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 Dystonia
2. Tics- can occur in bursts
3. Paroxysmal Exaggeration of Tremor
4. 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
TIAs
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
Szepetowskis 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 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 (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, Writers 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 Episodic Ataxia 2
Early childhood Late childhood
Provoked by startle Stress,alcohol
Duration minutes Minutes to hours
Interictal nystagmus
Interictal myokymia
Autosomal dominant
Autosomal dominant
Calcium channel gene
Potassium channel gene mutation CACNLIA
mutation KCNA-1 12P 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.