Update: Intentional traumatic brain injury

Intentional traumatic brain injury


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).


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).


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.

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.

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


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).



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.

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.

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.

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.

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.

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.

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.

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).


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.

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.

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.

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.

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.

Update: Pupil Reactivity Score

Pupil Reactivity Score

The GCS Pupils Score (GCS-P) was described by Paul Brennan, Gordon Murray and Graham Teasdale in 2018 as a strategy to combine the two key indicators of the severity of traumatic brain injury into a single simple index.

How do I calculate the GCS-P?

The GCS-P is calculated by subtracting the Pupil Reactivity Score (PRS) from the Glasgow Coma Scale (GCS) total score:


The Pupil Reactivity Score is calculated as follows.

see more at http://www.glasgowcomascale.org/what-is-gcs-p/

Information about early GCS scores, pupil responses, late outcomes on the Glasgow Outcome Scale, and mortality were obtained at the individual patient level by reviewing data from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9,045) study and the IMPACT(International Mission for Prognosis and Clinical Trials in TBI; n = 6855) database. These data were combined into a pooled data set for the main analysis.

Methods of combining the Glasgow Coma Scale and pupil reaction data varied in complexity from using a simple arithmetic score (GCS score [range 3-15] minus the number of nonreacting pupils [0, 1, or 2]), which Brennan et al., called the GCS Pupils score (GCS-P; range 1-15), to treating each factor as a separate categorical variable. The content of information about patient outcome in each of these models was evaluated using Nagelkerke R2.

Separately, the GCS score and pupil response were each related to outcome. Adding information about the pupil response to the GCS score increased the information yield. The performance of the simple GCS-P was similar to the performance of more complex methods of evaluating traumatic brain damage. The relationship between decreases in the GCS-P and deteriorating outcome was seen across the complete range of possible scores. The additional 2 lowest points offered by the GCS-Pupils scale (GCS-P 1 and 2) extended the information about injury severity from a mortality rate of 51% and an unfavorable outcome rate of 70% at GCS score 3 to a mortality rate of 74% and an unfavorable outcome rate of 90% at GCS-P 1. The paradoxical finding that GCS score 4 was associated with a worse outcome than GCS score 3 was not seen when using the GCS-P.

A simple arithmetic combination of the GCS score and pupillary response, the GCS-P, extends the information provided about patient outcome to an extent comparable to that obtained using more complex methods. The greater range of injury severities that are identified and the smoothness of the stepwise pattern of outcomes across the range of scores may be useful in evaluating individual patients and identifying patient subgroups. The GCS-P may be a useful platform onto which information about other key prognostic features can be added in a simple format likely to be useful in clinical practice 1).


Brennan PM, Murray GD, Teasdale GM. Simplifying the use of prognostic information in traumatic brain injury. Part 1: The GCS-Pupils score: an extended index of clinical severity. J Neurosurg. 2018 Jun;128(6):1612-1620. doi: 10.3171/2017.12.JNS172780. Epub 2018 Apr 10. PubMed PMID: 29631516.

Update: Overshunting associated myelopathy

Overshunting associated myelopathy” is a rare complication of CSF diversion that should be familiar to physicians who routinely evaluate patients with intracranial shunts 1) 2).

Only 12 previous cases have been reported in the literature 3).

OSAM has to be considered according to the Monro-Kellie hypothesis and is affected by an engorgement of the cervical epidural venous plexus, which can produce cervical myelopathy. Since it can be treated simply by increasing the shunt resistance, surgeons should be aware of the rarely detected overdrainage complication 4).

Classically, patients present with positional headache, but less common symptoms include neck pain and cranial nerve palsies.

A 45-year-old-patient with shunt-dependent, congenital hydrocephalus presented with an 8-year history of progressive tetraparesis and gait disorder in the Department of Neurosurgery, University of Tübingen, Germany. The patient was wheelchair-dependent. A new MRI scan of the head revealed slit ventricle syndrome and dural enhancement due to shunt overdrainage. An MRI and a CT-Phlebography of the cervical spine revealed engorgement of the epidural venous plexus with secondary compression of the spinal cord and myelomalacia. Surgery was performed during which we implanted a shunt valve. The patient recovered from surgery without any new deficits. The tetraparesis improved during the inpatient hospital stay. CT-Phlebography was performed 5 days after surgery and showed that the epidural venous plexus anterior to the cervical spinal cord had returned to nearly normal size. On follow-up examination 3 month after surgery, the patient´s strength had improved, and he was able to walk short distances with assistance and with ankle foot orthosis on the right side.

OSAM has to be considered according to the Monro-Kellie doctrine and is affected by an engorgement of the epidural cervical venous plexus, which can produce cervical myelopathy. Since it can be treated simply by increasing the shunt resistance, surgeons should be aware of the rarely detected overdrainage complication 5).

Ho et al., presented 2 cases of cervical myelopathy produced by engorged vertebral veins due to overshunting. Overshunting-associated myelopathy is a rare complication of CSF shunting. Coexisting cervical degenerative disc disease may further increase the difficulty of diagnosing the condition. Neurosurgeons and others who routinely evaluate patients with intracranial shunts should be familiar with this rare but possible diagnosis 6).

A 26-year-old woman with shunt-dependent, congenital hydrocephalus, presented with rapidly progressive cervical myelopathy following ventriculoperitoneal shunt revision. Imaging revealed engorgement of the cervical epidural venous plexus and mass effect on the cervical spinal cord. “Over-shunting associated myelopathy” is a rare complication of CSF diversion that should be familiar to physicians who routinely evaluate patients with intracranial shunts 7).

1) , 7)

Howard BM, Sribnick EA, Dhall SS. Over-shunting associated myelopathy. J Clin Neurosci. 2014 Dec;21(12):2242-4. doi: 10.1016/j.jocn.2014.05.014. Epub 2014 Jul 25. PubMed PMID: 25070631.

2) , 6)

Ho JM, Law HY, Yuen SC, Yam KY. Overshunting-associated myelopathy: report of 2 cases. Neurosurg Focus. 2016 Sep;41(3):E16. doi: 10.3171/2016.7.FOCUS16179. PubMed PMID: 27581312.

3) , 4) , 5)

Adib SD, Hauser TK, Engel DC, Tatagiba M, Skardelly M, Ramina K. Over-shunting associated myelopathy (OSAM) in a patient with bilateral jugular vein occlusion. World Neurosurg. 2018 Jun 1. pii: S1878-8750(18)31129-X. doi: 10.1016/j.wneu.2018.05.175. [Epub ahead of print] PubMed PMID: 29864573.

Update: Intramedullary spinal cord abscess

Intramedullary spinal cord abscess

Intramedullary spinal cord abscess due to congenital dermal sinus (CDS) is rare and often co-exists with an inclusion tumor such as dermoid/epidermoid cyst.

CDS are the commonest cause of intramedullary spinal cord abscess (IMSCA) 1).

Prasad et al. did a literature review to analyze all cases of pediatric IMSCA secondary to CDS by searching online databases starting from the oldest case reported.

Only 50 cases have been reported and were analyzed. Mean age was 22.6 months (range 1 month-15 years). Fever, acute flaccid lower limbweakness, and urinary disturbances were the most common presenting features. Dermal sinus was commonest in lumbosacral region. Inclusion cysts were observed in 50% of cases. Staphylococcus aureus was the most the common organism. Mean follow-up duration was 18.2 months (range 1 week-156 months). Majority of the cases underwent multilevel laminectomy with myelotomy and drainage of abscess. Outcome was good-to-excellent in around 60% cases with four deaths. Presence of fever and limb weakness was significantly associated with poor outcomes.

Intramedullary abscess secondary to CDS is very rare. Complete sinus tract excision, myelotomy and drainage of abscess, and decompression of co-existent inclusion cysts with prolonged antibiotic therapy remain the standard treatment. Approximately 60% cases achieve good outcomes. Fever and limb weakness portend poorer outcomes than those without 2).


Kanaheswari Y, Lai C, Raja Lope RJ, Azizi AB, Zulfiqar MA. Intramedullary spinal cord abscess: The result of a missed congenital dermal sinus. J Paediatr Child Health. 2014 Aug 7. doi: 10.1111/jpc.12707. [Epub ahead of print] PubMed PMID: 25099316.


Prasad GL, Hegde A, Divya S. Spinal Intramedullary Abscess Secondary to Dermal Sinus in Children. Eur J Pediatr Surg. 2018 Jun 1. doi: 10.1055/s-0038-1655736. [Epub ahead of print] PubMed PMID: 29857348.

Update: Central nervous system high grade neuroepithelial tumor with BCOR alteration

Central nervous system high grade neuroepithelial tumor with BCOR alteration

Central nervous system high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR) is a rare entity, identified as a small fraction of tumors previously institutionally diagnosed as so-called CNS primitive neuroectodermal tumors. Their genetic characteristic is a somatic internal tandem duplication in the 3′ end of BCOR (BCOR ITD), which has also been found in clear cell sarcomas of the kidney (CCSK) and soft tissue undifferentiated round cell sarcomas/primitive myxoid mesenchymal tumors of infancy (URCS/PMMTI), and these BCOR ITD-positive tumors have been reported to share similar pathological features.

CNS HGNET-BCOR display pathological overlap with CNS-PNET and other histological entities 1).

The high expression of IGF-2 may be a common feature of HGNET-BCOR and ependymoma and may represent a target for new approaches. Several monoclonal antibodies and TKIs for IGF1R are being tested in preclinical and early phase clinical studies and may become relevant in the management of this new and aggressive tumor entity 2).

High expression of altered BCOR transcripts in CNS HGNET-BCOR tumors suggests a different mechanism from BCOR loss-of-function mutations reported in other malignancies, such as medulloblastoma 3) 4).

Yoshida et al., performed a clinicopathological and molecular analysis of six cases of CNS HGNET-BCOR, and compared them with their counterparts in the kidney and soft tissue. Although these tumors had histologically similar structural patterns and characteristic monotonous nuclei with fine chromatin, CNS HGNET-BCOR exhibited glial cell morphology, ependymoma-like perivascular pseudorosettes and palisading necrosis, whereas these features were not evident in CCSK or URCS/PMMTI. Immunohistochemically, diffuse staining of Olig2 with a mixture of varying degrees of intensity, and only focal staining of GFAP, S-100 protein and synaptophysin were observed in CNS HGNET-BCOR, whereas these common neuroepithelial markers were negative in CCSK and URCS/PMMTI. Therefore, although CNS HGNET-BCOR, CCSK and URCS/PMMTI may constitute a group of BCOR ITD-positive tumors, only CNS HGNET-BCOR has histological features suggestive of glial differentiation. In conclusion, we think CNS HGNET-BCOR are a certain type of neuroepithelial tumor relatively close to glioma, not CCSK or URCS/PMMTI occurring in the CNS 5).

Kirkman et al., describe a pediatric male patient with CNS HGNET-BCOR who developed seeding of the tumor into the site of the surgical wound within months of surgery for resection of a residual posterior fossa tumor.

This case emphasises three important points. First, CNS HGNET-BCOR can be aggressive tumors that necessitate close clinical and radiological surveillance. Second, surveillance imaging in such cases should incorporate the surgical incision site into the field of view, and this should be closely scrutinised to ensure the timely detection of wound site seeding. Third, wound site seeding may still occur despite the use of meticulous surgical techniques 6).

Appay et al., reported in 2017, 3 new CNS HGNET-BCOR cases sharing common clinical presentation and pathologic features. The 3 cases concerned children aged 3 to 7 years who presented with a voluminous mass of the cerebellum. Pathologic features included proliferation of uniform spindle to ovoid cells with fine chromatin associated with a rich arborizing capillary network. Methylation profiling classified these cases as CNS HGNET-BCOR tumors. Polymerase chain reaction analysis confirmed the presence of internal tandem duplications in the C-terminus of BCOR (BCOR-ITD), a characteristic of these tumors, in all 3 cases. Immunohistochemistry showed a strong nuclear BCOR expression. In 2 cases, local recurrence occurred within 6 months. The third case, a patient who received a craniospinal irradiation after total surgical removal followed by a metronomics maintenance with irinotecantemozolomide, and itraconazole, is still free of disease 14 months after diagnosis. In summary, CNS HGNET-BCOR represents a rare tumor occurring in young patients with dismal prognosis. BCOR nuclear immunoreactivity is highly suggestive of a BCOR-ITD. Whether CNS HGNET-BCOR should be classified among the category of “embryonal tumors” or within the category of “mesenchymal, nonmeningothelial tumors” remains to be clarified. Because CNS HGNET-BCOR share pathologic features and characteristic BCOR-ITD with clear cell sarcoma of the kidney, these tumors may represent local variants of the same entity 7).


Sturm D, Orr BA, Toprak UH, Hovestadt V, Jones DTW, Capper D, Sill M, Buchhalter I, Northcott PA, Leis I, Ryzhova M, Koelsche C, Pfaff E, Allen SJ, Balasubramanian G, Worst BC, Pajtler KW, Brabetz S, Johann PD, Sahm F, Reimand J, Mackay A, Carvalho DM, Remke M, Phillips JJ, Perry A, Cowdrey C, Drissi R, Fouladi M, Giangaspero F, Łastowska M, Grajkowska W, Scheurlen W, Pietsch T, Hagel C, Gojo J, Lötsch D, Berger W, Slavc I, Haberler C, Jouvet A, Holm S, Hofer S, Prinz M, Keohane C, Fried I, Mawrin C, Scheie D, Mobley BC, Schniederjan MJ, Santi M, Buccoliero AM, Dahiya S, Kramm CM, von Bueren AO, von Hoff K, Rutkowski S, Herold-Mende C, Frühwald MC, Milde T, Hasselblatt M, Wesseling P, Rößler J, Schüller U, Ebinger M, Schittenhelm J, Frank S, Grobholz R, Vajtai I, Hans V, Schneppenheim R, Zitterbart K, Collins VP, Aronica E, Varlet P, Puget S, Dufour C, Grill J, Figarella-Branger D, Wolter M, Schuhmann MU, Shalaby T, Grotzer M, van Meter T, Monoranu CM, Felsberg J, Reifenberger G, Snuderl M, Forrester LA, Koster J, Versteeg R, Volckmann R, van Sluis P, Wolf S, Mikkelsen T, Gajjar A, Aldape K, Moore AS, Taylor MD, Jones C, Jabado N, Karajannis MA, Eils R, Schlesner M, Lichter P, von Deimling A, Pfister SM, Ellison DW, Korshunov A, Kool M. New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs. Cell. 2016 Feb 25;164(5):1060-1072. doi: 10.1016/j.cell.2016.01.015. PubMed PMID: 26919435; PubMed Central PMCID: PMC5139621.

Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012 Aug 2;488(7409):100-5. doi: 10.1038/nature11284. PubMed PMID: 22832583; PubMed Central PMCID: PMC3662966.

Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, Carneiro MO, Carter SL, Cibulskis K, Erlich RL, Greulich H, Lawrence MS, Lennon NJ, McKenna A, Meldrim J, Ramos AH, Ross MG, Russ C, Shefler E, Sivachenko A, Sogoloff B, Stojanov P, Tamayo P, Mesirov JP, Amani V, Teider N, Sengupta S, Francois JP, Northcott PA, Taylor MD, Yu F, Crabtree GR, Kautzman AG, Gabriel SB, Getz G, Jäger N, Jones DT, Lichter P, Pfister SM, Roberts TM, Meyerson M, Pomeroy SL, Cho YJ. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012 Aug 2;488(7409):106-10. doi: 10.1038/nature11329. PubMed PMID: 22820256; PubMed Central PMCID: PMC3413789.

Yoshida Y, Nobusawa S, Nakata S, Nakada M, Arakawa Y, Mineharu Y, Sugita Y, Yoshioka T, Araki A, Sato Y, Takeshima H, Okada M, Nishi A, Yamazaki T, Kohashi K, Oda Y, Hirato J, Yokoo H. CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue. Brain Pathol. 2017 Dec 11. doi: 10.1111/bpa.12585. [Epub ahead of print] PubMed PMID: 29226988.

Kirkman MA, Pickles JC, Fairchild AR, Avery A, Pietsch T, Jacques TS, Aquilina K. Early wound site seeding in a patient with CNS high-grade neuroepithelial tumor with BCOR alteration: A case report. World Neurosurg. 2018 May 30. pii: S1878-8750(18)31112-4. doi: 10.1016/j.wneu.2018.05.158. [Epub ahead of print] PubMed PMID: 29859355.

Appay R, Macagno N, Padovani L, Korshunov A, Kool M, André N, Scavarda D, Pietsch T, Figarella-Branger D. HGNET-BCOR Tumors of the Cerebellum: Clinicopathologic and Molecular Characterization of 3 Cases. Am J Surg Pathol. 2017 Sep;41(9):1254-1260. doi: 10.1097/PAS.0000000000000866. PubMed PMID: 28704208.

Update: Antiplatelet reversal

Antiplatelet reversal

Antiplatelet therapy is common and complicates the operative management of acute intracranial hemorrhage. Little data exist to guide antiplatelet reversal strategies.

The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes.

Data assessing the relationship between outcome and prehospital antiplatelet agents in the setting of ICH is conflicting in both the trauma and the stroke literature. Only one retrospective review specifically addressed outcomes after attempted reversal with platelet transfusion. Further study is needed to determine whether platelet transfusion ameliorates hematoma enlargement and/or improves outcome in the setting of acute ICH 1).

Raimondi et al., recommend discontinuation of the antiplatelet, as well as administration of platelet transfusions and desmopressin only in the setting of life-threatening bleeding 2).

An online survey detailing antiplatelet reversal strategies in patients presenting with acute operative intracranial hemorrhage (subdural hematoma(SDH), epidural hematoma (EDH), and intracerebral hemorrhage (ICH) was distributed to board certified neurosurgeons in the North America.

Of the 2,782 functional email addresses, there were 493 (17.7%) responses to question #1 and 429 (15.4%) completed surveys. Most respondents chose to perform no additional laboratory testing prior to surgical intervention, regardless of hemorrhage type. The most common antiplatelet reversal strategy in the presence of aspirin was platelet transfusion (SDH and ICH) or no intervention (EDH). The most common antiplatelet reversal strategy in the presence of an Adenosine diphosphate receptor inhibitor or DAPT was platelet transfusion or platelet transfusion with DDAVP administration. There was a statistically significant difference in management strategy depending on the antiplatelet therapy (p < 0.001).

When patients on antiplatelet medication present with operative intracranial hemorrhage, the majority of neurosurgeons do not perform qualitative platelet function testing. Antiplatelet reversal strategies are significantly influenced by the antiplatelet therapy with more aggressive reversal strategies employed in the presence of ADP antagonist3).



Campbell PG, Sen A, Yadla S, Jabbour P, Jallo J. Emergency reversal of antiplatelet agents in patients presenting with an intracranial hemorrhage: a clinical review. World Neurosurg. 2010 Aug-Sep;74(2-3):279-85. doi: 10.1016/j.wneu.2010.05.030. Review. PubMed PMID: 21492561.

Raimondi P, Hylek EM, Aronis KN. Reversal Agents for Oral Antiplatelet and Anticoagulant Treatment During Bleeding Events: Current Strategies. Curr Pharm Des. 2017;23(9):1406-1423. doi: 10.2174/1381612822666161205110843. Review. PubMed PMID: 27917717.

Foreman PM, Ilyas A, Mooney J, Schmalz PGR, Walters BC, Griessenauer CJ. Antiplatelet Medication Reversal Strategies in Operative Intracranial Hemorrhage: A Survey of Practicing Neurosurgeons. World Neurosurg. 2018 May 18. pii: S1878-8750(18)31017-9. doi: 10.1016/j.wneu.2018.05.064. [Epub ahead of print] PubMed PMID: 29783009.

Update: Selenium and glioma

Selenium and glioma

Reliable supply of selenium is important since selenium compounds can affect tumor microenvironment and neoangiogenesis in malignant gliomas via induction of apoptosis and alteration of matrix metalloproteinases expression.

In 1990 Philipov and Tzatchev added selenium tablets to the diet of 15 patients with malignant brain tumors. In twelve patients with glioblastoma multiforme this treatment didn’t prolong the postoperative survival 1).

Yakubov et al. summarized findings focusing on the anti-toxicity and cancer-preventive properties of selenium and their implication in current multimodal therapies including temozolomide (Temodal), cyclophosphamide (Endoxan), and cisplatin (DDP, Platiblastin, and Platinol).

They sheded light on unintended side effects in chemotherapy and the developments of novel combinatorial chemotherapeutics with selenium compounds. They found that selenium and selenium compounds have dual action profiles with direct anti-cancer and chemotherapy-intensifier effects as well as neuroprotective and cytoprotective agents 2).

Thioredoxin reductase (TrxR) as a selenium (Se)-containing antioxidase plays key role in regulating intracellular redox status. Selenocystine (SeC) a natural available Se-containing amino acid showed novel anticancer potential through triggering oxidative damage-mediated apoptosis. However, whether TrxR-mediated oxidative damage was involved in SeC-induced apoptosis in human glioma cells has not been elucidated yet. Herein, SeC-induced human glioma cell apoptosis was detected in vitro, accompanied by PARP cleavage, caspases activation and DNA fragmentation. Mechanically, SeC caused mitochondrial dysfunction and imbalance of Bcl-2 family expression. SeC treatment also triggered ROS-mediated DNA damage and disturbed the MAPKs and AKT pathways. However, inhibition of ROS overproduction effectively attenuated SeC-induced oxidative damage and apoptosis, and normalized the expression of MAPKs and AKT pathways, indicating the significance of ROS in SeC-induced apoptosis. Importantly, U251 human glioma xenograft growth in nude mice was significantly inhibited in vivo. Further investigation revealed that SeC-induced oxidative damage was achieved by TrxR1-targeted inhibition in vitro and in vivo.

The findings validated the potential of SeC to inhibit human glioma growth by oxidative damage-mediated apoptosis through triggering TrxR1-targeted inhibition 3).

In a case-control study of glioma, Peeri et al., examined the associations of selenium in toenails and genetic variants in the selenoenzyme pathwaywith the risk of glioma and patient survival. A total of 423 genetic variants in 29 candidate genes in the selenoenzyme pathway were studied in 1547 glioma cases and 1014 healthy controls. Genetic associations were also examined in the UK Biobank cohort comprised of 313,868 persons with 322 incident glioma cases. Toenail selenium was measured in a subcohort of 300 glioma cases and 300 age-matched controls from the case-control study.

None of the 423 variants studied were consistently associated with glioma risk in the case-control and cohort studies. Moreover, toenail selenium in the case-control study had no significant association with glioma risk (p trend = 0.70) or patient survival among 254 patients with high grade tumors (p trend = 0.70).

The present study offers no support for the hypothesis that selenium plays a role in the onset of glioma or patient outcome 4).



Philipov P, Tzatchev K. Selenium in the treatment of patients with brain gliomas. A pilot study. Zentralbl Neurochir. 1990;51(3):145-6. PubMed PMID: 1965466.


Yakubov E, Buchfelder M, Eyüpoglu IY, Savaskan NE. Selenium action in neuro-oncology. Biol Trace Elem Res. 2014 Dec;161(3):246-54. doi: 10.1007/s12011-014-0111-8. Epub 2014 Aug 28. Review. PubMed PMID: 25164034.


Fan CD, Fu XY, Zhang ZY, Cao MZ, Sun JY, Yang MF, Fu XT, Zhao SJ, Shao LR, Zhang HF, Yang XY, Sun BL. Selenocysteine induces apoptosis in human glioma cells: evidence for TrxR1-targeted inhibition and signaling crosstalk. Sci Rep. 2017 Jul 25;7(1):6465. doi: 10.1038/s41598-017-06979-2. PubMed PMID: 28743999; PubMed Central PMCID: PMC5526989.


Peeri NC, Creed JH, Anic GM, Thompson RC, Olson JJ, LaRocca RV, Chowdhary SA, Brockman JD, Gerke TA, Nabors LB, Egan KM. Toenail selenium, genetic variation in selenoenzymes and risk and outcome in glioma. Cancer Epidemiol. 2018 May 16;55:45-51. doi: 10.1016/j.canep.2018.05.002. [Epub ahead of print] PubMed PMID: 29777993.

Update: Translaminar approach

Translaminar approach

In 1998, Di Lorenzo et al. proposed a less invasive direct procedure by utilizing a translaminar approach (TLA) through a fenestration of the pars interarticularis, thus circumventing facetectomy or hemilaminectomy in many cases. The increasing availability of high-definition imaging modalities (MRI, CT) has contributed to the growing popularity of the TLA, since identifying the exact location and extent of the spinal lesion is crucial for surgical planning to limit unnecessary biomechanical damage and prevent intraoperative conversion to conventional approaches.

Several studies have demonstrated the feasibility, safety and efficacy of this technique to successfully treat disc herniations affecting the foraminal and preforaminal regions 1).

The translaminar approach is the only “tissue-sparing” technique viable in cases of cranially migrated lumbar disc herniation encroaching on the exiting nerve root in the preforaminal zones, for the levels above L2-L3, and in the preforaminal and foraminal zones, for the levels below L3-L4 (L5-S1 included, if a total microdiscectomy is unnecessary). This approach is more effective than the standard one, because it resolves the symptoms; it is associated with less postoperative pain and faster recovery times without the risk of iatrogenic instability, and it can also be used in cases with previous signs of radiographic instability. The possibility to spare the flavum ligament is one of the main advantages of this technique. For these reasons, the translaminar approach is a valid technique in terms of safety and efficacy. Vanni et al., extensively analyzed and highlighted the tips and tricks 2).

Case series


A consecutive series of 32 patients were divided, pre- and post-operatively, into 5 classes based on Oswestry Disability Index (ODI). Class 1: ODI 0-20% (minimal disability); class 2: 20-40 % (moderate disability); calss 3: 40-60% (severe disability); 60-80% (crippled); 80-100% (bed bound or exaggerating symptoms).

In terms of ODI, 4 (12.5%) patients upgraded of 1 class after the operation; 6 (18.7%) patients of 2 classes, 8 (25%) patients of 3 classes, 11 (34.4%) patients of 4 classes. Three (9.4%) patients did not modify their ODI score after the operation. After surgery, 7(21.9%) patients developed a mild low back pain. Mean follow-up was 25 months.

When performed by dedicated spinal neurosurgeons, the translaminar approach confirmed to be safe and effective in long-term follow-up. Moreover, the majority of patients showed an improvement of their ODI. Major pitfalls were related with surgical selection and the narrow working space 3).


Between May 2000 and July 2004, 104 patients (59 men)-presenting with upper lumbar root compression in 74% of the cases -underwent a translaminar approach. The mean age was 57 years (range, 27-80 yr). The lamina was approached either through the conventional subperiosteal route or via a muscle splitting access. Mostly intraforaminal disc fragments were removed through a translaminar hole 10 mm in diameter, and the disc space was cleared in cases of evident perforation of the annulus. Follow-up examinations were performed by an independent observer at 1 and 6 weeks; 3, 6, and 12 months; and once yearly thereafter (mean follow-up period, 32 mo).

Extruded (61%) or subligamentous (39%) disc fragments were found intra-operatively. Laminae L4 (44%) and L5 (26%) were mostly involved. In eight cases, the translaminar hole was enlarged to a conventional laminotomy. In 13 patients, the disc space was cleared. The outcomes according to the Macnab criteria were excellent (67%), good (27%), fair (5%), and poor (1%). The incidence of recurrent disc herniations was 7%. Functional radiography performed in the first 20 patients 6 months after surgery and an additional 12 patients complaining of postsurgical back pain excluded any instability.

The translaminar approach is recommended in disc herniations encroaching the exiting root, as an alternative to the conventional interlaminar route4).


Fifteen patients with far cranio-laterally extruded disc herniations underwent neurosurgical intervention using a translaminar approach. The paraspinal muscles were spread with a dilatator after performing a 1.5 cm skin incision. A 16 mm METRx tubular retractor system (Medtronic Sofamor Danek, Memphis, TN) was directly placed on the upper lamina. The next steps were performed through this channel using the surgical microscope. A small ovoid fenestration (10×5 mm) was performed using a high speed drill and the disc prolapse was removed in a standard manner. Follow-ups were routinely carried out 3 weeks postoperatively and reassessment was subsequently carried out by telephone inquiry 10 to 44 months (median 23 months) after treatment. These results were rated according to the modified MacNab criteria.

Five of the fifteen affected discs were at the level L3/4, eight at L4/5 and two at L5/S1. The average surgical time was 55 minutes. No complications occurred. In all patients sciatic pain disappeared immediately after the operation. One patient underwent fusion of the affected level one year later because of progression of a pre-existent pseudospondylolisthesis. Long-term follow-up demonstrated excellent results in six, good results in seven, a fair result in one and a poor result in one patient according to the modified MacNab criteria.

The translaminar approach in conjunction with a tubular retractor system seems to be an effective and safe alternative technique for treating the small entity of far cranio- laterally or foraminally extruded lumbar disc herniations. It combines the advantages of a blunt muscle-spreading approach that produces little damage to the soft tissues, and the avoidance of large bone removal that may jeopardize vertebral stability. Since this approach does not permit sufficient exploration of the intervertebral disc space of origin, it should be limited to patients without significant bulging of the disc itself 5).

Twenty-four patients with preforaminal and foraminal disc herniation underwent surgical treatment via a translaminar microsurgical approach. Excellent results were obtained in all patients in terms of pain relief, and all had improvement in motor strength except for 1 patient. No spinal instability was seen at the latest follow-up.

A classic interlaminar interspace approach combined with a very limited translaminar fenestration seem to be an acceptable surgical method for accessing a preforaminal disc herniation, and this technique has proven to be safe and did not cause any instability at the latest follow-up 6).


30 patients using the translaminar fenestration were analysed by a postoperative follow-up of 6 weeks and one year. The mean-age was 57.2 years. For resection of the disc herniation, a small round or oval fenestration (6-8 mm) in the hemilamina, craniomedially to the facet joint, was performed. No patient received a partial or total facetectomy.

RESULTS: The majority of affected discs were at the L4-L5 level (53%). An extruded fragment was found in 28 patients (93%). In 5 patients bleeding from epidural veins complicated the intra-operative course. In 50% the nerve root was visually exposed. 15 patients (50%) had an intervertebral discectomy additional to the fragment excision. One patient was re-operated on after 10 days because of persisting radicular pain by using the same translaminar approach. 28 patients showed complete or nearly complete relief of radicular pain. Using this approach we have seen no major complication or clinical instability during a follow-up of at least one year.

CONCLUSIONS: The translaminar approach is an effective and minimally invasive technique in both canalicular and cranio-dorsolateral disc herniations. It gives an additional possibility to avoid partial removal of the facet joints, can be performed in all lumbar segments and preserves structures important for segmental spinal stability. The approach allows access to the extruded disc fragment and intervertebral disc space comparable to classical approaches and is a frequently used operative technique in our department 7).


Di Lorenzo N, Porta F, Onnis G, Cannas A, Arbau G, Maleci A. Pars interarticularis fenestration in the treatment of foraminal lumbar disc herniation: a further surgical approach. Neurosurgery. 1998 Jan;42(1):87-9; discussion 89-90. PubMed PMID: 9442508.


Vanni D, Galzio R, Kazakova A, Guelfi M, Pantalone A, Salini V, Magliani V. Technical note: microdiscectomy and translaminar approach. J Spine Surg. 2015 Dec;1(1):44-9. doi: 10.3978/j.issn.2414-469X.2015.10.03. Review. PubMed PMID: 27683678; PubMed Central PMCID: PMC5039873.


Cossandi C, Fanti A, Gerosa A, Bianco A, Fornaro R, Crobeddu E, Forgnone S, Panzarasa G, Di Cristofori A. Translaminar approach for treatment of hidden zone foraminal lumbar disc herniations: considerations on the surgical technique and pre-operative selection of patients with a long term follow-up. World Neurosurg. 2018 May 18. pii: S1878-8750(18)31025-8. doi: 10.1016/j.wneu.2018.05.072. [Epub ahead of print] PubMed PMID: 29783010.


Papavero L, Langer N, Fritzsche E, Emami P, Westphal M, Kothe R. The translaminar approach to lumbar disc herniations impinging the exiting root. Neurosurgery. 2008 Mar;62(3 Suppl 1):173-7; discussion 177-8. doi: 10.1227/01.neu.0000317389.83808.16. PubMed PMID: 18424983.


Vogelsang JP. The translaminar approach in combination with a tubular retractor system for the treatment of far cranio-laterally and foraminally extruded lumbar disc herniations. Zentralbl Neurochir. 2007 Feb;68(1):24-8. PubMed PMID: 17487805.


Bernucci C, Giovanelli M. Translaminar microsurgical approach for lumbar herniated nucleus pulposus (HNP) in the “hidden zone”: clinical and radiologic results in a series of 24 patients. Spine (Phila Pa 1976). 2007 Jan 15;32(2):281-4. PubMed PMID: 17224827.


Soldner F, Hoelper BM, Wallenfang T, Behr R. The translaminar approach to canalicular and cranio-dorsolateral lumbar disc herniations. Acta Neurochir (Wien). 2002 Apr;144(4):315-20. PubMed PMID: 12021876.
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