CADASIL, SADB and Migraine

Katharina Eikermann-Haerter, M.D.

Department of Radiology Stroke and Neurovascular Research Laboratory Massachusetts General Hospital and Harvard Medical School

Executive Summary

Association Between Migraine & Vasculopathy

Question

What is the mechanism underlying the association of migraine and vasculopathies? Clinical implications?

Migraine and Clinical evidence for an association between migraine and acquired/genetic vasculopathies vasculopathies Insights from animal experiments and human studies Spreading depolarization Conclusion
Evidence for its role in migraine: Insights from animal experiments and human studies Spreading depolarizations in CADASIL mice Spreading depolarization may link migraine and vasculopathies
2

Executive Summary

Association Between Migraine & Vasculopathy

Question

What is the mechanism underlying the association of migraine and vasculopathies? Clinical implications?

Migraine and Clinical evidence for an association between migraine and acquired/genetic vasculopathies vasculopathies Insights from animal experiments and human studies

Acquired vasculopathies associated with migraine

Ischemic stroke Ischemic heart disease Arterial dissection Vascular anomalies: AV malformation, small angiomas Reversible cerebral vasoconstriction syndromes (RCVS)

Genetic vasculopathies and migraine

Retinal vasculopathy with cerebral leukodystrophy (RVCL) Hereditary infantile hemiparesis, retinal tortuosity, and leukoencephalopathy (HIHRATL) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Genetic vasculopathies associated with migraine

RVCL
Gene, protein Effect of mutated protein
TREX1, 3-5 exonuclease Altered subcellular localisation of Trex1 causes accumulation of DNA intermediates

MO (&MA) in 70% of patients Migraine Other neurological Cognitive and psychiatric disturbances, infarcts, focal symptoms manifestations

Neuroradiology findings

Contrast-enhancing cerebral mass lesions, calcifications, leukodystrophy small cerebral vessels, obliterative vasculopathy, necrosis, astrogliosis

Pathology findings Multilayered capillary basement membrane of

RVCL=HVR+CRV+HERNS
Hereditary Vascular Retinopathy (HVR)
- Cerebroretinal vasculopathy - Raynauds phenomenon - Migraine - Additional features:
neuropsychiatric symptoms stroke-like episodes pseudotumor subcortical MRI lesions

Storimans CW et al, Eur. J. Ophtalmol .1991 Terwindt GM, et al, Brain 1998

T2-weighted MRI showing white matter lesions

RVCL=HVR+CRV+HERNS
CRV
Dr. J. Atkinson, St. Louis

HERNS
Drs . R. Baloh & J. Jen, UCLA

- Autosomal dominant
- Retinopathy - Cerebral Vasculopathy - Pseudotumor

Grand et al., 1988

Jen et al., 1997

RVCL=HVR+CRV+HERNS

Abnormal localisation of RVCL protein

Wildtype TREX1 protein
YFP

TREX1

fs V235
Trex1

fs T249

TREX1 protein is a 3-5 exonuclease involved in C-term removing cytosolic DNA

John Atkinson and coworkers

Abnormal localisation of RVCL protein

RVCL TREX1 protein
YFP

TREX1

fs V235

fs T249

RVCL TREX1 protein has normal exonuclease activity and leads to accumulation of DNA intermediates in the cell
John Atkinson and coworkers

C-term

Genetic vasculopathies and migraine

Retinal vasculopathy with cerebral leukodystrophy (RVCL) Hereditary infantile hemiparesis, retinal tortuosity, and leukoencephalopathy (HIHRATL) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Genetic vasculopathies associated with migraine

HIHRATL
Gene, protein Effect of mutated protein Migraine
COL4A1, 1 chain of type IV collagen Disruption of vascular integrity MA (&MO)

Other neurological manifestations

Neuroradiology findings

Seizures, infantile hemiparesis, lacunar infarcts

Leukoencephalopathy, dilated perivascular spaces, hemorrhages, microbleeds, cerebral atrophy Complex basement membrane abnormalities in skin, kidney, and cerebral vasculature

Pathology findings

Genetic vasculopathies and migraine

Retinal vasculopathy with cerebral leukodystrophy (RVCL) Hereditary infantile hemiparesis, retinal tortuosity, and leukoencephalopathy (HIHRATL) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Migraine and genetic vasculopathies

CADASIL
Stereotyped clinical phenotype:

[Chabriat H, et al., Lancet Neurology 2009]

Migraine and genetic vasculopathies

CADASIL
Migraine in CADASIL patients:
Prevalence of 38% (14-72% in European studies vs 5% in Asian studies)
[Dichgans et al., Ann Neurol 1998; Liem et al., Cephalalgia 2010]

80-90% migraine with aura (44% typical aura, 56% also atypical aura)
[Dichgans et al., Ann Neurol 1998; Vahedi et al., Arch Neurol 2004]

In females: Earlier onset; more prevalent <51y; visual and aphasic aura more common compared to males [Gunda et al., Stroke 2012] 14% have an increase in attack frequency before the first ischemic event; after the first stroke, 54% report a decrease or cease of migraine attacks
[Dichgans et al., Ann Neurol 1998]

MRI findings dont differ between CADASIL patients with or without migraine [Vahedi et al., Arch Neurol 2004]

Migraine

Vascular Shared Neuronal endothelial genetic Mechanisms dysfunction factors

Acquired vasculopathies

Genetic vasculopathies

Executive Summary

Association Between Migraine & Vasculopathy

Question

What is the mechanism underlying the association of migraine and vasculopathies? Clinical implications?

Migraine and Clinical evidence for an association between migraine and acquired/genetic vasculopathies vasculopathies Insights from animal experiments and human studies Spreading depolarization
Evidence for its role in migraine: Insights from animal experiments and human studies Spreading depolarizations in CADASIL mice

18

Normal Transmembrane Ionic Equilibrium Na+

K+ Na+ K+

Ca2+
K+ K+

Ca2+
K+ Ca2+

K+

K+
K+

Ca2+

142mM

Na+ Na+
3-4mM

K+
130mM

15mM

K+

K+
Ca2+ K+

Na+

Na+

K+ K+ Ca2+

K+

K+
Na+ K+

Ca2+

Ca2+

K+

Na+

Spreading Depression Na+

K+ H2O Na+ K+

Ca2+
K+ H2O K+

Glu

Ca2+
K+

K+

K+
Vm K+ Vm

Ca2+

Glu

Ca2+

Na+
40-80 mM

Na+

K+

Vm

K+

Vm

K+
Ca2+

Na+

Na+
40-80 mM

K+
H2O K+ Ca2+

K+

K+
Na+ K+

K+ H2O

Ca2+

Ca2+

K+

Glu

Na+

Glu

Spreading Depolarization Trigger factors

Excitatory aminoacids

Electrical stimulation

Na+/K+inhibitors

Optogenetics

Spreading Depolarization

KCl

Microemboli

Ischemia/ Trauma

ET-1
21

Spreading Depolarization
DC E2 E1 CSD induction

10mV 2min

EEG

3 mm/min

120 100 80 60 40 20

CBF

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms

Scintillating Scotoma
(Lashley - Arch Neurol Psychiatry 1941)
23

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms Congruence between cerebrovascular changes during aura and during SD

24

BOLD fMRIMigraine During Visual Aura

Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms Congruence between cerebraovascular changes during aura and SD

25

Hadjikhani et al. PNAS 2001

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms Congruence between cerebrovascular changes during aura and during SD Activation of downstream nociceptive pathways by SD

26

[Noseda et al., Pain 2013]

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms Congruence between cerebrovascular changes during aura and during SD

Activation of downstream nociceptive pathways by SD

Factors modulate SD and migraine in the same direction

SD-Facilitation:
Migraine mutations

SD-Inhibition:
Migraine prophylactic drugs

Female gonadal hormones

Eikermann-Haerter et al., JCI 2009

Male gonadal hormones

27 Eikermann-Haerter et al., Ann Neurol 2010

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between the electrophysiological features of SD and aura symptoms Congruence between cerebrovascular changes during aura and during SD

Activation of downstream nociceptive pathways by SD

Factors modulate SD and migraine in the same direction Shared triggers for SD and migraine attacks

28

Migraine
Spreading depolarization (SD) as the underlying event: Evidence

Congruence between PFO the electrophysiological features of SD and aura symptoms (+) PFO (-) Congruence between cerebrovascular changes during aura and during SD Prevalence of

Activation of downstream nociceptive pathways by SD

Migraine Factors modulate Control SD and migraine in the same direction

Migraine with Aura

36%

13%

Shared triggers for SD and migraine attacks

Prevalence of PFO 24% 54%

with Aura

Migraine in patients with PFO + large R-L shunt OR=7.8 Migraine aura triggered by PFO testing (bubble test or valsalva)

29

Emboli trigger SD with or without tissue damage

Air (1 l), Microsphere (10 m), Cholesterol (<50 m), Fibrin (20m)

ECA ICA

Microembolic Ischemia Triggers SD: Infarcts Present in a Subset

Nozari et al. Ann Neurol 2010

SD as the link between migraine and CADASIL

Migraine in CADASIL patients:
Prevalence of 38% (14-72% in European studies vs 5% in Asian studies)
[Dichgans et al., Ann Neurol 1998; Liem et al., Cephalalgia 2010]

80-90% migraine with aura (44% typical aura, 56% also atypical aura)
[Dichgans et al., Ann Neurol 1998; Vahedi et al., Arch Neurol 2004]

In females: Earlier onset; more prevalent; visual and aphasic aura more common [Gunda et al., Stroke 2012] 14% have an increase in attack frequency before the first ischemic event; after the first stroke, 54% report a decrease or cease of migraine attacks
[Dichgans et al., Ann Neurol 1998]

SD as the link between migraine and CADASIL

Early disease stages: Migraine incidence SD susceptibility Transient ischemic events as SD trigger

SD as the link between migraine and CADASIL

SD-susceptibility after KCl in the migraine syndromes FHM and CADASIL

CADASIL (TgR90C mice):

Familial hemiplegic migraine (FHM1) mice:

36 Male Female

15

CSD frequency (#/h)

Cortical SD / hour

Male Female

32 28 24 20 16 12 8 4

S218L
*

10

WT

TgNotch3R90C

WT

HET

HOM

Eikermann-Haerter et al., Ann Neurol 2011

Eikermann-Haerter et al., JCI 2009

SD as the link between migraine and CADASIL

SD-susceptibility after ischemia in the migraine syndromes FHM and CADASIL

CADASIL (TgR90C mice):

Familial hemiplegic migraine (FHM1) mice:

R192Q S218L

WT PID frequency (#/h) Cumulative PID duration (sec) 2.7 0.3 146 31

TgR90C 4.4 0.7* 375 90*

Lee et al., unpublished data

Eikermann-Haerter et al., Circulation 2012

SD as the link between migraine and CADASIL

Early disease stages: Migraine incidence SD susceptibility Transient ischemic events as SD trigger

Late disease stages: Migraine incidence SD susceptibility Cerebral hypoperfusion

Astrogliosis

KCl-induced CSD frequency in aged Notch3-/18

5 months old

CSD frequency (#/h)

15
22 months old

12 9 6 3 0 WT Notch3-/*p<0.05 vs. WT, vs. aged n=8 each

Eikermann-Haerter et al., Ann Neurol 2011

SD as the link between migraine and CADASIL

Early disease stages: Migraine incidence SD susceptibility Transient ischemic events as SD trigger

Late disease stages: Migraine incidence SD susceptibility Cerebral hypoperfusion

Astrogliosis

Hypoperfusion and SD susceptibility

Eikermann-Haerter et al., Ann Neurol 2011

SD as the link between migraine and CADASIL

Early disease stages: Migraine incidence SD susceptibility Transient ischemic events as SD trigger

Late disease stages: Migraine incidence SD susceptibility Cerebral hypoperfusion

Astrogliosis

Astrogliosis after chronic cerebral hypoperfusion

GFAP

Sham

Bilateral CCA stenosis

Eikermann-Haerter et al., unpublished

Executive Summary

Association Between Migraine & Vasculopathy

Question

What is the mechanism underlying the association of migraine and vasculopathies? Clinical implications?

Migraine and Clinical evidence for an association between migraine and acquired/genetic vasculopathies vasculopathies Insights from animal experiments and human studies Spreading depolarization Conclusion
Evidence for its role in migraine: Insights from animal experiments and human studies Spreading depolarizations in CADASIL mice Spreading depolarization may link migraine and vasculopathies
42

SD may link migraine and vasculopathies

SD Migraine

Stroke
From: Dalkara et al., Lancet Neurol 2010

Acknowledgements
Stroke & Neurovascular Regulation Lab
Cenk Ayata, MD, and Michael A. Moskowitz, MD Christian Waeber, PhD Jeong Hyun Lee, PhD Christina Liu, PhD Chiho Kudo, MD Izumi Yuzawa, MD Esther Yu

Universit Paris, France

Anne Joutel, MD

University of Leiden, The Netherlands

Michel D. Ferrari, MD; Arn M.J.M. van den Maagdenberg, PhD

American Heart Association (10SDG2610275)

Potential clinical implications

Test treatment options in CADASIL patients that: Reduce the likelihood of ischemic events Suppress neuronal excitability

Larger cerebral infarcts

Infarcts [%]: 78% 100% 100%

 peri-infarct depolarizations in FHM mice

Stroke phenotype Migraineurs vs Non-migraineurs

Earlier anoxic depolarization

 Peri-infarct depolarizations

 peri-infarct depolarizations

Accelerated lesion growth on MRI during hyperacute stroke

Accelerated lesion growth on MRI during hyperacute stroke

Larger perfusion deficits during acute stroke

Larger perfusion deficits during acute stroke

Larger cerebral infarcts

0h 1h 24h

MCAO Ischemia

Reperfusion

Isoflurane

Awake

R192Q

S218L

Elevated CBF threshold for tissue survival

Anti-excitatory treatment abolishes the impact of FHM1 on stroke outcomes

Severe stroke phenotype in CADASIL mutant mice

PID
PID frequency (#/h) Cumulative PID duration (sec)

WT
2.7 0.3 146 31

TgR90C
4.4 0.7* 375 90*

Stroke

WT

TgR90C

(*p<0.05; SEM)

Migraine prophylactic drugs Lamotrigine and Topiramate suppress ischemic depolarizations

Migraine prophylactic drugs Lamotrigine and Topiramate suppress ischemic depolarizations

Migraine prophylactic drugs Lamotrigine and Topiramate improve stroke outcomes

Study population (MGH stroke database)

DWI/PWI Mismatch

6 hour DWI

6 hour MTT

Final infarct (Day-7 T2)

DWI/MTT (yellow/blue)

DWI/PWI Mismatch Migraineurs < Non-migraineurs

Migraine
Any Number of patients with DWI/PWI scans With aura

No migraine

25

25

DWI/PWI [median (range)]

Patients with DWI/PWI>0.9

0.8 (0.8)

1.0 (1.7)

0.5 (0.6)

9* (36%)

5 (56%)

1 (4%)

Receiver operating characteristics (ROC) curve for predicting migraine status by DWI/PWI

How can SD link migraine and CADASIL?

More severe effects of SD on CBF in CADASIL mice?:

No!
Eikermann-Haerter et al., Ann Neurol 2011

A) CSD-Threshold:

B) CSD-Frequency:

Electrical CSD threshold [C]

600 500 400 300 200 100 0

CSD frequency [#CSDs/h]

700

18 15 12 9 6 3 0
Notch3-/TgR90C

WT

TgR90C*

WT

Mutants*