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)

• 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.

Paroxysmal Dyskinesias

What is not considered to be a Paroxysmal Dyskinesia?

1. Action/Task Specific Dystonia2. Tics- can occur in bursts3. Paroxysmal Exaggeration of Tremor4. Action Myoclonus

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

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.

PKD -AGE DISTRIBUTION

Bruno et al 2004

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

PKD-Proposed Criteria

Bruno et al 2004

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

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.

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

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)

?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.

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

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

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

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

Sandifer Syndrome

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

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

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.

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

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 .

The RICH Area on Chromosome 16

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

Phenotypic Heterogeneity in PRRT2 Mutations

• Paroxysmal Kinesigenic Dyskinesia• Benign Familial Infantile Convulsions• ICCA Syndrome• Febrile Infantile Convulsions• Classic Migraine with PKD • Hemiplegic Migraine• Episodic AtaxiaLiu et al J Med Genetics,2011;49:79-82

Gurreni and Mink; Neurology 2012;79;2086

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

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)

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

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.

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)

OVERLAPS

• 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

• 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.

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)

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

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.