Brain death. Japanese perspective.

Araki T, Yokota H, Fuse A. Brain Death in Pediatric Patients in Japan: Diagnosis and Unresolved Issues. Neurol Med Chir (Tokyo). 2016 Jan 15;56(1):1-8.

Abstract

Brain death (BD) is a physiological state defined as complete and irreversible loss of brain function. Organ transplantation from a patient with BD is controversial in Japan because there are two classifications of BD: legal BD in which the organs can be donated and general BD in which the organs cannot be donated. The significance of BD in the terminal phase remains in the realm of scientific debate. As indicated by the increasing number of organ transplants from brain-dead donors, certain clinical diagnosis for determining BD in adults is becoming established. However, regardless of whether or not organ transplantation is involved, there are many unresolved issues regarding BD in children. Here, we will discuss the historical background of BD determination in children, pediatric emergencies and BD, and unresolved issues related to pediatric BD.

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From the article:

Essentially, abused children are not to be diagnosed for the aim of organ donation but as part of routine medical practice; therefore, a framework for the detection of any kind of abuse cases should not be prepared to enable organ donation from brain-dead donors. It has also been indicated that when responding to cases of past abuse, the prompt response to requests for the disclosure of information from child consultation centers is strongly encouraged.

The prohibition of organ donation from abused children is a rule that is only enforced in Japan. Furthermore, many physicians in Japan are also of the opinion that the requirement to investigate past instances of abuse places a heavy burden on those in medical practice. Currently, if there is even a slight suspicion of abuse, legal BD will not be determined.  Moreover, regardless of whether a child suffered BD or cardiac death, organs will not be donated if there is a suspicion that they were the victim of abuse. However, even children who suffer severe brain damage due to abuse may exhibit cerebral herniation. In such cases, if an irreversible arrest of all brain functions, including the brainstem is observed, then the patient may be diagnosed as medically brain dead. However, in such a case, a declaration of death cannot be made with this determination of BD…

The MHLW report “Research regarding Determination of Brain Death in Children and Organ Donation” found that chronic BD (long-term BD; it took at least 30 days to reach cardiopulmonary arrest after determination of BD) accounted for 20% of all cases. Baker et al. have hypothesized that developments in intensive care medicine have lengthened the time from BD determination to cardiopulmonary arrest. Currently, respiratory and circulation management is proactively performed even on brain-dead patients, and if care is taken with respect to elements such as prevention of infection and nutritional management, it is generally accepted that a heartbeat can be maintained over a long period. Chronic BD was previously considered to be specific to children, but this was greatly attributable to a report by Shewmon. In this report, he analyzed 56 brain-dead patients who survived for at least a week after diagnosis and concluded that patients who met the clinical criteria for BD have not necessarily lost integrated physical functioning, and many cases do not require intensive care equipment to stabilize their organs other than their brain. Wound healing, improvement from infection, fever, and growth can be observed even in brain-dead patients. Furthermore, integration of the individual is built on a reciprocal relationship between each part of the body, and it does not work in the way that the most important organs forcibly control other organs in a top-down manner. Because some of the reported cases of “BD” included cases that did not strictly meet the determination criteria, the precision of such diagnoses was criticized. Even to date, no conclusion has been reached regarding whether chronic BD should be considered as a pathology peculiar to a child or a result from the influence of intensive care medicine.

In 2008, when the President’s Council on Bioethics (PCBE) compiled the white paper “controversies in the determination of death,” cases of chronic BD were investigated. Results indicated that there are clear differences between the linguistic representation of the conventional definition of BD and the clinical state of patients diagnosed with BD, which is candidly accepted. Shewmon’s evidence required the abandonment of reasoning relying on the premise that the brain conferred integrative unity on the organism as a whole. He showed there was no necessary connection between brain activity and some integrative somatic unity. The white paper admits that if expressions of integrative somatic activity were sufficient to indicate the presence of a whole living organism, then the neurological criteria would have to be abandoned as a standard for ascertaining human organismic death. However, the white paper finally does concede Shewmon’s point about the role of the brain in mediating integrative unity and rejects the conclusion that some expressions of somatic integrative unity are expressions of a living whole. Eventually, it was determined that the term “brain death” was inappropriate, and they proposed to change it to complete brain failure. It is highly commendable that the PCBE considered a preconceived idea in its own country to be “unreliable” and redefined it.

BD in children based on certain criteria is determined in only a few countries around the world, and it is difficult to perform scientific analysis on pediatric patients. However, the amount of detailed information available regarding the epidemiology and pathology of BD in children has recently increased. In Japan, the perception that the BD diagnosis is performed for the purpose of organ donation remains strong. Furthermore, in many cases, BD is not determined and the family members are given explanations based on the practitioner’s subjective view such as “almost brain dead,” “a brain-dead state,” or “infinitely close to brain dead.” Therefore, the “limitations of life-saving” are presented before a diagnosis of BD and intent to donate organs by the family is confirmed at this point. The overuse of the term “BD” not only affects medical care but also legal interpretations and may eventually impede the understanding of the patient’s family and influences the trust of doctor–patient relationship.

Courtesy of Researchgate

Reanimation

New Delhi: Soon, dead brains may be brought back to life - if the Multi-Modality Approach or ReAnima Project becomes successful.

As per reports, a team of doctors from India and the US, led by Indian scientist Dr Himanshu Bansal, are working on an ambitious project to infuse life into those deemed brain dead.

As part of the project, the team has been granted ethical permission to recruit 20 patients declared clinically dead from traumaic brain injury.

The team will perform the first stage of the trial named ‘First In Human Neuro-Regeneration and Neuro-Reanimation’ at Anupam Hospital in Rudrapur, Uttarakhand India.

In the experiment, scientists will include a range of procedures and therapies which include injecting the brain with stem cells and a cocktail of peptides in a effort to revive the brains and brought back to life.

Dr Bansal, who works with Biotech companies Revita Life Sciences and Bioquark Inc, claimed that he had already had some success with two patients in the Gulf and Europe.

“We are now trying to create a definitive study in 20 subjects and prove that the brain death is reversible. This will open the door for future research and especially for people who loose there dear ones suddenly,” Dr Bansal was quoted as saying to Telegraph.

The peptides will be administered into the spinal cord - of those being kept alive solely through life support – on a daily basis via a pump, with the stem cells given bi-weekly, over the course of a 6 week period.

The groundbreaking project represents the first trial of its kind, which is also another step towards the eventual reversal of death in our lifetime.

http://zeenews.india.com/news/health/health-news/can-dead-be-brought-back-to-life-scientists-think-so_1883713.html

A trial to see if it is possible to regenerate the brains of patients who have been declared clinically dead has been approved. Reanima Advanced Biosciences aims to use stem cells, injections of peptides, and nerve stimulation to reverse “brain death as noted in clinical examination or EEG”, a project which at least scores highly on ambition.

There is a small problem with the study, however, and a major one. The first issue is our definition of brain death, which involves the irreversible end of function – if it is curable, then patients were never brain dead in the first place.

We can get around this if we recognise that being “irreversibly dead” is technology dependent. For a long time, a lack of breathing and pulse were regarded as hallmarks of death, until resuscitation methods improved. Today, drowning victims that suffer extreme hypothermia, lack of oxygen, and lack pulse and breathing for several hours can be revived(with luck and some heavy medical interventions). Even not having a heart isn’t death if you are on the transplant surgeon’s table.

Given historical precedent, then, we should not discount the possibility that some people currently regarded as irreversibly dead may be revivable by future medical technology. And if the Reanima project succeeds, we will have to revise our concept of brain death and possibly the status of some patients. Presumably, this also will make further research on patients in this state harder, since they are potentially savable and can be harmed by some interventions...

In the best possible case, the proposed Reanima treatment would miraculously restore the previously-declared dead person. They would regain full psychological continuity, the death certificate would be nullified, and they would continue their old life. They would clearly benefit because they would get a second chance at life.

But it is not hard to imagine that the treatment would not restore the brain completely: memories, personality and functions might be scrambled, lost, or replaced with newly-grown tissue. A new person may have a life worth living and enjoy existing. They could be said to have benefited in the same way a child benefits from being brought into the world. But if there is limited or no psychological continuity, then the original person won’t benefit: they are now truly dead, since their body and brain have become a new person.

Would it make sense to want this kind of treatment if it only makes new people? It is not a health-restoring treatment for anybody, merely an unusual way of reproduction. And though we may want some part of the original person to remain, we could equally well transplant the organs to benefit other people.

The real problem of course is the possibility of creating persons who have lives that are not worth living, or beings that are not people but who we still have a moral duty to care for...

The real problem may simply be that Reanima cannot deliver. Looking at their website leaves me wondering what the company actually is, beside a website offering an app. It wouldn’t surprise me if it turns out to be a viral campaign for some upcoming horror movie that fooled various news outlets. Still, it has registered a clinical trial and the CEO seems to be a real person with real ambitions.

Going after the high impact jugular rather than trying to tinker with small effects might be just what the doctor ordered for the medical industry, which has been criticised for not trying to solve the big problems. Disrupting death is unlikely to be easy, but as author Seth Godin said: “Waiting for perfect is never as smart as making progress.” 

http://theconversation.com/would-we-want-to-regenerate-brains-of-patients-who-are-clinically-dead-59107

Advances in status epilepticus

Trinka E, Brigo F, Shorvon S. Recent advances in status epilepticus. Curr Opin

Neurol. 2016 Apr;29(2):189-98.

Abstract

Purpose of review This review discusses advances in the understanding of the mechanisms of status epilepticus and its current treatment approaches. Many of these have been topics at the 5th London-Innsbruck Colloquium on status epilepticus 2015.

Recent findings A new definition and classification of status epilepticus was proposed, which is expected to improve treatment and stimulate research. A better understanding of the failure of seizure suppressing mechanisms and the initiation of self-sustaining seizures begins to translate into the clinical arena. Drugs, such as allopregnanolone, cannabinoids, sec-butylpropylacetamide and valnoctamide, may better target these seizure-perpetuating mechanisms. The concept of combinatorial treatments has further developed, but yet trials in humans are lacking. A new prognostic outcome-score and electroencephalography-criteria for nonconvulsive status epilepticus are ready for clinical use. Alternative routes, such as intranasal or buccal, have been explored in a number of trials suggesting that intramuscular midazolam is at least as effective as intravenous lorazepam and buccal or intranasal midazolam is at least as effective as rectal diazepam.

Summary Despite progress in basic science, translation into the clinical field remains difficult. There is hope, that the two large phase III studies in the established and refractory status that started recruitment in 2015 will better inform the clinicians in this emergency situation.

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From the article:

In 2015, a Task Force of the ILAE defined status epilepticus as a 'condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally, prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizure'. The timeframe for t1 was set at 5 min for generalized convulsive status epilepticus, and at 10 min for focal status epilepticus with impairment of consciousness (formerly designated as complex partial status epilepticus)...

Bhatnagar and Shorvon searched the genetic databases for genes associated with status epilepticus and identified mutations in 122 genes. The genetic mutations identified were found only in rare conditions and mostly in infants and young children with multiple other handicaps. Most of the genetic mutations can be subdivided into those associated with cortical dysplasias, inborn errors of metabolism, mitochondrial disease, or epileptic encephalopathies and childhood syndromes. To date, no 'pure status epilepticus genes' have been identified...

On the basis of these criteria, an expert panel at the 4th London Innsbruck Colloquium on acute Seizures in Salzburg, Austria proposed the working diagnostic criteria for NCSE (Table 2). EEG patterns with spatiotemporal evolution or epileptiform discharges faster than 2.5 Hz should deserve treatment. Conversely, more 'static' patterns such as diffuse polymorphic δ activity, spindle coma, α coma, low output voltage or burst suppression do not reflect nonconvulsive ongoing seizure activity. Finally, some patterns such as generalized periodic discharges or lateralized periodic discharges with a frequency of less than 2.5 Hz or rhythmic discharges faster than 0.5 Hz have uncertain clinical and diagnostic significance. In these cases, at least one of the additional criteria is required for a diagnosis of nonconvulsive status epilepticus: subtle clinical ictal phenomena, typical spatiotemporal evolution or response to antiepileptic drug treatment.

Generalized periodic discharges (GPD) are commonly encountered in metabolic encephalopathy and following cerebral hypoxia. Their clinical significance is unclear, and it is debatable whether in these conditions treatment with antiepileptic drugs is of any benefit...

The therapeutic principle 'time is brain' applies not only for stroke but also for status epilepticus, as the prognosis of status epilepticus worsens with increasing duration of seizure activity. Indeed, prompt recognition and earliest treatment of status epilepticus are associated with lower morbidity and mortality, fewer drugs required in hospitals and reduction in seizure duration. A timely administration of rescue medication in a prehospital setting may, therefore, prove useful to prevent progression to status epilepticus (in the case of isolated brief seizures or recurrent unprovoked seizures) and to limit the duration of ongoing seizure in the case of early status epilepticus. Intravenous administration requires gaining access to an intravenous route, which may prove difficult in some situations (e.g. patients with convulsive seizures or infants) resulting in a treatment delay...

A comprehensive systematic review assessed all studies reporting data on propofol used in refractory status epilepticus. Twenty-four studies with 143 cases of status epilepticus were included. Propofol administration led to complete status epilepticus termination in 68%, withdrawal seizures in 6%, breakthrough seizures in 1%, discontinuation because of side-effects in 6% and death during treatment in 8%.

One RCT comparing propofol with thiopental sodium in the treatment of refractory status epilepticus found no difference with regard to control of status epilepticus, mortality and return to baseline clinical conditions at 3 months. However, this study was terminated before completing because of difficulties in patient enrolment and was therefore underpowered...

This review shows that despite the enormous advances in the understanding of basic mechanisms, the translation into the clinical arena is still difficult. Clinical trials in this field are costly and logistically demanding. Newer drugs targeting various other mechanisms, such as allopregnanolone, cannabinoids or valproate derivatives, show promising results in preclinical animal models and first human trials. There is one phase III trial in superrefractory status epilepticus (NCT02477618) currently recruiting patients. Another remarkable phase III trial (NCT01960075) comparing the efficacy of levetiracetam, valproate and (fos)phenytoin in established status epilepticus (Established Status Epilepticus Trial) also started recruitment in 2015. This trial uses an innovative adaptive design and its results are expected to inform clinical practice in the future. The new definition and classification, EEG consensus criteria for nonconvulsive status epilepticus and a new outcome score will further help to better delineate patient cohorts and improve risk stratification in future clinical trials.

http://www.medscape.com/viewarticle/860055_8?nlid=104576_3001

Newborn genome sequencing

But families could learn much more. While the cost of testing an entire human genome is plummeting, the health data available from that testing continues to increase. A baby’s genome, if sequenced, might reveal some of the approximately 8,000 genetic disorders that are otherwise very hard to diagnose—disorders that, collectively, can account for as much as 35% of deaths during the first year of life. Wouldn’t combining genome sequencing with that prick on the heel save more lives?

Probably. But genetic screening—at any age—can also have a less positive side, uncovering genetic clues that lead to stress but few medical solutions. In fact, some people prefer not to know what their genes might predict. To untangle that knot, the National Institutes of Health started the Newborn Sequencing in Genomic Medicine and Public Health program. Known as NSIGHT, it is funding four pilot projects that seek answers to ethical, legal and social questions related to the genes of newborns.

“We need to ask if it provides clinical utility. Does it help the doctor treat the baby? Does the baby have better outcomes as a result?”

In some instances, the answer is yes. One of the four NSIGHT projects is studying babies in the neonatal intensive care units (NICUs) at Children’s Mercy Hospital in Kansas City and Rady Children’s Hospital–San Diego. Led by geneticist Stephen Kingsmore, clinicians developed techniques to rapidly test for 4,500 known diseases that might affect the health of the baby and have results returned in as little as 26 hours—a technological tour de force. Preliminary results showed 20 diagnoses in the 35 infants who underwent sequencing, and 13 of those led to treatments—which, Kingsmore says, is “unprecedented in the NICU.” He told of one infant who was in danger of dying from acute liver failure from an unknown cause. The sequencing revealed a treatable blood disease. The baby became symptom-free within seven days of treatment and is now healthy.

But in many other cases, learning genomic secrets may not offer any material benefit. Most of the thousands of rare genetic diseases are poorly understood and can’t currently be treated. Some, such as Huntington’s disease, will not strike for decades. Knowledge of such a condition may not bring any health benefits to the child and, instead, may hang over their childhood, causing harm and stress to both family and child. So another NSIGHT project at Brigham and Women’s Hospital in Boston and Boston Children’s Hospital, called the BabySeqproject, is enrolling healthy and sick newborns and their parents. The study will follow families—some of whom received a full genetic breakdown for their newborns, some of whom didn’t—and try to learn more about how the test affects the family in the baby’s first year of life...

Genetic data is not always straightforward: Many genes don’t predict a disease with certainty; they only increase the likelihood of developing it...

A lifetime with that knowledge might result in decades of worry and screening that, ultimately, do more harm than good. Full genome sequencing of infants would require intensive one-on-one counseling with the parents, according to Natasha Bonhomme, an executive at Genetic Alliance, a nonprofit organization: “And when you have a new baby, there is already so much going on that it’s a difficult time to process complex information.”

Genetic screening of newborns also raises questions about what rights patients have regarding their own genetic data—and especially, in light of the potential trauma of receiving murky genetic information, their right not to know about it. “One of the most important policy issues will be what options parents have for not receiving certain kinds of results,” says Catherine Wicklund, a researcher at the Center for Genetic Medicine at Northwestern University.  In a 2015 survey of genetics professionals, she found—amid much disagreement about particulars—broad consensus that genome sequencing of newborns should not be mandatory. It should involve an extensive consent process that allows parents to choose which results they want to learn and when; and it should require pre- and post-test genetic counseling for parents.

So looking into the genes of newborns offers something of a Faustian bargain. On one hand, the child and parents can gain a storehouse of important knowledge and the power to act on it. On the other, they risk needless confusion and worry. “That’s why we’re doing these NSIGHT studies,” explains Anastasia Wise, a program director with the National Human Genome Research Institute, another agency funding the study. For the moment, that means taking all of the clinical and psychological repercussions under investigation and proceeding with baby steps. 

http://protomag.com/articles/babies-the-open-books

Topical mTOR inhibitor therapy in tuberous sclerosis

Sergiusz Jóźwiak, Krzysztof Sadowski, Katarzyna Kotulska, Robert A. Schwartz.  Topical use of mTOR inhibitors in tuberous sclerosis complex – a comprehensive review of the literature.  Pediatric Neurology. In press.

Abstract

Background

Tuberous sclerosis complex (TSC) is a genetically determined multisystem disorder that may affect almost any human organ. The discovery of the mammalian target of rapamycin (mTOR) pathway and its involvement in TSC-related pathology has led to the introduction of mTOR inhibitors into clinical practice. Topical administration of mTOR inhibitors for skin lesions related to TSC may represent a reasonable alternative for more invasive procedures.

A growing number of patients have been described exhibiting positive therapeutic effects from the topical administration of mTOR inhibitors.

The aim of this review is to systematically analyze available literature on the use of topical mTOR inhibitors to treat dermatological lesions related to TSC.

Results

A comprehensive review of PubMed, Medscape and Cochrane databases between 1995 and 2015 was performed to identify available studies describing topical use of mTOR inhibitors in TSC patients.

In most published cases topical mTOR inhibitor application proved to be effective in the treatment of skin lesions related to TSC. Facial angiofibromas were the target lesions in most cases. Few studies reported clinical improvement of hypomelanotic macules.

mTOR inhibitors directly address the molecular defect related to TSC manifestations.

Conclusions

Currently available clinical data reviewed in this study suggest that topical application of mTOR inhibitors represents a significant progress in the treatment of facial angiofibromas associated with TSC. However, double-blinded studies on larger groups of patients are necessary.

Discordant holoprosencephaly in monozygotic twins with ZIC2 mutation

Nakayama J, Kinugasa H, Ohto T, Tanaka R, Nakayama T, Noguchi E, Arinami T, Iwasaki N. Monozygotic twins with de novo ZIC2 gene mutations discordant for the type of holoprosencephaly. Neurology. 2016 Mar 9. pii:10.1212/WNL.0000000000002567. [Epub ahead of print]

Middle interhemispheric variant of holoprosencephaly (MIH) is a rare brain malformation; hemispheric fusion does not occur at the rostral forebrain, but rather across the posterior frontal region. Barkovich and Quint first described and proposed MIH as part of the holoprosencephaly (HPE) spectrum in 1993. Although classic HPE and MIH share several similarities, they are related to different embryological mechanisms: classic HPE is caused by a defect in the formation of the embryonic floor plate, whereas MIH occurs after a disturbance to the roof plate formation. The gene ZIC2 is important for the differentiation of the roof plate in the dorsal midline of the neural tube of the developing embryo. In humans, ZIC2 mutations have been identified in 3%–4% of HPE cases, including individuals with MIH, thus confirming that MIH is a variant of HPE.

Monozygotic (MZ) twins with HPE are rare, and only 11 pairs have been reported thus far. Furthermore, MZ twins with MIH have not yet been reported.

We report a case of MZ twins with a ZIC2 mutation showing the discordant manifestations of semilobar HPE (twin A) and MIH (twin B)...

Brain MRI Figure. In twin A (A–C), MRI shows a crescent-shaped holoventricle. A large dorsal cyst is seen posteriorly. The interhemispheric fissure and falx cerebri are not identifiable. The thalami are partially separated. The septum pellucidum and the corpus callosum are absent. These findings indicate semilobar type holoprosencephaly. In twin B (D–F), MRI shows that the falx cerebri and interhemispheric fissure are partially formed in the anterior and posterior portions of the brain, but in the middle portion, the hemispheres are fused (arrow). These findings indicate middle interhemispheric fusion. (A, B, D, and E: T1-weighted images in the axial view; C: T1-weighted image in the sagittal view; F: T2-weighted image in the coronal view.)

Early swimming

See video:  http://video.foxnews.com/v/4881616600001/babys-swim-survival-lesson-draws-outrage-praise-online/?intcmp=hpvid1#sp=show-clips

https://www.youtube.com/watch?v=v0mUPr68x2U
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What is the earliest age I can enroll my child to learn to swim?

We teach students as young as 3 months old. If enrolling at that age, please see Tadpole and/or Swimboree.

Tadpole

3 Months to 35 Months with Parent (8 Children Max)

This is our starting program for all infants and helps us introduce them to the water for the first time, reducing their fear and the potential of tears. Using our parent-assisted approach, we will work with you and show you how to swim safely with your child.

Swimboree

3 Months to 35 Months With Parent (4 Children Max)

Focusing on water survival, babies are taught these skills on a one to one basis through a structured program of songs, games and fun. Entry into this class can only come after Tadpole enrollment and will be decided by the instructor.

http://britishswimschool.com/