Clinical Decisions in Cavernous Malformations and a Look at Research Advances

1
Clinical Decisions in Cavernous Malformations and
a Look at Research Advances

• Issam A. Awad, MD, MSc, FACS, MA (hon)
• Professor and Vice Chairman
• Department of Neurosurgery
• Northwestern University Feinberg School of
  Medicine Evanston Northwestern Healthcare
• Evanston, Illinois
• Chairman, Scientific Advisory Board
• Angioma Alliance (www.angiomaalliance.com)

2
The Northwestern Integrated Neurovascular Team

• Neurovascular Surgery-- Awad, Batjer, Bendok,
  Getch
• Neurocritical Care-- Naidich, Awad, Bleck
• Neuro-endovascular Therapy-- Bendok, Russell,
  Shaibani, Ankenbrandt,
• Stroke Neurology-- Alberts, Bernstein, Homer,
  Munson
• Skull Base Surgery-- Chandler, Ciric, Awad,
  Rosenblatt, Zhao
• Stereotactic Radiosurgery-- Awad, Chandler,
  Getch, Levy
• Clinical Trials Unit-- ENH Surgical Research
  Office, NW Clinical Research Center
• Outcomes Research Center-- CORE
• Vascular Biology Laboratory-- Awad, Shenkar, Shi,
  Bendok
• Neurovascular Genetics-- Awad, Gault, Rubinstein,
  Kaul
• Advanced Imaging-- Edelman, Meade, Wyrwicz,
  Ankenbrandt, Russell
• Community Outreach-- Angioma Alliance
  (www.angiomaalliance.org)
• Neuro-nursing, Rehabilitation

3
Clinical-Radiologic-Pathologic Spectrum of Human
Cerebrovascular Malformations
VENOUS ANGIOMA Venous developmental
anomaly Regional venous dysmorphism
CAVERNOUS MALFORMATION Hemorrhagic proliferative
dysangiogenesis
ARTERIOVENOUS MALFORMATION Arteriovenous shunting
(Robinson et al. 1989, 1992, 1993)
4
Projecting Natural Risk of CM

• Population prevalence 0.5-0.9 30-40 familial
  clustering (AD) gt30 lifetime risk of symptoms
  (seizures, focal neurologic deficits, stroke)
• Likelihood of overt hemorrhage? 0.5-1 /lesion/
  year (consider recent clinical behavior,
  clustering of hemorrhage, up to 5/ year for 1-2
  years after a bleed )
• Consequences of hemorrhage (consider
  lesion location)
• Impact of hemorrhage(s) over lifetime (consider
  hosts life expectancy)

5
Confirming the Diagnosis of CM and Assessing
Prognosis

• Is it a CM?
• Is it solitary or multiple/familial?
• Is there an associated VM?
• Risks and consequences of hemorrhage?

T1, T2, Gradient echo (T2), Gado enhanced
T1, Repeat MR after acute blood clears, Angiogram
rarely needed
6
Assessing Management Options

• Expectant-- medical therapy, regular surveillance
• CM microsurgical excision-- define threshold for
  intervention (preventive, after one or two
  bleeds, near disability, etc)
• Other options-- ? radiosurgery

7
Evaluate Options of Medical Therapy

• Seizure control, medicines and side effects
• Bleeding risk, consequences, anticoagulants etc
• Impact of living with the lesion or with
  epilepsy-- life decisions, careers, parenting,
  etc
• Do not wrap yourself in bubble-- few real
  restrictions

8
Microsurgical Excision of CM

• Hemorrhage or other symptoms
• Opportunity for cure (solitary, no large VM)
• Accessibility, approach
• Eloquence
• Risk-- defines the threshold for choosing surgery

Functional MR if lesion near eloquent
areas Intraoperative brain mapping
9
Consider and Respect Subcortical Tracts
Tensor Diffusion MR imaging
10
Case Study Transcallosal Approach to Thalamic
Lesion
11
Case Study Transsylvian Approach to Thalamic
Lesion
12
What About Radiosurgery ?

• Does not eliminate the lesion
• Alters natural risk after 2 years
• Complications high unless dosimetry is very low
• (? effective)
• Radiation and CM genesis
• Truly inaccessible/inoperable lesions with
  repeated bleeds

13
Special Considerations for Epilepsy and CM

• Single versus multiple lesions and epilepsy
• Lesion and seizure concordance--clinical,
  diagnostic, role of mapping
• Lesionectomy, versus lesionectomy plus
• Control versus cure (lesion-free, seizure-free,
  medication-free)

14
Special Considerations for Brainstem CMs

• Expensive real estate-- natural risk and
  treatment risks
• Higher stakes, higher threshold-- not surgery at
  any cost, but do not wait too long
• Approach and exposure-- experience
• Access, size, hematoma, associated VM-- what is
  operable?

15
Special Considerations for Brainstem CMs
16
Special Consideration for CM with associated VM

• Leave alone if large VM and many CMs
• Leave alone if extensive VM and minimal CM
• Excise CM if large, growing or symptomatic--
  preserve the VM, unless very tiny
• Consider SRS for focused CCM target

17
Special Considerations for Spinal CMs

• Not very different from brainstem CMs--
  pathoanatomy and clinical sequels
• Keep high index of suspicion
• Excise if solitary, accessible, growing, or
  symptomatic
• Do not wait till advanced symptoms

18
What About Pregnancy?

• CCMs may bleed during pregnancy (more likely ?)
• Great majority of patients and lesions have
  unremarkable pregnancies
• Epilepsy and pregnancy-- anticonvulsant
  medications ESSENTIAL
• Expectant management during pregnancy-- be aware
  and watch CLOSELY

19
Balance of Clinical Decisions

• Factors Favoring Expectant Management
• Multiple lesions
• Associated VMs (large)
• Deep lesions
• Longstanding quiescence
• Shorter life expectancy
• Risks of surgery

• Factors Favoring Surgery
• Solitary lesion
• Accessible lesion
• Symptomatic lesion
• Growing lesion
• Long life expectancy
• Bad consequences of lesion misbehavior

20
Surgical Adjuncts

• Microsurgery, stereotactic guidance
• Brain mapping-- preoperative, intraoperative
• Skull base approaches
• Team experience-- critical care, surgery,
  rehabilitation

21
Cerebral Vascular Malformations ResearchA
Legacy of Collaborations During Two Decades

• The clinical foundations-- BNI and Cleveland
  Clinic
• (Spetzler, Little, Robinson, Estes,
  DeCorletto, et al.)
• The translational science-- Yale
• (Lifton, Kim, Gunel, Rothbart, Wong, Baev,
  White, Awadallah, et al.)
• Genomics of lesions-- the Colorado team
• (Uranishi, Gault, Shenkar, Lepsch, Hu,
  Sarin, Elliott, et al.)
• A new horizon-- ENH and NWU Integrational
  Neuroscience
• Neuroimmunology and Advanced Imaging
• (Shenkar, Meade, Wyrwicz, Rowley, Zhao,
  Kohlmeir, Batjer, Edelman, et al.)

Support by NIH (NINDS) R01NS36194 K24NS02153,
Butcher Family Foundation, ENH Research Institute
22
Refining the Phenotype

• Structural and molecular dissection
• Ultrastructure

CCMs Defective inter-EC junctions and sub-EC
structure (Wong et al. 1998)
23
Refining the Phenotype

• Structural and molecular dissection
• Functional pathways -- angiogenesis

Angiogenesis factor upregulation different
roles in AVMs vs. CCMs ? (Rothbart et al. 1997,
Uranishi et al. 2000)
24
Refining the Phenotype

• Structural and molecular dissection
• Angioarchitecture
• Ultrastructure
• Functional pathways
• -- angiogenesis
• -- cell proliferation

Shenkar, Zhao and Awad, 2005
Mib ECs
Thrombin activated endothelial cell
proliferation-- mib, thrombomodulin (Shenkar et
al. 2005 Abe et al. 2005)
25
Refining the Phenotype
SMA
Myosin
Smoothelin

• Structural and molecular dissection
• Smooth muscle maturation

AVM
Defective SMC maturation in CCMs (Uranishi et al.
2001)
CCM
26
The Genetic Substrate of CCMs

• 20-40 familial (multiple lesions)
• Three gene loci (7q, 7p, and 3q) in familial
  cases
• Hispanic Americans of Mexican descent are CCM1
  (Q455X with preserved haplotype)-- founder
  mutation
• CCM1 gene is KRIT1--all CCM1 mutations result in
  premature truncation
• CCM2 gene is MGC4607
• CCM3 gene is PCD10

(Gunel et al., Tournier-Lasserve et al., others
1995-2005, Marchuck 2003, 2005)
27
Mutations in KREV INTERACTION TRAPPED 1 (KRIT1)
cause CCM1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
3UT

















Truncating (73), 15 intron
5UT
Retinal
Cutaneous
Hispanic

Amino Acid
coding
NPXY motif binds icap-1A ( integrin cytoplasnic
domain-assoc protein-1) cell-cell adhesion
Ankyrin Repeats (protein-protein interaction)
FERM domain (links cytoplasmic and transmembrane
proteins)
Gault and Awad, 2004
28
Genetic Clues to Molecular Mechanism of Disease
CCM-1

• KRIT1 is related to cytoskeletal
  proteins--cellular adhesion pathway
• KRIT1 is associated with tube formation during
  angiogenesis
• CCM1 and 2 proteins are expressed in perivascular
  glial cells (propensity to neural milieu),
  interact in common complex
• Working hypothesis-- KRIT1 mediated defective
  inter-EC junctions in neural milieu predispose to
  CCM lesion genesis

Serebriiskii et al 1997 Zhang et al. 2001, 2003,
2006 Zawistowski et al. 2002, 2003 Gunel et al.
2002 Marchuk 2005
29
Genetic Clues to Molecular Mechanism of Disease
Angiogenesis Growth Factors/Receptors (VEGF,
Angiopeotin, TGF-?, FGF-2)
Endothelial cells
Cell Adhesion Molecules (CD31)
Krev-1/rap1A (signaling)
Krit1-associated microtubules
ICAP-1?
Extracellular Matrix Proteins ?laminin,
?fibronectin,
Gault and Awad, 2004
30
Phenotype, Genotype and Clinical Behavior

• Solitary vs multiple lesions Gr Echo MR (T2) as
  surrogate endophenotype
• Venous angioma
• Previous irradiation
• Penetrance and aggressive behavior
• ( ? gene, mutation, promoter)
• Combined risk

Gault and Awad, Neurosurgery 06
31
Somatic Mutation in Human CM Lesion from Patient
with Germ Line Mutation in Second Copy of Same
Gene

• ? How common
• ? Transheterozygous
• ? Other second hits
• ? Sporadic lesions

Gault et al. (Stroke 2005) Somatic mutation in
endothelial cells (laser capture,
unpublished 2006)
32
Sporadic Lesions Hidden Germ Line or Somatic
Mutation ?

• Occult familiality--
• Incomplete penetrance--
• Rare in absence of family history or lesion
  multiplicity (0/gt100) MR with gradient echo
  excellent screen in suspected cases
• Somatic mutations--
• Two CCM cases reported (Kehrer-Sawatzki et al.,
  Gault et al ) in familial cases
• Sporadic mutation in CVM genes or related
  pathways-- Working hypothesis, unproven in
  sporadic cases

33
Double Hits and Lesion Genesis Transgenic Mice

• CCM1 or CCM2 mutations alone do not seem to
  produce CCM lesions in mice
• Combined genetic predisposition causes CCM
  lesions (ccm /-, P53 -/-)
• Opportunity to study CCM genesis and progression
  in vivo

T2 (GrEcho) MR of transgenic mouse brain 14 T
(collaboration Marchuk Awad, 2006)
34
Gene Interactions Differential Gene Expression
mRNA

• CCMs compared to AVMs and STAs
• 42 genes significantly upregulated
• 36 genes significantly downregulated
• AVMs compared to CCMs and STAs
• 48 genes significantly upregulated
• 59 genes significantly downregulated

Shenkar et al. 2003
35
Genomics Data Analysis
File containing mean
intensity for each gene
i
Scaling (equalize average intensity across chips)
File containing scaled data
Confirmation of
Gene Discovery
Differential Expression
of Known Genes
Matlab
GeneSpring
Genes that vary significantly
i
Genes of interest
Compare groups
i
InStat
Genes differentially expressed
Statistical Analysis
i
Expression Levels and Significance
36
Gene Interactions Differential Gene Expression
37
Genes upregulated gt20X in CCM over controls
38
Immune Response in CCM ?

• Leaky vessels and antigenic challenge
• Organizing thrombus
• ? Cell type
• ? Monoclonal or oligoclonal

B Cells and Plasma Cells
IGG
Shenkar, Awad, Lipton, Check, Rowley (in press
2006)
39
Oligoclonal (IgG) Immune Response in CCM Lesions
Shi, Shenkar, Check, Awad (in press 2006)
40
High Field MR of CCM Lesions
Proliferative States within CCM Lesions?
41
High Field MR of CM Lesions
1 mm
1 mm
10 mm
1 mm
0.1 mm
1.5 T

• Humans up to 4.5 T
• Animals up to 14 T
• Near histologic resolution

3.0 T
Wyrwicz, Edelman, Awad, Shenkar 2005
4.7T
42
Imaging Cellular Events in CM Lesions Tracking
Biologic Events
CCM Lesions Imaged at 14T

• Neoangiogenesis
• Inflammatory cells

43
Imaging Cellular Events in CCM Lesions
Resolution and Labeling
44
Dual Probes For Molecular Imaging of Individual
Cells
Meade et al. 2003-2005
45
Building Molecular Markers for MR Imaging and
Histologic Validation
46

Research Future Integrated Teams for Efficient
Translation
47
Team Assembly Mechanisms and the Creative
Enterprise

• Team self-assembly to critical mass regardless of
  discipline
• Balance of veterans and novices
• Diversity directly linked with productivity
• Team experience affects performance of simple and
  complex tasks

Guimera, et al. Science April 2005
48
Future DirectionsAn Evolving Story

• Enhancing Diagnosis and Therapy
• Explaining disease behavior
• Predicting disease behavior
• Modifying disease behavior