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 alpha-

subunit 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: 521–32

a number of case reports FHM with other neurological disorder

Seizure Migraine

FHM2 FHM3 AHC

EA2?

Ataxia

FHM1 EA2

SMEI Paroxysmal dyskinesia

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

• 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

Clinical characteristic

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 Episodic Ataxia type 2

Mode of inheritance Autosomal dominant Autosomal dominant

Age of onset Second decade Early childhood to teens

Clinical features

Ataxia Dizziness without vertigo 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

TriggersAbrupt 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

Neuromyotonia (continuous spontaneous muscle fiber activity) or myokymia occur during and between episodic of ataxia

Downbeating gaze evoked nystagmus in all directions between episodes. Impaired vestibular-ocular reflex, OKN and smooth pursuits. Some patient develop progressive cerebellar atrophy

Treatment Phenyltoin, carbamazepine Acetazolamide

Ion channel gene Potassium: KCNA1 Calcium: CACNA1A, allelic with

FHM and SCA6

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)”

1967s: Kertesz - described a new episodic disorder term

“paroxysmal kinesigenic choreo-athetosis (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”

The classification: historical note

ClassificationDemirkiran 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)

Aetiology -Idiopathic (AD,Sporadic)

-Symptomatic

+++

+

+++ (MR-1 gene)

+

++(GLUT1 gene)

(+)

Secondary paroxysmal dyskinesiaBlakeley 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

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.

Canon SC. Annu. Rev. Neurosci. 2006. 29:387–415

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, 205–223

Brain (1998), 121, 205–223

Previous diagnoses and misdiagnoses in patients with ADNFLE (n=40)

Autoimmune channelopathy

Channelopathies• Voltage-gated calcium channel (P/Q type)

• Paraneoplastic ataxia

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

• Limbic encephalitis

• GluR3 (AMPA receptor)

• Rasmussen’s 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

Rasmussen’s encephalitis (chronic focal encephalitis, CFE)

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

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

MRI Brain

Thank you for your attention