Deliberate termination of life of newborns with spina bifida, a critical reappraisal

Objects Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective.
“An infant with spina bifida cannot ‘suffer unbearably’. Infants might be able to experience unbearable pain, but spina bifida does not cause it.” (Chervenak 2006)
Introduction and historical overview of the treatment of newborns with MMC
Before the 1960s, most newborns with meningomyelocele (MMC) were not treated given the consideration that it was in the best interests of the child and family, in most cases resulting in the death of the child. They died from sepsis, meningitis, hydrocephalus, or renal failure. Contraindications to operation included “hydrocephalus, irreparable deformities, paralysis of the sphincters, complete paraplegia or any ulcerative process in the region of the spina bifida” [22]. The influence of the surgical approaches since the 1960s allowed gradually effective early treatment of the complicating hydrocephalus, resulting in many patients surviving into childhood. Early treatment of the spinal lesion and hydrocephalus resulted in decreased mortality and morbidity [66]. ‘Wait and see’ changed into active treatment. Lorber (1971) published the first large series of patients treated between 1959 and 1969 [44]. He found that only 7% of the survivors had less than “crippling disability”, “most had a quality of life inconsistent with self-respect, learning capacity, happiness, and even marriage”. To “spare children and families prolonged suffering” he proposed the well-known ‘Lorber selection criteria’. These four major adverse criteria are: severe paraplegia, gross enlargement of the head, severe kyphosis or scoliosis and associated gross congenital anomalies (such as heart disease) or major birth injuries. No active treatment was advised for children who had one or any combination of these criteria. The result of this proposed selection was to treat only those with lesions on lumbar and sacral level without any other major complication. Others would, according to Lorber, “die quickly”.
Since the Lorber era there have been tremendous successes in the treatment of patients with MMC [48, 50]. Over the last 30 years, continual progress has not only been made in the neurosurgical (closure of the back defect, shunting, or endoscopic techniques for the complicating hydrocephalus, treatment of tethered spinal cord and Chiari II malformation), orthopedic (treatment of scoliosis, correction of club feet), urological (preserving normal renal function, securing social continence), and psychosocial treatment of patients with MMC, but also in support for independence by modern rehabilitation programs.
Nevertheless, early decision making (for restriction) and selective treatment of newborns with MMC is still propagated [27, 69], resulting in approvals but also in critiques [7, 23, 41, 42, 49, 79].
What is considered ethical at one time, or in one country, can be considered unethical or unacceptable at/in another. The ethical debate on treating children with MMC is unique in the sense that these children will/can have a life of substantial and sometimes severe physical disability but often with normal mentation, this in contrast to severely psycho-motor handicapped children. Children and adults with MMC can be aware of their deficits.
Lorber (1971) stated that untreated children will die quickly [44]. However, he delivered the children anticonvulsants to prevent seizures, opioids and chloral hydrate to prevent pain [25]. One pediatrician has said that these untreated children received the same care and attention as others, being fed and loved, but they also received 60 mg/kg body weight of chloral hydrate, four times a day. This was being administered for pain, but the children who were operated on did not receive this regimen. Another physician just said: we don’t feed them [79]. Consequently, the duration of life seems to depend on the attitude of the responsible doctor.
In the United States, untreated children were not given morphine or anticonvulsant drugs and were fed every 4 h, resulting in many ‘survivors’ with severe handicaps. On the contrary, in the United Kingdom the children died quickly. However, the question remains if these children were really in pain or suffered from seizures; perhaps not.
Not all physicians did follow the ‘Lorber criteria’, but treated all children unselectively, regardless of the level of the lesion. This approach resulted in multidisciplinary MMC clinics and MMC teams. The nonselective treatment of newborns with MMC started in the early 1970s and gives us a picture of long-term outcome of newborns with MMC [4, 9, 32, 48, 52] and also of the quality of life and health status of adults with spina bifida [58, 63]. Some physicians became bitter after treating children with MMC for years [2].
In the early 1980s, the ‘Baby Jane Doe (‘Stony Brook baby’) case resulted in the United States in an ethical debate on the prospect physicians make about the future life of handicapped children born with MMC. This girl was born with MMC, complicated with hydrocephalus (although diagnosed by the attending physician as microcephalic). The team of physicians told the parents that the child would spend her life “lying in bed, bottle fed....She would experience no joy, sadness or any such emotion except response to pain and would develop no cognitive skills. She might survive for 20 years” [51].
Based on the given information, the parents agreed not to treat their child. However, the physicians turned out to be wrong. Although the child developed meningitis, sepsis, and hydrocephalus (which were only treated to some extent), she survived all these complications, was taken home, became ambulating and communicating on an acceptable level of intelligence, all this despite the partial treatment [24, 25].
After the introduction of alpha feto-protein (AFP) screening in the late 1980s (followed by amniocentesis) and ultrasound diagnosis, many fetus with MMC can now be detected early in pregnancy. Nowadays, after being counseled, most pregnant couples decide to abort a fetus with MMC (in many Western countries resulting in an abortion rate of 95%, resulting in fewer children with MMC born [13, 14, 53]), seen by many as ‘prevention’ of MMC. But what advice should neonatologists, neurologists, or neurosurgeons give the parents when a full-term child with MMC is born? Is the advice not to treat, or to terminate the life of the newborn deliberately (involuntary euthanasia) an ethically defendable one?
Deliberate and active termination of life in newborns with MMC is only discussed and practiced in an open way in the Netherlands [35, 38_40, 71_76, 78]. The judgment “unbearable and hopeless suffering” of the newborn and “the prospect of unbearable and hopeless suffering” in the future, together with the notion that there is “no other proper medical means to alleviate the unbearable suffering” form the basis for this decision [73]. Because these judgments are questioned, and to quantify the level of discomfort in these neonates, the “Rotterdam Prospective Study on Discomfort in Newborns with Spina Bifida” was started in 2005 in the Erasmus Medical Center (EMC)–Sophia Children’s Hospital (Rotterdam, the Netherlands). Although in due time the results of this study will be published, some important aspects will already be addressed in this paper by elaborating on the case of a newborn with a very severe form of MMC and hydrocephalus.
Deliberate termination of life in newborns with MMC in The Netherlands
The Dutch neurosurgeon De Lange analyzed the selection criteria for treatment of newborns with MMC in the Netherlands already in the 1970s [41, 42]. It became clear from an enquiry among Dutch neurosurgeons that a number of them advised against treatment on the basis of physical handicaps alone. Others regarded the expected mental abilities as an overruling factor. When basic communication skills could be expected, most children were treated. At the time, deliberate termination of life was never practiced. De Lange (1970) also concluded “If we were to decide that in our opinion patients with spina bifida who are below a certain level of physical or mental ability should not be kept alive, it should be illogical not to apply the same rules to other categories of handicap.” [41]
In the 1980s, the Dutch ethicist Hertogh (1988) published his paper “Ethical considerations on the dilemmas caused by the selective treatment of newborns with MMC” in the leading Dutch medical Journal [30]. He elaborated on the philosophical and ethical aspects of the Lorber selection criteria: “The objective medical fact of a physical shortcoming is something completely different than the subjective reality of ‘being-handicapped’ itself. Studies have shown that living as ‘being-handicapped’ does not correlate directly to the severity of physical shortcomings. The question as to what can be considered as an acceptable handicap transgresses, in other words, the scope of what can be ascertained in a medical-scientific way and this, therefore, refers inevitably to the subjective experience. It has to be questioned whether the quantification of qualitative aspects of medical treatment perhaps offers nothing more than pretence-rationality, caused by the used decisive terminology. In conclusion: up to date the criterion ‘quality of life’ appears to be more deceptive than clarifying in the medical decision about the possible continued existence of a newborn with spina bifida.” [30] He also referred to the ethics of the philosopher Levinas: “Ethos cannot be founded in scientific facts; it is founded in the human relationship itself. Mutual dependency, which is characteristic for ‘human being’, makes us responsible just by itself and therefore defines ‘the disposition of ethos’ as a rational fact. This relationship always precedes facts themselves.”[30] In other words: human beings, just because of the fact that they are human beings, have an intrinsic and mutual responsibility for the well-being of others, this responsibility itself preceding physical qualities. This thoughtful paper, however, was not given much attention in the Dutch medical press.
In 1993, baby Rianne was born in a small town in the Netherlands with a MMC at level of the first and second lumbar vertebrae complicated by hydrocephalus. The lower limbs were deformed and paralyzed. Computed tomography (CT) scan of the head confirmed the diagnosis of severe hydrocephalus. On the first day of her life, the decision was made by the pediatrician and the gynecologist in consultation with a neurologist, neurosurgeon, and pastor not to operate the back lesion and the hydrocephalus. On the fourth day of her life, at the request of the parents, the gynecologist Prins terminated the life of the baby by a lethal injection. In an interview, Prins stated [37]: “Closing the defect and fighting infections with maximal treatment could enable the child to survive for years. No one knows how long”. On the question of what an operation could have accomplished, Prins answered: “The defect would have been closed. The possibility of secondary infection, which was an immediate threat to her life, would have been diminished. Her brain pressure would rise, however, and it would have been necessary to implant a shunt”. On the question of how he would calculate the benefit of treatment, he answered: “It (the operation) would have prolonged her life without treating the symptoms and consequences of the defect because the operation would not have alleviated them. The operation would only have minimized the possibility of infection, but it would have created the necessity for repeated operations involving the shunt and the urological system because there were obstructions in the passage between the kidney and the bladder. Her brain damage was so extensive and the possibility of movement so limited. She would never have been able to walk or sit unsupported; she would have been incontinent in her bladder and bowel. There was sensory damage as well; she could not feel sensation in her lower body. She would have started life with repeated operations, need for persistent medical attention, no possibility for self-support, and very low communicative ability” [37]. As a definition of a severe handicap he stated: “This can relate to the estimated possibility of becoming happy” [37], and he further referred to the Dutch Association of Paediatrics who developed criteria, including the lack of capacity to communicate, lack of capacity for self-maintenance, persistent need for medical assistance, and the existence of pain. All these criteria grouped together gave a picture of the baby’s quality of life. Because most of the criteria were satisfied, the baby was considered to be severely handicapped, resulting in a very poor expected quality of life; the child was not operated on because of the severity of the expected handicaps.
On the necessity of life-termination, Prins (1997) explained: “The baby was in a great deal of pain and the normal analgesics did not work well. So it would have been necessary to use narcotic analgesics—morphine-like drugs. And that would have caused depression of consciousness. It is clear to me that the use of such drugs would have depressed normal functioning—behavior, expressions, and sensibility. Using morphine-like drugs would have caused a situation of floating between heaven and earth. It would have been dishonest and should be considered as unethical and unjust. There is no moral difference between killing and withholding useless medical treatment. There is an emotional difference. And there should not be a legal difference” [37].
Although elements of the offense of murder were proven, the physician was acquitted based on the unavoidable conflict of duties between his duty to prolong life and his duty to alleviate unbearable suffering [26].
In 1996, three Dutch child neurologists and one neurosurgeon questioned in the leading Dutch medical journal the active termination of life of newborns with MMC [59]. They defended the opinion that (severe) handicapped life could also be meaningful. Deliberate termination of life was not considered appropriate; sedation and the delivery of opioids were mandatory in the case of suffering. Not treating a child with MMC should not result in a more severe handicapped life; the decision to withhold treatment was only made in the case of severe pulmonary or cardiac complications with the prospect of early death. The possible suffering of the parents should not be an indication for deliberate termination of the life of a newborn with MMC. They referred to the study of Steinbok et al. (1992) [68] for their argument that the life of children and adults with (severe) MMC can be meaningful [59].
In 2003, the Dutch physician/medical ethicist Van de Vathorst stated that whenever it is decided not to treat a defective newborn, deliberate termination of the life of this newborn should be regarded as a moral demand, based on the principle of ‘mercy’ [72]. She illustrated her arguments with a case of a newborn with a thoracic MMC. Interestingly enough, the life of this child was not terminated. It died by itself, a few days old, because of pulmonary insufficiency. Although she received a national award for this paper, it resulted in several disapproving letters to the editor.
In January 2005, two pediatricians, one physician, and one pediatric neurologist reported on the deliberate termination of life of 22 newborns in the Netherlands between 1997 and 2004 [73]. Explaining the fact that all 22 cases were newborns with MMC and hydrocephalus, Verhagen et.al. referred to the ‘baby Rianne case’, stating that “her life was dominated by unbearable suffering” and “since this case it is established that newborns with a severe form of spina bifida do suffer severely” [73].
According to the authors, the deliberate termination of life was necessary because of the presence of “unbearable and hopeless suffering, acutely and long-term, with no other proper medical means of alleviating the suffering” [73]. All parents consented to the proposal of termination of life; in four cases, they explicitly requested for it. For the public prosecutor, the termination of life was acceptable if four requirements were properly fulfilled: (1) the presence of hopeless and unbearable suffering, (2) consent of the parents to termination of life, (3) consultation of another physician or of a multidisciplinary MMC team, and (4) a proper and careful execution of the termination. These four criteria eventually became the cornerstone of the so-called ‘Groningen Protocol’, a protocol meant to insure that the decision for life termination, the executing itself, together with reporting to the legal authorities, are all conducted in a proper way. This protocol was approved and adopted by the Dutch Association of Paediatrics in 2005.
The motivation for the judgement of ‘unbearable and hopeless suffering’ in the 22 cases of spina bifida was [73]:
‘suffering’ (acute and chronic pain, physical pain) (100% of the 22 cases);the ‘lack on ability to live or do things independently’ as the result of ‘severely disturbed sensomotoric development’ (100% of the 22 cases);the ‘lack of possibility to verbal and non-verbal communication’ (82% of the 22 cases);‘the prospect to dependency to the medical circuit as the result of frequent hospital admissions and operations’ (77% of the 22 cases)the ‘life expectation’ (‘the burden of severe suffering increases by a longer life span’) (in 59% of the 22 cases).
None of the cases led to prosecution; all cases were found to be in accordance with good medical practice.
This article of Verhagen et al. (2005a) gave rise to only a few reactions in the Netherlands. Kompanje et al. (2005) [38] questioned the validity of ‘unbearable suffering’ as a useful criterion. They also stated that with the use of modern palliative care, ‘suffering’ always can be dealt with in an adequate way, as did Laane (2005) [39, 40]. De Jong (2006) [35] made a plea for ‘letting them die’ instead of ‘making them die’ in the case of an untreated newborn with MMC.
On request of the editor of the New England Journal of Medicine, Verhagen and Sauer (2005) published another article concerning the Groningen protocol and the 22 cases [75] and a similar article appeared in Pediatrics [76]. The reactions in the international medical press were mostly negative. In his article “Control of suffering on the slippery slope of care” in the Lancet, Feudtner (2005) also addressed the poor quality and the insufficiency of the offered palliative care and questioned whether legalization of active termination of life might not lead to the abuse of it [21]. Saugstad (2005) stated in the Acta Paediatrica: “Neonatologists must be extremely careful not to start on the slippery slope ending in the Dutch practice of euthanasia of newborns. I would strongly warn against this attitude, which I find non-compatible with Western humanistic traditions” [61]. Jotkowitz and Glick (2006), in the Journal of Medical Ethics, were worried: “We feel an important line has been crossed if the international medical community consents to the active euthanasia of severely ill infants and are concerned about the extension of the policy to other at risk groups” [36]. Bondi et. al. (2006), in Pediatrics, made a plea for an open discussion: “Rather than performing an in-depth examination of the philosophical, ethical, and moral implications of this protocol, the authors focus on its technical details and acceptability within the European medical community. The Groningen Protocol centers not on patient self-determination, but instead on the perception of the patient’s current and future suffering. Although the authors note that an open discussion of these issues is ‘extremely important,” they fail to initiate it. We hope that thoughtful ethicists and legislators will initiate the open discussion that the authors advocate” [8]. In their article ‘Why the Groningen Protocol should be rejected’, Chervenak et al. (2006) concluded that: “The justification they offer is woefully inadequate. It relies on appeals to the concepts of “hopeless and unbearable suffering,” the “best interests of the patient,” and “medical-ethical values,” but it never explains these concepts, and it gives no ethical argument for their clinical application. In fact, not only is no argument for the Protocol given, none can hope to succeed. The Groningen Protocol should therefore be rejected as the basis for obstetric and neonatal practice in The Netherlands and throughout the world.” (11)
Manninen (2006a), finally, made an important contribution with her article “A case for justified non-voluntary active euthanasia: exploring the ethics of the Groningen Protocol” in the Journal of Medical Ethics [45]. She made a thoughtful plea for the ethics of the Groningen Protocol: “What the Groningen Protocol proposes to do is both ethical and also the most human alternative for these suffering and dying infants.” Newborns eligible for this protocol “do face no future at all—that is, the infants must be terminally ill”, “will die soon no matter what actions doctors undertake, modern medicine can do nothing to save them”, “have no prospects, have crossed the threshold into a comparatively valueless state of existence”, “will spend the remainder of their lives in a chronic state of nothing but pain and suffering” [45]. Interestingly enough, on November 23 an additional letter of herself, “Regarding the Groningen Protocol” [46], was published in the same journal. Some key passages of this letter: “It has recently been brought to my attention that the physicians of the Groningen Hospital who originally proposed the Groningen Protocol have proposed to violate the first two conditions of the original Groningen Protocol: (1) The suffering must be so severe that the infant has no prospects for a future; (2) There is no possibility that the infant can be cured or alleviated of her affliction with medication or surgery. For example, Dr. Verhagen has maintained that the Protocol could apply to infants that are not necessarily terminally ill, but nevertheless may face a compromising future. In essence, the Groningen Protocol has begun to make quality of life judgments. If the Groningen physicians have commenced making quality of life judgments, they have strayed away from the original purpose of the Protocol, and this, I believe, may have concerning ethical implications. As I write in my paper: “...the Groningen Protocol does not make quality of life judgments, and it is because of this very important requirement that the Protocol strikes me as humane and morally permissible, for it seems utterly vicious to extend the life of a suffering infant with no prospects for a future. If the infant did have a possible future ahead of her, I would be more hesitant to condone a legal practice that begins to make quality of life judgments, for such judgments can be, and have been, subject to error.” [46] In her opinion, in these end-of-life decisions ‘quality of life judgments’ should not be made and, in a way, with this letter she also highlights the inconsistencies in the reports by Verhagen et al. Being of crucial importance, the subject of ‘quality of life judgments’ will be discussed more extensively in paragraphs 4 and 5.
Finally, in 2006, in The Netherlands a national multidisciplinary expert review committee has been appointed. In the case of active termination of the life of a newborn, the responsible physician is supposed to inform this committee, which then has to determine whether the criteria for life termination have been met. Subsequently this committee has to advise the Public Persecutor’s Office (OM) whether the physician should be prosecuted or not. Although such a committee seems to guarantee more certainty, it can be doubted, however, if this ‘checking on afterhand’ is of much value for the newborn in question. It seems to be more sensible to change this procedure to a ‘checking on beforehand’. Legally, this might perhaps be difficult to establish, but it seems not justifiable that legal procedures themselves do dominate the question of appropriateness of life termination; errors in judgment being unacceptable (cf. the level of certainty required for a death penalty in crime in, e.g., the USA).
Analysis of the mentioned criteria for non-treatment and deliberate termination of life
Suffering
The actual presence of acute unbearable and hopeless suffering of the newborn and the prospect of future/chronic unbearable and hopeless suffering as the result of handicaps, pain, and discomfort is the most given argument for deliberate termination of life in neonates with MMC. In the recent Dutch series, this suffering was stated to be present in 100% of the 22 cases [73, 75, 76].
Acute pain Not any convincing evidence can be found in the literature that newborns with MMC actually do suffer from untreatable pain in the days after birth caused by their back lesion or by other complications. A pediatric surgeon who devoted much of his professional life of more than 30 years to the treatment of those who have been born with spina bifida stated: “I personally have seen little evidence that the babies have pain in the newborn period, nor have I found them unable to sleep.” [79] Delight and Goodall (1988; 1990) [17, 18] studied the experiences of parents of 44 children born with MMC, all managed without any surgery. All 44 children died before their first birthday. Only a quarter of them did require some medication such as analgesics and anticonvulsants; half of them were given drugs in the dying period. Analgesics were given in a low dose simply to enhance their quality of life [17, 18].
Chronic pain The literature on chronic pain in MMC is scarce. The first systematic examinations of the nature and prevalence of pain in children with MMC was published in 2005 [12]. Headache is not uncommon in adults with MMC and is associated with hydrocephalus. In this series, 56% of 68 patients reported experiencing pain once a week or more frequent. Of the shunted children, 88% reported headaches compared to 79% of the children without a shunt [12]. Children in this study reported frequent and sometimes intense pain at multiple locations associated with the physiological sequelae, equipment usage, and medical management of the disability. The authors concluded that children with spina bifida frequently report clinically significant, under-recognized and untreated pain, and they propagated proper care and adequate medical management of these children. In another series, 55% of 42 patients underwent investigations for one or more episodes of chronic headache due to shunt malfunction, ventriculostomy failure, or symptomatic Arnold–Chiari malformation [20]. Although all these problems sometimes can be fairly serious, the notion of ‘unbearable and hopeless suffering’ is never mentioned.
The ‘lack of ability to live or do things independently’ as the result of ‘severely disturbed senso-motoric development’
The second argument for unbearable and hopeless suffering is the prospect of lack of ability to live or do things independently as the result of severely disturbed senso-motoric development experienced by the patient in childhood, puberty, and adult life [73].
McLone reported in 1982 the results of the unselective treatment of 100 consecutive newborns with MMC [48]. After a follow-up period of 3.5 to 7 years there were 86 survivors. He concluded that the total percentage of children who could be independent and competitive is approaching 70–80%. Hunt and Oakeshott (2003) [32] and Oakeshott and Hunt (2003) [52] studied the outcome in 117 unselected and actively treated patients with MMC at age 35. The patients were treated between 1963 and 1971 without any attempt at selection. Forty-two patients had a severe lesion at a sensory level above Th11, 30 of whom died, most before their first birthday. They died mostly of cardio-respiratory or renal failure, hydrocephalus, or CNS infection. Two of the 12 survivors live independently, drive cars, and have an open employment; six have an IQ >80. In another study [62], 29% out of 60 adolescents with spina bifida had the lesion at a high lumbar or thoracic level. The authors studied the quality of life in these patients. They concluded that there were no significant relationships between the level of the lesion or spina bifida severity and the overall quality of life, which appeared to be 70 to 80 on a 100-point scale; both patients and their parents view the overall quality of life positively [62].
Besides these results, criteria such as ‘living independently’ or ‘doing things independently’ can be confusing when deciding about the future life of vital newborns. Most people who do live a meaningful life are dependent on others or interdependent on each other. In fact, interdependency and especially the willingness to care for other (perhaps dependent) people can be considered as a criterion of a truly civilized society, certainly so when this means to offer ‘something for nothing’ (this being real mercy).
The ‘lack of possibility of verbal and non-verbal communication’
In 18 of the 22 studied Dutch cases, it was predicted “(future) communication of and with the child would not be possible, neither verbally nor nonverbally” [73]. In other words, these babies were predicted to be or to become in a state of deep coma or in a persistent vegetative state. Neither of these states of very severe disturbed consciousness, however, is applicable to a newborn with MMC and hydrocephalus. Furthermore, several publications concerning the level of mental functioning of adults with MMC have been published [3, 4, 9, 32, 33, 47, 67, 68, 70]. Intellectual development varies between normal IQ (this being the case in 60% [9, 68] to 70% [32] of the studied population) and severe mental disability, but the predicted complete absence of the possibility to communicate is never mentioned. On the contrary: “Virtually all infants with spina bifida are capable of meaningful human relationships, independent of the level of the lesion. Indeed, most are of normal intelligence” [23]. Aside from this incorrect medical description there are some other important aspects that need to be highlighted. When all communication is claimed to be impossible, one wonders by what methods at all (the amount of) suffering can be established. Furthermore, when a person is in such a state of deep coma or in a persistent vegetative state, there simply is no cognitive experience whatsoever, also not of (unbearable) suffering. This was confirmed in a recent conviction of the Dutch Medical Disciplinary Committee against a general practitioner who euthanized a comatose patient; the ground of the verdict being “because of the comatose state there was no longer any question of unbearable suffering nor any question of euthanasia” [15].
‘The prospect of dependency to the medical circuit as the result of frequent hospital admissions and operations’
It seems hardly possible to quantify this criterion in such a way that it can be used to justify life termination of vital newborns. When compared to persons with other congenital malformations or congenital diseases or some acquired diseases, patients with MMC do not appear to need substantially more medical care than, e.g., patients with intracranial tumors or with chronic diseases such as severe pulmonary, cardiac, or neurological disorders. Furthermore, the claim of Verhagen (2004) that “this child would have to undergo at least 60 operations in the course of a year to temporarily alleviate its problems” [71] again cannot be substantiated: a retrospective survey of treated newborns with MMC over 2 years in the Sophia Children Hospital showed that three to four operations were needed in their first year of life.
‘Life expectation’ (‘the burden of severe suffering increases by a longer life span’)
It is clear that the longer a patient lives, the more medical care will be needed in a quantitative way. Whether this means that this will affect the experienced quality of life in a negative way remains totally unclear and cannot be predicted. Furthermore, patients with MMC do require relatively much of their medical care in their first two decades, this steadily decreasing when they grow older and when disabilities and coping with these disabilities are gradually stabilized.
Can ‘suffering’ be applied as a reasonable criterion in newborns?
Suffering, especially the ‘unbearable and hopeless’ aspects of it, is a complex psychosocial phenomenon and by definition strictly individualized: only the individual itself can experience the existence, the intensity, and hopelessness of it. Others (parents, physicians, nurses) can only to some degree make an estimation of it. It is therefore tentative whether ‘suffering’ can be applied to newborns at all. What is possible, however, is to establish quite precisely the level of ‘(dis)comfort’ of a newborn by making use of standardized score charts such as the Comfort score and the Visual Analogue Scale (VAS) (see below).
The Dutch physician Beijk(1998) stated it as follows: “suffering will be interpreted by every patient, by every doctor, and by every other involved person in a different way and therefore can lead to completely different conclusions. The bearableness is especially dependent on personal and environmental factors; it is all about the subjective experience of the individual itself who is suffering, about the durableness of the suffering, and about the wish to die” [6]. In 2005, in his Ph.D. thesis, also Hamburg (physician and jurist) concluded “for the criterion ‘suffering’ there are no objective or scientifically validated criteria available, with the consequence of decisions of life-termination being dependent of the subjective judgment of the doctor, leading to inconsistent decisions” [29]. Therefore, according to Hamburg, “in a time of evidence-based medicine ‘suffering’ is not acceptable anymore” [29], as also was suggested by Kompanje et al. (2005) [38]. Although Beijk and Hamburg are referring to the practice of euthanasia (which in the Netherlands is strictly referring to competent patients wishing to die), their statements are the more applicable to newborns, as in these cases predictions are being made about future suffering of others. According to Chervenak et al. (2006): “An infant with spina bifida cannot have and therefore cannot have lost the ability to realize intentions, desires, and hopes for the future; it can feel pain but cannot ‘suffer’ as a psychosocial phenomenon” [11]. Laane (2005a) came to the same conclusion: “having no biographical consciousness, ‘suffering’ cannot be applied to newborns [39]. To date, it is unclear why this improper use of ‘suffering’ still continues in this debate.
Can physicians predict quality of life?
Counseling the parents
In a time in which most fetuses with MMC will be detected by AFP and amniocentesis or by ultrasound diagnosis (in most cases being followed by iatrogenic abortion), the birth of a newborn with MMC is increasingly becoming a rare phenomenon [14]. The decision to terminate a pregnancy in the case of a fetus with MMC is usually made shortly after the diagnosis. It can be questioned whether there is enough time for proper counseling about the prospect of living with spina bifida, as a patient and also as parents. Freeman (1998) stated: “Decisions are made by the parents without knowledge of the child’s future; without knowing whether the child will have minimal deficit and walk with only short leg braces or walk with no braces at all, and without awareness of whether this child will have a thoracic lesion with high paraplegia and spend his or her life in a wheelchair. Few parents at that stage in the pregnancy know much about spina bifida or about what life will be like for that child and for that family. In other words, these rarely are informed decisions” [25]. He points in the same direction concerning physician experience: “Today, few younger physicians have experience with the decision-making process for spina bifida either before or after birth. Thus, physician advisors will lack experience with the joys of caring for a child, even a handicapped child, as well as experience with the pains and problems. They will have little experience with the feelings of the handicapped children themselves. With the lack of experience, how should the physician counsel? On what basis can the inexperienced physician advise uninformed parents? What decision should the parents make?” [25]
In their article “Tell the truth about spina bifida,” Bruner and Tulipan(2004) also showed their worries about the quality of counseling: “Unfortunately, many healthcare professionals are equally ignorant of the current prognosis of children with spina bifida who have ready access to comprehensive care in a modern multidisciplinary clinic. As a result, much of the information initially provided to couples with a newly diagnosed fetus is biased and misleading. As medical ethicists Bliton and Zaner at Vanderbilt University Medical Center observed, “To date we have met and held intense conversations with more than 150 pregnant women and their partners. Many times, couples admitted, the initial counseling they received from their obstetrician was slanted—both against disability and toward termination of pregnancy. What they remembered was how the initial obstetric consultation portrayed as grim a picture as possible about their future child’s prognosis.” [10]
The statements of Verhagen et al. (2005) mentioned earlier, together with other incorrect predictions (“these newborns have no prospect of a future and no chance to survive at all; are barely able to breathe”, “these children face a life of agonizing pain that cannot be alleviated by any proper medical means”, “the child would suffer such unbearable pain that it has to be constantly anaesthetized” [71], that “they all have spina bifida of the most severe form at level of the neck and all have non-functioning kidneys” [78]), unfortunately seem to confirm these worries, also in counseling the parents of a newborn with MMC. To date, it is not clear why such incorrect information is presented to parents, colleagues, and society as a whole. When parents are told that communication with and of their child never will be possible, that their child will face a life of agonizing pain and will suffer unbearably, that this suffering cannot be alleviated by any means, that annually at least 60 operations will be needed to offer some (but only temporary) relief, then these parents are left without any hope and their consent/decision to non-treatment, or to active termination of life, almost can be predicted. However, in such situations the fundamental concept of ‘informed decisions’ is obviously violated.
Does the level of the lesion matter?
Does the level of the lesion determine the amount and severity of disturbances? In general, the higher up the spine the lesion is, the more likely are severe neurological disabilities to be found. Cervical lesions often do not contain neural tissue and are simple meningoceles. At lower levels (thoracic and especially lumbar), the converse is true: the infant nearly always being (partially) paralyzed below the level of the lesion, the cord showing the classical features of dysplasia [66]. However, the extent of handicaps that a person with MMC experiences is determined not by the site of the lesion, but almost entirely by the neurological deficit. Verhoef (2005) concluded that young adults with a mild form of spina bifida (and subsequently with few disabilities), did experience their disabilities more often as problematic than contemporaries with a serious form of spina bifida [77]. Likewise, in the study of Seller (1990) [65], eight patients ended up with minimal handicaps, having bony lesions in the thoracic (one patient), lumbar (two patients), and lumbosacral (five patients) spine. Three others with lumbosacral bony lesions were among the most gravely handicapped [65]. According to Hetherington (2005), low lesions do not necessarily indicate a mild course; physical well-being was not related to the level of the spinal lesion [31]. Although persons with sacral lesions showed less impairment compared to persons with higher spinal lesions, Padua et al. (2002) did not find a correlation between quality of life (both physical and mental) and the site of the lesion [54]. According to Pit-ten Cate et al. (2002), lesion level, type of spina bifida, and gender were not significantly related to the quality of life in children with spina bifida [55]. This is in agreement with the results of the study of Sawin et al. (2002) [62]: no significant relationship with lesion level, spina bifida severity or shunt status and quality of life was found in 60 adolescents. Schoenmakers (2003) [64] concluded that being independent in mobility contributes more to quality of life than other functional abilities such as whether or not being wheelchair-dependent. And, although children with the most severe forms of MMC have significantly more and severe disabilities than children with milder forms of MMC, scores about self-esteem did not differ significantly between the two groups [64].
In conclusion, the level of the lesion does not correlate with the actual experience of the handicaps themselves.
Is the diagnosis ‘extensive brain damage’ easy to make?
There is little doubt that surgical procedures are unjustified in hydrocephalic newborns with little or no potential for independent survival, the decision as to what constitutes as irreversible and severe brain damage may however be difficult to make. Ventricular size alone cannot be used as a conclusive predictive criterion. It has been repeatedly demonstrated that there is no consistent correlation between the thickness of the cortex and the eventual psychomotor development. Barf et. al. (2003) [3] concluded that cognitive status was especially negatively influenced by multiple shunt revisions and by other pathologies associated with hydrocephalus. Amacher and Wellington (1984) [1] treated 170 children with hydrocephalus in 636 operative procedures and concluded that “there is no difference in results based upon measurement of the initial thickness of the cerebral mantle.” They found normal intelligence in 63% of the 5-year survivors. In a recent study also, Beeker et al. (2006) described the difficulty in making a reliable prognosis of the intellectual development based on ventricular size [5].
‘Quality of life’, to conclude
It seems impossible to predict with certainty the future quality of life of newborns with MMC. One also has to be aware of the fact that the self-reported quality of life of children with handicaps does not differ from that of children without disabilities, and health care professionals are known to underestimate disabled persons’ quality of life as compared to self-reports [11]. Generally speaking, prognostic judgments about quality of life are conceptually plausible; their failing is simply that, given the available evidence, they do not appear to be reliable [11]. Finally, and perhaps the most important, quality of life judgements are considered as being ethically unacceptable in end-of-life decisions [45, 46].
Non-discrimination principle
In his Ph.D. thesis, Dorscheidt (2006) raises the issue as to whether the deliberate termination of the life of disabled newborns is compatible with the ‘non-discrimination principle’, in particular the legal prohibition of discrimination on the ground of disability [19]. Deliberate termination of the life of newborns with spina bifida is always preceded by a non-treatment decision (as in the baby Doe case and the baby Rianne case) and according to Dorscheidt, the decision of non-treatment should be questioned with regard to the non-discrimination principle as well. He elaborates on two fundamental rights of the child, being the child’s right to life and its right to health(care), mentioned in international human rights instruments such as the Universal Declaration of Human Rights (UDHR), The United Nations Convention on the Rights of the Child, and the European Convention of Human Rights, and on the authoritative views of international human rights bodies such as the United Nations Children’s Rights Committee (UNCRC) and the Committee on Economic, Social and Cultural Rights (CESCR).
Some examples: Article 25, UDHR: “Everyone has the right to a standard of living adequate for the health and well-being of himself, including medical care and the right to security in the event of disability. All children shall enjoy the same social protection”. CESCR, par. 26: According to standard Rules: ”States should ensure that persons with disabilities, particularly infants and children, are provided with the same level of medical care within the same system as other members of society.” UNCRC: “In its examination of States parties reports, the Committee should commit itself to highlighting the situation of disabled children and the need for concrete measures to ensure recognition of their rights, in particular the right to live, survival and development”. UN, General Counsel: “We will take all measures to ensure the full and equal enjoyment of all human rights and fundamental freedoms, including equal access to health, education and recreational services, by children with disabilities and children with special needs, to ensure the recognition of their dignity, to promote their self-reliance and to facilitate their active participation in the community”. Proposal text of the American delegacy for the UN Convention to Promote and Protect the Rights and Dignity of Persons with Disabilities: ”States Parties reaffirm the inherent right to life of all persons with disabilities, shall take all necessary measures to ensure its effective enjoyment by them, and shall ensure that disability, or perceived quality of life, shall not serve as a basis for infringement of the right to life.” [19]
These international political statements and agreements are also reflected in the resolution of the International Federation for Spina Bifida and Hydrocephalus (IF) as formulated at the 12th International Conference (“The Right to be Different”) for Hydrocephalus and Spina Bifida in Toulouse [34]:
People with spina bifida and hydrocephalus can live a full life with equal value to that of any other citizen and they should not be seen as a medical condition. Their views should be sought and heard by governments and health professionals, who should acknowledge the right of people with spina bifida and hydrocephalus to speak for themselves.People with disabilities have the right to aim for lives as rewarding as those of their peers who have what is regarded as a normal life. Supportive systems must be in place when they are needed.Experience over the past 30 years has improved considerably the medical outcome and the quality of life of people with spina bifida and hydrocephalus.Most adults with spina bifida underline that their quality of life is not automatically—and should not be given as—a reason for abortion [34].
As a recognition of the importance of non-discrimination on the basis of disability (that is to say, present as well as expected disability) or (expected) quality of life in deciding whether or not a newborn child with, e.g., spina bifida should be treated or whether or not it is justified to deliberately terminate such a child’s life, Dorscheidt (2006) recommends to involve the legal concept of ‘objective justification’ in the medical-decision making process. By using a particular questionnaire, the physician in charge may take advantage of this concept when considering (and deliberating on) how to act properly and professionally. Through this, the physician can ensure the disabled newborn child’s rightful claim to equal protection of its right to life and its right to health(care). Doing so would offer possibilities to replace the usual doctor-centered approach of decision making by a more patient-centered approach as well.
To summarize from another perspective: “Prominent theories of justice emphasize equality of opportunity for human experience and development; if society has an obligation to provide citizens this very broad equality of opportunity, then it has an obligation to shoulder the burden of care associated with citizens who have spina bifida” [11].
Palliative care for untreated newborns with MMC
When a newborn with spina bifida is not treated, discomfort can be expected in the nearby future caused by the lesion itself (e.g., by becoming infected), by a subsequent meningitis/ventriculitis, or by raised intracranial pressure caused by an untreated hydrocephalus. Therefore, the decision not to treat should always be accompanied by offering proper palliative care. It is becoming increasingly evident that, taken modern palliative techniques in newborns seriously, pain and discomfort can always be dealt with in an adequate way [43, 57]. In their article “Strong opioids in pediatric palliative medicine” Hain et al. (2005) also stated that “clinical evidence is accumulating that strong opioids can be used safely and effectively; they should be used as part of a rational approach to the management of pain” [28]. This use of strong pain killers is also highlighted in the recent Oxford Textbook of Palliative Care for Children [16]. In the highly unlikely event of insufficient effect of modern pain medication, terminal palliative sedation should be the next step in the palliative approach [16]. With palliative sedation, the possible experience itself of discomfort can always be dealt with adequately. In the “Consensus guidelines on sedation and analgesia in critically ill children” by Playfor et al. (2006) in Intensive Care Medicine, some 20 guidelines are mentioned by which pain and discomfort in critically ill children can be treated in an efficient way; life termination not being mentioned at all [56].
When it is decided that surgical treatment is not a feasible option in a newborn with spina bifida, it is regarded by some to be an act of ‘mercy’ to terminate the life of the newborn [72]. This notion, however, is a misconception: they are not terminally ill because of the MMC and/or hydrocephalus per se; they are ‘terminally ill’ because of the decision not to treat their congenital malformations. The needs of these untreated newborns, however, are still the same as the needs of all newborns: proper care, feeding, comfort, respect and love; till death (and apparently not death itself). The ‘need’ for life termination in these patients can only be regarded as an indication of insufficient palliative care. Life termination as an act of mercy can only be applied to hopeless situations that can occur, e.g., on battlegrounds or in mountaineering, when there are no proper means indeed to alleviate real unbearable suffering. This is obviously not the case in a modern equipped hospital (at least, it should not be) with experience in palliative care and pain management.
This is all confirmed in the paper of Sauer in 2001, “Ethical dilemmas in neonatology: recommendations of the Ethics Working Group of the CESP (Confederation of European Specialists in Pediatrics)” in the European Journal of Pediatrics [60]. In this paper, some ethical principles, applicable to every newborn, are being formulated, like: “decisions to withhold or withdraw treatment should always be accompanied by optimal palliative therapy and dignified and comforting care” and “every form of intentional killing should be rejected in paediatrics” [60]. This is followed by: “However, giving medication to relieve suffering in hopeless situations which may, as a side effect, accelerate death, can be justified”.
To date, it is not clear why these recommendations should not hold for cases of untreated spina bifida and hydrocephalus in the Netherlands and why the Dutch Association of Paediatrics does not adopt these recommendations.
Illustrative case
After an uneventful pregnancy, a full-term female child was delivered spontaneously, Apgar scores being 4 and 5. Physical examination revealed a huge MMC at high thoracic level (Fig. 1), a very large head with a large but soft fontanel, a marked deformation of the thorax with scoliosis, and clubfeet. After counseling the parents, they persisted in their wish to treat the child, if this probably could save her life. The MMC team decided to respect the parents will and on day 3 the back lesion was closed by the neurosurgeon in collaboration with the plastic surgeon, making use of extensive rotational flaps together with free skin grafting (Fig. 2). Shunt placement could be postponed till day 9; a medium pressure valve being used. Because postoperatively the fontanel did not soften adequately, 2 weeks later the medium pressure valve was changed in a low-pressure valve, now with satisfying clinical results.
Fig. 1Photograph of the newborn, showing the extensive MMC, extending from +/− the 4th thoracic vertebra till the midlumbar regionFig. 2Photograph at the end of the surgical procedure. The MMC was closed by making use of extensive rotational flaps together with free skin grafting
All period long, from birth till 1 week after the shunt revision, the well-being of the baby was estimated by making use of the Comfort score and the VAS and also medication used for treatment of pain or discomfort (paracetamol and morphine) was recorded (Fig. 3a,b).
Fig. 3a Comfort scores during the first month of life (min = 5: no discomfort; max = 35: extreme discomfort). Green bars: only paracetamol (intermittently) being used. Green/black bars: low-dose morphine together with paracetamol being used. b The same as a, but now with the VAS (min = 0: no pain; max = 10: most severe pain) Note: The combination of a Comfort score of at least 17 and a VAS of at least 4 indicates that the well-being of the newborn is in jeopardy. In such a situation, the attending nurse is expected to determine the cause of the discomfort and to take adequate measures (changing a full nappy, feeding a hungry child, emptying a full bladder, giving adequate painkillers if appropriate, etc.) to secure the child’s well-being
Studying these data and particularly the amount of medication needed, several conclusions can be made:
When untreated (the first 3 days), the child was not discomfortable.Closing of the back lesion, in this case certainly a major procedure, did not contribute significantly (and only temporarily) to more discomfort. In other words, closing of the open spine can be qualified as a proportional treatment modality.The same holds true for placing a ventricular shunt.Treating an active hydrocephalus adequately contributes to the well-being of the patient.In 1 month’s time, this active treatment resulted in a stable situation of overall well-being in this patient.Only paracetamol and low-dose morphine were necessary in the treatment of actual discomfort.
In summary, this case not only demonstrates that there is no such thing as ‘suffering’ in these newborns, but also the incorrectness of the statement of Verhagen et al. (2005a) [73] that “the suffering of these newborns cannot be alleviated by any means in a proper medical way” (Fig. 4). The overall impression of this case is in accordance with the preliminary results of the Rotterdam Prospective Study on Discomfort in Newborns with MMC: there is no “acutely unbearable suffering” in these newborns (Figs. 5a,b)
Fig. 4The same child at 7 months old; fixating and following with the eyes, vocalizing, normal movements of the arms, moving both legs vigorously (perhaps nonvoluntary), still being partially fed by a nasogastric tubeFig. 5a and b Preliminary results of the Rotterdam Prospective Study on Discomfort in Newborns with MMC (n = 13)
Although in an interview Verhagen himself reported that “all 22 cases had a lesion of the most severe form, at level of the neck” [78], in their published articles Verhagen et al. [73_76] do not quantify the level of the lesion. However, it seems very unlikely that his statement is correct or that the levels of lesion in these 22 cases are of the same level and/or magnitude as in the case described.
Synthesis and conclusion
There is no evidence that newborns with MMC and hydrocephalus do either ‘suffer’ unbearably or hopelessly and certainly not without the prospect to relieve this suffering by standard care. ‘Suffering’ itself is a nonconclusive, and in newborns, inapplicable denominator that should not be used anymore in this debate. Although they will in their future life be confronted with handicaps, sometimes very severe, their future prospects and their actual experienced quality of life cannot be predicted with such certainty at birth that their lives can be regarded as hopeless or meaningless (‘quality of life judgments’ as such being unacceptable in this decision making). Possible discomfort in these newborns can easily be treated in a straightforward way by active treatment (closure of the defect and shunting the hydrocephalus) and, when necessary, by the use of a professional pain/symptom protocol.
The decision not to treat such a newborn, when based on expected handicaps, possibly violates the ‘non-discrimination’ principle (Dorscheidt, 2006). When not being treated, they are not terminally ill because of the MMC and/or hydrocephalus per se; they are ‘terminally ill’ because of this nontreatment decision. Not being terminally ill, it is not ‘humane’ or ‘merciful’ to terminate their life, this also being not in accordance with international legislation and international medical recommendations.
When untreated and when it is the intention to alleviate actual discomfort (this question of intent being crucial to a moral and legal analysis of end-of-life decisions including active termination of life), this can always be achieved in an effective way by using one of the widely accepted palliative protocols. Such a child can and should be cared for in a respectful and dignified way, providing all its actual needs (which apparently is not death itself). This being the case, there is no indication whatsoever for the deliberate termination of the life of children born with MMC.
While Verhagen et al. (2005, 2006) must be credited for bringing the discussion about deliberate termination of newborns in the open, to date, there does not seem to be much in their qualifications that can be quantified properly, especially not in cases of MMC, which is prone to quality of life judgments (and thereby neglecting the needs and rights of the newborn). To date, the Groningen protocol, therefore, cannot be regarded as very useful. Being a tool, it seems to have been changed in a means in itself. To gain more usefulness, at least it has to be extended in a way as proposed by Dorscheidt (2006), by adding charts such as the Comfort Score and the VAS and by adding palliative medication charts. Thus, it should be changed from a doctor-centered protocol to a patient-centered protocol.
To throw more light on these end-of-life decisions, Verhagen et al. should consider to extend their retrospective study, focusing on the medical aspects of the 22 cases. Thus, it must be possible to get a basic understanding of the extent of the malformations themselves, of possible co-morbidities, whether or not quality of life judgments were made, how ‘unbearable suffering’ was ascertained, how palliative care was offered, and why this failed. Such a study would contribute significantly to the open discussion they propagate. Verhagen is undoubtedly correct indeed in his appeal: “It’s time to be honest about the unbearable suffering endured by newborns with no hope of a future”. [71]
Finally, to date it remains unclear on what grounds the Dutch Association of Paediatrics has adopted the Groningen protocol and why international legislation, international human rights instruments, and international medical recommendations appear not to hold for the Netherlands, especially not in newborns with MMC.

termination of life
newborn
meningomyelocele
suffering
pain
quality of life
groningen protocol
palliative care


Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance

In Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) α-synuclein (αS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak’s and McKeith’s, currently in use for the assessment of αS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 αS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of αS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of αS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of αS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread αS pathology (Braak’s PD stages 5–6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer’s disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with αS pathology. However, finding that around half of the subjects with abundant αS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.
Introduction
There are two staging/categorization systems commonly in use for the assessment of the progressive regional distribution of the pathology seen in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Both of these staging/categorization systems are based on the assessment of misfolded α-synuclein (αS) protein within selectively vulnerable neuronal populations which is considered to be either directly responsible or at least intimately linked to the neuronal dysfunction seen in PD and DLB. In this respect, αS-immunoreactive (IR)-inclusions in the brainstem have been claimed to be responsible for the extrapyramidal symptoms (EPS), whereas dementia has been attributed to the limbic and neocortical spread of these lesions. Thus, PD and DLB are thought to form a clinico-pathologic continuum wherein the clinical manifestation of EPS and/or dementia depends on the anatomical distribution and the load of αS pathology [4, 17, 19, 25, 28, 30].
In 2003, Braak and colleagues reported that the αS pathology begins in clearly defined induction sites and advances, not in a random, but in a predictable sequence with increasing severity throughout the brain [4, 11]. Based on the analysis of the regional distribution of αS-IR inclusions in a cohort including both neurologically unimpaired subjects and patients with PD, a staging system was devised whereby αS pathology was divided into six successive stages. In the central nervous system, the proposed sequence begins in the dorsal motor nucleus of vagus (dmV), and then proceeds with an upward progression via locus coeruleus (LC) (stage 2) to the substantia nigra (SN) (stage 3), and then to the basal foreberain (BFB) and transentorhinal region (stage 4) until it finally reaches the neocortex (stages 5–6).
Already in 1996, the consortium on DLB international workshop proposed their consensus guidelines for the clinical and pathologic diagnosis of DLB [27] that later, in 2005 were somewhat revised [28]. These consensus criteria of DLB subdivide subjects into three different neuropathological categories; brainstem predominant, limbic/transitional and diffuse neocortical depending on the anatomical distribution of the αS-IR structures [28]. These criteria also include the semiquantitative grading of lesion density, although the pattern of regional involvement has been assumed to be more important than the actual count of inclusions. It is noteworthy that in the revised recommendations by McKeith et al from 2005 [28], it is emphasized that the concomitant pathologies should be taken into account when assessing the causative relationships between pathologies and symptoms. Thus, the most common pathology seen in aged demented individuals, i.e. Alzheimer’s disease (AD)-related pathology, should be evaluated while assessing the likelihood of causation, i.e. that the αS pathology is associated with a DLB clinical syndrome.
Herein, we assess the applicability of these two current staging/categorization systems of synucleinopathies in a large autopsy material collected, not on the basis of clinical presentation, but by αS immunoreactivity in some of the most vulnerable nuclei; dmV, SN and BFB. Thus, the selection of material was entirely based on the presence of αS pathology irrespective of clinical phenotype. All subjects, if applicable, were assigned a stage following in detail Braak staging recommendations and a McKeith neuropathological category following in detail recommendations by the consortium on DLB international workshop [4, 28]. The frequency of dementia and EPS was assessed in each stage and the likelihood that dementia was due to AD-related pathology or αS pathology was also examined.
Materials and methods
Selection of subjects and the clinical assessment
The flowchart delineates the logistics of this study (Fig. 1). A total of 1,720 elderly individuals (age at death >40 years) that had undergone an autopsy together with an examination of the brain during the years 1996–2005 in the Kuopio University Hospital were included in this study. From this large autopsy sample, we selected 248 (14%) subjects that displayed αS-IR structures in the SN and/or BFB nuclei: nucleus basalis of Meynert (nbM) and amygdaloid complex (AC). Screening of dmV was also carried out in 1996–2000 and revealed that in 24 subjects out of 904 (3%) αS-IR-structures were restricted to the lower brain stem nuclei (dmV and/or LC) [33]. Five subjects were excluded from the analysis because they had received a pathological diagnosis of MSA. Seventeen subjects were excluded due to lack of clinical information or inadequate amount of brain material required for the classification as recommended by Mc Keith and Braak [4, 28], and thus ultimately, this study examined 226 subjects.
Fig. 1The flowchart delineating the logistics of this study. a The αS-immunoreactive inclusions were screened in substantia nigra, amygdaloid complex and dorsal motor nucleus of vagus. b Schematic presentation of both Braak staging and McKeith categorization [4, 28] and c schematic presentation of assessment of likelihood that αS-immunoreactive inclusion are associated with dementia with Lewy bodies [28]
The diagnosis of dementia was based on the DSM-III criteria and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) [29]. The diagnosis of PD followed the criteria established by the United Kingdom Parkinson’s Disease Society Brain Bank whereby PD was considered present if the patient had at least two of the four cardinal symptoms (resting tremor, rigidity, hypokinesia and postural instability) and exhibited a positive response to levodopa [9]. The initial screening for both dementia and EPS had taken place in a primary health care centre. With respects to dementia, all patients scoring 26 or less in minimental State Examination (MMSE) had been referred to a neurologist for further evaluation and all patients scoring >26 in MMSE but displaying signs of memory impairment had been referred to a CERAD test. Consequently, many subjects had been examined by a neurologist and all had at least visited a general physician (within a maximum of 1 year before death). It is noteworthy that many of the subjects included in this study had been under continuous clinical follow-up due to some chronic disease. Admittedly, some subjects may have developed subtle extrapyramidal signs or mild cognitive impairment between the last clinical examination and death, but it is most unlikely that the presence of moderate or full-blown parkinsonian syndrome/dementia would have been overlooked.
Neuropathological assessment
According to the dissection protocol used in the Kuopio University Hospital, the brains were weighed, evaluated for grossly detectable lesions and vessel abnormalities, perfused with and immersed in 10% buffered formalin for at least one week and cut in coronal slices of 1 cm thickness. Brain specimens were embedded in paraffin and cut into 7 μm-thick sections. Immohistochemical (IHC) methodology was used to visualize the expression of αS and hyperphosphorylated τ (HPτ). The sections were deparaffinized and rehydrated according to a routine procedure. For αS IHC, the sections were autoclaved (120°C) in citrate buffer for 10 min and pretreated with 80% formic acid at room temperature for 5 min. Monoclonal antibodies to human αS1–140 (Novocastra, Newcastle upon Tyne, UK) at a dilution of 1:1,000 and to human HPτ at a dilution of 1:500 (Innogenetics, Ghent, Belgium) were applied. For detection, Histostain SP kit (Zymed, San Francisco, CA) was used with Romulin AEC chromogen (Biocare Medical, Walnut Creek, CA). The expression of αS was assessed in 10 brain regions: (1) medulla with dmV; (2) pons with LC and raphe nucleus (RN); (3) midbrain with SN; (4) BFB including nbM, AC, and transentorhinal cortex; (5) posterior hippocampus at the level of geniculate nucleus including the CA2 region of the hippocampus and temporo-occipital gyrus; (6) insular cortex; (7) anterior cingulate gyrus; (8) superior temporal gyrus (Broadman area 22); (9) frontal cortex (Broadman area and (10) parietal cortex (Broadman areas 39, 40). The selection of regions was based on the currently used staging systems [4, 28] (See Fig. 1). HPτ IHC was carried out on sections from hippocampus, temporal and occipital cortices and the regional distribution of AD-related neurofibrillary pathology was subdivided into 6 stages (I-VI) as has been described previously [6].
The number of αS-IR inclusions was counted within the microscopic field at ×200 magnification (diameter of 1 mm) and assessed semiquantitatively in all brain areas examined. The total thickness of the cortical grey matter and AC were assessed according to the established pathological guidelines [28] and rated as follows: 1 = mild (sparse inclusions at ×100); 2 = moderate (>1 inclusion in low power field at ×200 magnification); 3 = severe (≥4 inclusions in low power field at ×200 magnification); 4 = very severe (numerous inclusions). In the nbM and all subcortical regions, αS-IR inclusions were counted unilaterally within entire nuclei and assessed following an arbitrary grading system: in nbM and SN, + =mild (<25 inclusions); ++ = moderate (25–50 inclusions); +++ = severe (>50 inclusions), in LC and dmV, + = mild (1–2 inclusions); ++ = moderate (2–10 inclusion), +++ = severe (>10 inclusions). Several inclusions within one neuron were counted as a single inclusion. The αS-IR structures were designated as being present (+) or not (0) in raphe nucleus and CA2 region of the hippocampus. If no αS-IR inclusions were identified in the sections of medulla, pons, midbrain or BFB, the result was verified in at least 3–4 consecutive sections i.e. the subsequent 5th, 10th, 15th and 20th sections were stained. This was done in order to increase the likelihood of capturing incipient neurons with αS-IR inclusions.
Results
Assessment of clinical data
The 226 αS-positive subjects examined included 114 (50%) patients with a clinical diagnosis of a neurodegenerative disorder, 15 (7%) patients with other neurological disorders and 97 (43%) individuals in whom the clinical information indicated that they had no neurological impairment. The mean age at death was 77 ± 0.6 years, ranging from 44 to 98 years and the gender was rather evenly distributed (108 females/118 males).
Frequency of αS-immunoreactivity in the most vulnerable anatomical regions
The most frequently affected regions in the 226 αS-positive subjects were dmV (197/223) and SN (197/225) where the αS-IR was seen in 88% of the analyzed subjects. The LC was affected in 81% (181/223) of subjects, making this area the second most vulnerable nuclei. The large neurons in the nbM were αS-immunopositive in 78% of cases (171/219), whereas the involvement of AC, particularly the cortico-medial nuclear group, was seen in 73% (162/223) of subjects.
Staging of Parkinson disease-related αS pathology according to Braak and the frequency of dementia and extrapyramidal symptoms
Out of the 226 αS-positive subjects, 187 (83%) displayed a distribution pattern of αS-IR that was compatible with the current staging systems of PD/DLB-related synucleinopathies [4, 28]. Braak stage 1–2 was applicable for 22 subjects, 3–4 for 38 subjects and 5–6 for 127 subjects (Table 1). When all subjects with severe AD-related neurofibrillary pathology, i.e. Braak’s AD stage V-VI, were excluded, 168 cases of the 187 subjects remained. Notably, only 25–30% of the subjects with PD-related Braak stage 5 and 50% of subjects with PD-related Braak stage 6 were demented and/or had EPS. It is noteworthy that when only demented subjects were included in the analysis (53 out of 168), 91% (48/53) were assigned to PD-related Braak stages5–6. Similarly, when only subjects with EPS were included in the analysis (52 out of 168), 94% (49/52) were in the PD-related Braak stages 5–6.Table 1Applicability of Braak staging and the incidence of dementia and extrapyramidal signs (EPS) in each stage
Categorization of the distribution of αS pathology following the recommendations by the consortium on DLB international workshop, i.e. McKeith’s categorization, and the frequency of dementia and extrapyramidal symptoms
Sixty-six subjects fulfilled Mc Keith’s criteria for the brainstem predominant form, 30 for the limbic (transitional) and 91 for the diffuse neocortical form of DLB (Table 2).
Table 2Applicability of neuropathological categorization as recommended by the consortium on DLB international workshop, i.e. McKeiths categorization and the incidence of dementia and extrapyramidal signs (EPS) in each category
Fifty-seven percent of subjects with the diffuse neocortical form of DLB were demented and 47% displayed EPS (Table 2). When AD-related pathology was taken into account as suggested by McKeith and colleagues [28] (Table 3), the percentage of demented in the high likelihood category varied from 24 to 60%. Irrespective of the αS pathology, in Braak’s AD stage V-VI, all subjects were demented. Notably, when only demented subjects were included in the analysis and the subject with severe AD-related pathology (Braak’s AD stage V-VI) were excluded, 85% (45/53) were assigned to a high likelihood category of DLB.
Table 3Assessment of likelihood that the pathological findings are associated with a DLB clinical syndromeCategory of Lewy body type pathologyAlzheimer type pathologyBraak stage 0-IIBraak stage III-IVBraak stage V-VIBrainstem predominant n = 66Low n = 58 5 demented (9%) 5 with EPS (9%)Low n = 7 2 demented (29%) 0 with EPS (0%)Low n = 1 1 demented (100%) 0 with EPS (0%)Limbic transitional n = 30High n = 25 6 demented (24%) 9 with EPS (36%)Intermediate n = 1 1 demented (100%) 0 with EPS (0%)Low n = 4 4 demented (100%) 1 with EPS (25%)Diffuse neocortical n = 91High n = 63 30 demented (48%) 34 with EPS (54%)High n = 15 9 demented (60%) 4 with EPS (29%)Intermediate n = 13 13 demented (100%) 5 with EPS (36%)
Atypical cases i.e. cases that could not be classified as recommended
Thirty-nine cases were not classifiable as recommended and thus were assigned as being atypical i.e. neither Braak staging nor McKeith categorization systems could be applied. The deviating topographical distribution of αS-IR inclusions of these subjects is shown in Table 4. In four subjects, the BFB nuclei (AC predominant) were severely affected (cases 1–4) together with some cortical inclusions, whereas the brainstem had been preserved. Five subjects displayed isolated minor involvement of SN without any αS-IR inclusions in the lower brainstem nuclei (cases 5–9). In six subjects (cases 10–15) minor involvement of both SN and BFB nuclei was detected (cases 10–15). In addition to these two areas, three cases exhibited severe αS pathology in AC (cases 16–18, AC predominant). In seven subjects, some inclusions were seen in the BFB, SN and LC, but not in the dmV (cases 19–25). In the final 14 subjects (cases 26–39), inclusions were seen in the dmV and SN, but not in the LC, together with variable affection of BFB and other cortical regions. In only minority of these cases EPS symptoms were seen (13%), whereas dementia was more common (54%). In 14 cases dementia was due to AD-related neurofibrillary pathology (Braak stage V-VI), in six cases numerous multifocal microscopic infarcts and concomitant severe white matter rarefaction was considered as the causative agent regarding dementia and in one cases neuropathological lesions consistent with frontotemporal dementia with ubiquitin only lesions were seen.
Table 4Topographic distribution of αS immunoreactive lesions in the 39 atypical cases, i.e. not classifiable following current recommendationsIDAgeSexEPSDemAD stageTopographical distribution of αS-immunoreactive structuresdmVRNLCSNnbMACTrEnt CxCA2Temp-OccIns CxCGTCxFCxPCx179FNoYes400000410000000262FNoYes600000420100000374FNoYes20000+420201100479FYesYes60000+300011100586FNoNo4000+0000000000644MNoNo0000+0000000000768MNoNo1000+0000000000883MNoNo2000+0000000100983MNoNo10+0+00000000001075FNoNo0000++0000000001176MNoNo1000++0000002001270MNoNo0000++0000000001377FNoNo2000++2100000001473MYesYes2000+++0000001001571FNoYes6000++++0001111001679FNoYes5000+03300100001787FNoYes2000++4nana0000001874FNoYes6000+na4na+1000001962MYesYes000++00000000002079MNoYes000+++0000000002184FNoYes200++++0000000002285FNoNo000+++11nana000002382FNoYes300++++na200100002458MNoNo000++++++0000000002584MNoNo300+++++3201020002676MNoNo1+00+00000000002787FNoNo1+00++0000na00002878MNoNo1+00++2200000002984FNoYes5+00+01na+1000003075FYesYes5++00+01000000003160FNoNo0+++00+00000000003280MNoYes6+00++00000010003369MNoNo1+++0++++1100010003480MYesYes5++00+++32+1110003586FNoYes6++0+044+3001003664FNoYes6+00+na4na+na001003774FNoYes6+00++440na012003878MNoYes5+00++33+1211003989MNoNo2+00++220001110EPS extrapyramidal signs, Dem clinical signs of dementia, AD stage the stage of Alzheimer’s disease related neurofibrillary pathology stages as recommended by Braak from 0 to VI., dmV dorsal motor nucleus of vagus, RN raphe nucleus, LC locus coeruleus, SN substantia nigra, nbM nucleus basalis of Meynert, AC amygdaloid complex, TrEntCx transentorhinal cortex, CA2 CA2 region of the Cornu Ammonis of the hippocampus, Temp-Occ temporo-occipital gyrus, Ins Cx insular cortex, CG cingulate gyrus, TCx temporal cortex, FCx frontal cortex, PCx parietal cortex; na not available. The αS-immunoreactive inclusions were examined in the total thickness of the cortical grey matter and AC and rated as follows: 1 mild (sparse inclusions in ×100), 2 moderate (>1 inclusion in ×200 magnification), 3 severe (≥4 inclusions in ×200 magnification), 4 very severe (numerous inclusions), in the nbM and subcortical regions, αS- immunoreactive inclusions were counted unilaterally within entire nuclei and assessed following an arbitrary grading system: in nbM and SN, + mild (<25 inclusions), ++ moderate (25–50 inclusions), +++ severe (>50 inclusions), and in LC and dmV, + mild (1–2 inclusions), ++ moderate (2–10 inclusion), +++ severe (>10 inclusions). In Raphe nucleus and CA2 region of the hippocampus, αS-immunoreactive structures (inclusion and/or neurites) were marked to be present (+) or not (0)
Discussion
Most of our (83%) αS-positive cases could be assigned to one of the six PD stages as described by Braak and also into the brainstem, limbic or diffuse neocortical neuropathological category as recommended by McKeith and colleagues [4, 28]. Braak and colleagues depicted the topographical distribution of αS-IR structures by assessing 110 αS-positive subjects (69 incidental and 41 symptomatic PD patients) [4]. The initial intent of Braak and colleagues was not to correlate the designated neuropathological stages with clinical symptoms, however this was later contemplated [5]. Stages 1 and 2, i.e. stages where αS pathology is confined to the dmV and/or LC, are considered to be presymptomatic, whereas EPS appear and the cognitive decline increases with each stage. In stage 3, when SN is affected, EPS appear and subsequently in stage 4 when amygdaloid complex, transentorhinal region and temporo-occipital gyrus become involved, moderate cognitive impairment is observed (MMSE scores 21–24) and finally in stage 5 and 6 when the neocortex succumbs to the pathology, severe cognitive impairment is evident (MMSE scores 11–20 and 0–10, respectively) [5]. Our results also suggest that the risk of EPS increases with disease progression though not to the same extent as earlier reported. In our study, we found one subject with EPS already in stage 2, whereas none of our cases in stage 4 displayed EPS, and more importantly no EPS had been reported in 55% of subjects who exhibited widespread pathology (Braak stages 5–6), i.e. this being compared with the 14% previously reported by Braak and colleagues [4].
The initial decline in cognition was postulated to occur already during stages 3 and 4 i.e. around the same time when the initial manifestation of somatosensor dysfunction start to appear. When assessing 88 subjects, Braak and colleagues reported, that 36% of their subjects in stage 3, 67% in stage 4, 94% in stage 5 and 100% in stage 6 were demented [5]. This is clearly in odds with our results where the percentage of demented increased from none to 50% between stages 3–6. It is noteworthy that when only demented subjects were included, 91% were assigned to PD-related Braak stages 5–6 and when only subjects with EPS were included, 94% were in the PD-related Braak stages 5–6. Thus the key difference between our study when compared to most other clinico-pathological correlation studies that have reported good correlation between risk of disease and progression of pathology is the study design [5]. Consequently, when we only included subjects with clinical signs in our analysis the correlation between stage/severity of αS pathology and EPS/dementia was excellent in line with previous reports.
PD and DLB are distinguished as separate clinical entities and in 1996 the consortium of the DLB international workshop subdivided the neuropathological features of DLB into three categories: brainstem predominant, limbic and diffuse neocortical type [27]. The foundation of these three categories is also based on the progressive propagation of αS pathology along a caudo-striatal axis. Similarly to the Braak staging [4], when applying this categorization it is presumed that 100% of subjects with widespread αS pathology, i.e. in the diffuse neocortical stage all will be demented and display EPS. When we followed the classification strategy proposed by McKeith and colleagues [28], our results also differed from those expected, i.e. only a subset of our subjects who were classified to be in the diffuse neocortical category displayed dementia and/or EPS (57 and 47%, respectively). In line with the above, when only demented subjects were included in the analysis the correlation between αS pathology and dementia was close to excellent (85%).
The clinical relevance of cortical αS pathology in relation to dementia is a matter of intense debate. Some authors have emphasized their key causative role [1, 18, 21, 26], whereas others have reported that there may be abundant cortical pathology in non-demented PD patients [8] as well as in neurologically unimpaired subjects [10, 24, 32]. It is noteworthy that the current study differs significantly from most other studies since it is based on neuropathologiacal findings rather than on clinical presentation. Our results emphasize that abundant pathology may be detected in many subjects without notable signs of dementia (MMSE >26) (43%), if it is sought. This has one unexpected consequence, i.e. a detailed regional assessment of αS pathology cannot reliably predict the clinical status observed premortem [33].
There has been much discussion concerning the significance and influence of concomitant AD-related pathology, particularly as this is quite frequently seen in aged subjects. Therefore, the revised consensus criteria have recommended taking AD-related pathology into account while assessing subjects with suspected DLB [28]. It was presumed that this would increase the diagnostic specificity since it was believed that the pathological substrate behind DLB was indeed αS pathology. When we assessed our unique material, we found, that within the neuropathological high likelihood categories of DLB, i.e. those cases where limbic/diffuse neocortical αS pathology is combined with mild/moderate AD-related changes, 56% of subjects remained cognitively intact. However, when we examined only demented subjects without severe AD-related pathology (Braak’s AD stage V-VI), 85% were assigned to a high likelihood category of DLB. This shows that when αS pathology is examined in clinically demented subjects, the correlation received between particular pathologic change and dementia is good. It is noteworthy that with respect of AD-related neurofibrillary pathology, all cases in the neocortical stage (Braak stage V-VI) were indeed demented.
One important issue with respect to the pathogenesis of synucleinopathies is not only to understand the molecular mechanisms behind the intracytoplasmic aggregation of αS, but also to appreciate where this process first appears and how it may progress through the brain. Thus, many recent studies have attempted to localize the most vulnerable neuronal populations. In this study, dmV and SN were found to be equally susceptible nuclei, but even earlier affected structures have been reported to appear in the spinal cord, dmV, olfactory bulb and AC [2, 4, 11, 16, 22, 35]. Thus, mapping out the “trigger site” for αS pathology appears to depend on the screening process i.e. if one screens medulla alone, those cases where lesions are restricted to other areas (e.g. SN) are not found and vice versa.
At variance to the studies of Del Tredici and Braak [4, 11] we identified a number of subjects where dmV and/or LC were not affected but αS-IR inclusions were found in the SN, BFB and or other cortical regions, and thus, the distribution of αS pathology did not strictly follow the caudo-rostral propagation pattern described by Braak and colleagues [4]. Thus, the proposed ascending pathway is not the only possible route and our results indicate that pathology can emerge simultaneously in subcortical and cortical regions. Jellinger has also reported subjects with multiple αS-IR inclusions but with preservation of medullary nuclei [20]. Furthermore, in some subjects we found the AC to be devoid of pathology although αS-IR structures were detected elsewhere in the neocortex. This refutes the proposal that in order to have neocortical involvement then the subcortical lesions have to expand through the basal forebrain nuclei. In addition, according to Braak and colleagues [4], the αS pathology in previously involved regions should become exacerbated with disease progression. It is difficult to evaluate this proposal when one takes into account the increasing neuronal loss. If these two pathological hallmarks are linked in a causative chain, the load of αS-IR structures should show an inverted u-shape distribution over time where the number of inclusions would increases with the progression of the disease until the neurons start to die [12].
We observed some cases with severe αS pathology in AC and in that situation this structure was either only involved region or was affected together with BFB and SN. All these subjects were demented and exhibited coexistent severe AD-related pathology (Braak AD stage V-VI [6]). In one case, the dementia was considered to be vascular in origin. This is in line with the results of Uchikado and colleagues who have reported the AC predominant form to be common finding among patients with AD [35].
In conclusion, our results confirm that the current staging/categorization systems can readily be applied to most of the subjects when assessing regional distribution of αS-pathology. It is noteworthy, however, that outliers do exist and in these cases the presumed distribution may have been modified by other coexisting pathologies or genetic factors [23, 35]. It is intriguing that around every second subject displaying abundant pathology did remain neurologically intact. It is noteworthy that these results were seen when a rather unselected sample of cases was investigated. It has been suggested that the key lesions begin to develop a considerable time prior to the appearance of clinical symptoms [13], but based on our results there do seem to be some subjects who can tolerate substantial amounts of pathology. As only 50% of subjects with widespread αS pathology were demented (MMSE < 26) and displayed EPS, the clinical relevance of αS-IR inclusions as such still remains to be resolved. Hitherto, the aggregation of αS has been thought to lead to neuronal death but recent evidence has suggested that the formation of large inclusions may actually represent a protective process [3, 14, 34]. Many biophysical studies have suggested that it is a protofibrillar form of αS rather than the “mature” fibrils that are responsible for the cell death [7, 15, 36], and moreover, the fibrillar form that is typically observed at autopsy may actually be a sign of a well functioning neuroprotection [31, 34]. Thus, when we are assessing regional distribution of αS pathology, the question arises if we are really evaluating a stage of degeneration or conversely monitoring the level of functional neuroprotection.

α-synuclein
dementia
extrapyramidal symptoms
lewy body dementia
parkinson disease