Cerebral Localization: Definition

1. "Mapping of the cerebral cortex into areas, and the correlation of these areas with cerebral function"

2. "Diagnosis of the location of a brain lesion in the cerebrum, done either by
       Signs and symptoms manifested
                              or
       Using any investigation modality"

History of Cerebral Localization

1/12/2020 07:30:00 AM

Slide Text

Journal Club Presentation

Background

●     Intracranial bleeding is common after traumatic brain injury (TBI) and increases head injury-related death and disability 

●     Intracranial bleeding after traumatic brain injury (TBI) can cause brain herniation and death.

●     Tranexamic acid reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots (fibrinolysis)  

●     This trial aimed to assess the effects of tranexamic acid in patients with TBI.

Evidence before this study

●     CRASH-2 trial: administration of tranexamic acid within 3 h of injury reduces death in patients with traumatic extracranial bleeding reduces bleeding deaths by a third 

●     This raised the possibility that tranexamic acid might reduce death from traumatic intracranial bleeding

●     Before this study, a metanalysis of two small randomised trials of tranexamic acid in traumatic brain injury with a total of 510 patients showed a statistically significant reduction in death with tranexamic acid  (Perel P 2012, Yutthakasemsunt S 2013)

Methods 

Study design and participants 

●     international, multi­centre, randomised, placebo ­controlled trial

●     Between July 20, 2012, and Jan 31, 2019, recruited patients with TBI from 175 hospitals in 29 countries. 

Inclusion Criteria

●     Adults with TBI who were within 3 h of injury

●     time window for eligibility was originally within 8 h of injury. However, on Sept 6, 2016, in response to evidence external to the trial indicating that tranexamic acid is unlikely to be effective when initiated beyond 3 h of injury, it was amended to limit recruitment to within 3 h of injury

●     Had a Glasgow Coma Scale (GCS) score of 12 or lower

●     any intracranial bleeding on CT scan

●     no major extracranial bleeding

Exclusion Criteria

●     Extracranial bleeding

●     >8hrs since injury (limited to >3hrs from Sept 2016)

●     Prespecified sensitivity analysis excluding patients with GCS of 3 and those with bilateral non-reactive pupils

Randomisation and masking 

●     randomly allocated eligible patients to receive tranexamic acid or matching placebo (0·9% sodium chloride) by intravenous infusion. 

●     tranexamic acid was manufactured by Pfizer (Sandwich, UK) 

●     Ampoules and packaging were identical in appearance.

●     Entry form data were entered into a secure online database by the trial investigators.

●     Participants and study staff (site investigators and trial coordinating centre staff) were masked to allocation 

Procedures 

●     Patients were randomly allocated to receive a loading dose of 1 g of tranexamic acid infused over 10 min, started immediately after randomisation, followed by an intravenous infusion of 1 g over 8 h  or matching placebo.

●     Every patient was assigned a uniquely numbered treatment pack, which contained four ampoules of either tranexamic acid (500 mg) or placebo, one 100 mL bag of 0·9% sodium chloride 

Primary Outcome

Primary outcome was head injury­ related death in hospital within 28 days of injury in patients

Secondary Outcomes

●     early head injury ­related death (within 24 h after injury)

●     all ­cause and cause ­specific mortality

●     vascular occlusive events (myocardial

●     infarction, stroke, deep vein thrombosis, and pulmonary embolism)

●     Seizures

●     Complications

●     Neuro­surgery

●     Days in intensive care unit

●     Adverse events within 28 days of randomisation.

Trial Profile

Statistical analysis 

All analyses were on an intention to­ treat basis.

Reporting the effects of tranexamic acid on the primary outcome stratified by three baseline characteristics:

●     severity of head injury: Severity of head injury was assessed using the baseline GCS score—mild to moderate (GCS 9–15) and severe (GCS 3–8)—and by pupil reactivity. 

●     time to treatment: treatment (≤1, >1 to ≤3, >3 h) 

●     Age : 30 years or younger, 31–60 years, older than 60 years 

Results

Results: Deaths

●     reduction in the risk of head injury­ related death with tranexamic acid in patients with mild­ to ­moderate head injury (RR 0·78 [95% CI 0·64–0·95])

●     but in patients with severe head injury (0·99 [0·91–1·07]) there was no clear evidence of a reduction (p value for heterogeneity 0·030) 

●     Among patients with reactive pupils, head injury ­related deaths were reduced with tranexamic acid (0·87, [0·77–0·98]) 

Effect of tranexamic acid on head injury-related death stratified by baseline severity in patients

randomised within 3 h of injury 

Results: Time to Treatment

RR of head injury ­related death with tranexamic acid was

●      0·96 (95% CI 0·79–1·17) in patients randomly assigned within 1 h of injury

●     0·93 (0·85–1·02) in more than 1 h and less than 3 h after injury

●     0·94 (0·81–1·09) in more than 3 h after injury.

However, as anticipated in the statistical analysis plan, patients who are treated soon after injury often have more severe head injury and so the effect of time to treatment could be confounded by severity. 

Effect of tranexamic acid on head injury-related death by severity and time to treatment in all patients

The models were adjusted for GCS score, age, and systolic blood pressure. 537 patients with mild and moderate GCS scores (9–15) and 918 patients with severe GCS scores (4–8), excluding those with a GCS score of 3 and those with no reactive pupils, died because of head injury 

Results: Deaths in <24 hrs="" span="">

Because early head injury related deaths are more likely to result from intracranial haemorrhage than are late head injury related deaths  

●     The RR of head injury­ related death was 0·81 (95% CI 0·69–0·95) within 24 h.

●     When patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline were excluded, the RR was 0·72 (0·56–0·92) within 24 h 

Results: Age

no evidence of heterogeneity in the effect of tranexamic acid by patient age (p=0·45) 

Discussion

●     tranexamic acid to patients with TBI within 3 h of injury reduces head injury ­related death, with no evidence of adverse effects or complications. 

●     substantial reduction in head injury ­related deaths with tranexamic acid in patients with mild and moderate head injuries

●     no apparent reduction in those with severe head injury.

●     We found no increase in disability among survivors

●     Most patients with bilateral unreactive pupils already have extensive intracranial haemorrhage and brain herniation and so tranexamic acid is unlikely to improve the outcome in these patients. 

Discussion

●     Because haemorrhage expansion occurs in the hours immediately after injury, treatment delay would reduce the potential for tranexamic acid to prevent intracranial bleeding 

●     Patients with severe head injury might have less to gain from tranexamic acid treatment than patients with mild­ to moderate head injury because such patients already have extensive intracranial haemorrhage before treatment or other potentially life ­threatening intracranial pathologies that are not affected by tranexamic acid 

●     Limitations

●     CRASH-3 is technically a “negative” study, as the primary endpoint falls slightly short of reaching statistical significance (p&gt;0.05)

●     The use of 28-day head injury-related mortality as the primary endpoint probably biased the treatment effect towards the null because tranexamic acid is most likely to benefit patients with TBI with intracranial bleeding at risk of early mortality, whereas late deaths are unlikely to be affected by tranexamic acid.

●     In CRASH-2 and CRASH-3 trials , the tranexamic acid dosing regimens were very similar. Future study might be warranted to explore the effects of increased tranexamic acid doses in bleeding patients, or possibly alternative routes of administration such as intramuscular administration that might facilitate earlier intervention

●     Limitations

●     Originally planned for 10,000 patients to have a 90% powered to detect a 15% relative reduction in mortality

●     however with the change in time to intervention to within 3h of injury the targeted sample size was increased to 13,000 to have approximately 10,000 patients treated within 3hr of injury which they did not meet (≈9,200 patients)

Conclusion

On the basis of CRASH­2 trial results, tranexamic acid was included in guidelines for the pre­hospital care of patients with trauma.  However, patients with isolated TBI were specifically excluded.

The CRASH­3 trial provides evidence that tranexamic acid is safe in patients with TBI and that treatment will have maximum effects in following:

●     Early treatment (less than 3hrs)

●     Mild to moderate (GCS 9 – 15)

●     ICH on baseline head CT.

Further Reading

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext
https://emcrit.org/pulmcrit/crash3/
https://rebelem.com/crash-3-txa-for-ich/

10/16/2019 10:25:00 PM

Slide Outline

Introduction

• Vertebra compression fracture (VCF) is the reduction in the height of the individual vertebral by 20% or 4 mm 
• more than 700,000 pathologic vertebral body compression fractures reported annually with thoracic and lumbar locations being the most common 
• more than 25% of women older than 65 years sustain vertebral compression fractures.



Introduction

• Historically, the only alternative to nonoperative management of symptomatic vertebral fractures was open surgical decompression (anterior or posterior decompression and stabilization via internal fixation hardware and bone grafting), and this was usually reserved for those patients with gross spinal deformity or neurological impairment 
• Vertebra augmentation procedure (VAP) is a general term for several techniques used to treat VCFs. The VAPs aim to consolidate the fracture and, when possible, achieve height restoration 
• History
• Idea of strengthening the weakened vertebral body (VB) was initially raised by Galibert et al. in 1987 
• They treated an aggressive vertebral hemangioma at C2 by injecting polymethylmethacrylate (PMMA) into the involved bone.
• This percutaneous procedure caused almost immediate pain relief



Types of OCF

• Two distinct morphologic types. 
• Acute crush fracture, whereby the patient experiences sudden onset of pain and muscle spasm after any major or minor trauma. 
• Minimally symptomatic anterior wedge compression fracture that occurs over multiple levels in time and leads to a kyphotic deformity and loss of height.

Conservative Management

• Irrespective of aetiology, treatment of VCFs has largely been conservative: 
• bed rest
• narcotic analgesics
• antiresorptive medications 
• back bracing for several weeks
• The VERTOS III follow-up study evaluated the natural course of pain in a large cohort of symptomatic patients with VCFs and found that about halfof the patients had insufficient pain relief at 12 months, while in the other half, pain decreased progressively, particularly during the first 3 months. 

Clinical Indications

• Majority of osteoporotic compression fractures will heal with conservative treatment
• The typical indication for vertebral body augmentation (vertebroplasty: VP or kyphoplasty: KP) in OCF is refractory local back pain that is related to the fractured VB and not responding to standard medical treatment for 3 weeks

Other Clinical Indications

• Painful vertebrae due to benign bone tumours, like aggressive haemangioma, giant cell tumour and aneurysmal bone cyst 
• Painful vertebrae with extensive osteolysis due to malignant infiltration by multiple myeloma, lymphoma and metastasis 
• Painful fractures associated with osteonecrosis (Kummell’s disease) 
• Symptomatic vertebrae plana 
• Acute stable A1 and A3 traumatic fractures (Magerl’s classification) 
• Chronic traumatic fracture in normal bone with nonunion of fracture fragments or internal cystic changes 
• Need for vertebral body or pedicle reinforcement prior to posterior surgical stabilisation. 



Who Benefits More from Vertebral Augmentation?

• Patient who presented with acute OCF (<5 4="" additional="" an="" and="" associated="" be="" but="" calcitonin="" clinical="" conservatively="" correlating="" days="" deficit="" for="" fracture="" ibandronate="" is="" li="" medical="" neurologic="" option="" prevent="" ranelate="" should="" signs="" strontium="" symptomatic="" symptoms="" to="" treated="" treatment="" vertebral="" weeks="" with="" without="">
• Patient with persistent and severe focal back pain related to less than 4 OCFs benefits more from these procedures
• appropriate time for vertebral augmentation in symptomatic OCFs is between two and twelve months after the onset of complaints

Who Benefits More from Vertebral Augmentation?

• It is important to determine that the affected vertebra is the main culprit for pain.
• local vertebral pain aroused by tapping, 
• high signal intensity on fat suppression magnetic resonance imaging (MRI) scan, 
• increased uptake in osteoscintigraphy (difficulty in evaluating images and the considerable costs, it has been recommended if difficult to identify with MRI

Contraindications

• Acute OCF
• Improvement of symptoms with conservative treatment
• Asymptomatic VB fracture
• Tumor mass with spinal canal involvement
• Presence of osteoblastic metastasis,
• Pregnancy
• Concomitant uncorrectable coagulopathy

Contraindications

Absolute 

• Asymptomatic VCFs 
• Unstable spinal fracture. Patients with diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis are highly susceptible to unstable 3-column spine fractures, even with minimal trauma 
• Osteomyelitis, discitis or active systemic infection 
• Severe uncorrectable coagulopathy
• Allergy to bone cement or opacification agents. 

Contraindications

Relative

• Radicular pain.
• Tumour extension into the vertebral canal or cord compression.
• Fracture of the posterior column, as there is increased risk of cement leakage and posterior displacement of loose fragment(s) 
• Sclerotic metastasis, as the risk of cement leakage ishigh.
• Diffuse metastases ([5). 

Contraindications

• some challenging situations such as pedicle or posterior VB fracture, vertebra plana with severe vertebral collapse (more than one-third of the original VB height), spinal cord compression, or osteosclerosis of VB trabeculae may increase the complications or hamper needling

Time of Intervention 

• Ideally, the patient should present within four months of the fracture(onset of pain) and have at least 3 weeks of failure of conservative treatment. 
• In cases of chronic (>4 months old) osteoporotic VCFs, PVP can be proposed if there is imaging evidence of osteonecrosis or incomplete healing (persistence of bone oedema on MR or bone scintigraphy) 

Imaging

• Preoperative imaging is needed to identify the fracture (or fractures), estimate its age, define fracture anatomy, assess posterior vertebral body wall integrity [1] and exclude other causes of back pain (i.e. facet arthropathy, spinal canal stenosis and disc herniation) 
• MRI is a must in all patients considered for PVP as itprovides information regarding the age and healing statusof the fracture (acute vs chronic, incompletely healed vsconsolidated 
• Acute, subacute and nonhealed fractures are hypointense on T1W images and hyperintense on T2W and STIR sequences because of thebone marrow oedema 

Surgical Technique: Vertebroplasty  

• Basic equipment required for performing VP includes beveled trocars (J-type needle, etc.) PMMA cement, contrast media and a fluoroscope.
• transpedicular approach, and the extrapedicular posterolateral approach
• transpedicular approach has advantages of avoiding pleural parenchymal injury, lumbar psoas hematoma and cement leakage by lowering risk of cement leakage through a puncture hole

Surgical Technique: Vertebroplasty 

• Patient transferred to the prone position
• Very gentle trunk hyperextension force might be so effective in restoring anterior VB height
• High quality biplanar fluoroscopy and proper cement opacification are two most important prerequisites for safe and triumphant VP

Transpedicular approach  

• After locating the skin incision 1 to 1.5 cm lateral to the pedicle lateral margin, a trocar is positioned on the lateral margin of the pedicle using a fluoroscopic AP image
• Check the position of the cannular tip relative to the pedicular ring on anteroposterior fluoroscopic projections.
• When the cannular tip came into contact with the bone of the posterior vertebral element, the tip should be located at 2 and 10 o’clock in left and right pedicular rings, respectively 

Surgical Technique: Vertebroplasty  

• When the tip of the cannula passed the junction of middle and anterior third of the VB, 1–4 cc runny cement per side (in bilateral cases) under a relatively high pressure is injected into the weakened VB. 
• On lateral fluoroscopic view, if cement reached the posterior third of the VB, the injection should be stopped to avoid overfilling

Surgical Technique: Vertebroplasty  

• Extrapedicular posterolateral approach  
• can be used in conditions wherein it is difficult to perform the pedicle approach, like patients having a small pedicle, pedicular lysis or instruments like a pedicle screw
• Skin incision should be located 4th-5th finger width lateral to the spinous process
• Trocar should be located on the anterior 1/5the1/4th of the vertebral body 

Amount of Cement

• No strong correlation between the injected cement volume and the amount of VB strength and stiffness restoration, and the degree of clinical improvement available in literature
• It has been reported that as little as 2 mL cement volume injected into the involved vertebra may restore the initial stiffness  
• Vertebral augmentation aims to inject the minimum amount of cement required to obtain spinal stability; a good central distribution of cement inside the VB with a vertebral body fraction of 24% was proposed as the optimal fraction to be cemented

Surgical Technique: Kyphoplasty

• Like VP, initial attempt for vertebral closed reduction is carried out by positioning 
• Vertebral needling is similar to VP but needles should be replaced with larger cannulae to insert bone tamps through them
• In KP, the surgeon aims to centrally place one or two bone tamps inside the VB under biplanar fluoroscopic control

Surgical Technique: Kyphoplasty

• First, bone tamps are inflated under manometric control with radio-contrast medium (for visualization of VB expansion). 
• Usually a balloon pressure of 150 to 300 psi is necessary to reduce OCF. 
• If the procedure is carried out within 3 months of the OCF, usually it is possible to restore 30 to 50% of the primary VB height. 
• Then, balloons are deflated and 3.5 to 8.5 cc of high viscosity cement (with a tooth-paste-like viscosity) under direct image control is injected into the volume previously created by bone tamps 
• Difference between Vertebroplasty and Kyphoplasty
• Balloon is used in KP
• KP has advantages of lowering the risk of PMMA cement leakage : high viscosity cement is injected under less pressure
• KP can correct the compressed vertebral body : has the potential to improve spine biomechanics  

Postoperative care after cement augmentation

• Patients should take approximately 2 hours of bed rest after VP or KP
• they should be allowed to walk when their symptoms become tolerable.
• Although the operated vertebra is more stable than before, patients still need to wear a rigid brace for 2-3 months because cortical bone healing takes 2-3 months and recollapse might occur during that period.
• Discharge can be given on the same day or the next day of the operation.

Complications

• Cement leakage constitutes the most common complication of these minimally invasive procedures (27 to 75%)
• Fortunately, most of the cement extravasation phenomena are clinically asymptomatic. 
• Cement may leak into the intervertebral disc space (most common), anterior paravertebral area, throughout the needle tract, venous system, intervertebral foramen, or even epidural space (spinal canal) 

Complications

• “needle cast” or “cement tail” : due to the solidified cement in the trocar. 
• To avoid the complication, after injecting a proper quantity of the cement with a syringe, the inner cavity of the needle should be blocked with a stylus. 
• If the cement has solidified before the stylus is inserted, the J-type needle should be moved up-down and left-right to break the needle cast and eliminate it with the needle.  

Complications

• osteolytic tumoral fractures, due to increased possibility of posterior vertebral body fracture, augmentation may be associated with an increased rate of leakage and less predictable pain relief
• Central pulmonary cement embolism has also been reported

Complications

• Factors that have been cited to reduce the possibility of cement leakage during VP include: 
• Precise needling
• Sufficient cement visibility
• Low pressure cement injection
• Continuous fluoroscopic monitoring during cement injection

Complications

• Infection
• Rupture of the bone tamp

Kyphoplasty vs. Conservative Treatment

Vertebroplasty vs. Placebo

VERTEBROPLASTY VS. CONSERVATIVE  

KYPHOPLASTY VS. VERTEBROPLASTY  

Pain Relief

• According to a meta-analysis, the effect of pain reduction caused by VP or KP extended up to the 12th month after the operation [1]. 
• According to another meta-analysis, the pain and dysfunction caused by a OVF were reduced by approximately 90% after VP or KP [2]. 
• KP had a better pain reducing effect both in short-term and long-term VAS scores [2]. 
• The mechanism of the pain reducing effect of cement augmentationmight be related to improved micromotion of the fracturedvertebra or cytotoxic effect of PMMA cement  [3]

Ref

Richmond BJ. Vertebral augmentation for osteoporotic compression fractures. J Clin Densitom 2016;19:89e96 

Liang L, Chen X, Jiang W, Li X, Chen J, Wu L, et al. Balloon kyphoplasty orpercutaneous vertebroplasty for osteoporotic vertebral compression fracture? An updated systematic review and meta-analysis. Ann Saudi Med 2016;36: 165e74. 

Belkoff SM, Mathis JM, Jasper LE, Deramond H. The biomechanics of vertebroplasty. The effect of cement volume on mechanical behaviour. Spine (Phila Pa 1976) 2001;26:1537e41. 

Functional Improvement

Radiological results

• Theoretically, correction of sagittal alignment of the spine cancorrect the biomechanical behavior, reduce flexion of the spine andtension of the paraspinal muscles, maintain an upright posture andreduce the pain and risk of subsequent fracture. 
• Especially, the kyphotic angle is a key index that assesses postoperative results of a vertebral fracture. 
• One research has reported that KP can improve the kyphotic angle by 3.7° to 8° and VP can improve the kyphotic angle by 0.5 ° to 3° in a vertebral fracture [1]
• The reason behind why KP has a better kyphotic angle correction effectthan VP might be explained by the tamponade effect of the balloon,but the effect of posture in cement augmentation is also important. 

Ref

Kallmes DF, Comstock BA, Heagerty PJ, Turner JA, Wilson DJ, Diamond TH,et al. A randomized trial of vertebroplasty for osteoporotic spinal fractures. N Engl J Med 2009;361:569e79. 

Mortality Reduction

• In a Medicare research, the patients who underwent VP had a 10% survival benefit compared with those who received conservative treatment, the patients who underwent KP had a 23% less relative mortality risk than those who underwent VP [1]
• In another Medicare research, the 3-year survival rates in patients who underwent VP and KP were higher than those in patients who received conservative treatment, especially the 3-year survival rate in patients who underwent KP was 20% higher than that in those who underwent VP [2]
• Both are retrospective, no prospective studies

Ref

Edidin AA, Ong KL, Lau E, Kurtz SM. Mortality risk for operated and nonoperated vertebral fracture patients in the medicare population. J Bone Min Res 2011;26:1617e26. 

Papanastassiou ID, Filis A, Gerochristou MA, Vrionis FD. Controversial issues in kyphoplasty and vertebroplasty in osteoporotic vertebral fractures. Biomed Res Int 2014;2014:934206.  

10/11/2019 09:28:00 PM