PKD attacks generally last less than 30 \200\22360 seconds but can occur over 20 times dail y. Episode phenomenology is dystonia in over half of cases; mixed hyperkinesias are present in another third. Chorea and ballism alone occur rarely. Involved limbs may be unilateral or bilateral. When unilateral, the aff ected limbs may be consistently on one side or varia ble (6). Almost all PKD patients have their fi rst attack before age 20 and 90% have episodes prior to age 15. Episodes stop or decrease in the majority of PKD patients in their twenties. Whi le various antiepileptic drugs (AEDs) have been tried, 86% of PKD patients requiring medica tion responded to carbamazepine or phenytoin in one series (6). Similar benefi ts are seen in other PKD studies (7, 8). Oxcarbazepine may also be eff ective and has advantages given its diff erent side-eff ect profi le (9). Paroxysmal dyskinesias Paroxysmal dyskinesias are rare disorders characterized by attacks o f choreoathetosis, dystonia, and ballismus. Although phenome- nology is diverse, six have r eceived DYT designations (Table 26.1). Various clinical classifi cation schemes have been p roposed and revised over time, with four main subtypes \200\224paroxysmal kinesi- genic dys kinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD), paroxysmal exercise-induced dy skinesia (PED), and paroxysmal hypnogenic dyskinesia \200\224each with idiopathic and sec- ondary causes (1). Mixed forms are also described (2 \200\2234) with the suggestion that an additional classifi cation of \200\230paroxysmal dyski- nesias, mixed type \200\231 be co nsidered (3). Th ese categorizations based on clinically observed patterns are being furthe r refi ned as genetic causes are identifi ed. Familial PKD is more common than sporadic PKD, but clin- ical characteristics are similar ( 6). A small subset of familial PKD cases has an infantile-onset movement disorder with a mi ldly dif- ferent phenotype (6). Patients with familial PKD are more likely to have a person al and family history of infantile convulsions. Th is is unsurprising given that the loci f or benign infantile familial con- vulsions and paroxysmal choreoathetosis (ICCA) overlap wi th those for PKD (6, 7, 10). Adolescent- and adult-onset epilepsy (8, 10), migraine (6), an d writer \200\231s cramp (6) are also described in PKD patients and families. It remains un clear if these relate to the same underlying pathophysiology. Familial PKD shows autosomal dominant (AD) inheritance, but an associated gene has yet to b e identifi ed. Multiple studies link familial PKD to chromosome 16. Two diff erent loci (EK D1 and EKD2) are known, with others still suspected (7, 8, 10, 11). Despite these linkages, screening for abnormal genes has been unsuccessful (12, 13). It is generally assumed that PKD is related to an ion-channel mutation, but this is yet to be shown. With no avai lable genetic testing, diagnosis is based on clinical criteria (Box 26.1) supplemented by normal neurological examination, imaging, and electroencephalography (EEG). Paroxysmal kinesigenic dyskinesia PKD is the most common of the paroxysmal dyskinesias with an estimated prevalence of 1 in 150 000 (5). A series of 121 aff ected individuals evaluat ed in 2004 established the diagnostic criteria (Box 26.1) (6). Individuals aff ected by PKD have a normal interic- tal neurological examination. Dyskinetic episodes are triggered by activities such as standing up, walking, and running. Less com- mon triggers include startl e or focal movements such as stretch- ing. Uncommon triggers include caff eine and fatigue. Anxiety oft en Oxford Textbook of Movement Disorders 270 Table 26.1 Paroxysmal dyskinesias assigned a DYT designation Designation DYT8 Dystonia type Paroxysmal non-kinesigenic dyskinesia (PNKD1) Mode of inheritance AD Gene locus 2q35 Gene Myo \201 brillogenesis regulator 1 ( MR1 ) Unknown OMIM number 118800 DYT9 Paroxysmal choreoathetosis with episodic ataxia and spasticity AD 1p 601042 DYT10 Paroxysmal kinesigenic dyskinesia (PKD) AD 16p11.2-q12.1 Unknown 128200 DYT18 Paroxysmal exertion-induced dyskinesia (PED) with or without epilepsy and/or haemolytic ane mia AD 1p35-p31.3 Glucose transporter SLC2A1 612126 DYT19 Episodic kinesigenic dyskinesia 2 (EKD2) or PKD2 AD 16q13-q22.1 Unknown 611031 DYT20 Paroxysmal non-kinesigenic dyskinesia 2 (PNKD2) AD 2q31 Unknown 611147 AD, autosomal dominant; OMIM, Online Mendelian Inheritance of Man. Adapted from http://www.ncbi.nlm.nih.gov/omim. PNKD associated with MR- 1 mutations (DYT-8) Th e PNKD phenotype is consistent across eight kindreds with diff erent MR- 1 mutations. Attacks start at age 4 years on average (range 3 months to 12 years). PNKD attacks are superimposed on a normal baseline neurological exami nation. Positive and nega- tive emotions can lower attack threshold. Caff eine and alcohol are almost universal triggers. Less common triggers include heat, exercise, fatigue, menstr uation, and hunger. Sleep is commonly benefi cial (22). Most patients experience attacks at least weekly, though rare attacks are also described. Typical attacks last from 10 minutes to 1 hour, ranging from several minutes to 12 hours (22). Aura occurs in approximately 40% of patients and may involve focal limb numbness, stiff ening, or general anxiety. Attack p he- nomenology combines chorea and dystonia and can vary within an individual over time and between members of the same fam- ily. Less commonly reported phenomenology includes blepha ros- pasm, risus sardonicus, and diplopia. Speech involvement occurs in just under half of patients. Attacks tend to decrease in frequency with age, although natural history varies ( 22). Headache and migraine are commonly reported in PNKD families (22). Based on these clin ical fi ndings and comparison with gene-negative PNKD patients (see further discussion in t he next section), clini- cal diagnostic criteria for MR- 1 mutation PNKD have been pro- pos ed (Box 26.2) (22). Numerous reports hypothesize secondary causes for PKD pres- entations including cerebral pa lsy (14), peripheral trauma (2, 15), subcortical white matter ischaemia (16), cervical cord compression (17), primary central nervous system lymphoma (18), HIV (19), voltage-gated po tassium channel (VGKC) complex protein anti- body encephalitis (20), and hyperglycaemia (21 ). Whether these observations represent true causal links is unclear. Interestingly, severa l of these cases also respond to carbamazepine (2, 15, 17, 18). Phenytoin (14) and benzodia zepines (19) are benefi cial in other cases. In the patient with VGKC-complex protein antib ody encephalitis, PKD symptoms decreased aft er intravenous immu- noglobulin infusions (20) . Paroxysmal non-kinesigenic dyskinesia Attacks in PNKD are spontaneous rather than triggered by sud- den movements as in PKD. PNKD attacks also tend to be longer (lasting minutes to h ours) than those seen in PKD. With identi- fication of causative mutations in the myofibril logenesis regula- tor 1 ( MR- 1 ) gene, PNKD families are further divided into true PNKD (w ith the mutation) and \200\230PNKD-like \200\231 conditions without an identified mutation (22). Box 26.1 Clinical diagnostic criteria for paroxysmal kinesigenic dyskinesia (PKD) Non-benzodiazepine anticonvulsants are generally unsuccess- ful in preventing PNKD attacks. However, in a series of PNKD patients, 34 of 35 patients who tried benzodiazepines for eit her pre- ventive or abortive therapy responded favorably (22). While ben- zodiazepines are the mainstay of treatment, individual PNKD cases improved with valproate (22), levetiraceta m (23), oxcarbazepine (24), haloperidol (22), acetazolamide (22), and levodopa (22). 1. Dyskinetic attacks triggered by sudden movements. 2. Short duration attacks (<1 min). 3. No loss of consciousness or pain during attacks. 4. Antiepileptic drug responsiveness (particularly carbamazepine Familial PNKD follows an AD inheritance pattern. Aft er linking PNKD to the long arm of chr omosome 2 (2q32 \200\22336 locus), several studies identifi ed causative MR- 1 mutations (2 5 \200\22328). Penetrance is high (22, 26 \200\22328). Th e function of MR- 1 remains unkno wn (26, 28), but it is predicted to be an enzyme in a stress response pathway (25). or phenytoin). 5. Exclusion of other organic diseases. 6. Age of onset between 1 and 20 years if there is no family history. Adapted from Bruno MK, Hallett K, Gwinn-Hardy K, et al. Clinical eval- uation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology 2004; 63: 2280 \200 \2237. PNKD-like phenotypes without MR- 1 mutations Clinical features of six \200\230PNKD-like \200\231 kindreds without MR-1 muta tions have been compared with the gene-positive kindred s (22). Age of CHAPTER 26 Paroxysmal Movement Disorders 271 brachial plexus neuropathy (33), stroke (2), subcortical white matter ischaemia (16), intra cerebral calcifications second- ary to hypoparathyroidism (34), antiphospholipid syndrome ( 35), central trauma (2), kernicterus (2), HIV (19), cytomega- lovirus encephalitis (2), str eptococcal infection (36), multiple sclerosis (2), and migraine (2). Mixed PKD \200\223PNKD pheno- types secondary to stroke, peripheral trauma, central trauma, and meningovascular s yphilis are also proposed (2). Attack characteristics in these reports are not always consi stent with PNKD or PNKD-like pro cesses. Unsurprisingly, some patients with presumed second ary PNKD have abnormal neurological examinations at baseline (2, 19). Furthermore, attacks may be longer or shorter than those described in familial PNKD and PNKD-like processes (2, 34) and triggers other than stress are rare. Box 26.2 Clinical diagnostic criteria for MR- 1 mutation paroxysmal non-kinesigenic dyskine sia (PNKD) 1. Involuntary episodes of hyperkinetic movements (dystonia, chorea, or a combination). 2. Attack duration typically 10 minutes to 1 hour (up to 4 hours). 3. Normal interictal neurologic examination. 4. Exclusion of secondary causes. 5. Onset of attacks in infancy or early childhood. 6. Precipitation of attacks by caff eine and alcohol consumption. 7. Family history of movement disorder meeting criteria 1 \200\2236. Adapted from Bruno MK, Lee H-Y, Auburger GWJ, et al. Genotype \200\223 phenotype correlatio n of paroxysmal nonkinesigenic dyskinesia. Neurology 2007; 68: 1782 \200\2239. Pharmacological therapies described as eff ective in individuals with proposed secondary PN KD include anticonvulsants (e.g. car- bamazepine, phenobarbital) (2), valproate (33), levet iracetam (34), clonazepam (2), tetrabenazine (2), biperiden (33), trihexyphenidyl (2), and botulinum toxin injections (33). Clonazepam and other agents have been of no reported benef i t (2, 19, 33, 34). It is unclear whether treating the proposed underlying etiology aff ec ts PNKD symptoms. Various functional stereotactic neurosurgical proced- ures have been util ized for refractory secondary PNKD cases with reported success, including deep brain stimul ation (DBS) of the thalamus (33) and globus pallidus internus (GPi) (32). Bilateral GPi DBS also benefi ted a complicated patient with refractory PNKD of unknown etiology (37). onset is later than in MR-1 -positive patients (12.3 10.8 years versus 4.0 4.6 years) . Aura is reported in 63%, and triggers include exercise, caff eine, fatigue, emotional str ess, heat, and hunger. Exercise as a trig- ger is more common in these pedigrees (68% of pa tients) than in those with MR- 1 mutations (12%). Alcohol is not a trigger in PNKD-like pat ients, a notable distinction from MR- 1 mutation patients. Attack phenomenology includes dy stonia, chorea, ballism, and combina- tions. Attack duration is similar to MR-1 -positive P NKD attacks. Weekly attacks occur in a third of PNKD-like patients and are less frequent in the remainder. Of 22 PNKD-like patients, fi ve also had epilepsy (two of whom had basal ga nglia calcifi cations), two had mild ataxia on baseline examination, and single cases had m igraine without aura, cluster headache, attention defi cit hyperactivity disorder with auti sm, and a learning disability (22). Paroxysmal exercise-induced dyskinesia (PED) Th e category paroxysmal exercise (or exertion )-induced dyskinesia (PED) is assigned when episodes of dyskinesia are trigged by pro- long ed exertion or exercise as opposed to simple movement. PED is less common than both PKD and PNKD. In 2008, mutations in SLC2A1 were discovered in several families with PED and epilep sy. SLC2A1 codes for glucose transporter 1 (GLUT1), a blood \200\223brain barrier glucose t ransporter (38, 39). Th e gene is now labeled both SLC2A1 and GLUT1 . Familial PED demonstr ates AD inheritance with incomplete penetrance (38). PNKD-like patients may partially improve with benzodiazepine therapy (22). Partial response with valproate, carbamazepine, topiramate, gabapentin, and acetazolamide has also been des cribed in individual patients. Carbamazepine, phenytoin, and levodopa have worsened attacks (22). Causative genes for familial PNKD-like disorders have yet to be identifi ed. A Canadian fam ily links to a locus at 2q31 without mutations in MR- 1 (29). Consistent with the PNKD-like pheno- type identifi ed by Bruno and colleagues (22), age at onset in this family was high ly variable, attacks were not triggered by alcohol or caff eine, and there was no response to clonazepam (29). A genome-wide linkage scan of a family with AD generalized epi- lepsy a nd paroxysmal dyskinesia (GEPD) mapped to 10q22 with a mutation in KCNMA1 . Th is mutation is in the alpha subunit of a calcium-sensitive potassium channel. While the movement disord er in this family was labeled PNKD, and described as episodic dystonia and chorea triggered by alcohol, fatigue, and stress but not movement, features unusual for PNKD included very brief episode duration (10 s to 2 min) and a strong associa- tion with familial epilepsy (3 0). A four-generation family with intracranial calcifi cations and PNKD has no linkage iden tifi ed to date (31). Limited cases are available to establish a clinical picture of SLC2A1 \200\223GLUT 1 PED. I n SLC2A1 \200\223GLUT 1 families, movement disorder onset tends to occur during childhood ( median 8 years), though onset in individuals up to age 30 is described (38). By defi - niti on, the primary trigger is exertion, such as prolonged brisk walking. Typically, 15 \200 \22360 minutes of exercise is required (39). Other triggers include stress, starvation, and sleep deprivation. Alleviating factors include eating (particularly something with glu- co se or sugar), rest, and avoidance or cessation of provoking activi- ties (38). Aura, includ ing autonomic and sensory symptoms, occurs in some patients (38). Phenomenology includes ch oreoathetosis, dystonia, ballism, and combinations (38, 39). Legs are more com- monly aff e cted than the face or arms (38 \200\22340), possibly represent- ing preferential involvemen t of exercising limbs since attacks are common aft er walking. Localization can be consiste nt and focal or varied (38). Episode frequency ranges from weekly to yearly (38). Attacks g enerally last up to 15 min, but duration ranges from sec- onds to several hours (38, 39). D yskinesias may stop immediately with exercise cessation or may resolve gradually over hours (39). Secondary PNKD Sporadic PNKD is rarely reported, but case reports and small series posit se condary causes including peripheral trauma (32), Oxford Textbook of Movement Disorders 272 Numerous SLC2A1 \200\223GLUT1 mutations are now identifi ed in PED families and sporadic ca ses (38, 39, 41). PED attacks may result from reduced transportation of glucose across the blood \200\223brain barrier due to mutations aff ecting the GLUT1 transporter. It is hypoth - esized that because the basal ganglia are particularly sensitive to energy defi cits, the se areas may be preferentially aff ected (38, 39). Families with PED and epilepsy associate d with SLC2A1 \200\223GLUT1 mutations are distinct from the GLUT1 defi ciency syndrome asso - ciated with microcephaly, motor and cognitive developmental delay, epilepsy, spasticity, dystonia, ataxia, and other severe impair- ments (38, 39). Box 26.3 Clinical diagnostic criteria for SLC2A1 \200\223GLUT1 mutation paroxysmal exercise -induced dyskinesia (PED) 1. Childhood-onset intractable exercise-induced dyskinesias, sometimes with early-onset epilepsy. 2. Normal neurological examination between attacks. 3. Normal MRI. 4. Moderately low CSF glucose/serum glucose concentration (or demonstrated SLC2A1 \200\223GLUT1 mutation). 5. Family history of PED and/or epilepsy is supportive, but spor- While SLC2A1 \200\223GLUT1 mutations are now identifi ed in numer- ous families with a PED phenotype, at least two families with similar features have no SLC2A1 \200\223GLUT1 mutatio ns (39). Th e possibility of other gene involvement remains. Additionally, one family with PED and no mutation in SLC2A1 \200\223GLUT1 had a mutation in GTP-cyclohydrolase 1. Patient s in this fam- ily responded well to levodopa, consistent with a diagnosis of dopa-responsi ve dystonia (DRD). Clinical features diff ered slightly from the PED pattern described abov e; in addition to being levodopa-responsive, episodes were triggered more quickly than in S LC2A1 \200\223GLUT1 -associated PED (requiring only a few minutes of exercise) and occurred more frequently (daily or sev- eral times weekly). In the index case, CSF glucose/plasma g lucose ratio was borderline at 0.59, but the patient had abnormally low CSF neurotransmitte r levels consistent with DRD (43). PED is also reported in the context of AD familial acant hocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (FAPED), a rare neuroac anthocytosis syndrome associated with a glucose transporter mutation (44). adic mutations have been demonstrated. Adapted from Suls A, Dedeken P, Goffi n K, et al. Paroxysmal exercise-induced dyskinesia an d epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain 200 8; 131: 1831 \200\22344. As with the other paroxysmal dyskinesias, neurological examina- tion between attacks is gen erally normal, though mildly reduced intelligence or cognitive impairments in some mutation carriers is reported (38, 39). Mild permanent neurological abnormalities are also describe d in some individuals (39). PED symptom severity may lessen with age (38, 39). Clinical fea tures are summarized in Box 26.3. Sporadic cases of PED with SLC2A1 \200\223GLUT 1 mutations have clinical features similar t o those described in SLC2A1 \200\223GLUT1 PED families including childhood onset, exercise- induced episodes, attack resolution with rest, and normal or only mildly abnormal neurologi cal examination (41, 42). In four reported cases, two of whom were twins, writer \200\231s cramp, absence epilepsy, and migraine were each reported in three patients (41, 42). Rarely, alternative causes of non-familial PED are proposed. Exercise-induced dystonia is d escribed as a presenting feature of young-onset Parkinson \200\231s disease, but these pati ents were older than in classic PED (45, 46). Exercise-induced dystonia is also reported in a case of atypical DRD (without gene confi rmation) (47). Proposed secondary causes of PED include trauma (1, 48), moyamoya dis- ease (49), and hypoglycaemia related to insulinomas (48, 49). Each of the proposed secondary causes occurred in adults (1, 48 \200\22351). Othe r features distinct from those in SLC2A1 \200\223GLUT1 -associated PED exist; for example, episodes in the moyamoya disease case were triggered by working extra hours and occasionall y by exer- cise, a diff erent pattern from classic familial PED (49). One of the traumatic cases responded to low-dose baclofen (48), and both cases related to insulinoma responded t o removal of the tumor (50, 51). Epilepsy can occur in PED patients or in family members with or without PED. Associated epi lepsy syndromes include febrile, absence, generalized tonic \200\223clonic, myoclonic, and simple and complex partial seizures (38, 39, 41). Epilepsy starts in childhood, sometimes e arlier than the movement disorder (38). Haemolytic anemia also occurs in PKD families with certain SLC2A1 \200\223GLUT1 mutations (39). MRI is described as normal (38, 39) or showing T 2 hypointensi- ties in the caudal putamen (39). A PED case with a sporadic muta- tion showed mild cerebellar atrophy (41). Specialize d imaging modalities are described in select individuals (38, 39). Studies sug- gest that m utation carriers have moderately reduced cerebrospinal fl uid (CSF) glucose/serum glucose c oncentrations (range 0.37 \200\2230.59, normal >0.60). Th e reduction is generally less sev ere than that seen in patients with GLUT1 defi ciency syndrome (<0.40) (38, 39, 42). Paroxysmal hypnogenic dyskinesia/nocturnal paroxysmal dykinesia (nocturnal frontal lobe epi lepsy) Initially thought to be movement disorders or parasomnias, hyper- kinesias previousl y termed nocturnal paroxysmal dyskinesias are now widely accepted as epileptic in nature. T h ese are seen in noc- turnal frontal lobe epilepsy (NFLE) and its inherited form, auto- so mal dominant nocturnal frontal lobe epilepsy (ADNFLE). While these episodes represent seizu res they may come to the attention of the movement disorders specialist. In severely aff ected patients, a ketogenic diet has helped PED, epilepsy, and migraine sym ptoms, but diffi culty in adhering to the strict diet limits its usefulness (38, 39, 42). C arbohydrate-rich diets have been unsuccessful (38). Response to pharmacological agents is v ariable. AEDs may benefi t patients who also suff er from epilepsy, but the eff ect on PED symptoms is less clear (38, 39, 41). Carbonic anhydrase inhibitors (e.g. acetazolamide, dic lofenamide) are described as both benefi cial (39, 41) and unhelpful (41). Similarly, levod opa is described as being mildly benefi cial (41) and unhelp- ful (39). Haloperidol trigger ed an acute dystonic reaction in one patient with PED (41). A series of 100 patients with NFLE (52) provides the most thor- ough description of these p atients. Seizure onset occurred at a mean age of 14 years ( 10 years), but with a broad ra nge from 1 to CHAPTER 26 Paroxysmal Movement Disorders 273 (56, 57). Both carbamazepine and oxcarbazepine aff ect nicotinic ACh receptors, possibly ex plaining their eff ectiveness for NFLE (58). Topiramate was also eff ective as single or ad d-on therapy in a small series (59). 64 years. While patients complained of disrupted sleep, 72% were unaware of their nocturnal motor manifestations. Patients reported a mean of 20 11 seizures per month. Over a four th of patients experienced secondary generalized seizures at night; occasional daytime seiz ures also occurred. Various parasomnias (e.g. enuresis, sleepwalking) were described in a t hird of patients (52). Unsurprisingly, reports of possible secondary mechanisms are uncommon. In the NFLE series, 7% of patients reported peri- natal events, 3% had febrile seizures, and 3% had mild head t rauma preceding pediatric- and juvenile-onset seizures. It was unclear whether these histor ies related to the NFLE (52). A case of posttraumatic paroxysmal nocturnal right hemidyston ia was described in a teenager with right hemiplegia aft er a severe head injury. MRI revea led small left putaminal lesions and epi- sodes improved with acetazolamide therapy (60). S imilarly, baclofen-responsive paroxysmal nocturnal dystonia related to stroke is described (2). No epileptic correlates were reported in either of these cases. Hyperkinetic episodes seen in NFLE are classifi ed into four types: paroxysmal arousals, hy permotor seizures, asymmetric bilateral tonic seizures, and epileptic nocturnal wanderings. Each pattern can have phenomenology consistent with movement disor- ders. Paroxysmal arous als represent brief seizures lasting seconds. Patients open their eyes and sometimes sit an d appear frightened. Th ese arousals may be associated with mild dystonic posturing or fi n ger movements. Th ey can recur every 20 \200\22330 seconds through- out long portions of no n-rapid eye movement (non-REM) sleep. Hypermotor seizures consist of non-REM sleep attacks where patients appear to wake and perform complex movements, oft en appearing dystonic or c horeoathetotic. Semi-purposeful move- ments such as rocking or cycling can also occur. Atta cks may include vocalizations. Tachycardia and hypertension accompany episodes. Th e episod es tend to be highly stereotyped within an individual and can occur in a pulsatile manner t hroughout sleep, sometimes superimposed on other movements such as nocturnal myoclonus (53) . Other paroxysmal dyskinesias While the most common clinical and genetic patterns of paroxys - mal dyskinesias are detailed in the preceding sections, other par- oxysmal dyskinesias ha ve also been reported. Paroxysmal dystonic episodes triggered by sensory stimuli or passive movements were reported in a small series of boys with severe global retardation and thyro id abnormalities associated with X-linked mutations in the thyroid hormone transporter gene MCT8 (61). AD paroxys- mal choreoathetosis/spasticity (CSE) (DYT9) is a disorder where epi sodic dyskinesia is triggered by exercise, stress, lack of sleep, or alcohol. Episodes rang e from daily to annually and last approxi- mately 20 minutes. Acetazolamide or phenytoin be nefi t some patients. Patients may have a normal baseline or spastic paraple- gia. Genetic studies demonstrate linkage to chromosome 1p near a cluster of potassium-channel genes (62) . Asymmetric bilateral tonic seizures consist of several seconds of asymmetric tonic and dyst onic posturing, oft en involving all four limbs and sometimes facial and oral muscles. Epil eptic nocturnal wandering may start with one of the other seizure types but then progresses into a prolonged phase of complex semi-purposeful motor behaviors, including walking. Pati ents may display dys- tonic posturing during these events, which last for 1 \200\2232 minut es and may mimic sleepwalking (53). Most NFLE patients have episodes superimposed on a normal neurological baseline, though var ious neuroradiological abnormal- ities are reported in 14% (52). Over half of patients have normal interictal waking and/or sleep scalp EEG. In patients where interic- tal epileptic activity is seen on sleep EEG, 20% require sphenoidal leads to detect the abnormality. Almo st half of nocturnal ictal scalp EEG readings also fail to show epileptic activity, in part due to arte- facts related to motor behaviors (52). Psychogenic paroxysmal dyskinesia is described with cases oft en showing key atypical featu res (6, 63, 64). Psychogenic movement disorders and methods for making this diagnosis are c overed in Chapter 31. Transient and benign paroxysmal pediatric dyskinesias are also described in the literature, but are beyond the scope of this chap- ter. Examples include benign paroxysmal torticollis of infancy (65) and paroxysmal dystonic posturing seen in the context of gratifi ca- tion behavior (masturbation) in children between 3 months and 3 years old (66). In the series of 100 NFLE patients, 25% had a family history of epilepsy and 8% were though t to have ADNFLE. Almost 40% of patients described at least one fi rst-degree relative with a probable primary parasomnia (52). Genes implicated in ADNFLE include CHRNA2 , CHRNA4 , a nd C HRNB2 , each encoding for subunits on neuronal acetylcholine (Ach) receptors. Other li nkage loci are also known (54). Th e pathophysiological mechanism by which these mutations cause ADNFLE remains unclear, with diff erent mod- els showing diff erent eff ects on ACh r eceptors. A positron emis- sion tomography (PET) study in 2008 found reduced D1 receptor bi nding in patients with the 4-Ser248Phe mutation in CHRNA4 , preliminarily suggesting tha t cholinergic-dopaminergic interac- tions may play a role in the paroxysmal motor manifesta tions in ADNFLE (55). Episodic ataxias Unlike the paroxysmal dyskinesias which are historically cat- egorized by clinical characteristics, the episodic ataxias (EAs) are channelopathies categorized by gen etic mutations, although different mutations are associated with specific clinical phe- not ypes. Seven EA designations have been assigned to date (Table 26.2). Episodic ataxia type 1 (EA1) Th e phenotype of EA1 was a recognized clinical entity even pr ior to identifi cation of the causative gene in 1994 (67). Th e two car- dinal features of EA1 are episodic ataxia and interictal myokymia present on examination or electromyography (EMG). With the dis- covery of pathological mutations in KCNA1 , the associated clinical NFLE is non-progressive but rarely remits spontaneously. Carbamazepine is the fi rst-line t reatment, inducing complete epi- sode remission in 20% and greater than 50% seizure reducti on in another 48%. Th e remaining third of patients may be resistant to any antiepileptic d rug (52). Oxcarbazepine may also be benefi cial Oxford Textbook of Movement Disorders 274 Table 26.2 Episodic ataxias with EA designation Designation EA1 Episodic ataxia type Episodic ataxia type 1 Mode of inheritance AD Gene locus 12p13 Gene KCNA1 OMIM number 160120 Episodic ataxia with myokymia 176260 EA2 Episodic ataxia type 2 AD 19p13 CACNA1A 108500 Episodic ataxia with nystagmus, acetazolamide-responsive EA3 Episodic ataxia type 3 AD 1q42 Unknown 606554 Episodic ataxia with vertigo and tinnitus EA4 Episodic ataxia type 4 AD Unknown Unknown 606552 Periodic vestibulocerebellar ataxia (PATX) EA5 EA6 EA7 Episodic ataxia type 5 AD 2q22-q23 CACNB4 SLC1A3 Unknown 601949 Episodic ataxia type 6 AD 5p13 612656 Episodic ataxia type 7 AD 19q13 611907 AD, autosomal dominant; OMIM, Online Mendelian Inheritance of Man. Adapted from http://www. ncbi.nlm.nih.gov/omim phenotypes have broadened beyond EA and myokymia. Th e preva- lence is estimated at 1 in 50 0 000 (68). With identifi cation of associated KCNA1 mutations, the pheno- type of EA1 has broadened be yond the cardinal features. One family with classic EA1 also has paroxysmal dyspnoea both a lone and in association with the ataxic episodes (77). Epilepsy was mentioned in one of the earliest cases of EA1 (70), and was later described in two EA families (75, 78). Additiona lly, a family with a G724C mutation had epilepsy and myokymia but no episodic ataxia (76). Isolated myokymia was described in a family with a C731A muta- tion (76) and a Brazilian fa mily had a KCNA1 mutation associated with hypomagnesaemia, tremor, muscle cramps, tetanic e pisodes, and limb weakness (79). Presentations without the classic ataxia seen in EA1 are c onsidered allelic disorders. It is postulated that the phenotypic diversity seen with EA1 a nd allelic disorders may be related to the nature and degree of potassium channel dysfuncti on with diff erent mutations (80). While genotype \200\223phenotype corre- lations may expl ain some diff erences, aff ected individuals within the same family or with identical mutat ions may also exhibit sub- stantial heterogeneity. A recent description of markedly diff er ent presentations in pairs of identical twins with EA1 suggests that environmental factors may play a role (75). EA1 classically presents in childhood, usually before age 10, although early adolescent ons et is reported. Patients experience attacks of cerebellar dysfunction including imbalance, wide-based gait with or without falls, truncal and limb ataxia, tremor, jerking, head titub ation, dysarthria, and visual disturbances including blur- ring and oscillopsia (69 \200 \22375). Dizziness, nausea, and headache may also occur (70, 75). Conditions that can trigg er or lower the thresh- old for episodes include startle, exertion, emotional stress, men- struation, illness, fever, heat, hunger, caff eine, alcohol, and fatigue (69 \200\22372, 74 \200\22376). While no distinct aura is described, some patients may have a feeling of gene ral discomfort or weakness prior to attack onset (71, 73). Choosing to rest or sleep at att ack onset may help. Episode duration ranges from seconds to minutes. Frequency var- ies and ranges from multiple times daily to a few attacks per year (70 \200\22374). Descriptions o f changes in episodes over time and with age have been confl icting. 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