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Intracerebral Hemorrhage ICH incidence Causes Risk Factors

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Intracerebral Hemorrhage ICH incidence Causes Risk Factors Powered By Docstoc
					                                                                                                                                                                             12/1/2009




CURCUMIN ATTENUATES HEMATOMA                                                       Causes/Risk Factors
SIZE AND NEUROLOGICAL INJURY
                                                                                       • Risk factors: older age, male sex, hypertension, high alcohol intake
FOLLOWING INTRACEREBRAL                                                                  (>2 drinks/day), >5 caffeinated drinks/day, caffeine in drugs,
                                                                                         current cigarette smoking, diabetes, and menopause.
HEMORRHAGE IN MICE
                                                                                       • Platelet aggregation inhibitors (Plavix, etc) and aspirin associated
                                                                                         with an increased risk of cerebral microbleeds in older patients.

                                                                                       • Non-aspirin NSAIDS are NOT associated with increased risk of ICH.
         Jay McCracken
         JMS, MCG School of Medicine                                                   • Liver cirrhosis and alcoholic liver disease also associated with
         Department of Neurosurgery                                                      increased risk of ICH OR 4.8.




Intracerebral Hemorrhage                                                           Prognosis
                                                                                       • Primary ICH has very poor short and long term outcome

• Rupture of small arteries or
                                                                                       • Mortality
  arterioles leading to hemorrhage
  into brain parenchyma                                                                  ▫ 7.3% before hospital admission
                                                                                         ▫ 34.6% at 7 days
• 50% of ICH occurs in the putamen                                                       ▫ 50.6% within 28 days
                                                                                           5                     y
  (lenticulostriate branches) 20%                                                        ▫ 59% at 1 year.
  thalamus, 10% cerebellum, 10%
  pons, 5% cerebral white matter                                                       • Cumulative survival at 16 years 3.2% for men and 9.8% for women.
  (lobar hemorrhage)
                                                                                       • Other predictors of poor outcome include: hemorrhage extending to SA or lateral
• HTN is the most common cause                                                           ventricles, cerebellar hemorrhage, lobar hemorrhages >40 cm3 with GCS <13, and
                                                                                         regular ASA or Coumadin use at time of onset of ICH.
• Others include microangiopathy,
  occlusive hypertensive vascular                                                      • Hematoma volume directly correlates with neurological outcome
  disease, arteriolosclerosis




ICH incidence                                                                      ICH Score Predicts Mortality
                                                                                                                               100
 • Occurs in > 120,000 Americans each year                                                                                      90
                                                                                   •    GCS 3-4= 2 points                       80
                                                                                   •    GCS 5-12= 1 point                       70
 • ICH accounts for 15-20% of all strokes each year
                                                                                   •    GCS 13-15= 0 points                     60
                                                                                                                                50                                     30 day
 • Primary ICH: unrelated to congenital or acquired lesions. Accounts for 78-88%   •    1 point each for:
                                                                                                                                40                                     mortality
   of hemorrhagic stroke                                                                    8 /
                                                                                        ▫ >80 y/o,                              30
   ▫ Hypertensive arteriolosclerosis                                                    ▫ infratentorial                        20
   ▫ Amyloid angiopathy                                                                 ▫ volume >30 cm3                        10
                                                                                                                                 0
                                                                                        ▫ intraventricular hemorrhage                  0    1    2    3    4    5
 • Secondary ICH: acquired or congenital lesions. Minority of cases                                                                  30‐day mortality based on point score
   ▫ Coagulopathies                                                                                                                  •0 points: 0%
   ▫ Brain Tumors                                                                                                                    •1 point: 3‐13%
   ▫ Aneurysms                                                                                                                       •2 points: 26‐31%
   ▫ Vascular Anomalies                                                                                                              • 3 points: 61‐72%
   ▫ Thrombolytic treatment of ischemic stroke                                                                                       • 4 points: 88‐97%
                                                                                                                                     •5 points: 100% 




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 Treatment: Medical
  • ABCs. Give IV fluids and antiepileptic medication if indicated (for lobar
                                                                                            Hypothesis
    hemorrhages), but always aggressively control BP, ICP, and hyperglycemia.

  • Not enough evidence to support the use of mannitol after acute ICH.
                                                                                            Curcumin will reduce the size of
     ▫ No differences in rates of death, disability, or fatality rates between 3 separate
       trials.
       t i l
                                                                                             hematoma volume, limit the amount
                                                                                             of inflammation and edema, and
  • First clinical trial of rFVIIa (NovoSeven) showed that when given within 4
    hours of the acute bleed, it significantly reduced expansion of the                      improve neurological outcome after
    hematoma at 80 mcg/kg (-3.8 mL vs placebo, p=.009), and also appeared
    to modestly reduce mortality at 90 days (18% vs. 29%).                                   induced ICH in mice
  • Further trials (FAST trial) did not show any improvement in functional
    outcome or mortality when rFVIIa used to treat acute ICH.




 Treatment: Surgical
  • General recommendations from STICH trial
    ▫ Remove hemorrhage ASAP if CBL hemorrhage >3 cm with
      neurological deterioration, brainstem compression and/or
      hydrocephalus from ventricular obstruction

     ▫ Craniotomy can be useful in treatment of lobar clots within 1 cm
       of the surface with GCS >9.

     ▫ Further evidence is needed for recommendations of mechanical
       devices (stereotactics) or endoscopy, but there has been some
       promising results

     ▫ Operative removal within 12 hours has the most supportive
       evidence, especially if by less invasive procedures. Ultra-early
       craniotomy does not appear to offer substantial benefit, and may
       increase risk of re-bleeds




 Curcumin                                                                                   Procedure
• Used for centuries in Indian Ayurveda
  medicine in the treatment of wound-healing,
  ulcers, and arthritis

• Has significant antioxidant, anti-
  inflammatory, proliferative, carcinogenic,
  and angiogenic activity

• Recent clinical trials in patients with colon
  cancer, FAP, pancreatic cancer, and multiple
  myeloma

• Reduces oxidative damage and inflammation
  in animal models of Alzheimer’s disease, TBI,
  ischemic stroke, and SAH

• Very safe when taken orally, with minimal
  side effects




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                                                                                   72 HOURS
                                                                                  POST‐INJURY                                                                                                                  Brain Edema
                                                       ICH ONLY                                                                                          ICH + CURCUMIN
                                                                                                                                                                                                                                                         IPSI                            CONTRA                                                           IPSI                       CONTRA

                                                                                                                                                                                                                                       85                                            *                                                     85                                      ***




                                                                                                                                                                                                                                                                                                                   % Brain Water Content
                                                                                                                                                                                                              % Brain Water Content
                                                                                                                                                                                                                                                                                                                                           80




                                                                                                                                                                                                                                                                                                                                 C
                                                                                                                                                                                                                                       80




                                                                                                                                                                                                                            C
                                                                                                                                                                                                                                       75                                                                                                  75



                                                                                                                                                                                                                                       70                                                                                                  70
                                                                                                                                                                                                                                                   SHAM                      ICH          ICH + CCM                                                   SHAM                   ICH          ICH + CCM



                                                                                                                                                                                                                                                                         24h                                                                                                 72h
                    Posterior                                            Anterior                                                           Posterior                    Anterior
                                                                                                                                                                                                                                                                                              * p< 0.05, *** p< 0.001




                                                                                                                                                                                                               Blood Brain Barrier opening
      Hematoma Quantification                                                                                                                                                                                                                            SHAM                  ICH           CCM                                                             SHAM                   ICH             CCM
                                                                                                                                                                                               ( l plasm x mg brain wt -1 x hr-1)




                                                                                                                                                                                                                                                                                                           ( l plasm x mg brain wt -1 x hr-1)
                                                                                                                                                                                                                                            0.25                     *                                                                            0.035                 **
                                                                                                                                                                                                     Evan Blue Permeability




                                                                                                                                                                                                                                                                                                                 Evan Blue Permeability
                                                                                                                                                                                                                                                                                                                                                                                              ***
                                                                                                                                                                                                                                                                                                                                                  0.030
                                                                                                                                                                                                                                            0.20                                              6h
                                                           ICH                  ICH + CCM
                                                                                                                             125
                                                                                                                                                                                                                                                                                                                                                  0.025                                             24h
                      25                                                                                                                                                       ***                                                          0.15                                                                                                  0.020
           matoma




                                                                                                  Hemoglobin Content




                                                                                                                             100                                                                                                            0.10                                                                                                  0.015
                      20                                                            **
                                                                                                                                                                                                                                                                                                                                                  0.010
    Area (mm2)




                                                                                                                                                                                                        ma




                                                                                                                                                                                                                                                                                                                    ma
                                                                                                                                                                                                        ns




                                                                                                                                                                                                                                                                                                                    ns
                                                                                                                                                                                                                                            0.05
                                                                                                             C
                                                                                                            L)
Measured Hem
           m




                                                                                                                                    75
                                                                                                       (mg/dL




                      15                                                                                                                                                                                                                                                                                                                          0.005
                                                                                                                                                                                                                                            0.00                                                                                                  0.000
                      10                                                                                                            50                                                                                                                       IPSI                        CONTRA                                                                  IPSI                     CONTRA

                                                                                                                                    25
                              5
                                                                                                                                                                                                                                                             SHAM                  ICH            CCM
                                                                                                                                                                                                 (l plasma x mg brain wt -1 x hr-1)




                                                                                                                                            0                                                                                               0.045                        *
                              0                                                                                                                          SHAM      ICH           ICH + CCM
                                                                                                                                                                                                      Evans Blue Permeability




                                                           48HR                   72HR                                                                                                                                                      0.040
                                                                                                                                                                                                                                            0.035                                            12h
                                                                                                                                                                                                                                            0.030
                                                                                                                                                                                                                                            0.025
                                                                                                                                                                                                                                            0.020
                                                                                                                                                                                                                                            0.015
                                                                                                                                                                                                                                            0.010
                                                                          * p< 0.05, ** p< 0.01, *** p<0.001                                                                                                                                0.005
                                                                                                                                                                                                                                            0.000                                                                           * p< 0.05, ** p< 0.01, *** p<0.001
                                                                                                                                                                                                                                                                IPSI                      CONTRA




Inflammatory Gene Expression
                                                                                                                                                          IL-1β                                                Neurological Outcome
                                                                                                               Normalized Gene Expression




                                                                          ***                                                                      20                    ***
                                                            IL-6
                        Normalized Gene Expression




                                                                                                                 (fold change vs. sham)




                                                      35
                          (fold change vs. sham)




                                                      30
                                                      25                                                                                                                                                                                                             12.5
                                                      20                                                                                           10
                                                                                                                                                                                                                                                                                            SHAM                   ICH                                       ICH + CCM
                                                      15
                                                                                                                                                                                                                                                                     10.0
                                                                                                                                                                                                                                                    Behavior Score




                                                      10
                                                                                                                                                                                                                                                     (24pt scale)




                                                       5
                                                       0                                                                                           0
                                                                                                                                                         SHAM     ICH        ICH + CCM
                                                                                                                                                                                                                                                                         7.5
                                                           SHAM    ICH      ICH + CCM                                                                                                                                                                                                                                                            **
                                                                                                                                                                                                                                                           r
                                                                                                                                                                                                                                                           s




                                                                                                                                                                                                                                                                         5.0
                                                                                                                                                                                                                                                                                                                                                                 **
                                                                           **                                                                                            *
                    Normalized Gene Expression




                                                           TNF-α                                                                                         TNF-α
                                                                                                                      Normalized Gene Expression




                                                     7.5                                                                                           7.5                                                                                                                   2.5
                      (fold change vs. sham)




                                                                                                                        (fold change vs. sham)




                                                     5.0                                                                                           5.0
                                                                                                                                                                                                                                                                         0.0
                                                                                                                                                                                                                                                                                     0HR            24HR                                   48HR              72HR
                                                     2.5
                                                                                            24h                                                    2.5                                   72h

                                                     0.0                                                                                           0.0
                                                           SHAM    ICH          ICH + CCM                                                                SHAM     ICH        ICH + CCM


                                                                                                                                                                                                                                                                                         * p< 0.05, ** p< 0.01, *** p<0.001
                                                                           * p< 0.05, ** p< 0.01, *** p<0.001




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                                                                                                           12/1/2009




 Summary
• The final size of the hematoma                                   Acknowledgements
  after ICH stabilization is the best
  indicator of patient prognosis
                                                                   •   Dr. Cargill H. Alleyne, Jr., M.D.
• Curcumin grossly reduced the                                     •   Dr. Krishnan M. Dhandapani, Ph.D.
  volume of hematoma and down-
  regulated pro-inflammatory gene                                  •   Melanie King
  expression, decreased edema,                                     •   Mike Jensen
  and improved neurological
  outcome by 72 hours post-ICH

• Curcumin may be a useful
  adjunct to both surgical and
  medical management of ICH
  patients




 Future Directions
  • Currently working on 30 different novel analogues of the
    curcumin molecule to increase potency and
    bioavailability

  • Biodegradable curcumin nanoparticles used to increase
    the bioavailability and half-life, increase cellular uptake,
    and have a more potent anti-inflammatory effect than
    non-NP curcumin.

  • PPARγ induced hematoma resolution pathway, the
    target of glitazone drugs and curcumin.




 References
  •   Stroke 2009 Jun;40(6):1980
  •   Stroke 2005 Sep;36(9):1881
  •   Stroke 2009 Feb;40(2):394
  •   Neurology 2006 Aug 8;67(3):424
  •   Stroke 2005 Sep;36(9):1881
  •   Arch Neurol 2009 Jun;66(6):714
  •   Stroke 2003 Feb;34(2):387
  •       C Gastroenterol 2008 May 24;8:16
      BMC G                008    y 4;8 6
  •   Stroke 2009 Feb;40(2):394
  •   J Neurol Neurosurg Psychiatry 2005 Nov;76(11):1534
  •   Cerebrovasc Dis 2001;11(3):183
  •   Stroke 2006 Jan;37(1):129.
  •   Stroke 2001 Apr;32(4):891
  •   Stroke 2006 Apr;37(4):1038
  •   BMJ 2000 Nov 25;321(7272):1358
  •   N Engl J Med 2005 Feb 24;352(8):777
  •   N Engl J Med 2008 May 15;358(20):2127
  •   Stroke 2007 May 7; (38) 2001-2023.
  •   Biochemical Pharmacology 2009, Sept 1; (9) 10317
  •   Aggarwal, B. Biochem Pharm. 2009, Sept. 1. BCP-10317.
  •   Aronowski, J. Ann Neurology. 2007. 61:352–362




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