Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from

Review Unravelling of the paroxysmal Roberto Erro,1 Kailash P Bhatia2

►► Additional material is Abstract disease entities (ie, that one phenotype could be published online only. To view Paroxysmal dyskinesias (PxD) refer to a rare group only attributable to one single aetiology).5–7 Hence, please visit the journal online following a brief overview of the historical aspects (http://dx.​ ​doi.org/​ ​10.1136/​ ​ of clinically and genetically heterogeneous disorders jnnp-2018-​ ​318932). presenting with recurrent attacks of abnormal and the classification of PxD based on triggers (see movements, typically , or a combination below), a further in-depth section will be struc- 1Center for Neurodegenerative thereof, without loss of consciousness. Classically, PxD tured according to the different aetiologies that Diseases (CEMAND), have been categorised according to their triggers and produce PxD. This section will cover novel genetic Department of Medicine, Surgery and Dentistry “Scuola duration of the attacks, but increasing evidence suggests disorders that might encompass in their phenotype Medica Salernitana”, Universitá that there is a certain degree of clinical and genetic paroxysmal dystonia and/or chorea, but escape the di Salerno, Baronissi, Italy overlap and challenges the concept that one phenotype current classification of PxD. 2 Sobell Department For Motor is attributable to one single aetiology. Here we review A final section is meant to provide a diagnostic Neuroscience and Movement strategy to deal with PxD. This framework empha- Disorders, Institute of the increasing spectrum of genetic conditions, as well as Neurology, University College of other non-genetic disorders, that might present with sises that these diagnostic labels represent clin- London, London, UK PxD, provide criteria for case definition and propose a ical syndromes (and not disease entities), provide diagnostic workup to reach a definitive diagnosis, on criteria for case definition and endorse the approach Correspondence to which treatment is heavily dependent. recently used for dystonia in general8 (ie, isolated vs Roberto Erro, Department combined PxD, thereby discarding the former crite- of Medicine, Surgery and rion requiring normal neurological examination Dentistry “Scuola Medica Salernitana”,Universitá di between the attacks). On the basis of different clin- Salerno, Baronissi 84081, Introduction ical features including, but not limited to, triggers, Italy; rerro@​ ​unisa.it​ appropriate investigations are suggested to reach Paroxysmal dyskinesias (PxD) are a group of hetero- a definite diagnosis, on which treatment is heavily Received 5 June 2018 geneous syndromes that characteristically manifest dependent. It is not in the aims of the current copyright. Revised 12 August 2018 with recurrent attacks of abnormal movements, paper to review the pathophysiological mechanisms Accepted 14 August 2018 typically dystonia, chorea or a combination thereof, 1 underpinning this group of disorders and the inter- without loss of consciousness. ested readers are referred elsewhere.9 The search Considering the etymology and literal meaning strategy is detailed in box 1. of the words ‘paroxysmal’ and ‘’, one would realise that neither term is specific enough to unequivocally identify the entities that are clas- Historical definition and classification sically referred to as PxD. The term ‘paroxysmal’ of paroxysmal dyskinesias (from Greek paroxusmós—irritation, the severe fit Between 1940 and 1977, three main forms of of a disease) refers to sudden attack, recurrence or episodic movement disorders were recognised10–12 intensification of a disease.2 According to this defi- and classified based on the duration of attacks.12 nition, even waxing-and-waning conditions like Following this earlier classification,12 a subsequent tic syndromes or movement disorders that appear proposal by Demirkiran and Jankovic discarded the http://jnnp.bmj.com/ or worsen on action (action-myoclonus or action- duration of attacks as informative and focused on tremor for instance) would fit into this category. The the difference between triggers.13 They recognised term dyskinesia (from Greek, dys+kinesis, altered three subtypes, encompassing paroxysmal kine- movement) is also used in the medical literature sigenic (PKD), non-kinesigenic (PNKD) and with different meanings. Some medical dictionaries exercise-induced (PED) dyskinesias.13 The term propose that it should be used to indicate an impair- dyskinesia was privileged over others previously ment of the ability to execute voluntary move- adopted because the specific phenomenology on October 1, 2021 by guest. Protected ments,3 whereas others emphasise the hyper-kinetic of the attacks (ie, dystonia vs chorea) could only nature of the disorder and suggest that dyskinesias be presumed based on patients’ description. A are involuntary jerky or slow writhing movements, fourth subtype was also proposed (ie, paroxysmal often of a fixed pattern, including tics, myoclonus, hypnogenic dyskinesias (PHD) characterised by © Author(s) (or their chorea and dystonia.4 attacks occurring during sleep without identifiable employer(s)) 2018. No It appears clear that such definitions are too trigger),13 but this entity has been subsequently commercial re-use. See rights and permissions. Published broad and do not match with the meaning that suggested to be a form of autosomal dominant by BMJ. movement disorder experts give to the term ‘parox- nocturnal frontal lobe (ADNFLE) in most ysmal dyskinesias’. This calls for the need for a clear cases.14 To cite: Erro R, Bhatia KP. J definition of what should be intended as PxD, to Each of these forms could be further stratified Neurol Neurosurg Psychiatry 13 Epub ahead of print: [please avoid further ambiguity in the literature. into primary and secondary disorders. However, include Day Month Year]. Moreover, increasing knowledge regarding the the term ‘primary’ is increasingly dismissed as it doi:10.1136/jnnp-2018- possible aetiologies underlying the PxD has chal- carries the implication that there is absence of 318932 lenged the concept they could represent distinct detectable abnormalities,15 whereas most primary

Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 1 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from

Interestingly, PRRT2 mutations have been recently identified BOX 1 search strategy and selection criteria in 2 out of 11 patients (18.2%) with PHD,20 which supports the inclusion of PHD among the PxD. Moreover, PRRT2 muta- References for this Review were identified by searches of tions have been further associated with a phenotype reminiscent PubMed, EMBASE and Google Scholar, between 1940 and 21 of benign paroxysmal torticollis of infancy (BPTI) and, in the January 2018, and references from both relevant articles and case of biallelic mutations, with a complex phenotype including book chapters. The search terms ‘paroxysmal dyskinesias’, 22 neurodevelopmental delay. Complex phenotypes including ‘paroxysmal dystonia’, ‘PRRT2’, ‘MR-1’, ‘SCL2A1’, ‘GLUT1’, PKD along with developmental delays, intellectual disability and ‘KNCMA1’, ‘ADCY5’, ‘ATP1A3’, ‘PKD’, ‘PNKD’ and ‘PED’ were language abnormalities, minor dysmorphic facial features, and/ used. There were no language restrictions. The final reference list or autism spectrum disorder should also raise the suspicion of was generated on the basis of relevance to the topics covered in 23 S6 16p11.2 (micro)deletions. In such rare cases, conventional this Review. genetic testing for PRRT2 mutations might be uninformative and microarray-based comparative genomic hybridisation has to be performed.S6 Table 1 summarises the clinical features of PRRT2 PxD are in fact found to be secondary to a genetic defect. More- mutation as well as of the main genetic conditions producing over, it was suggested that patients with secondary PxD have PxD. interictal signs reflecting the underlying disorder,13 as opposed to cases with primary PxD. However, as anticipated above and MR-1 discussed in detail below, many patients with ‘primary’ genetic In 2004, MR-1 mutations were for the first time discovered forms of PxD do have interictal findings on examination. One in two unrelated families with PNKD.24 Onset of the attacks example is represented by SLC2A1 (GLUT1, glucose transporter is usually in the first decade.5 18 14 S7 There is always a domi- type 1) mutations, which can produce isolated PED (previously nant family history for similar attacks, no sporadic cases having 16 assigned the DYT18 number), PED with interictal spasticity been reported thus far.14 At the phenomenological level, attacks 17 (previously assigned the DYT9 number) as well as a number of encompass both dystonic and choreatic features and are gener- other different phenotypes. alised in about 50% of the patients.14 24 S7 S8 Attacks can be seldom complicated by dysarthria, dysphagia, oculogyric crises, inability to move and/or pain and might also be fatal.14 S9 The duration Disorders presenting with PxD of the attacks is variable but often lasts for a few hours.5 14 24 S7 PRRT2 S8 Although several non-kinesigenic triggers (ie, stress, tiredness, In 2011, Chen et al first reported PRRT2 mutations as the sustained exercise) can be present, in patients with MR-1 muta- copyright. genetic cause of PKD in eight families with PKD,18 opening the tions attacks are characteristically brought on by coffee and/or way to the identification of PRRT2 mutation in several clinical alcohol intake5 14 24 S7 S8 as compared with patients with PNKD syndromes previously associated with PKD such as the so-called but without mutations in this gene.S7 MR-1 carriers do not have infantile convulsions with choreoathetosis (ICCA) syndrome and associated clinical features, with the exception of migraine in benign familial infantile seizure syndrome.19 Currently, PRRT2 a few cases,5 and the interictal examination is always normal. is the major gene accounting for PKD, with a frequency ranging Clonazepam is the first-line pharmacological option when life- from about 40% to over 90%, depending on case ascertain- style modifications (ie, avoiding coffee and alcohol) are not effi- ment.14 19 S1 S2 Onset of PxD is in childhood, very rarely later cacious.14 Regardless of any treatment, there is a tendency for than 18 years of age. In patients with ICCA, PxD start after the attacks to reduce or remit in adulthood.5 14 S7 Rarely, MR-1 the onset of epilepsy (that develops within the first 2 years of mutations can manifest with very brief attacks triggered by life), usually after age 5, although some patients might exhibit sudden movements, therefore resembling classic PKD.S10 epileptic seizures at a later age.9 14 19 Virtually all PRRT2 cases have a clear kinesigenic trigger, http://jnnp.bmj.com/ although in up to 40%–50% of cases anxiety, stress, startle SLC2A1 or prolonged exercise can also induce attacks and very rarely Mutations in SLC2A1 encoding the GLUT1 have been discov- (about 1%–2% of patients) there are no kinesigenic triggers.14 ered to cause a spectrum of neurological phenotypes, including The episodes are very brief, usually lasting less than 1 min, PED.5 9 14–16 The latter is characterised by attacks of chorea feature both chorea and dystonia and tend to generalise.14 19 S1 and dystonia affecting mainly the lower limbs that are typically S2 About half of the patients experience a sensory at the triggered by sustained exercise.5 9 14–16 25 There is some pheno- initial site of the attacks that patients can use to predict attacks.14 type-genotype correlation, with splice site, non-sense, insertions on October 1, 2021 by guest. Protected Often patients have hundreds of episodes per day, although the or deletions leading to loss of function SLC2A1 mutations being frequency of attacks usually decreases with advancing age after associated with younger age at onset and a more severe clinical puberty and the syndrome can completely remit regardless of phenotype of GLUT1 deficiency syndrome, including epilepsy, any treatments.14 19 S1 S2 Carbamazepine is the first-line treatment hypotonia, spasticity, ataxia and developmental delay.14 25 option, being very effective at low doses (50–600 md/day).14 19 This compares with missense SLC2A1 mutations, which more S1-S4 A dramatic reduction in attacks is usually observed and this commonly present with PED in older patients,S11 the age at has been in fact suggested to be typical for patients with PRRT2 onset ranging from 1 to 50 years of age. As such, depending mutation as compared with similar cases of PKD and without on the specific underlying genetic defect, PED can manifest as such genetic defect.S3 S4 an isolated syndrome (about one-third of SLC2A1 cases) or be It is however now clear that PRRT2 mutations can induce associated with other neurological disorders.25 S11 Most cases additional phenotypes including episodic ataxia and migraine, with PED are de novo, whereas only 10% have a positive family often of the hemiplegic subtype.5 19 S5 As such, these features, history.15 16 Although autosomal recessive transmission has been whenever present in a single subject or in the family, make the described in rare cases of GLUT1 deficiency syndrome,S12 this presence of PRRT2 mutations likely. has not been reported in patients with PED. It is important

2 Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from

Table 1 Characteristics of mutations mainly associated with paroxysmal dyskinesias PDC deficiency (PDHA1, PRRT2 MR-1 SLC2A1 KNCMA1 SCN8A ECHS1 PDHX, DLAT) ADCY5 ATP1A3 CACNA1A GCH1 SLC16A2 Inheritance AD AD AD AD AD AR AR AD AD X linked Age at onset <18 years <18 years Variable Infancy Infancy Infancy Infancy Variable <18 months <1–2 years <18 years <1–2 months PxD subtype PKD PNKD PED PNKD PKD-like PED PED/PNKD PND PNKD BPTI PED PKD triggered (hemidystonic by passive attacks) movements Attack duration Very brief (<1 Long (>1 Intermediate Brief Brief Variable Variable Brief Variable Variable Variable Very brief min) hour) (5–40 min) (minutes) (minutes to (seconds to days) minutes) Isolated versus I/C I I/C C C I/C I/C C C I/C I/C C combined Other Epilepsy, Migraine Ataxia, Epilepsy Epilepsy – – PNKD Hemiplegia, EA2, FHM, – – paroxysmal migraine, (rare) epilepsy ataxia vomiting, disorders FHM, ataxia vertigo, paroxysmal tonic upgaze Other features – – Anaemia, Mental Mental Leigh Leigh Axial – – Parkinsonism Mental hypotonia, retardation retardation syndrome syndrome hypotonia, retardation spasticity non- paroxysmal dystonia and chorea AD, autosomal dominant; AR, autosomal recessive; BPTI, benign paroxysmal torticollis of infancy; EA2, episodic ataxia type 2; FHM, familial hemiplegic migraine; PDC, pyruvate dehydrogenase complex; PED, paroxysmal exercise-induced dyskinesias; PKD, paroxysmal kinesigenic dyskinesia; PND, paroxysmal nocturnal dyskinesias; PNKD, paroxysmal non-kinesigenic dyskinesias;PxD, paroxysmal dyskinesias. to remark that while PED is the most common type of PxD It is worthy of note that all patients described so far have pall- reported in SLC2A1 cases, other non-kinesigenic triggers have idal hyperintensity on T2-MRI sequences (despite being very also been described14 and patients can manifest other episodic mild in one patient with isolated PED,29 suggesting this might neurological disorders including episodic ataxia.5 S13 be a clue to suspect ECHS1 mutations. A possible benefit with PxD in the context of SLC2A1 cases have a positive but partial ketogenic diet or a mitochondrial cocktail including thiamine,

26 copyright. response to a ketogenic diet, which should be pursued to treat riboflavin, carnitine, coenzyme Q-10, vitamin B6 and vitamin C the underlying neuroglycopenia. has been reported in PxD.28 30

KNCMA1 Pyruvate dehydrogenase deficiency: PDHA1, PDHX and DLAT Mutations in KNCMA1, which encodes for a subunit of a calci- The mitochondrial pyruvate dehydrogenase complex (PDC) um-activated potassium channel, have been reported in 2005 to catalyses the rate-limiting step in the aerobic glucose oxida- 27 cause a syndrome of PNKD and epilepsy. Clinically, the PxD tion and comprises multiple copies of three subunits: pyruvate borne resemblance with the non-kinesigenic variant and alcohol dehydrogenase (E1, encoded by the PDHA1 gene), dihydroli- 27 was noted as a possible (but not constant) trigger. Two addi- poamide transacetylase (E2, encoded by the DLAT gene) and tional patients with PNKD with KCNMA1 mutations have been dihydrolipoamide dehydrogenase (E3), as well as an E3-binding subsequently reported to lack epilepsy, but they presented with protein (also known as component X and encoded by the PDHX S14 neurodevelopmental delay. As such, at variance from MR-1 gene).S16 Deficits in either subunit have been reported to cause patients, KCNMA1 mutations cause PNKD associated with either PxD usually, but not always, embedded in complex neurologic http://jnnp.bmj.com/ epilepsy or neurodevelopmental delay. PNKD in KNCMA1 pictures.31 32 S17 S18 27 S14 carriers variably responds to antiepileptic drugs. Mutations in the PDHA1 gene are typically associated with a wide range of clinical presentations.S16 S17 Most patients have ECHS1 severe, often lethal early encephalopathy with lactic acidosis. ECHS1 encodes for the short-chain enoyl-CoA hydratase Some cases have more chronic or subacute neurodegenerative protein, mutations of which have been reported as a cause of disorders ranging from Leigh syndrome, episodes of ataxia or early-onset Leigh syndrome (or a Leigh-like syndrome with recurrent acute flaccid paralysis.S16 S17 Interestingly, a subset on October 1, 2021 by guest. Protected atypical, often milder form with later onset).S15 ECHS1 muta- of patients manifest paroxysmal dystonia, which can be either tions have been further associated with PxD, which can be isolated or combined with the aforementioned phenotypes or either isolated or combined with a number of features sugges- other clinical signs/symptoms including hypotonia, epilepsy tive of a mitochondrial disease.28–30 S15 Thus, ECHS1 mutations and neurodevelopmental delay.S16 S17 The paroxysmal dystonia have been associated with intermittent episodes of long-dura- might be brought on by prolonged exercise, thus meeting the tion (30–50 min) opisthotonus with no identifiable trigger,S15 criteria for PED, or without any clear trigger, thus falling into but also with episodes of dystonia clearly induced by sustained the PNKD category.31 32 S17 S18 Attacks are sometimes reported to exercise.29 30 Although a previous report has labelled the latter be hemidystonic. Similar attacks have been reported in patients episodes as ‘kinesigenic’,28 a careful analysis of the original case with PDHX and DLAT mutations32 S16 S18 acknowledging that description reveals that the attacks were actually triggered by the latter two conditions are far less common than PDHA1 ‘physical strain’.28 Two more recent reports have confirmed that mutations. PxD due to ECHS1 mutations are more likely to be in the form Raised (serum or cerebrospinal fluid (CSF)) lactate and/or of PED, with or without normal interictal neurological exam- pyruvate levels along with pallidal hyperintensity suggesting ination.29 30 striatal necrosis are important clues to suspect PDC deficiency

Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 3 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from mutations,S16-S18 but it is important to recognise that these might ATP1A3 be lacking and, therefore, this condition should be considered ATP1A3 mutations cause different clinical syndromes including in the differential diagnosis of isolated PED/PNKD even in the AHC, rapid-onset dystonia parkinsonism and cerebellar ataxia absence of any detectable biochemical or imaging abnormality, with pes cavus and optic neuropathy, although there is increasing as it is a treatable condition that responds to thiamine supple- evidence of overlapping phenotypes.41 42 S23 S24 In the context mentation.S19 In other cases, beneficial outcomes have been also of this review, we will only cover AHC. It is a largely sporadic reported with a ketogenic diet,S17 which supports energy failure disorder with onset within the first 18 months, by defini- as the main pathophysiological mechanism for the PxD occur- tion.41 42 Despite its name, the highly distinguished feature of ring in the context of PDC deficiency. AHC is occurrence of frequent episodes of either hemidys- tonia or hemiplegia, which can manifest together with other paroxysmal neurological signs including nystagmus, anarthria, GCH1 dysphagia and seizures.41 42 S24 Duration of attacks ranges from a GCH1 codes for the GTP cyclohydrolase I, a rate-limiting few minutes to several days, and episodes occur from repeatedly enzyme in the synthesis of tetrahydrobiopterin from GTP, muta- within a day to several times a month.41 42 S24 Attacks are almost tions of which account for about 50% of dopa-responsive dysto- invariably induced by emotional stressors, such as excitement or nias. A few patients with GCH1 mutations have been described less frequently by physical stressors, including hypothermia or with a phenotype consistent with PED. In 2010, Dale and hyperthermia, respiratory tract infections and bright light.41 42 S24 colleagues described a family with two affected members with 33 Characteristically, there is a rostrocaudal gradient in the hemi- isolated PED. Attack duration was about 5 min and they never 41 42 S24 33 plegic/hemidystonic episodes (face/neck>arm>leg) which occurred at rest or during movement initiation. Moreover, can aid the differentiation from other types of hemidystonic Erro et al found two GCH1 carriers in a series of 16 patients attacks. Hemiplegic and hemidystonic episodes typically shift with PED (12.5%).34 The phenomenology was that of dystonia 34 from one side of the body to the other and typically disappear and attacks were localised to the lower limbs. As expected, 41 42 S24 34 falling asleep. Almost invariably the hemidystonic attacks patients had a dramatic benefit on levodopa supplementation. are combined with other (interictal) features such as develop- mental impairment, walking difficulties/ataxia, muscular hypo- SCN8A tonia, dysarthria and choreoathetosis. The mainstay of treatment is flunarizine (10–20 mg/day) as a prophylactic drug along with Recently mutations in SCN8A, which encodes for sodium volt- 41 42 S24 age-gated channel alpha subunit 8, have been suggested to be an avoiding trigger situations. Patients should be encouraged alternative cause of the ICCA syndrome (ie, PKD and infantile to sleep when attacks begin, using fast-acting benzodiazepines if 35 necessary. convulsions) in one recent report. However, this proposal has copyright. been subsequently questionedS20 based on the evidence that, in one affected case, a ‘PKD‘ spell was recorded by video-electroen- CACNA1A cephalography and a cortical signal was documented, suggesting Mutations in the CACNA1A gene, which encodes for the calcium that such attacks might in fact be epileptic in nature. Therefore, voltage-gated channel subunit alpha1 A, are associated with a it is unclear whether mutations in this gene truly cause PKD or number of phenotypes including SCA6, episodic ataxia type 2 not. However, it has to be acknowledged that in other reports as well as familial hemiplegic migraine.S25 In a minority of cases, SCN8A mutations have been associated with episodic dystonia, CACNA1A mutations have been suggested to account for some although the term paroxysmal dyskinesia was not explicitly cases of BPTI.43 44 It is characterised by episodes of head tilt with 36 used. As such, it is worth considering this condition in the onset within the first 18 months of life that usually resolve by differential diagnosis of PxD, especially when associated with age 5.43 44 The attack duration ranges from 10 min to several epileptic seizures, particularly those refractory to antiepileptic days and is frequently accompanied with vomiting, pallor 36 43 44 therapy, and/or with neurodevelopmental delay. and ataxia. BPTI usually resolves after infancy, but can be http://jnnp.bmj.com/ replaced by paroxysmal vertigo and/or migraine.43 44 The co-oc- currence of episodic ataxia, hemiplegic migraine and paroxysmal ADCY5 tonic upgaze in a single subject or in the family makes muta- Mutations in ADCY5, which encodes for the adenylate cyclase tions in this gene more likely.45 This condition is self-limiting and 5, have been reported to cause a spectrum of (non-paroxysmal) usually no treatment is required. movement disorders ranging from dystonia to chorea, some- times associated with axial hypotonia and PxD.37–39 PxD do not always fit clearly within previously identified PxD categories and SLC16A2 on October 1, 2021 by guest. Protected might be painful, a point of difference from PxD due to other SLC16A2 encodes for the monocarboxylate transporter type 8 genetic causes of PxD.37 39 Moreover, ADCY5-PxD may mani- (MCT8), which is required for transmembrane uptake of free fest, even within the same patient, as multiple subtypes, including triiodothyronine (fT3) from blood into neurons. MCT8 defi- PKD and PNKD.37 39 Of note, also at variance with other genetic ciency results in a complex, X linked disorder (also known as disorders that can produce PxD, ADCY5 carriers characteristi- Allan-Herndon-Dudley syndrome) characterised by proximal cally develop PxD during sleep.39 Night-time dyskinesias (along hypotonia with poor head control, generalised muscular hypot- with non-paroxysmal movement disorders) are therefore a clue rophy, microcephaly and marked developmental delay.46 to suspect ADCY5 mutations. Interestingly, Westenberger and The disorder is progressive and spasticity, ataxia and severe colleagues have recently reported two unrelated ADCY5 patients dysarthria complicate the clinical phenotype. In a subset of with attacks reminiscent of alternating hemiplegia of childhood patients, a specific sort of PKD is observed.46 47 Attacks are in (AHC; see below) in the context of a more complex neurolog- fact classically triggered by passive movements such as changing ical picture including dysarthria, hypotonia and non-paroxysmal of their clothes or nappies or by lifting the children from one choreodystonia.40 Partial benefit has been reported with both place to another.46 47 However, attacks can also be triggered by tetrabenazineS21 and deep brain stimulation.S22 excitement, happiness or crying.46 47 Attacks are brief, lasting

4 Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from

Proposed criteria for case definition and Table 2 Different aetiologies associated with episodic movement disorders resembling paroxysmal dyskinesias diagnostic strategy PxD represent clinical syndromes where the disorder of move- 48 S26 Immune- ment is intermittent in nature (and thus does not encompass mediated Acute disseminated encephalomyelitisS27 exacerbation of existing abnormalities). The intermittent char- disorders Voltage-gated potassium channel complex protein antibody encephalitisS28 acter of the disorder means it is not continuous or steady, but Anti-Caspr2 syndromeS29 should not be used to refer to disorders that wax-and-wane over Hashimoto encephalopathyS30 a period of time such as tics. S31 Antiphospholipid syndrome As to the phenomenology, the clinical spectrum ranges from S32 Parry-Romberg syndrome dystonia to chorea, with ballism being possible but does not Cryopyrin-associated periodic syndromeS33 encompass tremor or myoclonus. Such a clarification automati- Vascular Stroke48 S34 S35 S35 S36 cally excludes stimulus-sensitive myoclonus or startle syndromes Moyamoya Cerebral palsyS37 from this category. Moreover, excluded from this definition Metabolic Hypo/hyperglycaemiaS35 S38 S39 are those phenomena that are clearly drug induced (ie, acute causes Hypocalcaemia/hypoparathyroidism/pseudohypoparathyroidismS35 dystonic reaction or levodopa-induced dyskinesias in the context S40 S42 of Parkinson's disease, for instance). Thyrotoxicosis/hypothyroidismS43 S44 Using this definition, the first step for the differential diagnosis S45 Wilson’s disease is to decide whether the clinical abnormality is in fact a PxD Maple syrup urine diseaseS54 S55 or not. Epilepsy, tonic spasms, tetany, neuromyotonia, periodic Lesch-Nyhan disease paralyses and episodic ataxias, all of which can produce intermit- Trauma Central and peripheral48 S35 tent disordered movements, need to be excluded clinically and/ Other Basal ganglia calcificationsS46-S48 Central pontine myelinolysisS35 S50 or by ancillary investigations whenever appropriate. Moreover, Kernicterus48 S35 psychogenic/functional causes have to be ruled out. While some Encephalitis/postinfectious48 S35 S51 authors have suggested that the diagnosis of psychogenic/func- Brain neoplasmS35 S52 tional paroxysmal movement disorders is fundamentally one of Neurodegenerative disorders,including early-onset Parkinson's exclusion, we would rather support alternative claims that the diseaseS35 S53 diagnosis should be based on the presence of positive signs: these include profound within-subject phenomenological variability with marked increases in attack frequency and severity during seconds to few minutes, and are dystonic in nature.46 47 The examination, highly variable attack duration, presence of several copyright. hallmark of MCT8 deficiency is raised serum concentration of and non-specific triggers, frequent alteration of responsiveness fT3.46 during attacks, medically unexplained somatic or neurological symptoms and, finally, atypical response to medications.51 52 These clues will make a positive diagnosis of psychogenic/func- Other causes of PxD tional movement disorders likely, without the need for addi- Table 2 lists the conditions that have been associated with PxD 13 48 S26-S55 tional investigations in most, if not all, cases. or similar episodes of choreodystonia. These include Once the clinical syndrome of PxD is established, the second a variety of acquired, immunological and neurodegenerative causes that were formerly ascribed to secondary PxD.13 48 For step is to fully characterise the attacks in terms of trigger and this reason, we have also included here brain calcification, by duration, further exploring the presence of family history and virtue of the fact that a lesional mechanism is assumed in such additional clinical features (by history or on examination) and to cases.S35 S36 However, two PxD families have been recently set the identified clinical syndrome in the context of age at onset. reported on, in whom genetic analysis revealed novel mutations A clinical syndrome with onset in childhood, which is charac- http://jnnp.bmj.com/ in SLC20A2 and PDGFB genes, respectively.S48 S49 The fact that terised by attacks with specific triggers and duration, is most all affected members shared the phenotype of isolated PxD with likely to be genetic in nature. The definition of the trigger(s), normal interictal examinationS48 S49might support the idea that duration and body distribution of the attacks, as well as the pres- PxD are intrinsically associated with these mutations rather than ence of suggestive associated clinical features and the pattern of being merely secondary to basal ganglia calcification, as assumed inheritance should help the clinician to drive the genetic analysis in earlier reports of the pregenetic era.S49 This, however, remains (figure 1). Most of these disorders account for those forms that speculative, but it further exemplifies the ambiguity regarding were formerly considered primary PxD and include PKD, PNKD on October 1, 2021 by guest. Protected the concept of primary and secondary PxD. and PED. While supporting the trigger-based approach as very In general, PxD due to acquired, immunological or neurode- useful, we further suggest some modifications and clarifications. generative causes present usually at a later age compared with the For instance, the term non-kinesigenic does not carry any main genetic forms reviewed above and manifest with additional useful information rather than specifying that the trigger is not signs or symptoms that will easily drive the diagnostic workup kinesigenic. It reflects the absence, rather than the presence, of and lead to the correct diagnosis and appropriate management a clinical feature with the obvious implication that, with one in most cases. notable exception, the majority of non-kinesigenic triggers are Recently, DEPDC5S10 and CHRNA449 mutations have been non-specific and are shared across different PxD subtypes, being associated with the syndrome of PKD plus epilepsy in single therefore not predictive of the underlying genetic defect. The families. However, these two genes are also a cause of ADNFLE50 exception is represented by alcohol/caffeine in the case of MR-1 and it remains to be seen whether these episodes of paroxysmal mutations. The presence of this trigger is highly specific of MR-1 dystonia are epileptic in nature or not. Moreover, these results mutations, being present in about 95% of carriers. We therefore require replication before screening of these genes might be advocate considering alcohol/caffeine sensitivity as a distinctive recommended in clinical practice. trigger for PxD rather than relegating it within the (unspecific)

Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 5 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from

Figure 1 Suggested genetic mutations that should be tested for according to clinical presentations. ^Mimics include epilepsy, tonic spasms, tetany, neuromyotonia, periodic paralyses and episodic ataxias. #These might include stress, anxiety, fatigue, fasting, startle and sleep deprivation. §By history or on examination. −, none/negative; +, present; ≅, might have a kinesigenic trigger; *Including 16p11.2 deletion; **Should include glucose, lactate, pterins, and dopamine metabolites; A, axtaxia; AD, autosomal dominant; Au, autonomic dysfunction; E, epilepsy; EA, episodic ataxia; M, migraine; HP, hemiplegia; MR, mental retardation; MD, non-paroxysmal movement disorders; S, spasticity. copyright. subgroup of non-kinesigenic triggers (figure 1). The vagueness Whenever the attacks lack specific and consistent triggers, of the non-kinesigenic category further justifies the fact that, in have variable duration and when the onset is in adulthood, some instances, other clinical features such as the body distribu- ‘symptomatic’ causes (table 2) need to be excluded, especially tion of the attacks might prevail in the definition of the parox- in the absence of family history. Given the huge variability of ysmal movement disorders. This is the case of dystonic and symptomatic PxD forms in their clinical presentation, even hemiplegic attacks alternating from one body side to the other within the single subject, it is hard to identify any phenotypic (AHC) or episodic attacks of neck dystonia (BPTI). patterns suggestive of the underlying aetiology. In general, Moreover, we support the concept of PxD occurring during certain findings including painful attacks, fluctuating levels of sleep as a further trigger-based subtype. Although sleep is consciousness and dysautonomic crises that are not classically not strictly a trigger, it can be considered equivalent to other seen in the genetic conditions reviewed here should prompt the triggers since they all give an answer to the question of when clinician to rule out acquired causes. In such cases, an initial http://jnnp.bmj.com/ PxD occur (ie, after sudden movements, after alcohol/caffeine diagnostic workup including metabolic and electrolyte panels, ingestion, during sleep, and so on). investigation for autoimmune disorders and brain imaging will At variance with former classifications of PxD, we discard allow a definitive diagnosis to be determined in most cases. the criterion of normal interictal examination. As such, all the aforementioned trigger-based subtypes can be isolated or combined with additional features. This reiterates a previous Conclusions suggestion proposing the stratification of PxD into ‘pure’ and In recent years, great advances have led to a better under- on October 1, 2021 by guest. Protected ‘complicated’ forms,53 based on the absence or presence of standing of the broad spectrum of genetic conditions under- additional interictal neurological signs, respectively. We also lying the PxD. This has increasingly challenged the former advocate this approach for two main reasons. First, there is phenomenological classification as well as the idea that any evidence of clinical heterogeneity for single gene mutations. specific phenotypes were associated to single gene mutations. For instance, PRRT2 and SLC2A1 mutations can produce Such an argument reiterates previous proposals14 that classifi- either isolated or combined PxD. Second, we believe the cation of PxD should follow a two-pronged method, according syndromic approach will facilitate the differential diagnosis to which both the clinical phenotype and the specific genetic (figure 1). For instance, the presence of epilepsy in a patient mutation should be stated (i.e., PRRT2-PKD). with ‘classic’ PNKD will make the presence of MR-1 mutations It is worth specifying that our proposal does not represent very unlikely. Such a syndromic approach would also prioritise a classification scheme, but reflects an algorithmic approach some investigations over others. This might be the case for to help clinicians in the differential diagnosis. First, it gives PED in which CSF examination for glucose, pterin pathway clarity to the definition of PxD. Second, it has the merit of components, pyruvate and lactate would provide more infor- encompassing an increasing number of recently identified mation than imaging. conditions with PxD as a feature that would escape the current

6 Erro R, Bhatia KP. J Neurol Neurosurg Psychiatry 2018;0:1–8. doi:10.1136/jnnp-2018-318932 Movement disorders J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2018-318932 on 21 September 2018. Downloaded from classification. On the other hand, the phenotypic and genetic 18 Chen WJ, Lin Y, Xiong ZQ, et al. Exome sequencing identifies truncating mutations in heterogeneity of PxD highlighted here might render the test of PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 2011;43:1252–5. 19 ebrahimi-Fakhari D, Saffari A, Westenberger A, et al. The evolving spectrum of PRRT2- candidate genes, based on a specific clinical syndrome, unsuc- associated paroxysmal diseases. Brain 2015;138(Pt 12):3476–95. cessful. In this context, it might be argued that next generation 20 Liu XR, Huang D, Wang J, et al. Paroxysmal hypnogenic dyskinesia is associated with sequencing approaches would better apply to the need of a mutations in the PRRT2 gene. Neurol Genet 2016;2:66. rapid comprehensive genetic screening.54 This would further 21 Dale RC, Gardiner A, Antony J, et al. Familial PRRT2 mutation with heterogeneous reduce costs in comparison to single gene testing.55 paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Dev Med Child Neurol 2012;54:958–60. Of course there will be cases where no definitive cause for 22 Delcourt M, Riant F, Mancini J, et al. Severe phenotypic spectrum of biallelic mutations PxD can be found and treatment is to be pursued empirically. in PRRT2 gene. J Neurol Neurosurg Psychiatry 2015;86:782–5. These can be labelled as idiopathic forms while awaiting for 23 weber A, Köhler A, Hahn A, et al. Benign infantile convulsions (IC) and subsequent further elucidation of genetic or other causes. In turn, our paroxysmal kinesigenic dyskinesia (PKD) in a patient with 16p11.2 microdeletion syndrome. Neurogenetics 2013;14:251–3. proposal will require updating as soon as novel evidence is 24 Rainier S, Thomas D, Tokarz D, et al. Myofibrillogenesis regulator 1 gene mutations available. Additional references can be found in the online cause paroxysmal dystonic choreoathetosis. Arch Neurol 2004;61:1025–9. supplementary file 1. 25 Leen WG, Klepper J, Verbeek MM, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain Acknowledgements We thank Dr K Bertram for having edited the text. 2010;133(Pt 3):655–70. 26 Leen WG, Mewasingh L, Verbeek MM, et al. Movement disorders in GLUT1 deficiency Contributors RE: conception, writing the first draft. KPB: conception, reviewing syndrome respond to the modified Atkins diet. Mov Disord 2013;28:1439–42. the draft. 27 Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human Funding The authors have not declared a specific grant for this research from any epilepsy and paroxysmal movement disorder. Nat Genet 2005;37:733–8. funding agency in the public, commercial or not-for-profit sectors. 28 Korenke G, Nuoffer J-M, Alhaddad B, et al. Paroxysmal dyskinesia in ECHS1 defect with globus pallidus lesions. Neuropediatrics 2016;47(S 01):PS01–10. Competing interests RE received honoraria for speaking at meetings from 29 Olgiati S, Skorvanek M, Quadri M, et al. Paroxysmal exercise-induced dystonia within TEVA, ZAMBON and the International Parkinson’s Disease and Movement Disorders the phenotypic spectrum of ECHS1 deficiency. Mov Disord 2016;31:1041–8. Society. He receives royalties from publication of Case Studies in Movement 30 Mahajan A, Constantinou J, Sidiropoulos C. ECHS1 deficiency-associated paroxysmal Disorders–Common and uncommon presentations (Cambridge University Press, exercise-induced dyskinesias: case presentation and initial benefit of intervention. J 2017). KPB has received grant support from Welcome/MRC, NIHR, Parkinsons’s UK Neurol 2017;264:185–7. and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist 31 McWilliam CA, Ridout CK, Brown RM, et al. Pyruvate dehydrogenase E2 Handbook Parkinson’s Disease and Other Movement Disorders (Oxford University deficiency: a potentially treatable cause of episodic dystonia. Eur J Paediatr Neurol Press, 2008), of Marsden’s Book of Movement Disorders (Oxford University Press, 2010;14:349–53. 2012), and of Case Studies in Movement Disorders–Common and uncommon 32 Friedman J, Feigenbaum A, Chuang N, et al. Pyruvate dehydrogenase complex-E2 deficiency presentations (Cambridge University Press, 2017). He has received honoraria/ causes paroxysmal exercise-induced dyskinesia. Neurology 2017;89:2297–8. personal compensation for participating as consultant/scientific board member from 33 Dale RC, Melchers A, Fung VS, et al. Familial paroxysmal exercise-induced dystonia:

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