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Paroxysmal Dyskinesias
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Paroxysmal dyskinesias Sara McGuire, Swati Chanchani, Divya S. Khurana
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S1071-9091(17)30156-0 https://doi.org/10.1016/j.spen.2017.12.007 YSPEN701
To appear in: Seminars in Pediatric Neurology Cite this article as: Sara McGuire, Swati Chanchani and Divya S. Khurana, Paroxysmal dyskinesias, Seminars in Pediatric Neurology,doi:10.1016/j.spen.2017.12.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Paroxysmal Dyskinesias
Sara McGuire MD, Swati Chanchani MD, Divya S Khurana, MD
From the Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA
Address reprint requests to: Divya S Khurana, MD, Section of Neurology, Department of Pediatrics, St Christopher’s Hospital for Children, Drexel University College of Medicine,160 E Erie Avenue, Philadelphia, PA 19134. Email: [email protected]
Abstract: Paroxysmal dyskinesias (PD) are hyperkinetic movement disorders where patients usually retain consciousness. Paroxysmal dyskinesias can be kinesigenic (PKD), nonkinesigenic (PNKD) and exercise induced (PED). These are usually differentiated from each other based on their phenotypic and genotypic characteristics. Genetic causes of PD are continuing to be discovered. Genes found to be involved in the pathogenesis of PD include MR1, PRRT2, SLC2A1, KCNMA1. The differential diagnosis is broad as PDs can mimic psychogenic events, seizure or other movement disorders. This review also includes secondary causes of PDs which can range from infections, metabolic, structural malformations to
malignancies. Treatment is usually based on the correct identification of type of PD. PKD responds well to anti-epileptic medications whereas PNKD and PED respond to avoidance of trigger and exercise. In this article we review classification, clinical features, genetics, differential diagnosis and management of PD.
Introduction: Paroxysmal dyskinesias (PD) are rare hyperkinetic movement disorders which include chorea, dystonia, athetosis and ballism, isolated or in combination. Patients are asymptomatic between episodes. These episodes may or not be induced by movement, called kinesigenic (duration seconds to minutes) or non kinesigenic (minutes to hours).1
The first documented case consistent with PD was described in 1892 in a 23 year old Japanese man.2 The clinical syndrome was not fully described until 1940 by Mount and Reback.3 They wrote about a young male with episodes of dystonia and chorea caused by coffee and alcohol.
It was at the time termed “familial paroxysmal choreoathetosis”.3 In 1967, Kertesz4 described a group of patients with episodes that were very brief in duration and precipitated by sudden movement naming this “paroxysmal kinesigenic choreoathetosis”.4 In 1968, Richards and Barnett5 suggested the term “paroxysmal dystonic choreoathetosis of Mount and Reback” since the postural and tone changes accompanied the choreoathetoid movements described in the Canadian family in their study.5 In 1977, Lance6 described a family with attacks that were provoked by prolonged exercise which became classified as “paroxysmal exercise-induced dystonia”.6 In described cases of PD, there is significant overlapping of manifestations in regards to type of movements, duration and precipitating factors. They may present as dystonias, chorea, athetosis or ballism either individually or in varied combinations.
The most widely used classification for PDs was created by Demirkiran and Jancovic.7 Etiology and pathogenesis of PDs is still under investigation and not fully understood. Most cases are thought to be idiopathic. However, many secondary causes have been reported. 8 Due to the familial nature of this neurological disorder, the role of genetics is currently under extensive research.
Classification: The most widely used classification system cited in the literature was created by Demirkiran and Jankovic7 in 1995 based on phenotype, precipitating factors, duration and etiology7. The proposed classification divided paroxysmal dyskinesias into 4 categories based on clinical features: Paroxysmal Kinesigenic Dyskinesias (PKD), Paroxysmal Non-Kinesigenic Dyskinesias (PNKD), Paroxysmal Exercise-Induced Dykinesias (PED), Paroxysmal Hypnogenic Dyskinesias (PHD). Each clinical feature is further subdivided by duration into short (≤ five minutes) or long
(> 5 minutes). PD can be either idiopathic (familial or sporadic) or secondary (linked to another underlying medical condition).7,9,10
Paroxysmal hypnogenic dyskinesia (PHD), originally classified as PD, is now thought to a be form of epilepsy and called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients present with episodes of dystonia/chorea/ballism or a combination of these occurring during non-REM sleep without any preceding identifiable triggers. Attacks are short in duration (30-45 seconds). In most cases, these episodes are mesial frontal lobe seizures.1 Therefore, PHD will not be further discussed in this review.
Another scheme of classification of dystonic syndromes was created by the Human Genome Organization Gene Nomenclature Committee based on the DYTn coding system where ‘n’ was the label assigned to the gene loci which can be linked with a specific phenotype and associated genetic markers.11,12 This classification is less widely used due to many short comings including presence of unconfirmed loci, missing symbols or loci, duplication of loci, technical errors leading to erroneous linkage to disease, combining causative and risk factor genes in the same list and discordance between phenotype and list assignment. For example in patients with PD, the movement phenotype may be variable or mixed and may or may not be dystonic.13 An example of some of the more common DYTn classifications is shown in figure 1 which is modified from Camargo et al.14
Paroxysmal Kinesigenic Dyskinesia (PKD)
In PKD, the paroxysms are precipitated by sudden movement, sudden acceleration, change in the direction of movement or startle. Attacks can be characterized by dystonia, chorea, ballism or a combination. Dystonia is most commonly reported.15 These are usually brief dystonic attacks in one or more extremities lasting from a few seconds to a few minutes. There is no alteration of consciousness. The episodes can occur multiple times a day to once a month.15 Sensory auras such as limb paresthesias may be present.16 Speech can be affected if the jaw or face is involved. Episodes can be unilateral or bilateral and can affect any part of the body. 15 Electroencephalogram (EEG) and brain imaging studies are usually normal. Patient are reportedly normal between episodes.17 Onset occurs in the first to second decade of life and peaks at puberty with improvement or complete resolution during adulthood.15,18
In a study by Bruno et al19 with 121 patients with presumptive diagnosis of PKD, the diagnostic criteria was described as: identifiable attack triggers (sudden movements), short duration (<1 minute), lack of loss of consciousness or pain, antiepileptic drug responsiveness, exclusion of other organic diseases, and age at onset (1 to 20 years if no family history; less stringently if positive family history).
PKD can be familial or sporadic. Sporadic cases are more frequent in males whereas infantile convulsions are more common in the familial kindreds. Females have a higher remission rate than males. An infantile-onset group with a different set of characteristics was identified where parents observed the attacks during sleep and there was non-uniform response to anti-epileptic medications.19,20
Paroxysmal Non-Kinesigenic Dyskinesia (PNKD) PNKD is characterized by intermittent episodes of dystonia, chorea or athetosis. PNKD associated with myokymia has been described.21 PNKD is usually not triggered by sudden movements but can be triggered by caffeine, tea, sleep deprivation, alcohol and stress.22 It is seen more commonly in males than females (1.4:1).23 Similar to PKD, there is no impairment in consciousness. Frequency and severity usually peak at puberty with possible remission during adulthood. Attacks are longer compared to those in PKD (minutes to hours) and less frequent than PKD.15
There are no abnormalities noted between the attacks. However, a case report of PNKD with simultaneous tremor was described in an elderly woman. She presented attacks of difficulty speaking, abnormal sensation in extremities and episodes of stiffness with dystonia of trunk, chorea of upper and lower extremities starting at age 9. In between attacks, there was persistent head tremor and chorea of upper and lower extremities. Family history of similar episodes was present but no tremors. Genetic testing revealed mutation of myofibrillogenesis regulator (MR-1) gene.24
Bruno et al 10 described a family of 14 kindreds with familial dyskinesia not induced by movement. Eight had MR-1 mutations. Sleep benefit (resolution of attack with patient going to sleep during attacks) was seen in all patients with PNKD regardless the presence of MR-1 mutation. These patients were also diagnosed in early childhood and had a mixture of chorea and dystonia. The authors suggested that PNKD should be defined strictly based on age of onset with the clinical presentation of attacks precipitated by caffeine and alcohol. Penetrance
was found to be high at 98%.10 However incomplete penetrance and intra-familial variability has been described.25-27
PNKD is known to be non-life threatening. However, Zittel et al28 described a rare fatal case of PNKD. The patient initially presented with involuntary arm spasm that would also affect the neck and speech. Like all PNKD, triggers were caffeine, alcohol and stress and relief with sleep. Both the patient’s mother and maternal grandmother died from laryngeal dystonia and consequent respiratory distress during an attack.28
Paroxysmal Exercise-Induced Dyskinesia (PED) PED is triggered by sustained exercise. Other identified triggers include vibration, cold temperature, and electric nerve stimulation. The most common abnormal movement is dystonia (similar to PKD and PKND) but ballism, chorea or athetosis can also be present. Lower extremities are most commonly affected. The frequency of attacks is highly variable. Attacks last 5-30 minutes, be bilateral or unilateral and are not usually associated with a sensory aura. PED is usually inherited in an autosomal dominant fashion in familial cases.15,18, 29-31 Bozi and Bhatia32 described 2 patients with early onset Parkinson’s disease who initially presented with PED. In both patients, the PED predated the development of the typical parkinsonian features (1.5 and 5 years). In figure 2 we summarize the clinical features of PKD, PNKD, PED15,18,29
Genetics: It has been reported that 40%–70% of PD cases are familial. Many genes have been described are associated with PDs (Figure 3).
PRRT2 (proline-rich transmembrane protein 2) PRRT2 is a transmembrane protein highly expressed in the central nervous system including basal ganglia, cerebellum and hippocampus.33,34 PRRT2 is the most common gene involved in primary genetic PKD and is located on chromosome 16.33 Disease causing mutations are usually heterozygous and cause loss of function.35 Sporadic PKD have PRRT2 mutation as cause in almost half of the cases, according to Gardiner et al.35 It is usually inherited as autosomal dominant with incomplete penetrance.29 The full role of PRRT2 is not well understood but it is believed to be involved in neurotransmitter release and synaptic vesicle fusion with plasma membrane (SNAP25).35, 34 Phenotypically, patients with PRRT2 mutations are usually younger with higher frequency of attacks.15
Other disorders associated with PRRT2 mutation include hemiplegic and other types of migraines, episodic ataxia, febrile seizures, sporadic infantile convulsion, and paroxysmal torticollis.15 Patients with this genetic defect tend to have a family history of epilepsy.36 Cases of homozygous mutation to PRRT2 have been described to have a more severe phenotype with intellectual disability, episodic ataxia and absence epilepsy.37
MR-1/PNKD (myofibrillogenesis regulator 1) MR-1 is located on chromosome 2 (2q35, less commonly 2q31).38 Mutations that have been described are missense mutations. The normal function of MR-1 is to produce protein, spliced into 3 parts MR-1L (long), MR-1M (medium), MR-1S (small). Genetic defects are seen in the L and S protein which are involved in mitochondrial targeting sequence and protein transfer into the mitochondria.38 The genetic defect is inherited in autosomal dominant fashion with incomplete penetrance.25,39 It is more commonly found in young patients who develop PNKD around 12 years of age.10
Bruno et al.10 studied 49 patients with MR-1 mutations and found that 100% of patients had PNKD precipitated by caffeine or alcohol intake. In patients without MR-1 mutation, caffeine was sometimes a trigger but alcohol was not. Patients with MR-1 mutation were also more responsive to treatment. Treatment of choice was benzodiazepines.10,25-27,40 Attacks were often alleviated by sleep in patients with and without MR-1 mutation.10,25-27,40
SLC2A1 (solute carrier family 2 member 1) The SLC2A1 gene encodes glucose transporter 1 protein (GLUT1) and is located on chromosome 1p34.2. 15,41,42 GLUT1 isoform is present in the endothelium of the blood brain barrier and astrocytes facilitating glucose transport across the blood brain barrier.43-45 Interictal positron emission tomography (PET) showed decreased signal in glucose metabolism in the thalamus in cases of PED.46 Mutation inheritance has been reported as autosomal dominant as well as sporadic.47,48 PED associated with this genetic mutation is designated DYT18.47 SLC2A1 gene mutation is the most common cause of familial PED but can also manifest as PNKD. 29
A variable phenotype has been described including PED and encephalopathy. The wide spectrum ranges from severe (development delay, microcephaly, refractory seizures, ataxia, spasticity, hypoglycorrachia and decreased erythrocyte glucose uptake) to milder versions (seizures, isolated PED and episodic migraines). 15,49
KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) KCNMA1 gene mutation is most commonly inherited in an autosomal dominant pattern.50 KCNMA1 gene mechanism has been postulated as a pore forming alpha subunit of the big potassium channel which is sensitive to calcium.36
This mutation was first reported in 2005 in a family with PNKD and epilepsy51. It was again described in a study by Zhang et al52 in 2 unrelated children with PNKD and developmental delay. In the latter, the children developed PNKD at an earlier age and there was no associated epilepsy. No triggers were identified in either patient.53
A form of PNKD commonly associated with KCNMA1 gene mutation is characterized by spasticity and choreoathetosis.50 Patients present with a progressive spastic paraparesis. Other symptoms include ataxia, cognitive impairment and seizures. In a few studies, KCNMA1 mutation was found to be associated with GLUT1.47,50
Mutations in KCNMA1 have also been linked to another type of paroxysmal movement disorder, Episodic Ataxia Type 1.29,54
Other Genes There are many other genes implicated in PDs, mostly described in isolated case reports. A review article by Castiglioni et al55 describes one patient presenting with PED and comorbid developmental delay. He was found to have pyruvate dehydrogenase alpha 1(PDHA1) mutation consistent with pyruvate dehydrogenase deficiency. Treatment with thiamine improved her symptoms.55
Dale et al56 described a family with autosomal dominant inherited PED, found to have GTPcyclohydrolase 1 mutation. This family had associated restless legs syndrome, depression and adult onset Parkinsonism.56
Secondary Causes: In a study by Blakeley and Jankovic8, 92 patients with PDs were evaluated. Vascular causes were common in older patients whereas trauma was more common in younger individuals. Other causes included kernicterus, multiple sclerosis, cytomegalovirus encephalitis, meningovascular syphilis and migraines.
Acquired immunodeficiency syndrome (AIDS) and Subacute sclerosing panencephalitis (SSPE) have also been described.57 Many metabolic disorders such as Wilson’s disease, Maple syrup
urine disease, pseudophypoparathyroidism with basal ganglia calcification, hypoparathyroidism, thyrotoxicosis, hypoglycemia, insulinoma and hyperglycemia have also been associated with PDs.57-68 Malignancies like CNS lymphoma have reported in patients with PKD. 69 Structural malformations like cortical hyperplasia was reported to cause nocturnal PD.70 Drugs such as methylphenidate has shown to cause paroxysmal kinesigenic dystonia.68 Neuroacanthocytosis has been reported to be associated with PDs.71 Psychogenic causes are known to frequently mimic PD.8,72
Paroxysmal dyskinesias can be the presenting symptom of multiple sclerosis.8,73-75 Multiple sclerosis associated PD differs in characteristics with painful muscle contractions precipitated by aura, occurring many times a day and lasting seconds to minutes.
Strokes usually have PDs that occur after resolution of initial symptoms and are usually contralateral to the infarct. Many case reports site locations commonly affected as the thalamus, subthalamic, putamen, medulla. 76-79 PDs can be associated with transient ischemic attack, especially in cases of carotid hypoperfusion, usually presenting as a form of limb shaking.8,9,15,80,81
Head trauma, anoxic brain injury, spinal cord injury have been reported. 8 In the case of trauma, the abnormal movement does not necessarily occur immediately after the injury. 8,82,83 Scott and Jankovic 84 described 53 patients who developed abnormal movements after head trauma, with mean latency of 25.5 years.84
PDs linked to secondary causes were found to be commonly mixed in nature instead of fitting perfectly into a specific phenotypic category (PNKD, PKD and PED). Patients were also more likely to have neurologic deficits at baseline. Secondary PNKD usually have an exacerbating factor which included fatigue, stress and temperature changes.8 Recognizing signs of secondary causes is important as treatment of the underlying disease will improve or cure the movement disorder.8,85 Figure 4 summarizes different causes of secondary PD
Disorders that Mimic Paroxysmal Dyskinesias: Mimics of PDs include dopa-responsive dystonia, seizures and tics.30 Dopa-responsive dystonia is a type of dystonia presenting in childhood with diurnal fluctuation and excellent response to low doses of oral dopamine.86 Kim et al87 looked at proton magnetic resonance spectroscopy(MRS) in 5 patients with idiopathic PKD and noticed that 2 patients had significant decrease in choline and myoinositol in their unilateral basal ganglia and one patient just had decreased myoinositol in unilateral basal ganglia. They thought these findings to be conclusive of at least a partial involvement of basal ganglia cholinergic system.
Ko et al88 described a 14 year old boy with PKD who had EEG and magnetic resonance imaging (MRI). Ictal single-photon emission computed tomography (SPECT) using (99m)Tc ethyl cysteinate dimer revealed increased perfusion of the contralateral basal ganglia.
Abnormal EEGs have been reported in many patients with PKD. Lombroso and Fischman89 reported a boy with PKND who underwent invasive video EEG monitoring which demonstrated
that the movement disorder originated from the caudate nuclei instead of the cortex. A case by Falconer et al 90 describes a seizure that was induced by movement which. Patient was successfully treated with surgical removal of the underlying damaged brain tissue from a prior insult. Supplementary motor cortex was identified as the source in this case.
Kluge91 described that in patients with PED, SPECT analysis showed decreased ictal perfusion of frontal cortex and basal ganglia during motor attacks. Interestingly there was increased perfusion in the cerebellum but no cortical hyperperfusion suggestive of epilepsy was seen.
It is important to differentiate PDs from psychogenic movement disorders.30 Baik et al92 stated that one of the most important clinical features to identify psychogenic events is abrupt onset of symptoms. Other suggested features were ability to trigger attacks, variable frequency and duration of events as well as resolution of movements after treatment with placebo.
Diagnostic work up: A detailed history, family history and video documentation of events are paramount in the differential diagnosis of PDs. Frontal lobe epilepsy should be ruled out. Interictal EEG may be useful in ruling out seizures whereas video EEG monitoring may provide better characterization of the phenomenon. Brain MRI should be obtained in the absence of a family history, especially in older patients to rule out secondary causes. Blood work will rule out metabolic causes such as hypoglycemia/hyperglycemia. Genetic studies such as commercially available PD panels or whole exome sequencing should be considered.
Treatment: Proper treatment relies on adequate identification of the type of PD and primary vs secondary causes. PKD have shown good response to anti-epileptic drugs (AEDs) typically at lower doses than usually used to treat epileptic seizures. The most commonly used AEDs are carbamazepine/oxcarbazepine and phenytoin.93 In individual case studies or reviews, other AEDs have shown some success including phenobarbital, leviteracetam, gabapentin, valproate, lamotrigine and topiramate.94 Patients with PKDs do not appear to improve with avoidance of triggers or implementing other diet/lifestyle changes.15,29,93
For patient with PNKD, identification and avoidance of underlying triggers is recommended. AEDs are usually ineffective except for benzodiazepines (clonazepam, diazepam).93 There are individual cases reported that respond to haloperidol, anticholinergics, acetazolamide, leviteracetam and valproate.95,93 Neurosurgical procedures such as deep brain stimulation (DBS) are uncommon in children but have been performed in adults with refractory chorea, dystonia and/or tremor with improvement in select cases.15,29,93,96 Kaufman et al97 reports a case of a 26 year old male with diagnosis of PNKD refractory to medical treatment. DBS was performed with implantation in the globus pallidus internus with reported improvement of symptoms.97
PEDs are treated with avoidance but not discontinuing exercise. These movements are less commonly responsive to medications. AEDs, levodopa, acetazolamide have been tried with mixed results.15,29,93
In patients with PDs (exercise induced or non-kinesigenic) and GLUT 1 deficiency, ketogenic or modified Atkins diet is the mainstay of therapy. 98,99 Some authors have reported some success with acetazolamide.41,44,93,95 Triheptanoin, an odd chain triglyceride noted to add key substrates to the Krebs cycle in patients with GLUT1 was found to be effective in decreasing the movements in patients with PD.100
Patients with secondary paroxysmal dyskinesias, identification and proper treatment of underlying cause will improve or resolve the abnormal movement.
Conclusion: Paroxysmal dyskinesias are a rare form of hyperkinetic movement disorders with preserved consciousness. They are usually divided into groups of kinesigenic, non-kinesigenic and exercise induced based on phenotype. In genetic cases, mutations in PRRT2 are commonly implicated in patients with PKD whereas MR1 mutation is more often found in PNKD. Despite several genes recently found, we are just beginning to understand genotype/phenotype relationship and the complex genetics of patients with PD. Whole genome and exome sequencing studies will yield more information on the genetics and pathophysiology of this entity.
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Pearson TS, Akman C, Hinton VJ, Engelstad K, De Vivo DC. Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS). Curr Neurol Neurosci Rep. 2013;13(4):342. Leen WG, Klepper J, Verbeek MM, et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 2010;133(Pt 3):655-670. Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I, et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord. 2009;24(11):1684-1688. Auburger G, Ratzlaff T, Lunkes A, et al. A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics. 1996;31(1):9094. Du W, Bautista JF, Yang H, et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet. 2005;37(7):733-738. Zhang Z, Tian M, Gao K, Jian Y, Wu Y. De novo KCNMA1 mutations in children with early-onset paroxysmal dyskinesia and developmental delay. - PubMed - NCBI. 2017. Zhang Z, Tian M, Jiang Y, Wu Y. De Novo KCNMA1 Mutations in Children with Early-Onset Paroxysmal Dyskinesia and Developmental Delay. Movement Disorders. 2015;30(9):1290-1292. Jen JC, Graves TD, Hess EJ, et al. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain. 2007;130(Pt 10):2484-2493. Castiglioni C, Verrigni D, Okuma C, et al. Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. Eur J Paediatr Neurol. 2015;19(5):497-503. Dale RC, Melchers A, Fung VS, Grattan-Smith P, Houlden H, Earl J. Familial paroxysmal exerciseinduced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency. Dev Med Child Neurol. 2010;52(6):583-586. Ondo WG, Verma A. Physiological assessment of paroxysmal dystonia secondary to subacute sclerosing panencephalitis. Mov Disord. 2002;17(1):154-157. Micheli F, Tschopp L, Cersosimo MG. Oxcarbazepine-responsive paroxysmal kinesigenic dyskinesia in Wilson disease. Clin Neuropharmacol. 2011;34(6):262-264. Temudo T, Martins E, Poças F, Cruz R, Vilarinho L. Maple syrup disease presenting as paroxysmal dystonia. Ann Neurol. 2004;56(5):749-750. Thomas KP, Muthugovindan D, Singer HS. Paroxysmal kinesigenic dyskinesias and pseudohypoparathyroidism type Ib. Pediatr Neurol. 2010;43(1):61-64. Tabaee-Zadeh MJ, Frame B, Kapphahn K. Kinesiogenic choreoathetosis and idiopathic hypoparathyroidism. N Engl J Med. 1972;286(14):762-763. Fischbeck KH, Layzer RB. Paroxysmal choreoathetosis associated with thyrotosicosis. Ann Neurol. 1979;6(5):453-454. Schmidt BJ, Pillay N. Paroxysmal dyskinesia associated with hypoglycemia. Can J Neurol Sci. 1993;20(2):151-153. Shaw C, Haas L, Miller D, Delahunt J. A case report of paroxysmal dystonic choreoathetosis due to hypoglycaemia induced by an insulinoma. J Neurol Neurosurg Psychiatry. 1996;61(2):194-195. Hennis A, Corbin D, Fraser H. Focal seizures and non-ketotic hyperglycaemia. J Neurol Neurosurg Psychiatry. 1992;55(3):195-197. Morres CA, Dire DJ. Movement disorders as a manifestation of nonketotic hyperglycemia. J Emerg Med. 1989;7(4):359-364. Gonzalez-Alegre P, Ammache Z, Davis PH, Rodnitzky RL. Moyamoya-induced paroxysmal dyskinesia. Mov Disord. 2003;18(9):1051-1056. Gay CT, Ryan SG. Paroxysmal kinesigenic dystonia after methylphenidate administration. J Child Neurol. 1994;9(1):45-46.
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Rollnik JD, Winkler T, Ganser A. [A case of symptomatic paroxysmal kinesigenic dsykinesia with primary central nervous system lymphoma]. Nervenarzt. 2003;74(4):362-365. Lombroso CT. Nocturnal paroxysmal dystonia due to a subfrontal cortical dysplasia. Epileptic Disord. 2000;2(1):15-20. Tschopp L, Raina G, Salazar Z, Micheli F. Neuroacanthocytosis and carbamazepine responsive paroxysmal dyskinesias. Parkinsonism Relat Disord. 2008;14(5):440-442. Fahn S, Williams DT. Psychogenic dystonia. Adv Neurol. 1988;50:431-455. Berger JR, Sheremata WA, Melamed E. Paroxysmal dystonia as the initial manifestation of multiple sclerosis. Arch Neurol. 1984;41(7):747-750. Shibasaki H, Kuroiwa Y. Painful tonic seizure in multiple sclerosis. Arch Neurol. 1974;30(1):47-51. de Seze J, Stojkovic T, Destée M, Destée A, Vermersch P. Paroxysmal kinesigenic choreoathetosis as a presenting symptom of multiple sclerosis. J Neurol. 2000;247(6):478-480. Nijssen PC, Tijssen CC. Stimulus-sensitive paroxysmal dyskinesias associated with a thalamic infarct. Mov Disord. 1992;7(4):364-366. Lee MS, Marsden CD. Movement disorders following lesions of the thalamus or subthalamic region. Mov Disord. 1994;9(5):493-507. Merchut MP, Brumlik J. Painful tonic spasms caused by putaminal infarction. Stroke. 1986;17(6):1319-1321. Riley DE. Paroxysmal kinesigenic dystonia associated with a medullary lesion. Mov Disord. 1996;11(6):738-740. Haq IU, Tate JA, Siddiqui MS, Okun MS. Clinical Overview of Movement Disorders. In: Inc E, ed. Youmans and Winn Neurological Surgery. 7 ed.:573-585. Baquis GD, Pessin MS, Scott RM. Limb shaking--a carotid TIA. Stroke. 1985;16(3):444-448. Krauss JK, Tränkle R, Kopp KH. Post-traumatic movement disorders in survivors of severe head injury. Neurology. 1996;47(6):1488-1492. Drake ME, Jackson RD, Miller CA. Paroxysmal choreoathetosis after head injury. J Neurol Neurosurg Psychiatry. 1986;49(7):837-838. Scott BL, Jankovic J. Delayed-onset progressive movement disorders after static brain lesions. Neurology. 1996;46(1):68-74. Sen A, Atakli D, Guresci B, Arpaci B. A rare paroxysmal movement disorder: mixed type of paroxysmal dyskinesia. Ideggyogy Sz. 2014;67(11-12):426-429. Jankovic J. Parkinson Disease and Other Movement Disorders. In: Bradley's Neurology in Clinical Practice. 7 ed.: Elsevier Inc; 2016:1422-1460. Kim MO, Im JH, Choi CG, Lee MC. Proton MR spectroscopic findings in paroxysmal kinesigenic dyskinesia. Mov Disord. 1998;13(3):570-575. Ko CH, Kong CK, Ngai WT, Ma KM. Ictal (99m)Tc ECD SPECT in paroxysmal kinesigenic choreoathetosis. Pediatr Neurol. 2001;24(3):225-227. Lombroso CT, Fischman A. Paroxysmal non-kinesigenic dyskinesia: pathophysiological investigations. Epileptic Disord. 1999;1(3):187-193. FALCONER MA, DRIVER MV, SERAFETINIDES EA. SEIZURES INDUCED BY MOVEMENT: REPORT OF A CASE RELIEVED BY OPERATION. J Neurol Neurosurg Psychiatry. 1963;26:300-307. Kluge A, Kettner B, Zschenderlein R, et al. Changes in perfusion pattern using ECD-SPECT indicate frontal lobe and cerebellar involvement in exercise-induced paroxysmal dystonia. Mov Disord. 1998;13(1):125-134. Baik JS, Han SW, Park JH, Lee MS. Psychogenic paroxysmal dyskinesia: the role of placebo in the diagnosis and management. Mov Disord. 2009;24(8):1244-1245. Mink JW. Treatment of paroxysmal dyskinesias in children. Curr Treat Options Neurol. 2015;17(6):350.
94. 95. 96. 97. 98.
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Peng G, Wang K, Yuan Y, Zheng X, Luo B. Clinical analysis of nine cases of paroxysmal exerciseinduced dystonia. J Huazhong Univ Sci Technolog Med Sci. 2012;32(6):937-940. Anheim M, Maillart E, Vuillaumier-Barrot S, et al. Excellent response to acetazolamide in a case of paroxysmal dyskinesias due to GLUT1-deficiency. J Neurol. 2011;258(2):316-317. Mahlknecht P, Limousin P, Foltynie T. Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments. J Neurol. 2015;262(11):2583-2595. Kaufman CB, Mink JW, Schwalb JM. Bilateral deep brain stimulation for treatment of medically refractory paroxysmal nonkinesigenic dyskinesia. J Neurosurg. 2010;112(4):847-850. Ramm-Pettersen A, Nakken KO, Skogseid IM, et al. Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol. 2013;55(5):440-447. Leen WG, Mewasingh L, Verbeek MM, Kamsteeg EJ, van de Warrenburg BP, Willemsen MA. Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet. Mov Disord. 2013;28(10):1439-1442. Mochel F, Hainque E, Gras D, et al. Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency. J Neurol Neurosurg Psychiatry. 2016;87(5):550-553. Olgiati S, Skorvanek M, Quadri M, et al. Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency. Mov Disord. 2016;31(7):1041-1048.
Figure 1. The genetics of the Dystonias DYTn DYT8 DYT20 DYT10 DYT19 DYT18
Clinical Name Paroxysmal Non-kinesigenic Dyskinesia 1 Paroxysmal Non-kinesigenic Dyskinesia 2 Paroxysmal Kinesigenic Dyskinesia 1 Paroxysmal Kinesigenic Dyskinesia 2 Exercise-Induced Paroxysmal Dyskinesia
Chart modified from Camargo et al.
Gene Locus 2q 2q 16pq 16q 1p
Gene MR-1 PRRT2 SLC2A1 or GLUT1
14
Figure 2. Clinical features PKD, PNKD, PED Feature Duration Common Triggers Male to Female Ratio Frequency
PKD < 1minute Sudden Movement 2:1 100/day
Modified from Meneret et al, Hao et al, Singer et al.
PNKD Minutes to Hours Alcohol, caffeine, stress 1.5:1 Few a day 15,18,29
PED Minutes to Hours Exercise 1:1 Variable (usually 1/day)
Figure 3. Genes commonly associatiated with PDs.
Paroxysmal Dyskinesia
PKD
PNKD
PED
Genes:
Genes:
-PRRT2
-MR-1
-ADCY5
-PRRT2
-SCN8A
-ADCY5
-SLC16A2
-SLC2A1
-EKD2
-ATP1A3 -KCNMA1 -BCKD Complex -FGF14
Genes: -SLC2A1 -GCH1 -ADCY5
-PRRT2 -ATP1A3 -PARK2 -PDHA1, PDHX
-GAD-1
Updated from review by Meneret et. al, Ha and Jankovic, and Camargo et al.
-ECHS1
14,29,30,101
57
1. CNS infections
CMV, Syphilis, AIDS, SSPE
2. Metabolic abnormalities
Wilson’s disease , maple syrup urine disease , pseudohypoparathyroidism with basal ganglia 60 61 62 calcification , hypoparathyroidism , thyrotoxicosis , 63,64 65,66 hypoglycemia/insulinoma , hyperglycemia , hypocalcemia, diabetes
3. Trauma
Anoxic brain injury, spinal cord injury, cerebral palsy, head trauma
4. Vascular injuries
Moyamoya disease , TIA, stroke
5. Malignancies
Parasagittal meningioma, CNS lymphoma
6. Structural malformations
Arnold Chiari malformation with syringomelia, cortical 70 dysplasia
7. Drug induced
Methylphenidate therapy
8. Others
Progressive supranuclear palsy, Neuroacanthocytosis
58
59
67
69
68
Figure 4. Secondary PDs
Summary of several sources of literature.57-71
71
image
Paroxysmal dyskinesias Sara McGuire, Swati Chanchani, Divya S. Khurana
www.elsevier.com/locate/bios
PII: DOI: Reference:
S1071-9091(17)30156-0 https://doi.org/10.1016/j.spen.2017.12.007 YSPEN701
To appear in: Seminars in Pediatric Neurology Cite this article as: Sara McGuire, Swati Chanchani and Divya S. Khurana, Paroxysmal dyskinesias, Seminars in Pediatric Neurology,doi:10.1016/j.spen.2017.12.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Paroxysmal Dyskinesias
Sara McGuire MD, Swati Chanchani MD, Divya S Khurana, MD
From the Section of Neurology, Department of Pediatrics, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA
Address reprint requests to: Divya S Khurana, MD, Section of Neurology, Department of Pediatrics, St Christopher’s Hospital for Children, Drexel University College of Medicine,160 E Erie Avenue, Philadelphia, PA 19134. Email: [email protected]
Abstract: Paroxysmal dyskinesias (PD) are hyperkinetic movement disorders where patients usually retain consciousness. Paroxysmal dyskinesias can be kinesigenic (PKD), nonkinesigenic (PNKD) and exercise induced (PED). These are usually differentiated from each other based on their phenotypic and genotypic characteristics. Genetic causes of PD are continuing to be discovered. Genes found to be involved in the pathogenesis of PD include MR1, PRRT2, SLC2A1, KCNMA1. The differential diagnosis is broad as PDs can mimic psychogenic events, seizure or other movement disorders. This review also includes secondary causes of PDs which can range from infections, metabolic, structural malformations to
malignancies. Treatment is usually based on the correct identification of type of PD. PKD responds well to anti-epileptic medications whereas PNKD and PED respond to avoidance of trigger and exercise. In this article we review classification, clinical features, genetics, differential diagnosis and management of PD.
Introduction: Paroxysmal dyskinesias (PD) are rare hyperkinetic movement disorders which include chorea, dystonia, athetosis and ballism, isolated or in combination. Patients are asymptomatic between episodes. These episodes may or not be induced by movement, called kinesigenic (duration seconds to minutes) or non kinesigenic (minutes to hours).1
The first documented case consistent with PD was described in 1892 in a 23 year old Japanese man.2 The clinical syndrome was not fully described until 1940 by Mount and Reback.3 They wrote about a young male with episodes of dystonia and chorea caused by coffee and alcohol.
It was at the time termed “familial paroxysmal choreoathetosis”.3 In 1967, Kertesz4 described a group of patients with episodes that were very brief in duration and precipitated by sudden movement naming this “paroxysmal kinesigenic choreoathetosis”.4 In 1968, Richards and Barnett5 suggested the term “paroxysmal dystonic choreoathetosis of Mount and Reback” since the postural and tone changes accompanied the choreoathetoid movements described in the Canadian family in their study.5 In 1977, Lance6 described a family with attacks that were provoked by prolonged exercise which became classified as “paroxysmal exercise-induced dystonia”.6 In described cases of PD, there is significant overlapping of manifestations in regards to type of movements, duration and precipitating factors. They may present as dystonias, chorea, athetosis or ballism either individually or in varied combinations.
The most widely used classification for PDs was created by Demirkiran and Jancovic.7 Etiology and pathogenesis of PDs is still under investigation and not fully understood. Most cases are thought to be idiopathic. However, many secondary causes have been reported. 8 Due to the familial nature of this neurological disorder, the role of genetics is currently under extensive research.
Classification: The most widely used classification system cited in the literature was created by Demirkiran and Jankovic7 in 1995 based on phenotype, precipitating factors, duration and etiology7. The proposed classification divided paroxysmal dyskinesias into 4 categories based on clinical features: Paroxysmal Kinesigenic Dyskinesias (PKD), Paroxysmal Non-Kinesigenic Dyskinesias (PNKD), Paroxysmal Exercise-Induced Dykinesias (PED), Paroxysmal Hypnogenic Dyskinesias (PHD). Each clinical feature is further subdivided by duration into short (≤ five minutes) or long
(> 5 minutes). PD can be either idiopathic (familial or sporadic) or secondary (linked to another underlying medical condition).7,9,10
Paroxysmal hypnogenic dyskinesia (PHD), originally classified as PD, is now thought to a be form of epilepsy and called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). These patients present with episodes of dystonia/chorea/ballism or a combination of these occurring during non-REM sleep without any preceding identifiable triggers. Attacks are short in duration (30-45 seconds). In most cases, these episodes are mesial frontal lobe seizures.1 Therefore, PHD will not be further discussed in this review.
Another scheme of classification of dystonic syndromes was created by the Human Genome Organization Gene Nomenclature Committee based on the DYTn coding system where ‘n’ was the label assigned to the gene loci which can be linked with a specific phenotype and associated genetic markers.11,12 This classification is less widely used due to many short comings including presence of unconfirmed loci, missing symbols or loci, duplication of loci, technical errors leading to erroneous linkage to disease, combining causative and risk factor genes in the same list and discordance between phenotype and list assignment. For example in patients with PD, the movement phenotype may be variable or mixed and may or may not be dystonic.13 An example of some of the more common DYTn classifications is shown in figure 1 which is modified from Camargo et al.14
Paroxysmal Kinesigenic Dyskinesia (PKD)
In PKD, the paroxysms are precipitated by sudden movement, sudden acceleration, change in the direction of movement or startle. Attacks can be characterized by dystonia, chorea, ballism or a combination. Dystonia is most commonly reported.15 These are usually brief dystonic attacks in one or more extremities lasting from a few seconds to a few minutes. There is no alteration of consciousness. The episodes can occur multiple times a day to once a month.15 Sensory auras such as limb paresthesias may be present.16 Speech can be affected if the jaw or face is involved. Episodes can be unilateral or bilateral and can affect any part of the body. 15 Electroencephalogram (EEG) and brain imaging studies are usually normal. Patient are reportedly normal between episodes.17 Onset occurs in the first to second decade of life and peaks at puberty with improvement or complete resolution during adulthood.15,18
In a study by Bruno et al19 with 121 patients with presumptive diagnosis of PKD, the diagnostic criteria was described as: identifiable attack triggers (sudden movements), short duration (<1 minute), lack of loss of consciousness or pain, antiepileptic drug responsiveness, exclusion of other organic diseases, and age at onset (1 to 20 years if no family history; less stringently if positive family history).
PKD can be familial or sporadic. Sporadic cases are more frequent in males whereas infantile convulsions are more common in the familial kindreds. Females have a higher remission rate than males. An infantile-onset group with a different set of characteristics was identified where parents observed the attacks during sleep and there was non-uniform response to anti-epileptic medications.19,20
Paroxysmal Non-Kinesigenic Dyskinesia (PNKD) PNKD is characterized by intermittent episodes of dystonia, chorea or athetosis. PNKD associated with myokymia has been described.21 PNKD is usually not triggered by sudden movements but can be triggered by caffeine, tea, sleep deprivation, alcohol and stress.22 It is seen more commonly in males than females (1.4:1).23 Similar to PKD, there is no impairment in consciousness. Frequency and severity usually peak at puberty with possible remission during adulthood. Attacks are longer compared to those in PKD (minutes to hours) and less frequent than PKD.15
There are no abnormalities noted between the attacks. However, a case report of PNKD with simultaneous tremor was described in an elderly woman. She presented attacks of difficulty speaking, abnormal sensation in extremities and episodes of stiffness with dystonia of trunk, chorea of upper and lower extremities starting at age 9. In between attacks, there was persistent head tremor and chorea of upper and lower extremities. Family history of similar episodes was present but no tremors. Genetic testing revealed mutation of myofibrillogenesis regulator (MR-1) gene.24
Bruno et al 10 described a family of 14 kindreds with familial dyskinesia not induced by movement. Eight had MR-1 mutations. Sleep benefit (resolution of attack with patient going to sleep during attacks) was seen in all patients with PNKD regardless the presence of MR-1 mutation. These patients were also diagnosed in early childhood and had a mixture of chorea and dystonia. The authors suggested that PNKD should be defined strictly based on age of onset with the clinical presentation of attacks precipitated by caffeine and alcohol. Penetrance
was found to be high at 98%.10 However incomplete penetrance and intra-familial variability has been described.25-27
PNKD is known to be non-life threatening. However, Zittel et al28 described a rare fatal case of PNKD. The patient initially presented with involuntary arm spasm that would also affect the neck and speech. Like all PNKD, triggers were caffeine, alcohol and stress and relief with sleep. Both the patient’s mother and maternal grandmother died from laryngeal dystonia and consequent respiratory distress during an attack.28
Paroxysmal Exercise-Induced Dyskinesia (PED) PED is triggered by sustained exercise. Other identified triggers include vibration, cold temperature, and electric nerve stimulation. The most common abnormal movement is dystonia (similar to PKD and PKND) but ballism, chorea or athetosis can also be present. Lower extremities are most commonly affected. The frequency of attacks is highly variable. Attacks last 5-30 minutes, be bilateral or unilateral and are not usually associated with a sensory aura. PED is usually inherited in an autosomal dominant fashion in familial cases.15,18, 29-31 Bozi and Bhatia32 described 2 patients with early onset Parkinson’s disease who initially presented with PED. In both patients, the PED predated the development of the typical parkinsonian features (1.5 and 5 years). In figure 2 we summarize the clinical features of PKD, PNKD, PED15,18,29
Genetics: It has been reported that 40%–70% of PD cases are familial. Many genes have been described are associated with PDs (Figure 3).
PRRT2 (proline-rich transmembrane protein 2) PRRT2 is a transmembrane protein highly expressed in the central nervous system including basal ganglia, cerebellum and hippocampus.33,34 PRRT2 is the most common gene involved in primary genetic PKD and is located on chromosome 16.33 Disease causing mutations are usually heterozygous and cause loss of function.35 Sporadic PKD have PRRT2 mutation as cause in almost half of the cases, according to Gardiner et al.35 It is usually inherited as autosomal dominant with incomplete penetrance.29 The full role of PRRT2 is not well understood but it is believed to be involved in neurotransmitter release and synaptic vesicle fusion with plasma membrane (SNAP25).35, 34 Phenotypically, patients with PRRT2 mutations are usually younger with higher frequency of attacks.15
Other disorders associated with PRRT2 mutation include hemiplegic and other types of migraines, episodic ataxia, febrile seizures, sporadic infantile convulsion, and paroxysmal torticollis.15 Patients with this genetic defect tend to have a family history of epilepsy.36 Cases of homozygous mutation to PRRT2 have been described to have a more severe phenotype with intellectual disability, episodic ataxia and absence epilepsy.37
MR-1/PNKD (myofibrillogenesis regulator 1) MR-1 is located on chromosome 2 (2q35, less commonly 2q31).38 Mutations that have been described are missense mutations. The normal function of MR-1 is to produce protein, spliced into 3 parts MR-1L (long), MR-1M (medium), MR-1S (small). Genetic defects are seen in the L and S protein which are involved in mitochondrial targeting sequence and protein transfer into the mitochondria.38 The genetic defect is inherited in autosomal dominant fashion with incomplete penetrance.25,39 It is more commonly found in young patients who develop PNKD around 12 years of age.10
Bruno et al.10 studied 49 patients with MR-1 mutations and found that 100% of patients had PNKD precipitated by caffeine or alcohol intake. In patients without MR-1 mutation, caffeine was sometimes a trigger but alcohol was not. Patients with MR-1 mutation were also more responsive to treatment. Treatment of choice was benzodiazepines.10,25-27,40 Attacks were often alleviated by sleep in patients with and without MR-1 mutation.10,25-27,40
SLC2A1 (solute carrier family 2 member 1) The SLC2A1 gene encodes glucose transporter 1 protein (GLUT1) and is located on chromosome 1p34.2. 15,41,42 GLUT1 isoform is present in the endothelium of the blood brain barrier and astrocytes facilitating glucose transport across the blood brain barrier.43-45 Interictal positron emission tomography (PET) showed decreased signal in glucose metabolism in the thalamus in cases of PED.46 Mutation inheritance has been reported as autosomal dominant as well as sporadic.47,48 PED associated with this genetic mutation is designated DYT18.47 SLC2A1 gene mutation is the most common cause of familial PED but can also manifest as PNKD. 29
A variable phenotype has been described including PED and encephalopathy. The wide spectrum ranges from severe (development delay, microcephaly, refractory seizures, ataxia, spasticity, hypoglycorrachia and decreased erythrocyte glucose uptake) to milder versions (seizures, isolated PED and episodic migraines). 15,49
KCNMA1 (potassium calcium-activated channel subfamily M alpha 1) KCNMA1 gene mutation is most commonly inherited in an autosomal dominant pattern.50 KCNMA1 gene mechanism has been postulated as a pore forming alpha subunit of the big potassium channel which is sensitive to calcium.36
This mutation was first reported in 2005 in a family with PNKD and epilepsy51. It was again described in a study by Zhang et al52 in 2 unrelated children with PNKD and developmental delay. In the latter, the children developed PNKD at an earlier age and there was no associated epilepsy. No triggers were identified in either patient.53
A form of PNKD commonly associated with KCNMA1 gene mutation is characterized by spasticity and choreoathetosis.50 Patients present with a progressive spastic paraparesis. Other symptoms include ataxia, cognitive impairment and seizures. In a few studies, KCNMA1 mutation was found to be associated with GLUT1.47,50
Mutations in KCNMA1 have also been linked to another type of paroxysmal movement disorder, Episodic Ataxia Type 1.29,54
Other Genes There are many other genes implicated in PDs, mostly described in isolated case reports. A review article by Castiglioni et al55 describes one patient presenting with PED and comorbid developmental delay. He was found to have pyruvate dehydrogenase alpha 1(PDHA1) mutation consistent with pyruvate dehydrogenase deficiency. Treatment with thiamine improved her symptoms.55
Dale et al56 described a family with autosomal dominant inherited PED, found to have GTPcyclohydrolase 1 mutation. This family had associated restless legs syndrome, depression and adult onset Parkinsonism.56
Secondary Causes: In a study by Blakeley and Jankovic8, 92 patients with PDs were evaluated. Vascular causes were common in older patients whereas trauma was more common in younger individuals. Other causes included kernicterus, multiple sclerosis, cytomegalovirus encephalitis, meningovascular syphilis and migraines.
Acquired immunodeficiency syndrome (AIDS) and Subacute sclerosing panencephalitis (SSPE) have also been described.57 Many metabolic disorders such as Wilson’s disease, Maple syrup
urine disease, pseudophypoparathyroidism with basal ganglia calcification, hypoparathyroidism, thyrotoxicosis, hypoglycemia, insulinoma and hyperglycemia have also been associated with PDs.57-68 Malignancies like CNS lymphoma have reported in patients with PKD. 69 Structural malformations like cortical hyperplasia was reported to cause nocturnal PD.70 Drugs such as methylphenidate has shown to cause paroxysmal kinesigenic dystonia.68 Neuroacanthocytosis has been reported to be associated with PDs.71 Psychogenic causes are known to frequently mimic PD.8,72
Paroxysmal dyskinesias can be the presenting symptom of multiple sclerosis.8,73-75 Multiple sclerosis associated PD differs in characteristics with painful muscle contractions precipitated by aura, occurring many times a day and lasting seconds to minutes.
Strokes usually have PDs that occur after resolution of initial symptoms and are usually contralateral to the infarct. Many case reports site locations commonly affected as the thalamus, subthalamic, putamen, medulla. 76-79 PDs can be associated with transient ischemic attack, especially in cases of carotid hypoperfusion, usually presenting as a form of limb shaking.8,9,15,80,81
Head trauma, anoxic brain injury, spinal cord injury have been reported. 8 In the case of trauma, the abnormal movement does not necessarily occur immediately after the injury. 8,82,83 Scott and Jankovic 84 described 53 patients who developed abnormal movements after head trauma, with mean latency of 25.5 years.84
PDs linked to secondary causes were found to be commonly mixed in nature instead of fitting perfectly into a specific phenotypic category (PNKD, PKD and PED). Patients were also more likely to have neurologic deficits at baseline. Secondary PNKD usually have an exacerbating factor which included fatigue, stress and temperature changes.8 Recognizing signs of secondary causes is important as treatment of the underlying disease will improve or cure the movement disorder.8,85 Figure 4 summarizes different causes of secondary PD
Disorders that Mimic Paroxysmal Dyskinesias: Mimics of PDs include dopa-responsive dystonia, seizures and tics.30 Dopa-responsive dystonia is a type of dystonia presenting in childhood with diurnal fluctuation and excellent response to low doses of oral dopamine.86 Kim et al87 looked at proton magnetic resonance spectroscopy(MRS) in 5 patients with idiopathic PKD and noticed that 2 patients had significant decrease in choline and myoinositol in their unilateral basal ganglia and one patient just had decreased myoinositol in unilateral basal ganglia. They thought these findings to be conclusive of at least a partial involvement of basal ganglia cholinergic system.
Ko et al88 described a 14 year old boy with PKD who had EEG and magnetic resonance imaging (MRI). Ictal single-photon emission computed tomography (SPECT) using (99m)Tc ethyl cysteinate dimer revealed increased perfusion of the contralateral basal ganglia.
Abnormal EEGs have been reported in many patients with PKD. Lombroso and Fischman89 reported a boy with PKND who underwent invasive video EEG monitoring which demonstrated
that the movement disorder originated from the caudate nuclei instead of the cortex. A case by Falconer et al 90 describes a seizure that was induced by movement which. Patient was successfully treated with surgical removal of the underlying damaged brain tissue from a prior insult. Supplementary motor cortex was identified as the source in this case.
Kluge91 described that in patients with PED, SPECT analysis showed decreased ictal perfusion of frontal cortex and basal ganglia during motor attacks. Interestingly there was increased perfusion in the cerebellum but no cortical hyperperfusion suggestive of epilepsy was seen.
It is important to differentiate PDs from psychogenic movement disorders.30 Baik et al92 stated that one of the most important clinical features to identify psychogenic events is abrupt onset of symptoms. Other suggested features were ability to trigger attacks, variable frequency and duration of events as well as resolution of movements after treatment with placebo.
Diagnostic work up: A detailed history, family history and video documentation of events are paramount in the differential diagnosis of PDs. Frontal lobe epilepsy should be ruled out. Interictal EEG may be useful in ruling out seizures whereas video EEG monitoring may provide better characterization of the phenomenon. Brain MRI should be obtained in the absence of a family history, especially in older patients to rule out secondary causes. Blood work will rule out metabolic causes such as hypoglycemia/hyperglycemia. Genetic studies such as commercially available PD panels or whole exome sequencing should be considered.
Treatment: Proper treatment relies on adequate identification of the type of PD and primary vs secondary causes. PKD have shown good response to anti-epileptic drugs (AEDs) typically at lower doses than usually used to treat epileptic seizures. The most commonly used AEDs are carbamazepine/oxcarbazepine and phenytoin.93 In individual case studies or reviews, other AEDs have shown some success including phenobarbital, leviteracetam, gabapentin, valproate, lamotrigine and topiramate.94 Patients with PKDs do not appear to improve with avoidance of triggers or implementing other diet/lifestyle changes.15,29,93
For patient with PNKD, identification and avoidance of underlying triggers is recommended. AEDs are usually ineffective except for benzodiazepines (clonazepam, diazepam).93 There are individual cases reported that respond to haloperidol, anticholinergics, acetazolamide, leviteracetam and valproate.95,93 Neurosurgical procedures such as deep brain stimulation (DBS) are uncommon in children but have been performed in adults with refractory chorea, dystonia and/or tremor with improvement in select cases.15,29,93,96 Kaufman et al97 reports a case of a 26 year old male with diagnosis of PNKD refractory to medical treatment. DBS was performed with implantation in the globus pallidus internus with reported improvement of symptoms.97
PEDs are treated with avoidance but not discontinuing exercise. These movements are less commonly responsive to medications. AEDs, levodopa, acetazolamide have been tried with mixed results.15,29,93
In patients with PDs (exercise induced or non-kinesigenic) and GLUT 1 deficiency, ketogenic or modified Atkins diet is the mainstay of therapy. 98,99 Some authors have reported some success with acetazolamide.41,44,93,95 Triheptanoin, an odd chain triglyceride noted to add key substrates to the Krebs cycle in patients with GLUT1 was found to be effective in decreasing the movements in patients with PD.100
Patients with secondary paroxysmal dyskinesias, identification and proper treatment of underlying cause will improve or resolve the abnormal movement.
Conclusion: Paroxysmal dyskinesias are a rare form of hyperkinetic movement disorders with preserved consciousness. They are usually divided into groups of kinesigenic, non-kinesigenic and exercise induced based on phenotype. In genetic cases, mutations in PRRT2 are commonly implicated in patients with PKD whereas MR1 mutation is more often found in PNKD. Despite several genes recently found, we are just beginning to understand genotype/phenotype relationship and the complex genetics of patients with PD. Whole genome and exome sequencing studies will yield more information on the genetics and pathophysiology of this entity.
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Figure 1. The genetics of the Dystonias DYTn DYT8 DYT20 DYT10 DYT19 DYT18
Clinical Name Paroxysmal Non-kinesigenic Dyskinesia 1 Paroxysmal Non-kinesigenic Dyskinesia 2 Paroxysmal Kinesigenic Dyskinesia 1 Paroxysmal Kinesigenic Dyskinesia 2 Exercise-Induced Paroxysmal Dyskinesia
Chart modified from Camargo et al.
Gene Locus 2q 2q 16pq 16q 1p
Gene MR-1 PRRT2 SLC2A1 or GLUT1
14
Figure 2. Clinical features PKD, PNKD, PED Feature Duration Common Triggers Male to Female Ratio Frequency
PKD < 1minute Sudden Movement 2:1 100/day
Modified from Meneret et al, Hao et al, Singer et al.
PNKD Minutes to Hours Alcohol, caffeine, stress 1.5:1 Few a day 15,18,29
PED Minutes to Hours Exercise 1:1 Variable (usually 1/day)
Figure 3. Genes commonly associatiated with PDs.
Paroxysmal Dyskinesia
PKD
PNKD
PED
Genes:
Genes:
-PRRT2
-MR-1
-ADCY5
-PRRT2
-SCN8A
-ADCY5
-SLC16A2
-SLC2A1
-EKD2
-ATP1A3 -KCNMA1 -BCKD Complex -FGF14
Genes: -SLC2A1 -GCH1 -ADCY5
-PRRT2 -ATP1A3 -PARK2 -PDHA1, PDHX
-GAD-1
Updated from review by Meneret et. al, Ha and Jankovic, and Camargo et al.
-ECHS1
14,29,30,101
57
1. CNS infections
CMV, Syphilis, AIDS, SSPE
2. Metabolic abnormalities
Wilson’s disease , maple syrup urine disease , pseudohypoparathyroidism with basal ganglia 60 61 62 calcification , hypoparathyroidism , thyrotoxicosis , 63,64 65,66 hypoglycemia/insulinoma , hyperglycemia , hypocalcemia, diabetes
3. Trauma
Anoxic brain injury, spinal cord injury, cerebral palsy, head trauma
4. Vascular injuries
Moyamoya disease , TIA, stroke
5. Malignancies
Parasagittal meningioma, CNS lymphoma
6. Structural malformations
Arnold Chiari malformation with syringomelia, cortical 70 dysplasia
7. Drug induced
Methylphenidate therapy
8. Others
Progressive supranuclear palsy, Neuroacanthocytosis
58
59
67
69
68
Figure 4. Secondary PDs
Summary of several sources of literature.57-71
71