Channelopathies of

CNS
Surat Tanprawate, MD, FRCPT
Division of Neurology, Chiangmai University

one disease from several channelopathy

one channel can cause several disease

Clinical suspected of
channelopathies

Episodic

Abnormal neurological symptoms/signs-> positive

symptoms; may be negative symptoms

Response to AED, acetazolamide

Classification of
Channelpathies of CNS

Migraine: Familial Hemiplegic Migraine (FHM)

Movement disorders channelopahty - Paroxysmal

dyskinesia, episodic ataxia (EA), Spinocerebellar
ataxia-6 (SCA-6), Hyperexplexia

Channel defect in Epilepsy

Autoimmune and paraneoplastic channelopathies

Case 1

A 51 years old woman

chronic episodic headache since she was 30 years old

headache characters: throbbing pain, preceding by

seeing bright light vision, numbness, and right
hemiparesis

some episode, she had sudden transient loss of

consciousness with tonic posture for a few second
before having headache

Familial Hemiplegic Migraine

Occipital lobe Epilepsy

Hemiplegic Migraine

Rare disorder: Population based study (Denmark):

0.01 %

Age of onset 12-17 (range 1-51)

2 forms (same phenotype)

Familial Hemiplegic Migraine (FHM)

Sporadic Hemiplegic Migraine (SHM)

Familial Hemiplegic
Migraine

Characterised by lateralised motor weakness of at

least 1 attack with variable intensity, and duration

FHM -> 3 foci on chromosome

FHM 1: mutation in the CACNA1A gene (1996)

FHM 2: mutation in the ATP1A2 gene (2003)

FHM 3: mutation in the SCN1A gene (2005)

FHM 1

CACNA1A encodes the pore forming alphasubunit of the P/Q type Ca2+channel

Cav2.1 channels are located in presynaptic

terminals and somatodendritic membranes
(cerebral cortex, the trigeminal ganglia, and
brainstem nuclei involved in the central control of
nociception, cerebellar Purkinje cell)

controlling neurotransmitter release at central

excitatory synapses
Pietrobon D. The Am Soc for Exp Neurother 2007;4:274-284

FHM 1

mutant human Cav2.1 channels enhance channel

Ca2+ influx in a wide range of mild depolarizations,
increase channel open probability

Mutation in CACNA1A cause different dominantly

inherited neurological disorders including EA2 and
SCA6 and benign paroxysmal torticollis of infancy
Pietrobon D. The Am Soc for Exp Neurother 2007;4:274-284

FHM 2

associated with mutations in the ATP1A2 gene on

chromosome 1q23 -> encodes a catalytic subunit of a Na/K
ATPase

first demonstrate in 2 Italian families (2003)

Impaired clearance of K+ and glutamate by astrocyte during

cortical neuronal activity -> depolarized neurons and enhance
glutamate concentration in the synaptic cleft -> impaired
recovery from neuronal excitation

ATP1A2 associated with migraine with brainstem aura, several

type of epilepsy, and alternating hemiplegia of childhood

FHM 3

penetrate : 100 % ; first identify in German

family

associated with mutations in the SCN1A gene

on chromosome 2q24 -> encodes
transmembrane alpha subunit of the brain
sodium channels

Lancet Neurol 2007; 6: 52132

a number of case reports FHM with other neurological disorder

Seizure

FHM2
FHM3
AHC

SMEI
Paroxysmal
dyskinesia

Migraine

EA2?

Ataxia

FHM1
EA2

Sporadic hemiplegic
migraine

First member of their family to have hemiplegic

migraine are classify as having sporadic
hemiplegic migraine

Some SHM: genetic mutations that cause FHM

Mutation in population based studies: CACNA1A

and ATP1A2 gene in 10-20 % of SHM cases

Report of SHM + Seizure + Ataxia -> SLC1A3

mutation (impair glutamate transporter)
Jen JC et al. Neurology 2005:65(4):525

Clinical characteristic

Clinical feature of FHM is similar to SHM

Headache: typical migraine headache attacks with

motor weakness at the aura phase (most patient have
to have headache together with motor weakness)

Aura: hemiplegia (usually 2 or more aura)

typically visual->sensory->motor->aphasic

aura symptoms associated with migraine with

brainstem aura

Clinical characteristic

Motor weakness

most often start in the hand, and gradually spread up to arm

and face

hemiplegia may switch side between or during the attacks

and bilateral -> 1/3

degree can be mild to severe

onset: can develop acutely (stroke mimic)

duration: > 60 mins(41-58%), > 24 hrs(2-8%), some last up to

4 weeks

Diagnosis

Genetic testing for the underlying mutation is not

widely available

the diagnosis relies on the history, physical

examination, family history

FHM are more likely to have speech/sensory

symptoms

Treatment

Try of following drug

Verapamil

Acetazolamide

Valproic acid

Flunarizine

Lamotrigine

Acetazolamide

mechanism: 1. suppress cortical spreading depression in

animal model
2. restore function of Ca channel with PH change
3. good effect in FHM, EA, but fail efficacy in
migraine with/without aura

Ayata C, Jin H, Kudo C, et al. Ann Neurol. 2006;59:652-661.

Episodic Ataxia

Inherited syndromes of intermittent ataxia often with

completely normal cerebellar function between the
attack

2 types

Episodic ataxia type 1: AD involve both CNS (ataxia)

and PNS (myokymia)

Episodic ataxia type 2: AD with markedly impaired

truncal ataxia and interictal nystagmus and often
develop cerebellar atrophy

Episodic Ataxia type 1

Mode of
inheritance
Age of onset

Episodic Ataxia type 2

Autosomal dominant

Autosomal dominant

Second decade

Early childhood to teens

Ataxia
Dizziness without vertigo
Clinical features
Visual blurring
No nystagmus

Ataxia, truncal instability which may

persist between attacks, dysarthria,
nystagmus
Dizziness without vertigo
Visual blurring
No nystagmus Associated with
vertigo, nausea,
vomiting, and headache
Weakness may occur during spells
and can precede onset of episodic
ataxia

Triggers

Abrupt postural change,

emotion, startle, vestibular
stimulation

Physical or emotional stress

Duration of
attack

Brief, attacks last minutes

Attack often last 30 minutes to >

24 hours

Episodic Ataxia 1

Episodic Ataxia 2

Additional
features

Downbeating gaze evoked

Neuromyotonia (continuous
nystagmus in all directions
spontaneous muscle fiber
between episodes. Impaired
activity) or myokymia occur
vestibular-ocular reflex, OKN
during and between episodic and smooth pursuits. Some
of ataxia
patient develop progressive
cerebellar atrophy

Treatment

Phenyltoin, carbamazepine

Acetazolamide

Potassium: KCNA1

Calcium: CACNA1A, allelic with

FHM and SCA6

Ion channel
gene

case 1

Diagnosis?
What is your treatment?

case 2

case 2

Diagnosis?
Do you treat him similar to
the first case?

Paroxysmal Dyskinesia
(PDs)

PDs are a rare group of hyperkinetic movement

disorders

characterised by their episodic nature of abnormal

movement

Neurological examination may normal during the attacks

the abnormal movement may be dystonic, choreic,

ballistic, other or mixed

cause can be acquired or inherited

1940s: Mount & Reback

described 23- y.o. with episode
of choreo-dystonia last for
several hour-called paroxysmal
choreoathetosis
later called paroxysmal dystonic
choreoathetosis (PDC)

The classification: historical note

1967s: Kertesz - described a

new episodic disorder term
paroxysmal kinesigenic choreoathetosis (PKC) as the attacks
induced by sudden movement
and the attacks were very brief
1977s: Lance - described the
third form reporting a family that
had attacks lasting from 5 to 30
mins by prolonged exercise, this
was referred to Paroxysmal
exercise-induced dyskinesia
(PED) or the intermediate type

Classification
Demirkiran and Jankovic (1995)
1. Paroxysmal kinesegenic dyskinesia (PKD)

if the attack induced by sudden movement

2. Paroxysmal nonkinesigenic dyskinesia (PKND)

the attack is not induced by movement

3. Paroxysmal exercise-induced dyskinesia (PED)

the attack occurs after exercise

4. Hypnogenic paroxysmal dyskinesia (HPD)

dyskinesia occur during sleep at night, but later it

become form of nocturnal frontal lobe epilepsy

PKD

PNKD

PED

Precipitation

+++

+
(triggers: caffeine,
alcohol, stress)

+++

Frequency

+++

++

Treatment
response

+++
CBZ. PHT,
Acetazolamide

++
(Clonazepam)

+
(ketogenic diet,
gabapentin)

+++

+++ (MR-1 gene)

++(GLUT1 gene)

(+)

Aetiology
-Idiopathic
(AD,Sporadic)
-Symptomatic

Secondary
paroxysmal
dyskinesia
Blakeley J, Jankovic J
Move Dis 2002 (4)17: 726-734

LONDON

Kirstein L 1958.

Hereditary Hyperexplexia

Hyperekplexia (exaggerated surprise) is a neurological

disorder classically characterised by pronounced startle
responses to tactile or acoustic stimuli and hypertonia

The GLRB gene that control glycine neurotransmission (glycine

is a inhibitory neurotransmitter)

Subtypes

major, generalized stiffness;hypertonia and excessive

startle reflex

"minor" form, with the minor form being characterized by an

excessive startle reflex, but lacking stiffness

Schematic of a hyperekplexia patient illustrating the sequence of

movements during a startle reflex. (Numbers represent elapsed time in ms.)
Bode and Lynch Molecular Brain 2014, 7:2

Treatment

Clonazepam

Levetirazetam

Neuronal channelopathies in
Epilepsy

Epileptic seizures: many cause, but 40 % - no

antecedent brain lesion (idiopathic generalised
epilepsy)

Mutation in more than 10 ion channel genes have

been identified

Epilepsies established as channelopathies of the

central nervous system

Canon SC. Annu. Rev. Neurosci. 2006. 29:387415

ADJME, autosomal dominant juvenile myoclonic epilepsy; ADNFLE, autosomal dominant nocturnal frontal lobe
epilepsy; BFNC, benign familial neonatal convulsions; CAE, childhood absence epilepsy; EGMA, epilepsy with
grand mal seizures on awakening; FS, febrile seizures; GEFS+, generalized epilepsy with febrile seizures plus;
GEPD, generalized epilepsy with paroxysmal dyskinesia; ICEGTC, intractable childhood epilepsy with
generalized tonic-clonic seizures; JAE, juvenile absence epilepsy; JME, juvenile myoclonic epilepsy; SMEI,
severe myoclonic epilepsy of infancy.

Neuronal channelopathies in
Epilepsy

Febrile seizure plus (GEFS+): sodium channel and

GABAA receptor

Autosomal Dominant Nocturnal Frontal Lobe

Epilepsy (ADNFLE): neuronal nicotinic receptor
mutation

some idiopathic generalised epilepsy; JME,

absence epilepsy: Ca2+ mutation

GEFS+

GEFS+ is a common epilepsy syndrome of

childhood, with AD inheritance and mild seizures
that initially present in the setting of fever, but then
persist beyond age six as afebrile seizures, the
plus feature, of mixed type (absence, myoclonic,
atonic).

Treatment depended on the seizure type: VA, LMT,

ETX, clobazam

Autosomal Dominant Nocturnal

Frontal Lobe Epilepsy (ADNFLE)

ADNFLE is a partial epilepsy disorder characterised by

brief violent seizures during sleep.

Semiology: complex, consisting of arm and leg

movements, fist clenching, and vocalisations such as
yelling and moaning

Pathophysiology: Thalamocortical loop, gene mutation

(CHRNA4, CHRNB2, CHRNA2 encode nicotinic
acetylcholine receptor

Treatment of choice: CBZ, other AEDs

Pattern of nocturnal attacks in patients with

ADNFLE observed during video-polysomnography
(n=40)

Age of onset/evaluation = 11.8/23.8

Pt with seizure also during wakefulness = 36.8%
Brain (1998), 121, 205223

Previous diagnoses and misdiagnoses in

patients with ADNFLE (n=40)

Brain (1998), 121, 205223

Autoimmune
channelopathy

Channelopathies

Voltage-gated calcium channel (P/Q type)

Voltage-gated potassium channel (Kv1.1, 1.2, 1.6)

Limbic encephalitis

GluR3 (AMPA receptor)

Paraneoplastic ataxia

Rasmussens encephalitis

NR2 (NMDA receptor)

anti-NMDA encephalitis

A 17 Y.O. woman with

alteration of conscious with
orobuccal dyskinesia
Dx Anti-NMDA encephalitis
with ovarian teratoma

Rasmussens encephalitis (chronic focal encephalitis, CFE)

Symptoms: seizure, loss of motor skills and speech,
hemiparesis, encephalitis
anti-NR2A antibodies

MRI Brain
gradual shrinkage of the
affected hemisphere with
signs of inflammation or
scarring

Thank you for your

attention