Brain death

Brain death

The published World Brain Death Project aims in alleviating inconsistencies in clinical guidelines and practice in the determination of death by neurologic criteria. However, critics have taken issue with a number of epistemic and metaphysical assertions that critics argue are either false, ad hoc, or confused.

Lazaridis disscussed the nature of a definition of death; the plausibility of neurologic criteria as a sensible social, medical, and legal policy; and within a Rawlsian liberal framework, reasons for personal choice or accommodation among neurologic and circulatory definitions. Declaration of human death cannot rest on contested metaphysics or unmeasurable standards, instead it should be regarded as a plausible and widely accepted social construct that conforms to best available and pragmatic medical science and practice. The definition(s) and criteria should be transparent, publicly justifiable, and potentially allow for the accommodation of reasonable choice. This is an approach that situates the definition of death as a political matter. The approach anticipates that no conceptualization of death can claim universal validity, since this is a question that cannot be settled solely on biologic or scientific grounds, rather it is a matter of normative preference, socially constructed and historically contingent 1).

The concept of brain death has periodically come under criticism 2).

Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances.

The current U.S. approach to determining death was developed in response to the emergence of technologies that made the traditional standard of cardiopulmonary death problematic. In 1968, an ad hoc committee at Harvard Medical School published an influential article arguing for extending the concept of death to patients in an “irreversible coma.“ 3). The emerging neurologic criteria for death defined it in terms of loss of the functional activity of the brain stem and cerebral cortex. Although clinical criteria were developed in the 1960s, it took more than a decade for consensus over a rationale for the definition to emerge. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research provided a philosophical definition of brain death in terms of the loss of the critical functions of the organism as a whole 4).

Shortly thereafter, the National Conference of Commissioners on Uniform State Laws produced the Uniform Determination of Death Act, which has been adopted in 45 states and recognized in the rest through judicial opinion 5).

see Computed tomography angiography for brain death.

Changes in S100B protein, especially the levels of this dimer 48 hours after trauma can be used as marker to predict brain death. Alongside other known prognostic factors such as age, GCS and diameters of the pupils, however, this factor individually can not conclusive predict the patient’s clinical course and incidence of brain death. However, it is suitable to use GCS, CT scan, clinical symptoms and biomarkers together for a perfect prediction of brain death 6).

Near-Infrared Spectroscopy for Brain death

The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow 7).

The level of knowledge of medical students at Centro Universitário Lusíada – UNILUS- Santos (SP), Brazil, regarding brain death and transplantation is limited, which could be the result of inadequate education during medical school 8).

Brain death criteria.

In a editorial, Hibi et al., aimed to provide an outline of the world history of liver transplantation (LT), with a special focus on the innovation, development, and current controversies of living donor (LD) LT from East Asian and Western perspectives. In 1963, Starzl et al. (University of Colorado, U.S.) performed the world’s first human LT for a 3-year-old child with biliary atresia. The donor was a 3-year-old patient who had suffered from brain death following neurosurgery9).


1)

Lazaridis C. Defining Death: Reasonableness and Legitimacy. J Clin Ethics. 2021 Summer;32(2):109-113. PMID: 34129526.
2)

Truog RD, Miller FG, Halpern SD. The dead-donor rule and the future of organ donation. N Engl J Med 2013;369:1287-1289
3)

A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337-340
4)

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Defining death: a report on the medical, legal and ethical issues in the determination of death. Washington, DC: Government Printing Office, 1981.
5)

National Conference of Commissioners on Uniform State Laws. Uniform Determination of Death Act, 1981 (http://www.uniformlaws.org/shared/docs/determination%20of%20death/udda80.pdf).
6)

Shakeri M, Mahdkhah A, Panahi F. S100B Protein as a Post-traumatic Biomarker for Prediction of Brain Death in Association With Patient Outcomes. Arch Trauma Res. 2013 Aug;2(2):76-80. doi: 10.5812/atr.8549. Epub 2013 Aug 1. PubMed PMID:24396798.
7)

Luchtmann M, Beuing O, Skalej M, Kohl J, Serowy S, Bernarding J, Firsching R. Gadolinium-enhanced magnetic resonance angiography in brain death. Sci Rep. 2014 Jan 13;4:3659. doi: 10.1038/srep03659. PubMed PMID: 24413880.
8)

Reis FP, Gomes BH, Pimenta LL, Etzel A. Brain death and tissue and organ transplantation: the understanding of medical students. Rev Bras Ter Intensiva. 2013 Oct-Dec;25(4):279-283. Portuguese, English. PubMed PMID: 24553508.
9)

Hibi T, Eguchi S, Egawa H. Evolution of living donor liver transplantation: A global perspective. J Hepatobiliary Pancreat Sci. 2018 Jun 28. doi: 10.1002/jhbp.571. [Epub ahead of print] PubMed PMID: 29953731.

Deep brain stimulation for Meige syndrome

Deep brain stimulation for Meige syndrome

A well-established therapeutic option is deep brain stimulation (DBS), and the target in bilateral globus pallidus internus (GPi DBS) demonstrated satisfactory short- and long-term efficacy. However, some patients present minor or suboptimal responses after GPi DBS, and in those cases, rescue DBS may be appropriate 1).


A retrospective study to assess the efficacy and safety of bilateral GPi stimulation in 40 patients with primary Meige syndrome who responded poorly to medical treatments or botulinum toxin injections. All participants were postoperatively followed up at the outpatient clinic, and their motor functions were assessed using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The severity of patients’ dystonia was evaluated before surgery and at follow-up neurostimu-lation.

Results: The implanted stimulator was turned on 1 month after surgery. All 40 patients received monopolar stimulation using the following parameters: voltage 2.5-3.5 V (average: 2.6 ± 0.8 V), frequency 60-160 Hz (average: 88.0 ± 21.3 Hz), and pulse width 60-185 μS (average: 90.0 ± 21.1 μS). In 28 of 40 patients, the symptoms had signifi-cantly improved within 1 week of stimulation. Most of the patients had been followed up for 6-24 months (average: 15.0 ± 7.8 months). The clinical symptoms of all patients had significantly improved. At 6, 12, and 24 months after surgery, the BFMDRS subscores of eyes, mouth, speech, and swallowing were significantly lower, and subscores of mouth movement showed progressively decreased with prolonged stimulation time. The overall improvement rate was 83%. Five adverse events occurred in the 40 patients; all of these events resolved without permanent sequelae.

Bilateral GPi-DBS demonstrated satisfactory long-term efficacy in the treatment of primary Meige syndrome and could serve as an effective and safe option 2).


A study explored the predictors of clinical outcome in patients with Meige syndrome who underwent DBS.

Twenty patients who underwent DBS targeting the bilateral subthalamic nucleus (STN) or globus pallidus internus (GPi) at the Chinese People’s Liberation Army General Hospital from August 2013 to February 2018 were enrolled in the study. Their clinical outcomes were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale at baseline and at the follow-up visits; patients were accordingly divided into a good-outcome group and a poor-outcome group. Putative influential factors, such as age and course of disease, were examined separately, and the factors that reached statistical significance were subjected to logistic regression analysis to identify predictors of clinical outcomes.

Four factors showed significant differences between the good- and poor-outcome groups: 1) the DBS target (STN vs GPi); 2) whether symptoms first appeared at multiple sites or at a single site; 3) the sub-item scores of the mouth at baseline; and 4) the follow-up period (p < 0.05). Binary logistic regression analysis revealed that initial involvement of multiple sites and the mouth score were the only significant predictors of clinical outcome.

The severity of the disease in the initial stage and presurgical period was the only independent predictive factor of the clinical outcomes of DBS for the treatment of patients with Meige syndrome 3).


A total of 6 patients seen between 2002 and 2010 with craniofacial and craniocervical dystonia symptoms were identified from the University of Florida Institutional Review Board approved database. Patients were videotaped using a standardized protocol, and tapes were randomized and blindly reviewed by a movement disorders neurologist. The Unified Dystonia Rating Scale improved 31.6 ± 23.2% (range: 3.4-63.2%) at 6 months and 63.7 ± 35.3% (range: 6.3-100%) at 12 months. The Burke-Fahn-Marsden Dystonia Rating Scale improved 45.3 ± 29.5% (range: 4.7-75.0%) at 6 months and 61.8 ± 30.9% (range: 16.6-100%) at 12 months. One patient significantly had a very large improvement with little evidence of residual dystonia. Blepharospasm improved in all patients, whereas speech and swallowing did not improve in this cohort. Two patients improved with unilateral GPi-DBS, although one required a contralateral DBS later in the disease course. Two patients were managed with low-frequency stimulation (<100 Hz). Two patients had less than 20% benefit. GPi-DBS for cranio-facial and craniocervical symptoms is an effective strategy to manage a subset of patients who remain unresponsive to optimized medical management. Unilateral stimulation may be an option for some patients, but it remains unclear whether response to single-sided stimulation will be sustainable. The mixed results of this GPi-DBS case series highlight the need for a careful re-examination of selection criteria, alternative brain targets, and possibly rescue leads for patients who are non-responders to the GPi target 4).


Lyons report the long-term results of bilateral globus pallidus internus (GPi) or subthalamic nucleus (STN) stimulation in 3 patients with Meige syndrome and 1 patient with Parkinson’s disease and associated craniofacial dystonia treated at their center.

Initial 12-month and long-term follow-up Burke-Fahn-Marsden scores were substantially improved in all 4 patients compared with preoperative scores.

Bilateral GPi DBS may be an effective and safe treatment for medically refractory Meige syndrome. The results are comparable with those reported in the literature. Sustained and long-term improvement in symptoms does appear to be reproducible across reports. The authors’ patient with Parkinson’s disease and associated craniofacial dystonia syndrome undergoing bilateral STN DBS noted immediate and sustained improvement in his symptoms. Further study is required, but these results, along with the other reports, suggest that bilateral GPi DBS is an effective treatment for medically refractory Meige syndrome 5).


Sobstyl M, Ząbek M, Mossakowski Z, Zaczyński A. Pallidal deep brain stimulation in the treatment of Meige syndrome. Neurol Neurochir Pol. 2014;48(3):196-9. doi: 10.1016/j.pjnns.2014.05.008. Epub 2014 Jun 6. PubMed PMID: 24981184.


1)

Aragão VT, Barbosa Casagrande SC, Listik C, Teixeira MJ, Barbosa ER, Cury RG. Rescue Subthalamic Deep Brain Stimulation for Refractory Meige Syndrome. Stereotact Funct Neurosurg. 2021 Apr 23:1-3. doi: 10.1159/000515722. Epub ahead of print. PMID: 33895729.
2)

Tian H, Yu Y, Zhen X, Zhang L, Yuan Y, Zhang B, Wang L. Long-Term Efficacy of Deep Brain Stimulation of Bilateral Globus Pallidus Internus in Primary Meige Syndrome. Stereotact Funct Neurosurg. 2019;97(5-6):356-361. doi: 10.1159/000504861. Epub 2020 Jan 10. PMID: 31927550.
3)

Wang X, Mao Z, Cui Z, Xu X, Pan L, Liang S, Ling Z, Yu X. Predictive factors for long-term clinical outcomes of deep brain stimulation in the treatment of primary Meige syndrome. J Neurosurg. 2019 Apr 5:1-9. doi: 10.3171/2019.1.JNS182555. [Epub ahead of print] PubMed PMID: 30952124.
4)

Limotai N, Go C, Oyama G, Hwynn N, Zesiewicz T, Foote K, Bhidayasiri R, Malaty I, Zeilman P, Rodriguez R, Okun MS. Mixed results for GPi-DBS in the treatment of cranio-facial and cranio-cervical dystonia symptoms. J Neurol. 2011 Nov;258(11):2069-74. doi: 10.1007/s00415-011-6075-0. Epub 2011 May 7. PMID: 21553081.
5)

Lyons MK, Birch BD, Hillman RA, Boucher OK, Evidente VG. Long-term follow-up of deep brain stimulation for Meige syndrome. Neurosurg Focus. 2010 Aug;29(2):E5. doi: 10.3171/2010.4.FOCUS1067. PMID: 20672922.

Brain metastases from Head and Neck Cancer

Brain metastases from Head and Neck Cancer

Limited data is available on head and neck cancer (HNC) patients presenting with brain metastases (BM) at initial diagnosis.

Survival was significantly influenced by Eastern Cooperative Oncology Group (ECOG) performance score, number of cerebral lesions and extracranial metastatic disease. These characteristics were included in a score.

Scoring was based on 6-month survival data: ECOG 0-1=1 point, ECOG 2-3=0 points, 1-3 cerebral lesions=1 point, ≥4 cerebral lesions=0 points, lack of extracranial metastases=1 point, and presence of extracranial metastases=0 points. Addition of these points for each patient resulted in 0-3 points. Three groups were built comprising 0-1, 2 and 3 points. Six-month survival rates for these groups were 0%, 50% and 100%, respectively.

This instrument guides physicians in choosing optimal irradiation programs for patients with cerebral metastases from head-and-neck cancer 1),


Messing et al. sought to evaluate the incidencemanagement, and treatment outcomes of these patients using the National Cancer Database (NCDB).

They identified 465,925 patients diagnosed with HNC between 2010 and 2015 in the NCDB. 14,583 of these patients presented with metastatic disease to any site. 440 of these patients had BM at the time of initial diagnosis. Overall survival was compared using the Kaplan-Meier estimatorCox Proportional hazards modelpropensity score matching, and subgroup analyses were performed.

The median age overall was 62.0 years. Nasopharynx NOS (13.2%) and Parotid Gland (10.9%) were the most common anatomical sites with the highest frequency of BM. The overall median survival time was 7.1 months. Predictors for the presence of BM included distant metastasis to the bone, liver, or lung on univariate analysis, and bone or lung on multivariate analysis. High-risk Human Papilloma Virus status was associated with a lower chance of BM. No pattern was determined when comparing lymph node level involvement and BM. The median survival for patients receiving radiation therapy and multi-agent chemotherapy was 8.4 and 11.7 months, respectively. Immunotherapy administered as first course therapy did not influence median survival. Most patients received radiation (62.7%) therapy and chemotherapy (50.2%).

The data extracted and analyzed from the NCDB should work to aid in the surveillance and management of BM in patients with HNC 2).


Out of 9432 HNC patients, 88 patients developed BM (0.9%, median follow-up 3.4 years). On average, the BM were diagnosed 18.5 months after the primary diagnosis and tended to arise after distant metastases to extracranial sites (85%) such as the lungs (78%). At BM presentation, 84% were symptomatic and two thirds had a poor performance status (ECOG ≥ 2, 68%). The median post-BM survival was 2.5 months (95% CI 2.1-3.3 months). On multivariable analysis, management of BM with radiotherapy (RT) alone (3.3 months, 95% CI 2.3-4.6, p = 0.005) and RT with surgery (4.4 months, 95% CI 2.8-6.9, p < 0.001) was associated with longer survival compared to best supportive care alone (1.4 months, 95% CI 1.0-2.0 months). Age, sex, performance status, sub-localization of the primary HNC, presence of extracranial metastases, and number of intracranial metastases were not associated with post-BM survival (all p ≥ 0.05).

BM occur late in the course of HNC and carry a poor prognosis. Treatment with intracranial radiotherapy both with and without surgery was associated with improved survival 3).

see Brain metastases from Head and Neck squamous cell carcinoma.


1)

Rades D, Dziggel L, Hakim SG, Rudat V, Janssen S, Trang NT, Khoa MT, Bartscht T. Predicting Survival After Irradiation for Brain Metastases from Head and Neck Cancer. In Vivo. 2015 Sep-Oct;29(5):525-8. PMID: 26359409.
2)

Messing I, Goyal S, Sherman JH, Thakkar P, Siegel R, Joshi A, Goodman J, Ojong-Ntui M, Rao YJ. Incidence and Prognosis of Brain Metastases in Head and Neck Cancer Patients at Diagnosis. Laryngoscope. 2021 Feb 18. doi: 10.1002/lary.29448. Epub ahead of print. PMID: 33599979.
3)

Liu AK, Wu J, Berthelet E, Lalani N, Chau N, Tran E, Hamilton SN. Clinical features of head and neck cancer patients with brain metastases: A retrospective study of 88 cases. Oral Oncol. 2021 Jan;112:105086. doi: 10.1016/j.oraloncology.2020.105086. Epub 2020 Nov 10. PMID: 33186892.
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