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
1.
2.
3.
4.
What is not considered to be a Paroxysmal
Dyskinesia?
Action/Task Specific Dystonia
Tics- can occur in bursts
Paroxysmal Exaggeration of Tremor
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
pseudohypoparathyroi
dism (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 DyskinesiaPathophysiology
– 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 DyskinesiasGenetics
• 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 Ataxia
Liu 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 (MTSGhezzi 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 kindstress
• 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 DyskinesiasManagement
• 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.