diagnosis of EA2 clinically without genetic confi rmation as num erous patients and families with EA2-like presentations are negative for CACNA1A mutations, including individuals later categorized as EA6 and EA7. Th is distinction may become incre asingly important as therapies targeting mutated channels become available. (107). A few individuals demonstrated mild cerebellar fi ndings on examination, but only on e patient \200\224with congenital nystagmus \200\224 displayed interictal oculomotor abnorm alities. One EA3 patient and two siblings without EA had epilepsy. Acetazolamide reduced at tack frequency (106). Genome-wide screening of this family with AD inheritance links EA3 to 1q42, but the aff ected gene remains unknown (107). EA4 is an AD disorder described in three North Carolina kin- dreds with suspected common an cestry (108). It is also termed PATX (periodic ataxia). Unlike other EAs, attack onset is i n adult- hood (23 \200\22360 years) (108, 109). Attack frequency ranges from daily to rarel y, with years separating episodes. Attack duration is gen- erally minutes, but attacks last ing for months are described (109). Triggers include sudden changes in head position or obj ects mov- ing across one \200\231s vision (108, 109). Ataxia, vertigo, and diplopia form th e characteristic episode triad. Tinnitus, oscillopsia, nausea, and vomiting are also report ed. One family experienced decreased episode frequency and severity with the antihistamine dimenhy- drinate (109). Acetazolamide is ineff ective (110) or not tolerated (108). Lying q uietly with the eyes closed helps episodes resolve (108). Tinnitus occurs between attacks i n some patients. Interictal nystagmus is common, and over half of patients with serial exam i- nations develop interictal cerebellar ataxia of varying degrees, sometimes severe (109). Formal ocular motility testing shows gaze-evoked nystagmus, abnormal smooth pursuits, and inability to suppress the vestibulo-ocular refl ex (108). Linkage to several AD ataxias and EAs has been excluded, but the genetic basis of EA4 remains unknown (110). A comparison in 2010 of EA2 patients with CACNA1A mutations and mutation-negative patients suggests that CACNA1A mutation carriers may present at a younger age, have more frequent at tacks, respond more frequently to acetazolamide, and demonstrate more interictal abnormalit ies in pursuit and saccades but less interictal ataxia than the mutation-negative patients (though screening for deletions and duplications was not performed). Only age at onset and the presence of pursuit and saccade abnormalities remained statistically signifi cant aft e r Bonferroni correction (91). EA associated with mutations in CACNB4 on chromosome 2q22 \200\22323, designated EA5 , was identifi ed in one family when 71 families with EA were screened for this mutation. Limited clinical data for this French Canadian family suggest that episodes of vertigo and ataxia began in adulthood (around 20 \200\22330 years old) and lasted for hours to days. Intericta l neurological examination may reveal mild ataxia, dysarthria, and nystagmus. Acetazolamide prevents attacks (111). Th e same CACNB4 missense mutation was identifi ed in a family wit h generalized epilepsy and no ataxia (111). CACNA1A codes for the Cav2.1 subunit of P/Q type voltage-gated calcium channels, which has roles including pore-forming and voltage-sensing. Th ese channels are expressed in the cere bellum and presynaptically at the neuromuscular junction. Th e mecha- nism underpinning the episodic attacks in EA2 remains unknown (80). A full discussion of the evolving understand ing of the patho- physiology of EA2 is complicated, but a summary of the current knowledge regarding changes in Cav2.1 channels with CACNA1A mutations is available (104). Th e role o f abnormally prolonged hyperexcitability is also under investigation as an explanation of t he paroxysmal nature of EA2 attacks (105). Further studies are required to elucidate the pa thophysiology of this disease. EA6 relates to mutations in SLC1A3 which encodes the glutamate transporter EAAT1. An SLC1A3 mutation was initially identifi ed in a child with sporadic disease. Th is 10-year-old boy had a severe clinical phenotype, including motor developmental delay, pro- gressive ataxia , superimposed episodic ataxia and slurred speech starting at age 6 months, alternating hem iplegia and migraine start- ing at age 6 years, and seizures (112). Subsequent screening of 20 additional EA patients identifi ed a novel EAAT1 mutation in the proband of a Dutch fam ily. Th e clinical phenotype in this family was similar to that seen in EA2. Attacks starte d in childhood (3 \200\22314 years old) and were triggered by exercise, stress, fatigue, al cohol, and caff eine. Attack frequency ranged from monthly to every few months and most epi sodes lasted hours. Ataxia, vertigo, nausea, vomiting, dysarthria, photophobia, and phonoph obia occurred during attacks, but not headache. Acetazolamide markedly reduced attack frequ ency. Interictal neurological examination showed hori- zontal gaze-evoked nystagmus in the proband (113). In both stud- ies, the mutant EAAT1 demonstrated varying degrees of reduced uptake of glutamate (112, 113). Other episodic ataxias Th e other EAs, while labeled through to EA7 (see Table 26.2), are s ubstantially less common than EA1 and EA2. Each is only reported in three or fewer families . Rare late-onset EAs without an offi cial designation are also described. EA3 was described in a large Canadian Mennonite kindred. Ataxic episodes in the family occu rred daily and lasted for 10 \200\22330 minutes (106). Median age of onset was 13 (107). Tr iggers included exertion, certain movements, stress, fatigue, and arousal from sleep. Th e epi- sodic ataxia was frequently accompanied by falls. Ataxic episodes commonly included ve rtigo, tinnitus, headache, and visual blurring or diplopia (106). Almost half the aff ected individuals described episodes of myokymia (106), but EMG did not reveal abnormalities A single report described the EA designated EA7 (114). Th e aff ected family had attack ons et in childhood. Episodes lasted for hours to days but were infrequent, ranging from monthl y to CHAPTER 26 Paroxysmal Movement Disorders 277 every few years. Triggers included excitement and exercise, and episodes were characterized by ataxia, weakness, and dysarthria. Associated vertigo was variable and migraines, apart from attacks, occurred in some family members. Attack frequency tended to decrease with age . Baseline neurological examination was nor- mal. Aff ected family members linked to chromo some 19q13, but sequencing of the suspected genes KCNC3 and SLC17A7 showed no mutations (11 4). Episodic ataxia type 2 (EA2) is characterized by acetazolamide- responsive episodic ataxia and interictal nystagmus and is related to mutations in CACNA1 . \227\206 References 1. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classifi cation . Ann Neurol 1995; 38 : 571 \200\2239 . 2. Blakeley J, Jankovic J. Secondary paroxysmal dyskinesias . Mov Disord Late-onset episodic ataxias without offi cial designations are also reported. Julien and co lleagues (115) describe four unrelated patients with onset of episodic ataxia aft er age 60 . Episodes occurred daily to several times per week, lasted for minutes to hours, and were unre- sponsive to acetazolamide (500 mg daily). Nystagmus and slowly progressive ataxia wer e noted on examination (115). Four families with late-onset (40 \200\22364 years) episodic oscillopsia were reported with progressive gait ataxia but without clear episodic ataxia. 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