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PAROXYSMAL MOVEMENT DISORDERS

Kapil D Sethi MD FAAN FRCP(UK) Professor Emeritus of Neurology MCG a unit of Augusta University Augusta Georgia

PAROXYSMAL DYSKINESIAS

What is not considered to be a Paroxysmal Dyskinesia? 1. Action/Task Specific Dystonia 2. Tics - can occur in bursts 3. Paroxysmal Exaggeration of Tremor 4. Action Myoclonus

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PAROXYSMAL MOVEMENT DISORDERS

• Paroxysmal Dyskinesias-Primary and Secondary • Episodic Ataxias • Alternating Hemiplegia of Childhood • Paroxysmal Tremor • Paroxysmal Torticollis of Infancy

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PAROXYSMAL DYSKINESIAS (PDYS)

• Heterogeneous -characterized by the abrupt onset of abnormal involuntary movements usually out of a background of normal motor behavior • A combination of chorea, ballism and dystonia.

PAROXYSMAL DYSKINESIAS

• Four groups PKD,PNKD,?PHD,PED • -Idiopathic (primary) or secondary • Idioathic group may be familial or sporadic • Overlaps

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PAROXYSMAL KINESIGENIC DYSKINESIA

• Precipitated by sudden movement or startle and sometimes by stress • Frequency up to 100 per day • Sensory aura and a refractory period • Asymmetric dystonia • common while others may have chorea

PKD-PROPOSED CRITERIA

Bruno MK, et al. Clinical evaluation of idiopathic paroxysmal kinesigenic dyskinesia: new diagnostic criteria. Neurology. 2004;63(12):2280-2287 doi:10.1212/01.wnl.0000147298.05983.50

Bruno et al 2004

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PAROXYSMAL NONKINESIGENIC DYSKINESIA

• Precipitated factors - alcohol,fatigue,and caffeine. • In one series 98% of cases with MFR-1 mutation had this clinical correlate.(Bruno,2007) • Predominant dystonia in some and some have chorea. • Frequency 3/day to 2/year. • Duration minutes to hours

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PAROXYSMAL EXERCISE-INDUCED DYSKINESIA

• Usually dominant • Overlap between PNKD and PED. • PED may precede parkinsonism (Bruno MK, 2004) • DRD patients may have PED at beginning

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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)

A few caveats about PED

Video in Presentation

Courtesy Kailash Bhatia

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8 year boy- intermittent dystonia of either/both sides, legs>arms, attacks lasting several hours Full recovery between episodes Not provoked by sudden movement or by exercise

Clinical phenotype Paroxysmal Non-kinesigenic Dyskinesia

Videos of clinical Episodes

 Symptoms could be  Right sided  Left sided  Bilateral  last for several hours  Some disabling  Falls

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MRI BRAIN

Bilateral pallidal Hyperintensities

Other sequences T1- Normal SWI- Normal Homozygous PDHB Mutation T2 MRI

ECHS1 MUTATIONS AND PED

Olgiati et al Movement Disorders, Vol. 31, No. 7, 2016

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? PAROXYSMAL HYPNOGENIC DYSKINESIA

• First description by Joynt and Green in a patient with multiple sclerosis. • Attacks occur during Non-REM sleep. • Mdial frontal lobe seizures in most cases. • ADCY 5 mutation carriers my have predominantly night time attacks and some individuals with mixed PKD and PNKD may have nighttime attacks

A 9 YEAR OLD GIRL WITH PAROXYSMS

• 1. Arching • 2. Vertical ocular oscillations • 3. Right body stiffening • Age 8, occurring daily, lasts minutes to hours • Exam • Increased tone LE bilaterally with hyperreflexia • Slow, wide based gait

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ATP1A3 GENE MUTATION

• ATP1A3 • Chromosome 19q13.31 • ATPase, Na+/K+ transporting, alpha 3 polypeptide • Mutations in alpha 3 subunit associated associated with • Alternating Hemiplegia of Childhood • Rapid-onset Dystonia Parkinsonism • Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS)

GENETICS

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GENETICS OF PKD THE RICH AREA ON CHROMOSOME 16

PROLINE RICH TRANSMEMBRANE PROTEIN 2(PRRT2) LOCATION OF 23 MUTATIONS IN PKD

Brain. 2011 Dec;134(Pt 12):3493-3501. Epub 2011 Nov 26.

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PRRT2 FUNCTION

PHENOTYPIC HETEROGENEITY IN PRRT2 MUTATIONS

• Paroxysmal Kinesigenic Dyskinesia • Benign Familial Infantile Convulsions • ICCA Syndrome • Febrile Infantile Convulsions • Nocturnal Convulsions • Classic Migraine with PKD • Hemiplegic Migraine • Episodic Ataxia • Paroxysmal Nonkinesigenic Dyskinesia • Paroxysmal Exertional Dyskinesia

Liu et al J Med Genetics,2011;49:79-82 Gurreni and Mink; Neurology 2012;79;2086

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PNKD- GENETICS

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

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SECONDARY PAROXYSMAL DYSKINESIAS

• Multiple sclerosis • Cerebral Palsy • Hypoparathyroidism and pseudohypoparathyroidism • Hypoglycemia • Head trauma • Cerebrovascular disease • Neuroacanthocytosis • Psychogenic

MISCELLANEOUS CAUSES OF SEC PDX

• Cytomegalovirus Encephalitis • Neurosarcoidosis • Migraine • Cervical Cord lesions • Primary CNS Lymphoma • Kernicterus • Hypoglycemia • Urea Cycle defects and aminoacidurias

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SECONDARY PAROXYSMAL DYSKINESIA- MULTIPLE SCLEROSIS

• Known as tonic seizures • Presenting feature in some. • Unilateral , bilateral attacks described more in the Japanese.\ • Hyperventilation precipitates the attack. Painful

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POSTTRAUMATIC PKD

Video in Presentation

SECONDARY PAROXYSMAL DYSKINESIA - VASCULAR

• PDys as a manifestation of TIA’s • Limb shaking TIA well described in the literature • These attacks may herald a major infarction • A variant is orthostatic paroxysmal dystonia in severe bilateral large vessel disease

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VASCULAR PDYS

Video in Presentation

CTA NECK

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Courtesy Dr Balamurugan

METABOLIC DISORDERS

• PNKD in hypoparathyroidism • PNKD and PKD in pseudohypoparathyroid ism (Dure,1998) • May respond to Vitamin D and Calcium

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Video in Presentation

FACIOBRACHIAL DYSTONIC SEIZURES (FBDS)

• Late-onset, frequent and brief (often<5 secs) • Involve Upper limb, face and are dystonic in nature. • VGKC-complex antibodies and/or LGI1- antibody • Hyponatremia (SIADH) • Skin rash with anticonvulsants • May respond to immunotherapy

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SANDIFER SYNDROME

Video in Presentation

PSYCHOGENIC PAROXYSMAL DYSKINESIA-CLINICAL FEATURES

• Mean age of onset 38.6 years. • Female predominance (73%). • Most had long attacks • High within-subject variability for • Attack phenomenology, duration and frequency • 69.2% of the patients had mixed or complex PxD Unusual Triggers • Unusual alleviating strategies

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PAROXYSMAL DYSKINESIAS- MANAGEMENT

• Look for an underlying cause especially if the age of onset is atypical as in adulthood • Anticonvulsants in low dosages for PKD (almost all anticonvulsants have been used)

PAROXYSMAL DYSKINESIAS MANAGEMENT

• PNKD does not respond well to drugs. Levitracetam may be beneficial. Alternate day oxazepam, l-dopa and rarely botulinum toxin. • Rare severe cases thalamic or GPi stimulation (T.J. Loher et al Neurology 2001,Yamada,2006, Kaufmann,2009) • Short lasting PHD may respond to anticonvulsants

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PAROXYSMAL DYSKINESIAS -TREATMENT • PED- Hard to treat. Restrict exercise. • Some cases respond to levodopa • GLUT-1 cases ketogenic diet • Secondary PDys in MS - carbamazepine and/or acetazolamide • Address underlying disorders.

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