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Paroxysmal Dyskinesias

Paroxysmal Dyskinesias. Kapil D Sethi MD FAAN FRCP(UK) Director Movement Disorders Program MCG a unit of GRU Augusta Georgia Senior Medical Expert Merz Pharmaceuticals. HYPP in a Quarter Horse. Paroxysmal Dyskinesias (PDys).

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Paroxysmal Dyskinesias

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  1. Paroxysmal Dyskinesias Kapil D Sethi MD FAAN FRCP(UK) Director Movement Disorders Program MCG a unit of GRU Augusta Georgia Senior Medical Expert Merz Pharmaceuticals

  2. HYPP in a Quarter Horse

  3. Paroxysmal Dyskinesias (PDys) • A heterogeneous group of disorders characterized by the abrupt onset of abnormal involuntary movements.These usually arise out of a background of normal motor behavior • The attacks are often not witnessed by the physician and the movements are varied with a combination of chorea, ballism and dystonia.

  4. Paroxysmal Dyskinesias What is not considered to be a Paroxysmal Dyskinesia? • Action/Task Specific Dystonia • Tics- can occur in bursts • Paroxysmal Exaggeration of Tremor • Action Myoclonus

  5. Paroxysmal Dyskinesias • There are four groups PKD,PNKD,PHD?,PED • These basic four groups can be idiopathic (primary) or secondary to a known disorder • The idiopathic group may be familial or sporadic • These disorders can be further subdivided into short (less than 5 minutes) or long (greater than 5 minutes) • Many cases cannot be compartmentalized in any of the above categories

  6. Paroxysmal Kinesigenic Dyskinesia • Term PK Choreoathetosis was coined by Kertesz (1967) • In one review out of 111 patients,49 were familial • Usually inherited in an autosomal dominant mode and rarely recessive. • Male to female 89/22 (4:1) • Age of onset 5-15 in familial cases and variable in sporadic cases.

  7. PKD -AGE DISTRIBUTION Bruno et al 2004

  8. Paroxysmal Kinesigenic Dyskinesia • Attacks precipitated by sudden movement or startle and sometimes by stress • Frequency up to 100 per day of short lasting (Patients may have a sensory aura before the attack and there is often a refractory period • Most have asymmetric dystonia while others may have chorea

  9. PKD-Proposed Criteria Bruno et al 2004

  10. Paroxysmal Nonkinesigenic Dyskinesia • Mount and Reback(1940) described 28 members of a large family with Paroxysmal Dystonic Choreoathetosis • Often inherited as an autosomal dominant trait • More often in males (2:1) • As in PKD attacks start in childhood and decrease in adulthood

  11. Paroxysmal Nonkinesigenic Dyskinesia • Attacks precipitated by alcohol,fatigue,and caffeine. In one series 98% of cases with MFR-1 mutation had this clinical correlate.(Bruno,2007) • Some families have predominant dystonia while others have chorea. • Frequency 3/day to 2/year. • Duration minutes to hours rarely under 5 minutes.

  12. Paroxysmal Exercise-Induced Dyskinesia • Lance described the intermediate attacks • Frequency 1 per day to two/month • The duration is intermediate between PKD and PNKD (5-30 minutes) • Prolonged exercise precipitates attack • The legs are more affected but the exercise limited to upper extremity may involve upper limbs alone

  13. Paroxysmal Exercise-Induced Dyskinesia • Usually,inherited in a dominant mode but sporadic attacks described as well • In some families there is an overlap between PNKD and PED. • PED may precede parkinsonism in familial PD (Bruno MK, 2004)

  14. ?Paroxysmal Hypnogenic Dyskinesia • First description by Joynt and Green in a patient with multiple sclerosis. • Attacks occur during Non-REM sleep. Attacks represent medial frontal lobe seizures in most cases. • In rare cases the long lasting attacks may be basal ganglia origin.

  15. Secondary Paroxysmal Dyskinesias • Multiple sclerosis • Cerebral Palsy • Hypoparathyroidism and pseudohypoparathyroidism • Hypoglycemia • Head trauma • Cerebrovascular disease • Neuroacanthocytosis • Psychogenic

  16. Miscellaneous Causes of Sec PDx • Cytomegalovirus Encephalitis • Neurosarcoidosis • Migraine • Cervical Cord lesions • Primary CNS Lymphoma • Kernicterus • Hypoglycemia

  17. Secondary Paroxysmal Dyskinesia- Multiple Sclerosis • Also known as tonic seizures and may be the presentation of the disease. Unilateral , bilateral attacks described more in the. Japanese. Hyperventilation precipitates the attack. Painful

  18. Metabolic Disorders • PNKD may occur in Idiopathic hypoparathyroidism • PNKD and PKD reported in pseudohypoparathyroidism (Dure,1998) • The dyskinesia may respond to Vitamin D and Calcium

  19. Secondary Paroxysmal Dyskinesia - Vascular • It is important to recognize that PD may occur as a manifestation of TIA’s • These attacks may herald a major infarction • A variant is orthostatic paroxysmal dystonia in severe large vessel disease

  20. Sandifer Syndrome

  21. Psychogenic paroxysmal Dyskinesias • Very Common • In one series 21/76 cases had Psychogenic PDx second in frequency only to the familial cases • There may or may not be obvious psychopathology or secondary gain

  22. Paroxysmal Kinesigenic Dyskinesia-Pathophysiology • Attributed to basal ganglia dysfunction • Electrophysiology reveals ncreased excitability of cortex and spinal cord • Surface EEG is normal in most cases • Lombroso(1996) reported invasive depth electrodes recordings in a patient with PKD • Spikes were recorded in the SMA that spread to the caudate nucleus

  23. PNKD- Pathophysiology • An invasive study demonstrated that the PNKD did not originate from the cortex, while a discharge was registered from the caudate nuclei. • An 18FDG PET scan failed to show metabolic anomalies. • A 18FDOPA and a 11C raclopride PET scans revealed a marked reduction in presynaptic dopa decarboxylase activity in the striatum, together with an increased density of postsynaptic dopamine D2 receptors.

  24. Genetics of paroxysmal dyskinesia- a Journey • Many cases of PKD have inter-ictal myoclonus • Szepetowski’s was the first to mention an association between PKD and infantile convulsions(ICCA) syndrome. They documented the linkage to the pericentromeric region of chromosome 16 • Swoboda (Neurology 2000) et al confirmed the presence of infantile convulsions and the later onset of PKD in 11 families and reported linkage to the same area. • Tomita reported the linkage of PKD to chromosome 16

  25. Paroxysmal Dyskinesias-Genetics • PKD is genetically heterogenous-The abnormal gene is localized to chromosome 16. (EKD1). There are two other known loci (EKD 2 and 3) . The gene is unknown at present. • A Chinese family described with linkage to chromosome 3 (Zhonghua Yi Xue ,2009) RE-WC-PED maps to the same chromosome but not exactly at the same location. • A newly described entity is X-linked PKD and MR due to a mutation in the MCT 8 gene .

  26. The RICH Area on Chromosome 16

  27. Proline Rich Transmembrane Protein 2(PRRT2) Location of 23 mutations in PKD

  28. Phenotypic Heterogeneity in PRRT2 Mutations • Paroxysmal Kinesigenic Dyskinesia • Benign Familial Infantile Convulsions • ICCA Syndrome • Febrile Infantile Convulsions • Classic Migraine with PKD • Hemiplegic Migraine • Episodic Ataxia Liu et al J Med Genetics,2011;49:79-82 Gurreni and Mink; Neurology 2012;79;2086

  29. PRRT2 gene Mutations • Most likely a dominant loss of function • PRRT2 interacts with SNAP-25 a protein in the SNARE family involved in vesicular fusion to the membrane and is important for neurotransmitter release • As a transmembrane protein it may form complexes with ion channels and may be important for their function

  30. PNKD- Genetics • Mutations in the Myofibrillogenesis regulator gene.(MR-1) on chromosome 2q resulting in a substitution of alanine to valine have been described in most cases of familial PNKD (Lee,2004) • Later onset PNKD like patients may not have this mutation. • Some reported PNKD families lack this mutation. (Spacey,2006) • One new locus for PNKD and generalized epilepsy on chromosome 10q22– a calcium sensitive K channelopathy (Nature Genetics ,2005)

  31. PNKD-Genetics • MR-1 gene is predominantly a neuronal protein expressed widely in the cortex hippocampus and the striatum. • Recent work suggests a problem with mitochondrial targeting sequence (MTS- Ghezzi D, 2009). • MR-1 gene is homologous to HAGH gene that functions to detoxify methylglyoxal a compound found in coffee and alcohol

  32. MR-1 Transgenic Mouse • Attacks precipitated by IP injections of any kind- stress • Knock-out mice look normal-suggesting that this is a gain of function • c-Fos right after attack in LGP SNr and STN • The role of Adenosine A-2 A receptor antagonism is being investigated.

  33. GLUT 1 deficiency syndrome • Expanding phenotype • Classical (De Vivo 1991) - majority of cases, usually de novo • DD, seizures, acquired microcephaly, variable ataxia/spasticity/dystonia • New phenotypes emerging - milder, adult onset, often familial • Infancy onset MD without seizures • Familial PED and epilepsy (+/- haemolytic anaemia), sporadic PED • Carbohydrate responsive phenotypes • PED, Writer’s cramp,migraine and absence seizures • Absence seizures • DYT 9 – paroxysmal choreoathetosis/spasticity, with episodic ataxia (Auburger 1996) + these twins • Realignment with DYT 18 (GLUT1-DS due to SLC2A1 mutations)

  34. Episodic Ataxia 1 Early childhood Provoked by startle Duration minutes Interictal myokymia Autosomal dominant Potassium channel gene mutation KCNA-1 –12P Episodic Ataxia 2 Late childhood Stress,alcohol Minutes to hours Interictal nystagmus Autosomal dominant Calcium channel gene mutation CACNLIA—19P Rarely myasthenic syndrome ( Jen et al ,02) OVERLAPS

  35. Overlaps • Facial myokymia and dystonic/choreic movements (FDFM) is a dominant disorder with dyskinesia that is episodic but may become constant with increasing age. • Localized to chromosome 3.(Raskind WH,2009). • Ion channel dysfunction is a well known mechanism for myokymia.

  36. Paroxysmal Dyskinesias-Management • Look for an underlying cause especially if the age of onset is atypical as in adulthood • PKD responds well to anticonvulsants and the patients are exquisitely sensitive to these drugs making monitoring levels unnecessary (almost all anticonvulsants have been used)

  37. Paroxysmal Dyskinesias Management • PNKD does not respond well to drugs. Anticonvulsants may be tried and recent reports indicate levitracetam may be beneficial. Alternate day oxazepam, l-dopa and rarely botulinum toxin has been used. • In rare cases of PNKD thalamic or GPi stimulation has been successfully employed (T.J. Loher et al Neurology 2001,Yamada,2006, Kaufmann,2009) • Short lasting PHD may respond to anticonvulsants

  38. Paroxysmal Dyskinesias -Treatment • PED- Hard to treat. Restrict exercise. • Some cases respond to levodopa • In GLUT-1 cases ketogenic diet is advised • Secondary PDys in MS may respond to carbamazepine and/or acetazolamide • Underlying disorders must be addressed in other cases of secondary PDys.

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