Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

Retinodural haemorrhage of infancy, abusive head trauma, shaken baby syndrome: The continuing quest for evidence.

The shaken baby syndrome was originally proposed in the 1970s without any formal scientific basis. Once data generated by scientific research was available, the hypothesis became controversial. There developed essentially two sides in the debate. One side claimed that the clinical triad of subdural haemorrhage, retinal haemorrhage, and encephalopathy, or its components, is evidence that an infant has been shaken. The other side stated this is not a scientifically valid proposal and that alternative causes, such as low falls and natural diseases, should be considered. The controversy continues, but the contours have shifted. During the last 15 years, research has shown that the triad is not sufficient to infer shaking or abuse and the shaking hypothesis does not meet the standards of evidence-based medicine. This raises the issue of whether it is fit for either clinical practice or for the courtroom; evidence presented to the courts must be unassailable. WHAT THIS PAPER ADDS: There is insufficient scientific evidence to assume that an infant with the triad of subdural haemorrhage (SDH), retinal haemorrhage, and encephalopathy must have been shaken. Biomechanical and animal studies have failed to support the hypothesis that shaking can cause SDH and retinal haemorrhage. Patterns of retinal haemorrhage cannot distinguish abuse. Retinal haemorrhages are commonly associated with extracerebral fluid collections (including SDH) but not with shaking. Infants can develop SDH, retinal haemorrhage, and encephalopathy from natural diseases and falls as low as 1 foot. The shaking hypothesis and the literature on which it depends do not meet the standards of evidence-based medicine.

Thrombosis is not a marker of bridging vein rupture in infants with alleged abusive head trauma.

AIM: Thrombosis of bridging veins has been suggested to be a marker of bridging vein rupture, and thus AHT, in infants with subdural haematoma. METHODS: This is a non-systematic review based on Pubmed search, secondary reference tracking and authors' own article collections. RESULTS: Radiological studies asserting that imaging signs of cortical vein thrombosis were indicative of traumatic bridging vein rupture were unreliable as they lacked pathological verification of either thrombosis or rupture, and paid little regard to medical conditions other than trauma. Autopsy attempts at confirmation of ruptured bridging veins as the origin of SDH were fraught with difficulty. Moreover, microscopic anatomy demonstrated alternative non-traumatic sources of a clot in or around bridging veins. Objective pathological observations did not support the hypothesis that a radiological finding of bridging vein thrombosis was the result of traumatic rupture by AHT. No biomechanical models have produced reliable and reproducible data to demonstrate that shaking alone can be a cause of bridging vein rupture. CONCLUSION: There is no conclusive evidence supporting the hypothesis that diagnostic imaging showing thrombosed bridging veins in infants correlates with bridging vein rupture. Hence, there is no literature support for the use of thrombosis as a marker for AHT.

Infants dying suddenly and unexpectedly share demographic features with infants who die with retinal and dural bleeding: a review of neural mechanisms.

The cause of death in infants who die suddenly and unexpectedly (sudden unexpected death in infancy [SUDI]) remains a diagnostic challenge. Some infants have identified diseases (explained SUDI); those without explanation are called sudden infant death syndrome (SIDS). Demographic data indicate subgroups among SUDI and SIDS cases, such as unsafe sleeping and apparent life-threatening events. Infants dying suddenly with retinal and dural bleeding are often classified as abused, but in many there is no evidence of trauma. Demographic features suggest that they may represent a further subgroup of SUDI. This review examines the neuropathological hypotheses to explain SIDS and highlights the interaction of infant oxygen-conserving reflexes with the brainstem networks considered responsible for SIDS. We consider sex- and age-specific vulnerabilities related to dural bleeding and how sensitization of the dural innervation by bleeding may influence these reflexes, potentially leading to collapse or even death after otherwise trivial insults.

The histopathology of polymicrogyria: a series of 71 brain autopsy studies.

AIM: Polymicrogyria (PMG) is one of the most common forms of cortical malformation yet the mechanism of its development remains unknown. This study describes the histopathological aspects of PMG in a large series including a significant proportion of fetal cases. METHOD: We have reviewed the neuropathology and medical records of 44 fetuses and 27 children and adults in whom the cortical architecture was focally or diffusely replaced by one or more festooning bands of neurons. RESULTS: The pial surface of the brain overlying the polymicrogyric cortex was abnormal in almost 90% of cases irrespective of the aetiology. This accords with animal studies indicating the importance of the leptomeninges in cortical development. The aetiology of PMG was highly heterogeneous and there was no correlation between cortical layering patterns and aetiology. PMG was almost always associated with other brain malformations. INTERPRETATION: The inclusion of many fetal cases has allowed us to examine the early developmental stages of PMG. The study indicates the significance of surface signals responsible for human corticogenesis and the complex interaction between genetic and environmental factors leading to this common endpoint of cortical maldevelopment.

Patterns and pathways of calcification in the developing brain.

AIM: To determine specific cell types and pathways involved in calcification of the developing brain. METHOD: We examined the detailed histopathology of samples from 28 autopsied brains aged from 22 weeks' gestation to 14 years. The samples were selected because they showed calcification associated with a range of different diseases. Samples were examined with routine stains as well as stains to show calcification and specific markers for endothelium and macrophages. RESULTS: Our observations indicate that calcification develops via two main pathways: dystrophic and vascular. Dystrophic calcification results from membrane disruption and uncontrolled calcium entry into necrotic (dead) cells in ischaemia and infections. Vascular calcification appears to be initiated in protein globules, sometimes intracellular, but outside the endothelium of small vessels. One case with mutation of the occludin gene, implicating impaired endothelial integrity, showed this pattern, but identical vascular calcification was seen in other conditions, including Sturge-Weber syndrome. Another form of vascular calcification involved the adventitia of arteries; the endothelium was always spared. INTERPRETATION: Calcification in the developing brain that is not associated with tissue necrosis is initiated in cells associated with blood vessels. Calcium incrustation of blood vessels imposes rigidity, reduced vascular compliance, and altered permeability. This would explain associated atrophy, gliosis, and (in the developing brain) malformations of the cortex. Our findings suggest that pericytes initiate non-dystrophic brain calcification, but further studies are needed to explore this possibility.

26 cm fall caught on video causing subdural hemorrhages and extensive retinal hemorrhages in an 8-month-old infant.

Severe, too many to count retinal hemorrhages (RH) in infants have been associated with abusive head trauma, but can occur in short falls. An 8-month-old male fell backward from a height of 26 cm, landing on his buttocks then hitting the back of his head on a vinyl floor. The fall was videotaped. Acute subdural hemorrhages were found along with extensive, too many to count intra-RH in both eyes. Falls from small heights on to the occiput can lead to extensive RH of the type often associated with abusive head trauma.

Congenital toxoplasmosis: continued parasite proliferation in the fetal brain despite maternal immunological control in other tissues.

BACKGROUND: Congenital toxoplasmosis is a serious condition but little is known of the natural history of parasite development and associated fetal tissue destruction. METHODS: Two cases identified by ultrasound underwent induced abortion at 21 and 30 weeks' gestation. At autopsy, the placenta and fetal organs were examined by histology and immunocytochemistry employing anti-Toxoplasma stage-specific antibodies to confirm diagnosis and also provide information on the stage of parasite development. RESULTS: In both cases, maternal serology prior to termination showed both specific immunoglobulin M (IgM) and immunoglobulin G (IgG), whereas retrospective analysis of an earlier sample (12-14 weeks' gestation) showed only IgM reactivity consistent with infection occurring in the first trimester. The finding of a number of tissue cysts but few or no tachyzoites within the placenta and fetal adrenal and heart is characteristic of a chronic infection. However, in contrast, there were still areas of the fetal brain with large numbers of actively dividing, tissue-destructive tachyzoites. CONCLUSIONS: These observations show that continued parasite proliferation and tissue destruction can occur within the fetal brain even when there is a marked maternal immune response including maternal IgG. This finding strongly suggests that there may be benefits from treating cases of recently acquired congenital infection to destroy any remaining proliferating parasites located in immunologically protected sites such as the fetal brain.

Recessive mutations in the gene encoding the tight junction protein occludin cause band-like calcification with simplified gyration and polymicrogyria.

Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is a rare autosomal-recessive neurological disorder showing highly characteristic clinical and neuroradiological features. Affected individuals demonstrate early-onset seizures, severe microcephaly, and developmental arrest with bilateral, symmetrical polymicrogyria (PMG) and a band of gray matter calcification on brain imaging; as such, the disorder can be considered as a "pseudo-TORCH" syndrome. By using autozygosity mapping and copy number analysis we identified intragenic deletions and mutations in OCLN in nine patients from six families with BLC-PMG. The OCLN gene encodes occludin, an integral component of tight junctions. Neuropathological analysis of an affected individual showed similarity to the mouse model of occludin deficiency with calcification predominantly associated with blood vessels. Both intracranial calcification and PMG are heterogeneous in etiology. Neuropathological and clinical studies of PMG have suggested that in utero ischemic or vascular insults may contribute to this common cortical abnormality. Tight junctions are functional in cerebral blood vessels early in fetal development and continue to play a vital role in maintenance of the blood-brain barrier during postnatal life. We provide evidence that the tight junction protein occludin (encoded by the OCLN gene) is involved in the pathogenesis of malformations of cortical development.

Clinical assessment determines the diagnosis of inclusion body myositis independently of pathological features.

BACKGROUND AND OBJECTIVE: Historically, the diagnosis of sporadic inclusion body myositis (IBM) has required the demonstration of the presence of a number of histopathological findings on muscle biopsy--namely, rimmed vacuoles, an inflammatory infiltrate with invasion of non-necrotic muscle fibres (partial invasion) and amyloid or 15-18 nm tubulofilamentous inclusions (Griggs criteria). However, biopsies of many patients with clinically typical IBM do not show all of these histopathological findings, at least at presentation. We compared the clinical features at presentation and during the course of disease in 67 patients with histopathologically diagnosed IBM and clinically diagnosed IBM seen within a single UK specialist muscle centre. METHODS AND RESULTS: At presentation, using clinically focused diagnostic criteria (European Neuromuscular Centre (ENMC) 2011), a diagnosis of IBM was made in 88% of patients whereas 76% fulfilled the 1997 ENMC criteria and only 27% satisfied the histopathologically focused Griggs criteria. There were no differences in clinical features or outcomes between clinically and histopathologically diagnosed patients, but patients lacking the classical histopathological finding of rimmed vacuoles were younger, suggesting that rimmed vacuoles may be a later feature of the disease. CONCLUSIONS: These findings have important implications for diagnosis and future studies or trials in IBM as adherence to histopathologically focused diagnostic criteria will exclude large numbers of patients with IBM. Importantly, those excluded may be at an earlier stage of the disease and more amenable to treatment.

Long-term observational study of sporadic inclusion body myositis.

We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients [57% males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale <3/5 in 48%, distal British Medical Research Council scale <3/5 in 40%, swallowing problems in 46%). During their follow-up, 75% of patients had significant walking difficulties and 37% used a wheelchair (after a median duration from onset of 14 years). The sporadic inclusion body myositis weakness composite index, which correlated with grip strength (correlation coefficient: 0.47; P < 0.001) and Rivermead Mobility Index (correlation coefficient: 0.85; P < 0.001), decreased significantly with disease duration (correlation coefficient: -0.47; P < 0.001). The risk of death was only influenced by older age at onset of first symptoms. Seventy-one (52%) patients received immunosuppressive treatments [prednisone in 91.5%, associated (in 64.8%) with other immunomodulatory drugs (intravenous immunoglobulins, methotrexate or azathioprine) for a median duration of 40.8 months]. At the last assessment, patients who had been treated were more severely affected on disability scales (Walton P = 0.007, Rivermead Mobility Index P = 0.004) and on the sporadic inclusion body myositis weakness composite index (P = 0.04). The first stage of disease progression towards handicap for walking was more rapid among patients receiving immunosuppressive treatments (hazard ratio = 2.0, P = 0.002). This study confirms that sporadic inclusion body myositis is slowly progressive but not lethal and that immunosuppressive treatments do not ameliorate its natural course, thus confirming findings from smaller studies. Furthermore, our findings suggest that immunosuppressant drug therapy could have modestly exacerbated progression of disability. The sporadic inclusion body myositis weakness composite index might be a valuable outcome measure for future clinical trials, but requires further assessment and validation.