ISCHEMIC STROKE
Ischemic penumbra
David Goldemund M.D.
Updated on 20/08/2024, published on 20/06/2023
Updated on 20/08/2024, published on 20/06/2023
Definition
The ischemic penumbra is the area of the brain that is ischemic but remains viable for a limited time due to partially preserved collateral blood flow. Timely intervention can salvage this tissue.
Concept of ischemic penumbra
- the extent of brain damage during a stroke depends on the severity and duration of the cerebral blood flow (CBF) disorder → Regulation of cerebral blood flow
- within the ischemic area, two major zones of injury are identified :
- core
- penumbra
- as blood flow decreases, an initial loss of function occurs while structural integrity remains intact (functional threshold)
- with a further decrease in CBF or prolonged blood flow deficit, irreversible loss of membrane functions and permanent morphologic changes occur (morphologic threshold)
- a decrease in regional flow to < 55 mL / 100g of tissue/minute leads to inhibition of proteosynthesis
- < 35 mL – stimulation of anaerobic glycolysis begins
- < 20 mL – loss of electrical function occurs
- < 10 – 12 mL – necrosis
- neurons in areas where CBF falls below the morphologic threshold (infarct core) represent tissue that is already dead or only viable for a very limited time
- brain tissue with perfusion values between the two thresholds (CBF 12-18 ml/100g/min) is termed the “ischemic penumbra“; this tissue may remain viable for several hours
- without early reperfusion, cells in the penumbra will eventually die, as collateral circulation cannot sustain the neuronal demand for oxygen and glucose indefinitely ⇒ penumbra shrinks with prolonged arterial occlusion
- neurons of the hippocampus, basal ganglia, and some cortical areas are particularly vulnerable
| core | penumbra | normal tissue |
|
|
CBF mL/100g/min
|
< 12
|
12-18
|
> 18
|
|
EEG
|
0
|
reduced
|
normal
|
|
SSEP
|
0
|
reduced
|
preserved
|
|
histology
|
infarction
|
normal |
normal
|
|
membrane potential
|
0
|
0 (reversible)
loss of neuron function |
normal
|
|
vitality
|
no
|
preserved
|
normal
|
Penumbra detection
- assessment of the size and stability of the penumbra using advanced imaging techniques like perfusion-weighted MRI or CT perfusion can significantly influence clinical decisions
- studies such as DEFUSE 3 and DAWN have demonstrated that patients with a favorable penumbra-to-core ratio, as identified by advanced imaging, can benefit from thrombectomy up to 24 hours after symptom onset
- the integration of AI and machine learning algorithms into imaging platforms has revolutionized the analysis of perfusion data. AI-driven software (such as RAPID or Viz.ai) can automatically identify and quantify the ischemic core and penumbra with high accuracy, reducing interobserver variability and speeding up decision-making processes
CT perfusion (CTP)
- CT perfusion (CTP) can help differentiate between irreversible ischemia (core) and ischemic penumbra (viable tissue with reduced perfusion), as well as benign oligemia
- software packages use various combinations of parameters to define core and penumbra
- a common definition of penumbra:
- hypoperfused brain at risk of progression to infarction, yet salvageable
- increased T-max >6 seconds, or mean transit time (MTT) or time to peak (TTP) > 145% of the healthy hemisphere
- moderate decrease of cerebral blood flow (CBF); > 30% compared to the contralateral (normal) side
- normal or ↑ cerebral blood volume (CBV) – due to autoregulation
- a common definition of core:
- infarcted, unsalvageable tissue
- ↑ T-max (↑TTP, MTT)
- ↓↓ CBF (< 30% of normal values); correspondïng to a DWI lesion on MRI)
- ↓↓ CBV (< 40% of normal)
- infarcted, unsalvageable tissue
|
CBV
|
CBF
|
MTT
|
|
|
ischemic core
|
↓↓
|
↓↓↓
(< 30%) |
↑↑
|
|
penumbra
|
N or ↑
|
↓↓
(> 30%) |
↑↑
|
|
benign oligemia
|
N or ↑
|
↓
|
↑ or ↑↑
|
|
chronic, compensated occlusion/stenosis
|
N
|
N
|
↑ or ↑↑
|
MR perfusion (PWI)
- MR perfusion imaging (PWI) uses the “first-pass bolus” technique, utilizing intravenous gadolinium
- the same parameters as with CTP can be obtained (CBV, CBF, MTT, TTP)
- tissue with reduced blood flow (indicated by a prolonged MTT) encompasses:
- infarct (core)
- penumbra
- benign oligemia regions
- infarct (core)
- the ischemic core closely correlates with restricted diffusion lesion (DWI lesion) and is characterized by decreased CBF and CBV
- the difference between the tissue volume showing a perfusion deficit (on PWI) and the tissue volume already infarcted (on DWI) is termed the PWI/DWI mismatch
- PWI/DWI mismatch represents the ischemic penumbra
Therapeutic implications of ischemic penumbra
The concept of ischemic penumbra is pivotal in the current acute management of ischemic stroke beyond the standard therapeutic time window. Stroke teams are focused on detecting and salvaging this at-risk but viable brain tissue, thereby reducing the extent of permanent brain injury.
Reperfusion
- extended therapeutic time window for thrombolysis and mechanical recanalization substantially improve outcomes in stroke patients
- criteria are discussed in a separate chapter → Recanalization therapy
Penumbra preservation
- to extend the therapeutic window, innovative approaches to preserve the ischemic penumbra are being explored
- ImpACT-24B trial investigates sphenopalatine ganglion stimulation to enhance collateral blood flow and improve outcomes in patients with cortical infarcts
- SETIN trial – focuses on induced hypertension in patients who are ineligible for thrombectomy, aiming to sustain collateral flow and thus preserve the penumbra. This approach has also demonstrated improved outcomes, particularly in cases where mechanical intervention is not an option.
- Butylphthalide trial evaluated the efficacy of DL-3-n-butylphthalide (NBP) as an adjunctive therapy in acute ischemic stroke. This drug targets multiple pathways associated with neuroprotection and has been shown to increase the likelihood of favorable outcomes when used alongside standard reperfusion therapies
- ZODIAC trial assessed whether maintaining a 0-degree head-of-bed (HOB) position, as opposed to an elevated 30-degree position, enhances clinical stability in patients with a hyperacute large vessel occlusion (LVO) during the pre-thrombectomy period. The trial demonstrated significant improvements in neurological function for patients with 0-degree compared to 30-degree HOB positioning
- hypothermia – a potential neuroprotective strategy aimed at reducing metabolic demand and slowing the progression of ischemic injury within the penumbra
FAQs
- the ischemic penumbra refers to brain tissue that is hypoperfused due to an ischemic stroke but remains potentially salvageable if blood flow is restored promptly
- penumbra is typically identified using imaging techniques such as CT perfusion or MRI diffusion and perfusion studies
- these techniques help to differentiate the penumbra from the infarct core by showing areas of reduced blood flow that have not yet been irreversibly damaged
- reperfusion therapies such as intravenous thrombolysis (using alteplase or tenecteplase) and mechanical thrombectomy (endovascular removal of the clot). These treatments aim to restore blood flow to the penumbra as quickly as possible
- neuroprotective strategies reduce metabolic demand and slow ischemic injury progression
- the survival time of the ischemic penumbra can vary significantly among individuals, generally ranging from tens of minutes to several hours post-stroke
- the exact duration depends on various factors, including the severity of the blood flow reduction and the presence of collateral blood vessels
- it depends on how quickly reperfusion therapy is administered and how reperfusion is established
- early and effective treatment increases the likelihood of saving most, if not all, of the penumbral tissue
- if the ischemic penumbra is not treated promptly, it is likely to undergo irreversible damage and become part of the infarcted core
