It belongs to the SMAD family of signaling molecules. It acts as an inhibitory SMAD, meaning that it negatively regulates signaling pathways activated by transforming growth factor-beta (TGF-beta) and bone morphogenetic proteins (BMPs). SMAD6 plays a role in various biological processes such as cell proliferation, differentiation, and apoptosis,
SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signaling pathway. Until now, SMAD6 deficiency has been associated with three distinctive human congenital conditions, i.e., congenital heart diseases, including left ventricular obstruction and conotruncal defects, craniosynostosis, and radioulnar synostosis. Intriguingly, a similar spectrum of heterozygous loss-of-function variants has been reported to cause these clinically distinct disorders without a genotype-phenotype correlation. Even identical nucleotide changes have been described in patients with either a cardiovascular phenotype, craniosynostosis or radioulnar synostosis. These findings suggest that the primary pathogenic variant alone cannot explain the resultant patient phenotype 1).
SMAD6 mutations led to poorer mathematics, performance intelligence quotient, full-scale intelligence quotient, and motor coordination, even after controlling for exogenous factors. Genetic testing may be critical for advocating early adjunctive neurodevelopmental therapy 2)
Mechanisms to explain the remarkable diversity of phenotypes associated with SMAD6 variants remain obscure 3).
Among 101 infants tested in the Department of Pediatric Neurosurgery, French Referral Center for Craniosynostosis, Hôpital Femme Mère-Enfant Hospices Civils de Lyon, University of Lyon, Department of Genetics, Lyon University Hospitals, INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, Department of Pediatric Cranio-Maxillo-Facial Surgery, Hôpital Femme Mère Enfant, Université Claude Bernard Lyon 1, Lyon, and Department of Genetics, Robert Debré Hospital, Inserm 1132, Université de Paris Cité, Paris, France, 13 carried a total of 13 variants; that is, 12.9% of the infants carried a variant in genes known to be involved in craniosynostosis. Seven infants carried SMAD6 variants, 2 in FGFR2, 1 in TWIST1, one in FREM1, one in ALX4, and one in TCF12. All variants were detected at the heterozygous level in genes associated with autosomal dominant craniosynostosis. Also, neurodevelopmental testing showed especially delayed acquisition of language in children with than without variants in SMAD6. In conclusion, a high percentage of young children with isolated midline craniosynostosis, especially in isolated trigonocephaly, carried SMAD6 variants. The interpretation of the pathogenicity of the genes must take into account incomplete penetrance, usually observed in craniosynostosis. The results highlight the interest in molecular analysis in the context of isolated sagittal and/or metopic craniosynostosis to enhance an understanding of the pathophysiology of midline craniosynostosis4).
Luyckx I, Verstraeten A, Goumans MJ, Loeys B. SMAD6-deficiency in human genetic disorders. NPJ Genom Med. 2022 Nov 21;7(1):68. doi: 10.1038/s41525-022-00338-5. PMID: 36414630; PMCID: PMC9681871.
Di Rocco F, Rossi M, Verlut I, Szathmari A, Beuriat PA, Chatron N, Chauvel-Picard J, Mottolese C, Monin P, Vinchon M, Guernouche S, Collet C. Clinical interest of molecular study in cases of isolated midline craniosynostosis. Eur J Hum Genet. 2023 Feb 3. doi: 10.1038/s41431-023-01295-y. Epub ahead of print. PMID: 36732661.
There are multiple strokeguidelines globally. To synthesize these and summarize what existing stroke guidelines recommend about the management of people with stroke, the World Stroke Organization (WSO) Guideline committee, under the auspices of the WSO, reviewed available guidelines. They identified areas of strong agreement across guidelines, and their global coverage.
To systematically review the literature to identify stroke guidelines (excluding primary stroke prevention and subarachnoid hemorrhage) since 1st January 2011, evaluate quality (AGREE II), tabulate strong recommendations, and judge applicability according to stroke care available (minimal, essential, advanced).
Searches identified 15400 titles, 911 texts were retrieved, 203 publications scrutinized by the three subgroups (acute, secondary prevention, rehabilitation), and recommendations extracted from most recent version of relevant guidelines. For acute treatment, there were more guidelines about ischemic stroke than intracerebral hemorrhage; recommendations addressed pre-hospital, emergency, and acute hospitalcare. Strong recommendations were made for reperfusion therapies for acute ischemic stroke. For secondary prevention, strong recommendations included establishing aetiological diagnosis, management of hypertension, weight, diabetes, lipids, lifestyle modification; and for ischemic stroke: management of atrial fibrillation, valvular heart disease, left ventricular and atrial thrombi, patent foramen ovale, atherosclerotic extracranial large vessel disease, intracranial atherosclerotic disease, antithrombotics in non-cardioembolic stroke. For rehabilitation there were strong recommendations for organized stroke unit care, multidisciplinary rehabilitation, task specific training, fitness training, and specific interventions for post-stroke impairments.Most recommendations were from high income countries, and most did not consider comorbidity, resource implications and implementation. Patient and public involvement was limited.
The review identified a number of areas of stroke care in there was strong consensus. However there was extensive repetition and redundancy in guideline recommendations. Future guidelines groups should consider closer collaboration to improve efficiency, include more people with lived experience in the development process, consider comorbidity, and advise on implementation 1).
American Heart Association Guidelines for the Early Management of Patients With Acute Ischemic Stroke
2. features that correlate with favorable response to shunt. These features suggest that the hydrocephalus is not due to atrophy alone. Note: atrophy / hydrocephalus ex vacuo, as in conditions such as Alzheimer’s disease, lessens the chance of, but does not preclude responding to a shunt (cortical atrophy is a common finding in healthy individuals of advanced age1))
a) periventricular low density on CT or high intensity on T2WI MRI: may represent Transependymal edema. May resolve with shunting
b) compression of convexity sulci (as distinct from dilatation in atrophy). Note:focal sulcal dilation may sometimes be seen and may represent atypical reservoirs of CSF, which may diminish after shunting and should not be considered as atrophy 2).
b) ventricular enlargement in iNPH deforms the corpus callosum,including:
● upward bowing and thinning (best appreciated on sagittal MRI)
● impingement on the falx, producing an acute callosal angle (≤ 90°, demonstrated on a coronal MRI perpedicular to the AC-PC line , passing through the posterior commissure (PC)
2. phase-contrast MRI may demonstrate hyperdynamic flow of CSF through the aqueduct Although some patients improve with no change in ventricles, clinical improvement most often accompanies reduction of ventricular size.
In the sagittal volumetric T2 sequence, there is no clear occupation of the cerebral aqueduct, also observing the passage of cerebrospinal fluid through the aqueduct. He also appreciates flow artifact on T2 in the 3rd ventricle. The 3rd ventricle presents a slight increase in caliber with the 4th ventricle of normal size, however, the increase in the 3rd ventricle is much less than the lateral ventricular dilatation. Signs of chronic small vessel ischemic zone distributed in both cerebral hemispheres. A small area of encephalomalacia and right occipital gliosis due to sequelae of an old ischemic infarction.
NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as periventricular hyperintensity (PVH). Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis4).
An MRI-based diagnostic scheme used in a multicenter prospective study (Study of Idiopathic Normal Pressure Hydrocephalus on Neurological Improvement [SINPHONI]) appears to suggest that features of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) are meaningful in the evaluation of NPH 5).
Schwartz M, Creasey H, Grady CL, et al. Computed Tomographic Analysis of Brain Morphometrics in 30 Healthy Men, Aged 21 to 81 Years. Ann Neurol. 1985; 17:146–157
Holodny AI, George AE, de Leon MJ, et al. Focal Dilation and Paradoxical Collapse of Cortical Fissures and Sulci in Patients with Normal-Pressure Hydrocephalus. J Neurosurg. 1998; 89: 742–747
Mori E, Ishikawa M, Kato T, et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir (Tokyo). 2012; 52:775–809
Tullberg M, Blennow K, Månsson JE, Fredman P, Tisell M, Wikkelsö C. Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus. Eur J Neurol. 2007 Mar;14(3):248-54. PubMed PMID: 17355543.
Hattori T, Ito K, Aoki S, Yuasa T, Sato R, Ishikawa M, et al: White matter alteration in idiopathic normal pressure hydrocephalus: tract-based spatial statistics study. AJNR Am J Neuroradiol 33:97–103, 2012
It is possible for a neurosurgical resident to be pregnant, as there are no specific restrictions on pregnant individuals becoming or remaining neurosurgical residents. However, pregnant residents may need to make accommodations for their pregnancy, such as modifying their work schedule or duties, in order to ensure the safety of both the resident and the patient. It is important for the resident to discuss their pregnancy with their program director and to stay in close communication with their obstetrician throughout their pregnancy.
A Women in Neurosurgery survey evaluated female neurosurgeons’ perception and experience regarding childbearing of female neurosurgeons and identified several recommendations regarding family leave policies. Additionally, pregnancy may carry higher risk in surgical fields, yet little guidance exists to aid both the pregnant resident and her training program in optimizing the safety of the training environment with specific considerations to risks inherent in neurosurgical training. A review of current literature aims to address best practices that can be adopted by pregnant neurosurgery residents and their training programs to improve the well-being of these residents while considering the impact on their education and the educational environment for their colleagues 2)
Gupta M, Reichl A, Diaz-Aguilar LD, Duddleston PJ, Ullman JS, Muraszko KM, Timmons SD, Germano IM, Abosch A, Sweet JA, Pannullo SC, Benzil DL, Ben-Haim S. Pregnancy and parental leave among neurosurgeons and neurosurgical trainees. J Neurosurg. 2020 May 29;134(3):1325-1333. doi: 10.3171/2020.2.JNS193345. PMID: 32470929.
Tomei KL, Hodges TR, Ragsdale E, Katz T, Greenfield M, Sweet JA. Best practices for the pregnant neurosurgical resident: balancing safety and education. J Neurosurg. 2022 Nov 8:1-8. doi: 10.3171/2022.9.JNS221727. Epub ahead of print. PMID: 36683192.
Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS).
The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice.
This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low-grade gliomas, vestibular schwannomas, and metastatic brain tumors 2).
Despite the frequency of brain metastases, prospective trials in this patient population are limited, and the criteria used to assess response and progression in the CNS are heterogeneous 1).
This heterogeneity largely stems from the recognition that existing criteria sets, such as RECIST 2)3).
Genes involved
Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown.
Brastianos et al. detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases 4).
There is a lack of prospective randomized studies. Based on retrospective case series, international guidelines recommend the harvesting (if required, stereotactically guided) of tissue for histological and molecular diagnosis in cases of unknown or possibly competing for underlying systemic malignant diseases, in cases of suspected tumor recurrence, and with regard to the evaluation of targeted therapies taking into account molecular heterogeneity of primary and secondary tumors. Surgical resection is particularly valuable for the treatment of up to three space-occupying cerebral metastases, especially to achieve clinical stabilization to allow further non-surgical treatment For cystic metastasis, a combination of stereotactic puncture and radiotherapy may be useful. Meningeal carcinomatosis can be treated with intrathecal medication via an intraventricular catheter system. Ventriculoperitoneal shunts represent an effective treatment option for patients with tumor-associated hydrocephalus.
Neurosurgical procedures are of central importance in the multimodal treatment of cerebral metastases. The indications for neurosurgical interventions will be refined in the light of more effective radiation techniques and systemic treatments with new targeted therapeutic approaches and immunotherapies on the horizon 5).
Zhu et al. reported a medium-throughput drug screening platform (METPlatform) based on organotypic cultures that allow evaluating inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastases, they identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastases, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. The work validates METPlatform as a potent resource for metastases research integrating drugscreening and unbiased omics approaches that are compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere 6).
NU Lin, EQ Lee, H Aoyama, et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group Lancet Oncol, 14 (2013), pp. e396–e406
EA Eisenhauer, P Therasse, J Bogaerts, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer, 45 (2009), pp. 228–247
P Therasse, SG Arbuck, EA Eisenhauer, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada J Natl Cancer Inst, 92 (2000), pp. 205–216
Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT, Van Allen EM, Lawrence MS, Horowitz PM, Cibulskis K, Ligon KL, Tabernero J, Seoane J, Martinez-Saez E, Curry WT, Dunn IF, Paek SH, Park SH, McKenna A, Chevalier A, Rosenberg M, Barker FG 2nd, Gill CM, Van Hummelen P, Thorner AR, Johnson BE, Hoang MP, Choueiri TK, Signoretti S, Sougnez C, Rabin MS, Lin NU, Winer EP, Stemmer-Rachamimov A, Meyerson M, Garraway L, Gabriel S, Lander ES, Beroukhim R, Batchelor TT, Baselga J, Louis DN, Getz G, Hahn WC. Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov. 2015 Sep 26. [Epub ahead of print] PubMed PMID: 26410082.
Zhu L, Retana D, García-Gómez P, Álvaro-Espinosa L, Priego N, Masmudi-Martín M, Yebra N, Miarka L, Hernández-Encinas E, Blanco-Aparicio C, Martínez S, Sobrino C, Ajenjo N, Artiga MJ, Ortega-Paino E, Torres-Ruiz R, Rodríguez-Perales S; RENACER, Soffietti R, Bertero L, Cassoni P, Weiss T, Muñoz J, Sepúlveda JM, González-León P, Jiménez-Roldán L, Moreno LM, Esteban O, Pérez-Núñez Á, Hernández-Laín A, Toldos O, Ruano Y, Alcázar L, Blasco G, Fernández-Alén J, Caleiras E, Lafarga M, Megías D, Graña-Castro O, Nör C, Taylor MD, Young LS, Varešlija D, Cosgrove N, Couch FJ, Cussó L, Desco M, Mouron S, Quintela-Fandino M, Weller M, Pastor J, Valiente M. A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis. EMBO Mol Med. 2022 Feb 17:e14552. doi: 10.15252/emmm.202114552. Epub ahead of print. PMID: 35174975.
Cerebellar mutism (CM) was first described by Rekate et al. in 1985 following posterior fossa surgery in children 1) ;since then, it has increasingly been reported, mainly occurring as a postoperative complication.
It has also been reported in both children and adults following several other cerebellar insults, including vascular events, infections, and trauma 4).
The uncertain etiology of PFS, myriad of cited risk factors and therapeutic challenges make this phenomenon an elusive entity.
Cerebellar mutism is a rare occurrence following paediatric trauma 5)6)7)8). , this phenomenon has rarely been reported following other insults, such as trauma, and its pathophysiology remains poorly understood.
A seven-year-old child who presented to the casualty department of Sultan Qaboos University Hospital in Muscat, Oman, in May 2013 with a traumatic right cerebellar contusion. The child presented with clinical features of cerebellar mutism but underwent a rapid and spontaneous recovery 9).
The pathogenic mechanism is likely due to the damage occurring to the proximal efferent cerebellar pathway, including the dentate nucleus, the superior cerebellar peduncle, and its decussation in the mesencephalic tegmentum 10).
Superior and inferior cerebellar peduncles and the superior part of the cerebellum were related to CMS, especially the right side 11).
Clinical features
This syndrome involves a variety of signs and symptoms including cerebellar mutism or speech disturbances, dysphagia, decreased motor movement, cranial nerve palsy and, emotional lability. These signs and symptoms develop from an average range of 24 to 107 hours after surgery and may take weeks to months to resolve.
Diagnosis
Multi-inflow time arterial spin-labeling shows promise as a noninvasive tool to evaluate cerebral perfusion in the setting of pediatric obstructive hydrocephalus and demonstrates increased CBF following the resolution of cerebellar mutism syndrome 12).
Differential diagnosis
The importance of olivary hypertrophic degeneration as a differential diagnosis in cerebellar mutism syndrome 13).
Early recognition of this syndrome could facilitate preventive and restorative patient care, prevent subsequent complications, decrease length of hospital stays, and promote patient and family understanding of and coping with the syndrome 14).
Case series
20 cases of PFS (8%), 12 males and 8 females. Age ranged from 1.5 to 13 years (mean = 6.5). Of the 20, 16 were medulloblastoma, 3 ependymoma and 1 astrocytoma. There was a 21 % incidence (16/76) of PFS in medulloblastoma of the posterior fossa. The incidence for ependymoma was 13% (3/24) and 1% (1/102) for astrocytoma. All 20 cases (100%) had brainstem involvement by the tumor. The most frequent postoperative findings included mutism, ataxia, 6th and 7th nerve palsies and hemiparesis. Mutism had a latency range of 1-7 days (mean = 1.7) and a duration of 6-365 days (mean = 69.2, median = 35). Although mutism resolved in all cases, the remaining neurologic complications which characterized our findings of PFS were rarely reversible. We describe potential risk factors for developing PFS after surgery with hopes of making neurosurgeons more aware of potential problems following the removal of lesions in this area. Early recognition of PFS would further promote patient and family understanding and coping with this síndrome 15)
19 children diagnosed with posterior fossa syndrome 16)
Catsman-Berrevoets C E, Van Dongen HR, Mulder PG, et al. Tumour type and size are high risk factors for the syndrome of “cerebellar” mutism and subsequent dysarthria. J Neurol Neurosurg Psychiatry. 1999; 67:755–757
Gudrunardottir T, Sehested A, Juhler M, Schmiegelow K. Cerebellar mutism: Review of the literature. Childs Nerv Syst. 2011;27:355–63. doi: 10.1007/s00381-010-1328-2.
Erşahin Y, Mutluer S, Saydam S, Barçin E. Cerebellar mutism: Report of two unusual cases and review of the literature. Clin Neurol Neurosurg. 1997;99:130–4. doi: 10.1016/S0303-8467(97)80010-8.
Fujisawa H, Yonaha H, Okumoto K, Uehara H, le T, Nagata Y, et al. Mutism after evacuation of acute subdural hematoma of the posterior fossa. Childs Nerv Syst. 2005;21:234–6. doi: 10.1007/s00381-004-0999-y.
Yokota H, Nakazawa S, Kobayashi S, Taniguchi Y, Yukihide T. [Clinical study of two cases of traumatic cerebellar injury] No Shinkei Geka. 1990;18:67–70.
Kariyattil R, Rahim MI, Muthukuttiparambil U. Cerebellar mutism following closed head injury in a child. Sultan Qaboos Univ Med J. 2015 Feb;15(1):e133-5. Epub 2015 Jan 21. PubMed PMID: 25685374; PubMed Central PMCID: PMC4318595.
Fabozzi F, Margoni S, Andreozzi B, Musci MS, Del Baldo G, Boccuto L, Mastronuzzi A, Carai A. Cerebellar mutism syndrome: From pathophysiology to rehabilitation. Front Cell Dev Biol. 2022 Dec 2;10:1082947. doi: 10.3389/fcell.2022.1082947. PMID: 36531947; PMCID: PMC9755514.
Yang W, Li Y, Ying Z, Cai Y, Peng X, Sun H, Chen J, Zhu K, Hu G, Peng Y, Ge M. A presurgical voxel-wise predictive model for cerebellar mutism syndrome in children with posterior fossa tumors. Neuroimage Clin. 2022 Dec 13;37:103291. doi: 10.1016/j.nicl.2022.103291. Epub ahead of print. PMID: 36527996; PMCID: PMC9791171.
Ballestero M, de Oliveira RS. The importance of olivary hypertrophic degeneration as a differential diagnosis in cerebellar mutism syndrome. Childs Nerv Syst. 2022 Dec 21. doi: 10.1007/s00381-022-05815-x. Epub ahead of print. PMID: 36542117.
Kirk EA, Howard VC, Scott CA. Description of posterior fossa syndrome in children after posterior fossa brain tumor surgery. J Pediatr Oncol Nurs. 1995 Oct;12(4):181-7. PubMed PMID: 7495523.
Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
They are arbitrarily defined as those hematomas presenting 21 days or more after injury. These numbers are not absolute, and a more accurate classification of a subdural hematoma usually is based on imaging characteristics.
cSDHs have a tendency to persist and gradually increase in volume over time. The disease is thought to be related to a cycle of chronic inflammation and angiogenesis. An original hemorrhage forms and fibrinolysis ensues with the liquefaction of the initial clot. The subsequent blood breakdown products stimulate inflammation and thickening of the inner dural layer (ie, ‘dural border cells). This process incites angiogenesis with the ingrowth of immature capillaries, which chronically leak blood. These microhemorrhages result in the progressive enlargement of the collection with increased fibrinolytic activity, inflammation, and further angiogenesis, membrane formation, and vessel proliferation. The rate of accumulation of blood products outpaces physiological reabsorption and the collection gradually enlarges. Thus the entire basis for the pathology is the formation of leaky vascular membranes, which incite a positive feedback cycle of continued hemorrhage, inflammation, and angiogenesis 1)2)
Chronic subdural hematoma (CSDH) is characterized by an “old” encapsulated collection of blood and blood breakdown products between the brain and its outermost covering (the dura).
It is delimited by an outer and inner membrane. In between are blood, plasma, cerebrospinal fluid, membranes, and a mixture of inflammatory angiogenic fibrinolytic and coagulation factors. These factors maintain a self-perpetuating cycle of bleeding, lysis, and growing of neo-membranes and neo-capillaries 3).
The association between the biomarkers of inflammation and angiogenesis, and the clinical and radiological characteristics of CSDH patients, need further investigation. The high number of biomarkers compared to the number of observations, the correlation between biomarkers, missing data and skewed distributions may limit the usefulness of classical statistical methods.
Pripp et al. explored lasso regression to assess the association between 30 biomarkers of inflammation and angiogenesis at the site of lesions, and selected clinical and radiological characteristics in a cohort of 93 patients. Lasso regression performs both variable selection and regularization to improve the predictive accuracy and interpretability of the statistical model. The results from the lasso regression showed analysis exhibited lack of robust statistical association between the biomarkers in hematoma fluid with age, gender, brain infarct, neurological deficiencies and volume of hematoma. However, there were associations between several of the biomarkers with postoperative recurrence requiring reoperation. The statistical analysis with lasso regression supported previous findings that the immunological characteristics of CSDH are local. The relationship between biomarkers, the radiological appearance of lesions and recurrence requiring reoperation have been inclusive using classical statistical methods on these data, but lasso regression revealed an association with inflammatory and angiogenic biomarkers in hematoma fluid. They suggest that lasso regression should be a recommended statistical method in research on biological processes in CSDH patients 4).
Subdural effusion in the setting of dural metastases is very rare and may be difficult to be distinguished from chronic subdural hematoma. Such lesions could be missed and could be the cause of recurrence in CSDH. A contrast-enhanced brain CT scan is recommended to diagnose dural metastases.
Rosai–Dorfman disease may be mistaken for a CSDH on imaging. This disease is an uncommon, benign systemic histioproliferative disease characterized by massive lymphadenopathy, particularly in the head and neck region, and is often associated with extranodal involvement. CSDH can also develop in multifocal fibrosclerosis (MFS) which is a rare disorder of unknown etiology, characterized by chronic inflammation with dense fibrosis and lymphoplasmacytic infiltration into the connective tissue of various organs. The mechanism of the formation of CSDH is presumed to involve reactive granular membrane together with subdural collection. On the other hand, the extramedullary erythropoiesis within CSDH can be confused with metastatic malignant tumors, such as lymphoma, carcinoma, and malignant melanoma 5).
A 44-year old woman with gastric adenocarcinoma was presented with headache and a hypodense subdural collection in right fronto-parietal in brain CT. Burr-hole irrigation was performed with the impression of chronic subdural hematoma, but nonhemorrhagic xantochromic fluid was evacuated without malignant cell. Brain CT on the 11th day depicted fluid re-accumulation and noticeable midline shift, necessitating craniotomy and removing the affected dura.
Because the affected dura can be supposed as the main source of subdural effusion, resection of the involved dura is obligatory for the appropriate palliative management of such patients 6).
The progression of CSDH is an angiogenic process, involving inflammatory mediators that affect vascular permeability, microvascular leakage, and hematoma thickness.
A bibliometrics retrieved 1424 CSDH-related articles published since the beginning of the twenty-first century. There was a general increase in both the number of published articles and the mean number of citations. The authors, institutions, and journals that contributed the most to the field of CSDH were Jianning Zhang, Tianjin Medical University General Hospital, and world neurosurgery, respectively. The reference co-citation network identified 13 clusters with significant modularity Q scores and silhouette scores (Q = 0.7124, S = 0.8536). The major research categories were (1) the evolution of the therapeutic method and (2) the etiology and pathology of CSDH. Keyword analysis revealed that ‘middle meningeal artery embolization‘ was the latest burst keyword.
This study identified the most influential countries, authors, institutions, and journals contributing to CSDH research and discussed the hotspots and the latest subjects of CSDH research 7)
Attempts to create CSDH have been made in mice, rats, cats, dogs and monkeys. Methods include injection or surgical implantation of clotted blood or various other blood products and mixtures into the potential subdural space or the subcutaneous space. No intracranial model produced a progressively expanding CSDH. Transient hematoma expansion with liquification could be produced by subcutaneous injections in some models. Spontaneous subdural blood collections were found after creation of hydrocephalus in mice by systemic injection of the neurotoxin, 6-aminonicotinamide. The histology of the hematoma membranes in several models resembles the appearance in humans. None of the models has been replicated since its first description.
D’Abbondanza et al. did not find a report of a reproducible, well-described animal model of human CSDH 8).
Retracted articles
Zhuang Y, Jiang M, Zhou J, Liu J, Fang Z, Chen Z. Surgical Treatment of Bilateral Chronic Subdural Hematoma. Comput Intell Neurosci. 2022 Jun 27;2022:2823314. doi: 10.1155/2022/2823314. Retraction in: Comput Intell Neurosci. 2022 Dec 25;2022:9806807. PMID: 35795746; PMCID: PMC9252673.
Ito H , Yamamoto S , Komai T , et al . Role of local hyperfibrinolysis in the etiology of chronic subdural hematoma. J Neurosurg 1976;45:26–31.doi:10.3171/jns.1976.45.1.0026
Edlmann E , Giorgi-Coll S , Whitfield PC , et al . Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy. J Neuroinflammation 2017;14:108.doi:10.1186/s12974-017-0881-y
Frati A, Salvati M, Mainiero F, Ippoliti F, Rocchi G, Raco A, Caroli E, Cantore G, Delfini R (2004) Inflammation markers and risk factors for recurrence in 35 patients with a posttraumatic chronic subdural haematoma: a prospective study. J Neurosurg 100:24–32
Pripp AH, Stanišić M. Association between biomarkers and clinical characteristics in chronic subdural hematoma patients assessed with lasso regression. PLoS One. 2017 Nov 6;12(11):e0186838. doi: 10.1371/journal.pone.0186838. eCollection 2017. PubMed PMID: 29107999.
Mirsadeghi SM, Habibi Z, Meybodi KT, Nejat F, Tabatabai SA. Malignant subdural effusion associated with disseminated adenocarcinoma: a case report. Cases J. 2008 Nov 18;1(1):328. doi: 10.1186/1757-1626-1-328. PubMed PMID: 19019205; PubMed Central PMCID: PMC2611978.
Chen R, Wei Y, Xu X, Zhang R, Tan Y, Zhang G, Yin H, Dai D, Li Q, Zhao R, Huang Q, Xu Y, Yang P, Liu J, Zuo Q. A bibliometric analysis of chronic subdural hematoma since the twenty-first century. Eur J Med Res. 2022 Dec 27;27(1):309. doi: 10.1186/s40001-022-00959-7. PMID: 36572939.
For qualitative and quantitative data synthesis, they included five RCTs (n = 321) with a mean age was 47.5 ± 11.9 years for the intervention group and 47.2 ± 11.9 years for the control group. The meta-analysis showed that the administration of TXA is associated with decreased total blood loss of standardized mean difference (SMD) of -1.40 (95% CI [-2.49, -0.31]), anesthetic time SMD -0.36 (95% CI [-0.63, -0.09]), and blood transfusion requirements RR 0.58 (95% CI [0.34, 0.99]).
The current study showed that TXA was associated with reduced intraoperative blood loss and intraoperative and postoperativeblood transfusion. However, the studies are small. More RCT studies with a greater sample size are favorable 1).
Randomized controlled trials
Patients with supratentorial meningiomas and deemed suitable for surgical resection will be recruited in the trial. Patients will be randomized to receive either a single administration of 20 mg/kg TXA or a placebo of the same volume with a 1:1 allocation ratio after anesthesia induction. The primary endpoint is the cumulative incidence of early postoperative seizures within 7 days after craniotomy. Secondary outcomes include the incidence of non-seizure complications, changes in hemoglobin level from baseline, intraoperative blood loss, erythrocyte transfusion volume, Karnofsky Performance Status, all-cause mortality, length of stay, and total hospitalization cost.
Ethics and dissemination: This trial is registered at ClinicalTrial.gov and approved by the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200224). The findings will be disseminated in peer-reviewed journals and presented at national or international conferences relevant to the subject fields.
conducted a prospective, randomized double-blind clinical study. The patient scheduled to undergo excision of intracranial meningioma were randomly assigned to receive intraoperatively either intravenous TXA or placebo. Patients in the TXA group received an intravenous bolus of 20 mg/kg over 20 min followed by an infusion of 1 mg/kg/h up to surgical wound closure. Efficacy was evaluated based on total blood loss and transfusion requirements. Postoperatively, thrombotic complications, convulsive seizure, and hematoma formation were noted.
Ninety-one patients were enrolled and randomized: 45 received TXA (TXA group) and 46 received placebo (group placebo). Total blood loss was significantly decreased in the TXA group compared to the placebo (283 ml vs. 576 ml; P < 0.001). Transfusion requirements were comparable in the two groups (P = 0.95). The incidence of thrombotic complications, convulsive seizure, and hematoma formation were similar in the two groups.
TXA significantly reduces intraoperative blood loss but did not significantly reduce transfusion requirements in adults undergoing resection of intracranial meningioma 3).
Case series
Thirty patients aged 18-65 years undergoing elective meningioma resection surgery were given either tranexamic acid or placebo (0.9% saline), tranexamic acid at a loading dose of 20 mg/kg, and infusion of 1 mg/kg/h during surgery. The intraoperative blood loss, coagulation profile, and the surgical field using the Likert scale were assessed.
The patients in the tranexamic group had significantly decreased intraoperative blood loss compared to the placebo group (616.42 ± 393.42 ml vs. 1150.02 ± 416.1 ml) (P = 0.02). The quality of the surgical field was better in the tranexamic group (median score 4 vs. 2 on Likert Scale) (P < 0.001). Patients in the tranexamic group had an improved coagulation profile and decreased blood transfusion requirement (p=0.016). The blood collected in the closed suction drain in 24 h postsurgery was less in the tranexamic acid group compared to the placebo group (84.7 ± 50.4 ml vs. 127.6 ± 62.2 ml) (P = 0.047).
Tranexamic acid bolus followed by infusion reduces perioperative blood loss by 46.43% and blood transfusion requirement with improved surgical field and coagulation profile in patients undergoing intracranial meningioma resection surgery 4).
In the Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India, Sixty adults undergoing elective craniotomy for meningioma excision were randomized to receive either tranexamic acid or placebo, initiated prior to skin incision. Patients in the tranexamic acid group received an intravenous bolus of 20mg/kg over 20min followed by an infusion of 1mg/kg/h till the conclusion of surgery. Intraoperative blood loss, transfusion requirements, and estimating surgical hemostasis using a 5-grade scale were noted. Postoperatively, the extent of tumor excision on CT scan and complications were observed. Demographics, tumor characteristics, amount of fluid infusion, and duration of surgery and anesthesia were comparable between the two groups. The amount of blood loss was significantly less in the tranexamic acid group compared to the placebo (830mlvs 1124ml; p=0.03). The transfusion requirement was less in the tranexamic acid group (p>0.05). The patients in the tranexamic acid group fared better on a 5-grade surgical hemostasis scale with more patients showing good hemostasis (p=0.007). There were no significant differences between the groups regarding the extent of tumor removal, perioperative complications, hospital stay, or neurologic outcome. To conclude, the administration of tranexamic acid significantly reduced blood loss in patients undergoing excision of meningioma. Fewer patients in the tranexamic acid group received blood transfusions. Surgical field hemostasis was better achieved in patients who received tranexamic acid 5).
Case reports
A man in his 40s with a history of coronary artery disease previously treated with a drug-eluting stent presented for elective craniotomy and resection of an asymptomatic but enlarging meningioma. During his craniotomy, he received desmopressin and tranexamic acid for surgical bleeding. Postoperatively, the patient developed chest pain and was found to have an ST-elevation myocardial infarction (MI). Because of the patient’s recent neurosurgery, standard post-MI care was contraindicated and he was managed symptomatically in the intensive care unit. The echocardiogram on a postoperative day 1 demonstrated no regional wall motion abnormalities and an ejection fraction of 60%. His presentation was consistent with the thrombosis of his diagonal stent. He was transferred out of the intensive care unit on postoperative day 1 and discharged home on postoperative day 3 6).
Raghavendra et al. report the intraoperative use of tranexamic acid to secure complete hemostasis as a rescue measure in intracranial meningioma resection in uncontrollable bleeding 7).
Three of 13 patients with intracranial meningiomas showed the pre-and postoperative elevation of tissue-type plasminogen activator (t-PA) related fibrinolytic activity in euglobulin fractions (EFA). During the operation, two of these three patients showed a significant elevation of the level of fibrinogen degradation products and oozing in the operating field. However, oozing was not observed in the third patient who had been given tranexamic acid preoperatively. Fibrin autography revealed that a broad lytic band of mol wt 50-60 kDa, probably free t-PA, appeared in the plasma obtained from two of the three patients after the operation when EFA elevated significantly. In all patients studied, the t-PA antigen levels were normal preoperatively but increased both during and after the operation, and correlated mainly with the intensities of a lytic band of mol wt 110 kDa, probably t-PA complexed with its major inhibitor (PAI-1). These results suggest that excessive fibrinolysis can induce local hemorrhagic diathesis during operation and may be related to t-PA function in plasma 8).
Wijaya JH, July J, Quintero-Consuegra M, Chadid DP. A systematic review and meta-analysis of the effects of tranexamic acid in surgical procedure for intracranial meningioma. J Neurooncol. 2023 Jan 12. doi: 10.1007/s11060-023-04237-2. Epub ahead of print. PMID: 36633801.
Li S, Yan X, Li R, Zhang X, Ma T, Zeng M, Dong J, Wang J, Liu X, Peng Y. Safety of intravenous tranexamic acid in patients undergoing supratentorial meningiomas resection: protocol for a randomized, parallel-group, placebo control, non-inferiority trial. BMJ Open. 2022 Feb 2;12(2):e052095. doi: 10.1136/bmjopen-2021-052095. PMID: 35110315; PMCID: PMC8811564.
Ravi GK, Panda N, Ahluwalia J, Chauhan R, Singla N, Mahajan S. Effect of tranexamic acid on blood loss, coagulation profile, and quality of the surgical field in intracranial meningioma resection: A prospective randomized, double-blind, placebo-controlled study. Surg Neurol Int. 2021 Jun 7;12:272. doi: 10.25259/SNI_296_2021. PMID: 34221603; PMCID: PMC8247710.
Hooda B, Chouhan RS, Rath GP, Bithal PK, Suri A, Lamsal R. Effect of tranexamic acid on intraoperative blood loss and transfusion requirements in patients undergoing excision of intracranial meningioma. J Clin Neurosci. 2017 Mar 7. pii: S0967-5868(16)31491-6. doi: 10.1016/j.jocn.2017.02.053. [Epub ahead of print] PubMed PMID: 28283245.
Westfall KM, Ramcharan RN, Anderson HL 3rd. Myocardial infarction after craniotomy for asymptomatic meningioma. BMJ Case Rep. 2022 Dec 29;15(12):e252256. doi: 10.1136/bcr-2022-252256. PMID: 36581354; PMCID: PMC9806024.
Tsuda H, Oka K, Noutsuka Y, Sueishi K. Tissue-type plasminogen activator in patients with intracranial meningiomas. Thromb Haemost. 1988 Dec 22;60(3):508-13. PMID: 3149049.
Unfortunately, symptomatic radiation necrosis is notoriously hard to diagnose and manage. The features of RN overlap considerably with tumor recurrence and misdiagnosing RN as tumor recurrence may lead to deleterious treatment which may cause detrimental effects on the patient 1)
Differentiating radiation necrosis from tumor progression remains a diagnostic challenge and advanced imaging modalities are often required to make a definitive diagnosis. If diagnostic uncertainty remains following conventional imaging, a multi-modality diagnostic approach with perfusion MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission spectroscopy (SPECT), and radiomics may be used to improve diagnosis.
Several imaging modalities exist to aid in the diagnosis of radiation necrosis. Future studies developing advanced imaging techniques are needed 2).
Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. PMID: 30324090; PMCID: PMC6172328.
Mayo ZS, Halima A, Broughman JR, Smile TD, Tom MC, Murphy ES, Suh JH, Lo SS, Barnett GH, Wu G, Johnson S, Chao ST. Radiation necrosis or tumor progression? A review of the radiographic modalities used in the diagnosis of cerebral radiation necrosis. J Neurooncol. 2023 Jan 12. doi: 10.1007/s11060-022-04225-y. Epub ahead of print. PMID: 36633800.
Mangesius J, Mangesius S, Demetz M, Uprimny C, Di Santo G, Galijasevic M, Minasch D, Gizewski ER, Ganswindt U, Virgolini I, Thomé C, Freyschlag CF, Kerschbaumer J. A Multi-Disciplinary Approach to Diagnosis and Treatment of Radionecrosis in Malignant Gliomas and Cerebral Metastases. Cancers (Basel). 2022 Dec 19;14(24):6264. doi: 10.3390/cancers14246264. PMID: 36551750; PMCID: PMC9777318.
