Update: Intentional traumatic brain injury

Intentional traumatic brain injury

Epidemiology

Intentional injury has been associated with certain demographics and socioeconomic groups. Less is known about the relationship of intentional traumatic brain injury (TBI) to injury severity, mortality, and demographic and socioeconomic profile.


A planned secondary analysis of a prospective multicentre cohort study was conducted in 10 emergency departments EDs in Australia and New Zealand, including children aged <18 years with head injury (HI). Epidemiology codes were used to prospectively code the injuries. Demographic and clinical information including the rate of clinically important traumatic brain injury (ciTBI: HI leading to death, neurosurgery, intubation >1 day or admission ≥2 days with abnormal computed tomography [CT]) was descriptively analysed.

Intentional injuries were identified in 372 of 20 137 (1.8%) head-injured children. Injuries were caused by caregivers (103, 27.7%), by peers (97, 26.1%), by siblings (47, 12.6%), by strangers (35, 9.4%), by persons with unknown relation to the patient (21, 5.6%), other intentional injuries (8, 2.2%) or undetermined intent (61, 16.4%). About 75.7% of victims of assault by caregivers were <2 years, whereas in other categories, only 4.9% were <2 years. Overall, 66.9% of victims were male. Rates of CT performance and abnormal CT varied: assault by caregivers 68.9%/47.6%, by peers 18.6%/27.8%, by strangers 37.1%/5.7%. ciTBI rate was 22.3% in assault by caregivers, 3.1% when caused by peers and 0.0% with other perpetrators.

Intentional HI is infrequent in children. The most frequently identified perpetrators are caregivers and peers. Caregiver injuries are particularly severe 1).


A study identified 1,409 (8.0%) intentional TBIs and 16,211 (92.0%) unintentional TBIs. Of the intentional TBIs, 389 (27.6%) was self-inflicted TBI (Si-TBI) and 1,020 (72.4%) was other-inflicted TBI (Oi-TBI). The most common cause of Si-TBI was “jumping from high places” (32.1%), followed by “firearms” (30.6%). About half of Oi-TBI was because of “fight and brawl” (48.3%), followed by “struck by objects” (26.1%). Si-TBI was associated with younger age, female gender, and having more alcohol/drug abuse history. For Oi-TBI, younger age, male gender, having more alcohol/drug abuse history were independently associated.

This research provides the first comprehensive overview of intentional TBI based in Canada.

The comprehensive data set (CDS) of the Ontario trauma registry (OTR) provided the ability to identify who is at risk for intentional TBI. Prevention programs and more targeted rehabilitation services should be designed for this vulnerable population 2).

Outcome

Intentional injury is associated with significant morbidity and mortality.

Caregiver injuries are particularly severe in children 3).

Prospective data were obtained for 2,637 adults sustaining TBIs between January 1994 and September 1998. Descriptive, univariate, and multivariate analyses were conducted to determine the predictive value of intentional TBI on injury severity and mortality.

Gender, minority status, age, substance abuse, and residence in a zipcode with low average income were associated with intentional TBI. Multivariate analysis found minority status and substance abuse to be predictive of intentional injury after adjusting for other demographic variables studied. Intentional TBI was predictive of mortality and anatomic severity of injury to the head. Penetrating intentional TBI was predictive of injury severity with all injury severity markers studied.

Many demographic variables are risk factors for intentional TBI, and such injury is a risk factor for both injury severity and mortality. Future studies are needed to definitively link intentional TBI to disability and functional outcome 4).

References

1) , 3)

Babl FE, Pfeiffer H, Dalziel SR, Oakley E, Anderson V, Borland ML, Phillips N, Kochar A, Dalton S, Cheek JA, Gilhotra Y, Furyk J, Neutze J, Lyttle MD, Bressan S, Donath S, Hearps SJ, Crowe L; Paediatric Research in Emergency Departments International Collaborative (PREDICT). Paediatric intentional head injuries in the emergency department: A multicentre prospective cohort study. Emerg Med Australas. 2018 Nov 26. doi: 10.1111/1742-6723.13202. [Epub ahead of print] PubMed PMID: 30477046.
2)

Kim H, Colantonio A. Intentional traumatic brain injury in Ontario, Canada. J Trauma. 2008 Dec;65(6):1287-92. doi: 10.1097/TA.0b013e31817196f5. PubMed PMID: 19077615.
4)

Wagner AK, Sasser HC, Hammond FM, Wiercisiewski D, Alexander J. Intentional traumatic brain injury: epidemiology, risk factors, and associations with injury severity and mortality. J Trauma. 2000 Sep;49(3):404-10. Erratum in: J Trauma 2000 Nov;49(5):982. PubMed PMID: 11003315.

Update: Ochronosis

Ochronosis

Accumulation of homogentisic acid (HGA), and its metabolites in tissues causes ochronosis. The word ochronosis refers to the dark bluish-black discoloration of connective tissues including the sclera, cornea, auricular cartilage, heart valves, articular cartilage, tendons, and ligaments.

Alkaptonuria frequently occurs in association with lumbar disc disease. In patients with no other signs of alkaptonuria or ochronosis, early detection of the disease is important to treat involvement of other systems (e.g., cardiovascular and urinary) 1).

Neurogenic claudication resulting from focal ligamentum flavum hypertrophy in the lumbar spine due to ochronotic deposits has only been previously reported once in the literature. In a article, Yucetas and Ucler from Adiyaman present a 71-year-old male patient with alkaptonuria-associated degenerative L3-L4-L5 stenosis, diagnosed after lumbar decompressive laminectomy 2).


A rare case of ochronosis presenting with cervical compressive myelopathy 3).


A 45-year-old previously healthy female patient who was operated on for prolapsed lumbar disc herniation, and in whom the nucleus pulposus was discovered to be black intraoperatively. The alkaptonuria was diagnosed after histopathological examination of the black disc material. Elevated urinary concentration of homogentisic acid confirmed the diagnosis 4).


A 58-year-old woman with back pain. Radiographs and magnetic resonance imaging (MRI) revealed characteristic features of ochronotic spondyloarthropathy 5).


Kalevski et al. published a case of a 33-year old patient with alcaptonuria and lumbar disc herniation. After the surgical treatment the patient’s complaints were alleviated and almost no complaints were registered, during the next follow-up.

The most common symptoms seen in alkaptonuria are complaints of pain in large joints and back pain. They are usually associated with the main disease. This case demonstrates that even there is a small likelihood for a prolapsed lumbar disk, it should be sought in such patients as the surgical treatment is able to yields a positive results 6).


In 1994 Koh et al published a case of alkaptonuria with root canal stenosis 7).


Kaufmann et al. reported a patient with alkaptonuric ochronosis and multiple intracranial aneurysms presenting with subarachnoid hemorrhage. The ruptured aneurysm was surgically treated, with a satisfactory outcome. In view of the well-known association of other connective tissuedisorders with intracranial aneurysms, a potentially causal relationship is suggested between cerebral aneurysms and alkaptonuric ochronosis 8).

References

1)

Emel E, Karagöz F, Aydín IH, Hacísalihoğlu S, Seyithanoğlu MH. Alkaptonuria with lumbar disc herniation: a report of two cases. Spine (Phila Pa 1976). 2000 Aug 15;25(16):2141-4. PubMed PMID: 10954648.
2)

Yucetas SC, Ucler N. Black-Colored Ligamentum Flavum Due to Alkaptonuria. J Neurol Surg A Cent Eur Neurosurg. 2018 Nov 26. doi: 10.1055/s-0038-1675784. [Epub ahead of print] PubMed PMID: 30477028.
3)

Nelanuthala M, Kotta S, Talari S, Terapalli VK. A rare case of ochronosis presenting with cervical compressive myelopathy. Neurol India. 2018 Jul-Aug;66(4):1178-1181. doi: 10.4103/0028-3886.236956. PubMed PMID: 30038118.
4)

Kahveci R, Ergüngör MF, Günaydin A, Temiz A. Alkaptonuric patient presenting with “black” disc: a case report. Acta Orthop Traumatol Turc. 2013;47(2):134-8. Review. PubMed PMID: 23619548.
5)

Al-Mahfoudh R, Clark S, Buxton N. Alkaptonuria presenting with ochronotic spondyloarthropathy. Br J Neurosurg. 2008 Dec;22(6):805-7. doi: 10.1080/02688690802226368. Review. PubMed PMID: 19085367.
6)

Kalevski SK, Haritonov DG, Peev NA. Alcaptonuria with lumbar disc prolapse: case study and review of the literature. Spine J. 2007 Jul-Aug;7(4):495-8. Epub 2006 Dec 29. Review. PubMed PMID: 17630148.
7)

Koh KB, Low EH, Ch’ng SL, Zakiah I. A case of alkaptonuria with root canal stenosis. Singapore Med J. 1994 Feb;35(1):106-7. PubMed PMID: 8009267.
8)

Kaufmann AM, Reddy KK, West M, Halliday WJ. Alkaptonuric ochronosis and multiple intracranial aneurysms. Surg Neurol. 1990 Mar;33(3):213-6. PubMed PMID: 2315833.

Update: Cerebral cavernous malformation pathogenesis

Cerebral cavernous malformation pathogenesis

Genes mutated in cerebral cavernous malformation (CCM) encode proteins that modulate junction formation between vascular endothelial cells.

Most cerebral cavernous malformations are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2(MGC4607), or CCM3 (PDCD10).

How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 1).

Although a role for these three genes in the formation of these intracranial vascular lesions has been established since the 1990s, additional works have further elucidated the molecular mechanisms by which mutations in these genes and the resultant aberrant proteins interact, leading to the formation of CCMs.

Therefore, it is reasonable to assume that a molecular pathway exists that requires all three proteins to function together correctly for proper cellular function. Moreover, research is demonstrating how each component protein is capable of interacting with numerous other signaling and cytoskeletal molecules allowing for a diverse range of functions in molecular signaling pathways via unique protein–protein interactions.

Significant research findings from 2000 to 2015 have further enhanced our understanding of the pathogenesis of CCM formation. The use of advanced sequencing technologies to characterize genomic mutations and the identification of new signaling pathways and protein–protein interactions have led to great strides in understanding the molecular genetics involved in the development of CCMs. However, many unanswered questions remain, and future studies are clearly needed to improve our understanding of CCM pathogenesis. “Gene to protein to disease” mechanisms involved in the pathogenesis of CCMs should shed further light on potential therapeutic targets. 2).

The Phosphoinositide 3 kinase (PI3K)/Akt pathway is known to play a major role in angiogenesis. Studies have shown that the phosphatase and tensin homologue deleted on chromosome ten (PTEN), a tumor suppressor, is an antagonist regulator of the PI3K/Akt pathway and mediates angiogenesis by activating vascular endothelial growth factor (VEGF) expression.

Understanding the biology of these proteins with respect to their signaling counterpart will help to guide future research towards new therapeutic targets applicable for CCM treatment 3).


Studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics 4).

CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified.


Tang et al. identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of cerebral cavernous malformationformation. Activation of TLR4 by Gram negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment 5).


In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need 6).

References

1) , 4)

Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30. Erratum in: Nature. 2016 May 25;536(7617):488. PubMed PMID: 27027284; PubMed Central PMCID: PMC4864035.
2)

Baranoski JF, Kalani MY, Przybylowski CJ, Zabramski JM. Cerebral Cavernous Malformations: Review of the Genetic and Protein-Protein Interactions Resulting in Disease Pathogenesis. Front Surg. 2016 Nov 14;3:60. Review. PubMed PMID: 27896269.
3)

Kar S, Samii A, Bertalanffy H. PTEN/PI3K/Akt/VEGF signaling and the cross talk to KRIT1, CCM2, and PDCD10 proteins in cerebral cavernous malformations. Neurosurg Rev. 2015 Apr;38(2):229-36; discussion 236-7. doi: 10.1007/s10143-014-0597-8. Epub 2014 Nov 19. PubMed PMID: 25403688.
5)

Tang AT, Choi JP, Kotzin JJ, Yang Y, Hong CC, Hobson N, Girard R, Zeineddine HA, Lightle R, Moore T, Cao Y, Shenkar R, Chen M, Mericko P, Yang J, Li L, Tanes C, Kobuley D, Võsa U, Whitehead KJ, Li DY, Franke L, Hart B, Schwaninger M, Henao-Mejia J, Morrison L, Kim H, Awad IA, Zheng X, Kahn ML. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature. 2017 May 10. doi: 10.1038/nature22075. [Epub ahead of print] PubMed PMID: 28489816.
6)

Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H, Pasqualini R, Arap W. Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review. JAMA Neurol. 2018 Nov 26. doi: 10.1001/jamaneurol.2018.3634. [Epub ahead of print] PubMed PMID: 30476961.
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