Naomi Ijichi

Ignorance of Helsinki Declaration

Sir—In medical research, the first step to protect patients’ rights and dignity is an adequate and full explanation of the experimental details. Although it is within physicians’ discretion to use unproven or new therapeutic measures for a previously untreatable disorder, these measures should be made the object of research according to the strict rules for medical progress and ultimate benefit of patients with the same disorder. Takeyoshi Shimoji and colleagues have described a putative surgical treatment for particular children with developmental delays, most of whom have a minor form of trigonocephaly (earlier closure of the metopic suture) that does not require cosmetic surgery. They claim that the cranioplasty revises the spatial environment for brain development in these patients whose developmental problems include mental retardation, autistic tendency, hyperactivity, speech difficulties, and delayed motor development. Surprisingly, however, in around 140 operated cases, the informed consent has been obtained from the parents without explanation of the experimental details, and most ethical principles for medical research are disregarded. In the consensus of surgical treatments of isolated trigonocephaly, even in apparent synostosis cases, the reduced volume of the frontal lobes is not generally enough to explain the severe mental deficiency that can arise. This disparity may be in line with the spatial and functional plasticity of brain development. Together with the difficulties in assessing cognitive and behavioural changes in developmental disorders, radical cranioplasty in patients with a minor form of trigonocephaly as a treatment for developmental delays is an unproven and novel therapeutic measure, which should be made the object of well designed research. In a series of arguments, lack of epidemiological basis for the causal relation, the empirical study design, and issues of informed consent have so far been pointed out. Written informed consent and review by the hospital ethics committee were introduced at our request in 2000. However, the committee reviewed this clinical trial as a medical intervention. To correct the inappropriate relation between clinical researchers and patients, further worldwide ethical discussions should immediately be encouraged. *Shinji Ijichi, Naomi Ijichi

The scientific establishment of a new therapeutic intervention for developmental conditions: practical and ethical principles

BackgroundAlthough the randomized controlled trial (RCT) is a major methodological breakthrough extending the limits of objectivity in clinical medical science, clinical trials of surgery have seldom included placebo surgery as a control, for ethical reasons. Especially in clinical studies intended eventually to establish a new intervention for developmental conditions, it has been recognized that there is huge examiner bias. In addition, the many miraculous cases that have been reported in nonsurgical open trials for developmental conditions and have eventually been evaluated as nonspecific positive outcomes in RCTs suggest that empirically promising interventions must be subjected to scientific scrutiny as soon as possible in the field of developmental conditions.Application to pediatric neurosurgeryTherefore, in childhood neurosurgery, clinical studies to establish a new therapeutic measure for developmental conditions should be designed as rigorously as possible using optimized scientific methods. The worldwide ethical guideline, the Declaration of Helsinki issued by the World Medical Association, can provide principles for the establishment of a new intervention in the treatment of a patient when proven therapeutic methods do not exist or methods used thus far have been ineffective. Physicians’ discretion to use unproven or new therapeutic measures for such patients is approved in the presence of efforts of an ethical and scientific approach. Even if the measure is a very promising intervention, the research aspects must completely be demonstrated for informed consent and review by the ethical committee and the trial must be regarded as a clinical research. Especially when an RCT is not possible for ethical reasons, appropriate epidemiological data or animal experiments should suggest that the new measure is effective before a clinical trial. In a clinical setting, where neither epidemiological studies nor animal experimentation can be introduced, if necessary the researcher should collaborate with experts to obtain multidisciplinary justification for clinical testing.

Type IIa hyperlipoproteinemia masquerading as cerebrotendinous xanthomatosis

We describe an adult patient with type IIa hyperlipoproteinemia, presenting with Achilles tendon xanthomas, cataracts, dementia, ataxia, pyramidal tract signs, and peripheral neuropathy, which are commonly seen in cerebrotendinous xanthomatosis (CTX). However, the diagnosis of CTX was excluded on the basis of the cholestanol level and the normal cholestanol/cholesterol ratio in his serum and tendon. The pathomechanism for some of the clinical manifestations in type IIa hyperlipoproteinemia and CTX might be caused by a common biochemical disturbance.

The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Tail of a Complex Dimensional Trait

Autism is a developmental lifelong condition of the human brain, and a behavioral characterization as a spectrum (autism spectrum disorder: ASD) is the best way to illustrate this complex trait (Frith, 2001; Rapin, 1997; Wing, 1997). The predominant presence of autistic cases without comorbidity (idiopathic or primary ASD) (Freitag, 2007) clearly means that the biological effects associated with the known concomitant medical conditions (cytogenic abnormalities, fragile X syndrome, tuberous sclerosis, congenital infections, maternal thalidomide use, epilepsy, etc.) cannot be the common prerequisite for ASD at least in the majority of the cases. The presence of a strong genetic contribution is evident from the results of twin studies, which demonstrated that 70-90% of monozygotic twins are concordant for ASD, and the concordance in dizygotic twins and the recurrence rate in the proband’s siblings are both less than 10% (Rapin & Katzman, 1998). A broadening of the criteria of diagnosis leads the monozygotic concordance ratio to more than 90%, but 100% concordance is never obtained (Rapin & Katzman, 1998). Therefore, it is claimed that genetic factors contribute about 90% to ASD with environmental factors contributing no more than 10% (Garber, 2007). Although a flood of genetic information in the field of ASD is continuously growing, even the newest genome-wide molecular studies cannot detect the universal genetic prerequisite for idiopathic cases with ASD, compelling some researchers to speculate that ASD has a huge inter-case heterogeneity of the related gene variants. Many gene variants, which seem to affect brain development and synaptic functions, have been reported in association with the autistic development (Betancur, 2011; Garber, 2007; Persico & Bourgeron, 2006; Pinto et al., 2010). In families with the candidates for autism gene variants, however, the strict co-segregation, in which the gene variant is found only in individuals with ASD among family members including parents, is still exceptional (Table 1). To explain this fact, the broader distribution of the more primary phenotype or prebehavioral phenotype (endophenotype) beyond the categorical border is introduced as the speculative solution through this research maze (Viding & Blakemore, 2007). It may be quite difficult to detect and evaluate such endophenotypes because of the configurational or hierarchical structures of human cognitions and behaviors. Even if such speculations were

Quantitative Nature of Social Vulnerability and Autism: An Important Paradigm Shift in the DSM-5 for Autism Spectrum Disorder.

In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), autistic characteristics in social interaction and communication are described as qualitative impairments. However, the difference between autistics and nonautistics in the draft of the 5th edition (DSM-5 draft) is quantitative rather than qualitative. The word “qualitative” is deleted in the draft text, and it is specified that the relation between social demands and individual limited capacities is critical for symptom manifestation (criterion C). Because the proposed levels of support requirement in the draft are mere observable outcomes of social vulnerability, the boundary between level 1 and nonautistic condition is determined by the relation between social demands and individual capacities. In addition to the introduction of the single category (autism spectrum disorder (ASD)) to cover the entire case spectrum, the DSM-5 draft is clearly based on a conviction that ASD is indistinguishable from the normal behavioral range. This concise review provides an explanation for this implicit paradigm shift from qualitative to quantitative. Importantly, the conditional role of social demands for symptom manifestation in the draft can be plausibly interpreted using a unique liability-probability model.

Ethical fallacies, tricky ambiguities, and the misinterpretation of the outcomes in the cranioplasty for mild trigonocephaly

Dear Editor: Surgery is not indicated for mild trigonocephaly, as clearly described in the introduction of Dr. Shimoji’s newest paper [1]. The introduction also specifically says Bthe use of surgical interventions is not generally accepted for children with mild trigonocephaly complicated by clinical manifestations^ [1]. Indeed, reference 15 in the paper supports Shimoji’s significant finding that individuals with a very mild form of trigonocephaly can have developmental problems, but the conclusion of the reference is that Bthe frequency of these problems is not related to the severity of the trigonocephaly^ [2]. In Shimoji’s cases, the intraoperative intracranial pressure (ICP) values were not correlated with the level of postoperative clinical changes [1]. Every neurosurgeon knows that these facts are themain reasons for the general consensus that Bneither the neurological findings nor the severity of deformity nor the intracranial pressure provide any arguments favoring a mechanical cause of brain dysfunction^ in isolated trigonocephaly cases [3, 4]. Therefore, the continuous implementation of this unaccepted surgical procedure as a therapeutic intervention is underpinned by ethical fallacies, tricky ambiguities, and the misinterpretation of the outcomes. Most of the following points had already repeatedly been presented [5–9].

Mild trigonocephaly with clinical symptoms

Published online: 21 November 2002

Cranioplasty for isolated mild trigonocephaly with developmental conditions and continuing ignorance of Helsinki declaration

The ignorance of Helsinki declaration is continuing in Japan for approximately 20 years. More than 400 children including preschoolers with developmental conditions including temper tantrums, hyperactivity, and/or autistic characteristics have been already operated. The cranioplasty for isolated mild trigonocephaly had been empirically introduced by a physician to re-establish the brain spatial environment, and a government-granted and multi-centered clinical observation study is now in operation without scientific verification of the procedure’s validity. The characteristic of the skull shape are too mild and sometimes too subtle to be recognized by the parents and health checkup doctors. A physician may tentatively and extraordinarily use an unproven procedure in exceptional circumstances where proven and effective interventions do not exist. However, the intervention must as soon as possible be subjected to scientific scrutiny according to ethical principles in order to stop the utilization in case of misprediction (no evidence of the efficacy).

Reflux of HTLV-I infected lymphocytes from the privileged compartment(s) to peripheral blood flow in patients with HTLV-I-associated myelopathy.

Abstract To understand the mechanisms involved in the pathogenesis of human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), three in vivo phenomena which have been observed in the peripheral blood of patients and differing from that in asymptomatic HTLV-I carriers must be taken into consideration: (a) the presence of increased HTLV-I viral load, (b) a higher immune responsiveness against HTLV-I antigens, and (c) biased nucleotide substitutions in the HTLV-I pX region which indicate a decreased selection pressure for viral amino acid changes. We now propose a hypothesis which focuses on the in vivo dynamics of HTLV-I infected lymphocyte migration and which incorporates these features. In addition, the hypothesis assumes the existence of a deviation in immune surveillance for HTLV-I in the central nervous system (CNS) in spite of the presence of frequent specific immune effectors. We suggest that in the active phase of HAM/TSP, accompanied with or following autoaggressive interactions between infected lymphocytes and immunocompetent cells in the CNS, there is a consequential reflux of the infected lymphocytes to the peripheral blood. The reflux of infected cells would be expected to provide peripheral blood with tissue-derived HTLV-I proviruses which have been indulged and propagated in an immune-privileged site. This process would result in and account for the observed increase in viral load and the substitution bias in HTLV-I sequences in the peripheral blood.

A concise checklist to determine if the cognitive and/or behavioral changes are attributable to the effect of an intervention

Dear Editor: Dr. Shimoji and colleagues are still using the line, Bsurgical intervention improved clinical symptoms in nearly all patients^ in a case series of midline craniosynostosis [1] in addition to mild trigonocephaly cases. In spite of our repeated requests [2–8], they never correct their conclusion that Bsymptoms were improved by adding a surgical procedure^ [1, 9]. The ethical fallacies, tricky ambiguities, and the misinterpretation of the outcomes in the cranioplasty may be associated with their blind belief that the postoperative beneficial changes are all introduced by the intervention [4, 7, 8]. Actually, they described Bwe believe that surgery is providing an important positive effect^ [9]. This blind belief makes them more blind to the physician’s strict rules to protect the patients’ rights and dignity [4, 7], and the reply to our letter did not address most of their problems which had been listed in our letter [9]. A comparative review of our letter and the reply can easily detect many irrelevant answers to our questions in the reply letter, which may be made just to record and pretend that the questions were dealt with once [8, 9]. The trickymanner of their stance is characterized by ambiguity and double-dealing. They clearly described Bthe children in this study had pervasive developmental disorder (PDD)^ in mild trigonocephaly papers [10, 11]. At present, there is no erratum for this description. Because autism had been classified in PDD in the former behavioral diagnostic criteria, the inconsistency with the answer, Bwe are not treating autism [9],^ may cause parents’ confusion. The informed consent form for the mild trigonocephaly cases says that Bthis treatment is not generally accepted [9],^ and the annual review abstract of their government-granted research says Bit has not been concluded that the surgical intervention has beneficial effects [12].^