Bernard M. Churchill, MD, FRCS(C), FAAP

• Judith and Robert Winston Chair in Pediatric Urology,
• and Director of Wendy and Ken Ruby Fund for Academic
• Excellence in Pediatric Urology, Department of Urology,
• David Geffen School of Medicine, University of California at
• Los Angeles
• Director, Clark-Morrison Children? Urological
• Center, The Mattel Children? Hospital at the Ronald Reagan
• Medical Center, Los Angeles, California

The relative incidence of different chromosomal types has been remarkably constant in recorded series shoulder pain treatment options 2 mg artane purchase visa. The incidence of trisomy increases with advancing maternal age natural pain treatment for shingles order 2 mg artane with mastercard, whereas a higher proportion of translocations occurs in children of younger mothers pain medication for dogs dose order 2 mg artane otc. The pathogenesis of the condition pain treatment center riverbend calgary discount artane 2 mg with visa, or the mechanism by which an additional chromosome groin pain treatment video cheap 2 mg artane overnight delivery, which in 95 per cent is maternal in origin, can cause a wide range of abnormalities with variable expressivity, has been the subject of abundant speculation and yet remains obscure. Cerebellar heterotopias and excessive numbers of neuroblasts in dentate and cochlear nuclei are also notable. Deletions Deletions of part of one chromosome are often associated with intellectual disability and microcephaly; examples include 5p- in the cri du chat syndrome, 4p- in the Wolf­Hirschhorn syndrome associated with convolutional defects, heterotopias, dysplasia of the lateral geniculate, dentate and olivary nuclei and hyperplasia of the corpus callosum,394 and 17p13- in Miller­Dieker syndrome601 (see earlier, Agyria [Lissencephaly] and Pachygyria). Fragile X Syndrome Fragile X syndrome is now accepted as the second most frequent chromosomal disorder associated with developmental disability. An estimated incidence of 1 in 1000 liveborn males makes it the most common familial form of mental retardation. The fragile X site at position Xq27 can be induced in cells cultured at low folic acid and thymidine concentrations. The scanty neuropathological information available includes microcephaly, neuronal heterotopias292 and, in one autopsied case studied by light and electron microscopy, dendritic spine abnormalities associated with synaptic immaturity. Hypotrophic infants usually have a large brain in relation to body weight and within normal limits for gestational age. However, in only a very few cases of a large series of infants showing retarded intrauterine growth was the brain weight two standard deviations below the mean, i. The external configuration of the brain corresponds to gestational age and cytoarchitecture and myelination are not significantly modified in the neonatal period. Placental deficiency, which usually develops during the second half of pregnancy, probably does not affect the number of neurons but may possibly damage glial cells and impair subsequent myelination, which could play a part in the pathogenesis of so-called minimal brain damage. Dobbing and Sands emphasized the vulnerability of the fetal brain at certain periods of its development and it is possible that microcephaly may be induced by undernutrition. Anomalies of the eye (optic atrophy, choroidoretinitis, abnormal retinal pigmentation) are much more common in these cases than in microencephaly of genetic origin. Four histologically examined cases in which therapeutic irradiation had been carried out during pregnancy were quoted by Cowen and Geller. To these cases may be added that of Uiberrack, which showed pachygyria of the cerebral cortex and defective development of the vermis. Less than 5 per cent of infected neonates have a rapidly fatal systemic disorder, with involvement of the brain reported in 10­80 per cent. Severe necrotizing lesions of the ependyma and periventricular tissue are notable453,686 and may form cavitating lesions, such as porencephaly or hydranencephaly. Perivascular calcifications are usually found in periventricular tissue but may be present in the cortex and basal ganglia. Coronal section showing a large collection of heterotopias in the white matter on the left and longitudinal callosal (Probst) bundle on the right. Other Viruses In one series, herpes simplex infection was associated with chorioretinitis, microcephaly, hydranencephaly and microphthalmia. Maternal varicella zoster infection in the first or second trimester may, on some occasions, produce a characteristic embryopathy involving skin, muscle, eye and brain. An early stage of hydranencephaly was the result of a rare case of intrauterine purulent encephalitis. Megalencephaly includes a variety of clinical and pathological conditions and no classification is entirely satisfactory. Males are affected twice as often as females and, in the majority of patients, the large head is noticed within the first year of life. Mental retardation and neurological disorders of some sort were present in the majority of patients. Personal observations in several autistic subjects have disclosed megalencephaly as well as olivary heterotopia. Megalencephaly may be present at birth or may become manifest during the early postnatal years. A particular form of megalencephaly described as cerebral gigantism was reported by Sotos et al. There have been sporadic as well as familial cases,426 and autosomal dominant inheritance has been described. The nosology is unclear, although there is considerable overlap with neurocutaneous disorders. In a 17-year-old girl, the right cerebral and cerebellar hemispheres and the right side of the pons were enlarged, possibly resulting from an absolute increase in neuronal numbers, but no malformations were found. Morphological findings are varied and include polymicrogyria, pachygyria and cortical dysplasia. The affected ventricle may be reduced in size and the contralateral cavity enlarged. The pathogenesis is obscure, although a developmental impairment, taking place between weeks 9 and 15 of gestation, has been implicated. In the line of obliteration of the ventricle astrocytosis, fibrillary gliosis, ependymal tubules and iron-laden macrophages were observed. Third Ventricular Obliteration Neonatal-onset hydrocephalus in association with congenital fusion of the thalamus is extremely rare: it has been reported in two siblings162 and in a 6-month-old boy with a unique combination of anomalies including atresia of the aqueduct and upper fourth ventricle and rhomboencephalosynapsis. The tendency is to follow phylogenetic principles, but this approach cannot always encompass the great variety of transitional forms that straddle the normally accepted categories. Moreover, the correlation between phylogenetic and morphological subdivision is not precise. Additional complications are the heterogeneity of associated malformations, the multiplicity of postulated aetiological factors and, most importantly, the very prolonged development of the cerebellum, which extends well into postnatal life. The dividing line between malformative and degenerative processes becomes increasingly blurred in the later stages of gestation. Noxious agents that would be purely destructive elsewhere in the brain may influence granule cell proliferation, differentiation and the late growth spurt of the cerebellum; conversely, secondary atrophy in the wake of perinatal hypoxic­ischaemic injury, epilepsy or a consequence of anticonvulsant therapy may contribute significantly to the final morphological result. Coronal section of the striatum and frontal lobe showing obliteration of the frontal horn and body of the lateral ventricle, with adhesion between the corpus callosum and head of the caudate nucleus. Differential growth in the rhombencephalon during week 5 of gestation results in formation of the pontine flexure, widening the neural tube at this point with thinning of its roof, which becomes transversely creased. Within this crease, or plica choroidea, the choroid plexus will develop, whereas caudal to it the membranous roof of the fourth ventricle forms a pouch-like evagination in many species;94 in humans this perforates, forming the foramen of Magendie by 12 weeks,119 whereas the foramina of Luschka open later, probably around 16 weeks. Also anterior to the plica, the lateral parts of the alar plates undergo intense neuroblastic proliferation, enlarging to form the rhombic lips, the paired primordia of the cerebellum that gradually extend dorsomedially, meeting the roof of the fourth ventricle at around 6 weeks of gestation and then fusing together in the midline during month 3. Cerebellar growth, which has been entirely intraventricular, now becomes extraventricular and the various subdivisions begin to appear: first the posterolateral or flocculonodular fissure at 9 weeks, demarcating the vestibular or archicerebellum from the rest, and then at 12 weeks the primary fissure separating anterior from posterior lobes, the spinocerebellum or palaeocerebellum from the pontocerebellum or neocerebellum. It is this last, phylogenetically youngest, portion of the cerebellum that becomes predominant in mammals, and its various fissures form 4­8 weeks after those of the vermis and flocculonodular lobes. The neurons of the cerebellar cortex and deep nuclei as well as the pontine and inferior olivary nuclei all derive from the alar plates, ventral migrations into the pontine grey and olivary ribbons, and lateral migration into the rhombic lips from where there are two divergent pathways. The first is inwards through the cerebellar plate, the path followed by the Purkinje cells and neurons of the deep nuclei. The second pathway forms the external granular layer, via migration around the inferior border of the rhombic lip and then cephalad and lateral over the surface of the developing cerebellum. The cells from this layer migrate inward along Bergmann glia, past the Purkinje cell layer to form the internal granular layer. It is this population of neurons that has a major influence on folial development. Early reports, such as those of Combette and Priestley describing, respectively, an 11-year-old child with epilepsy and mental retardation185 and an infant aged 4 months with hydrocephalus, spasticity 4. The floor of the fourth ventricle (arrow) is exposed by the total absence of cerebellar tissue. Pathology of Malformations 347 and spina bifida,835 were without histological verification. Ricardi and Marcus859 reported two brothers with congenital hydrocephalus who died early in infancy: autopsy of one child showed cerebellar agenesis. Patients with total or near-total absence of the cerebellum usually have developmental disability, both mental and physical, but the cerebellar defect may not be suspected during life. The clinical and radiological diagnosis of these syndromes and the complexities of their differential diagnosis are reviewed by Bordarier and Aicardi. Other structures are absent or dysplastic, including the palaeocerebellar roof nuclei, dorsal accessory olive and inferior olive. The cerebellar anomaly may be combined with other midline anomalies, septo-optic dysplasia,913 commissural abnormalities369 and fusion of the thalami. This is often hugely dilated, its cystic roof sometimes herniating upwards through the 4. Absence of the left cerebellar hemisphere and middle cerebellar peduncle and marked reduction in the size of the contralateral pontine nuclei. Horizontal section of the hindbrain showing absence of the vermis and fusion of the hemispheric cortex and dentate nuclei. Sagittal section of brain stem and cerebellum, showing preservation of the superior vermis and incorporation of the rudimentary inferior vermis into the cyst wall. Inferior surface of the cerebellum, showing the defect in the vermis and the line of attachment of the tent-like cyst. The inner aspects of the cerebellar hemispheres­deep white matter overlaid by attenuated ependyma­form the smooth white lateral walls of the 4. The delicate membrane of the posterior fossa cyst ruptures readily during the dissection. Horizontal section of the hindbrain showing absence of vermis, and hypoplastic right cerebellar hemisphere and dentate nucleus. There is complete absence of the vermis, and remnants of cerebellar tissue (arrow) are incorporated into the cyst wall. The choroid plexus is abnormally positioned in the lateral recesses and bordering the medullary insertion of the roof membrane. The patency of the fourth ventricle foramina has been much argued over, but in a majority of cases they are patent. The usual clinical presentation is early in life with hydrocephalus and a prominent occiput, which may be transilluminable posteriorly. Poor head control, motor retardation, spasticity and respiratory failure also occur. Clinical signs in older children­nystagmus and ataxia­simulate those of a posterior fossa space-occupying lesion. Presentation in adulthood is also described,363 as well as asymptomatic cases found incidentally post mortem. Early workers attached great importance to foraminal atresia, believing that this caused hydrocephalus and subsequent bulging of the anterior membranous area. There are two insurmountable objections: the fourth ventricle foramina are more often patent and, embryologically, they become patent only after the paired cerebellar primordia fuse and the anterior membranous area becomes incorporated into the vermis. A more acceptable explanation is a developmental arrest of the hindbrain, which would also account for the atretic foramina as well as the associated brain stem anomalies and the occasional involvement of the 350 Chapter 4 Malformations cerebellar hemispheres. All of this suggests that the Dandy­ Walker malformation originates before the third month. There is also supporting experimental evidence from the hydrocephalic mouse,99,120 in which the anterior membranous area persists and expands between the vermis and the choroid plexus, comparable to the Dandy­Walker cyst. Galactoflavin administration to mice induced a similar defect and callosal agenesis. This family has its basis in mutations in ciliary structural proteins and thus falls into ciliopathies. The ventricular system may be moderately dilated, including the fourth ventricle, although this is slight compared with the cystic dilation in the Dandy­ Walker malformation. The tiny cerebellar hemispheres have few, rudimentary folia, whereas the vermis and flocculi are much better preserved. Note the disparity between neocerebellum and vermis and flocculi, the hypoplastic middle cerebellar peduncles and basis pontis, the dentate nuclei broken into islands and the simplified olives. Pathology of Malformations 351 absent or represented by a few rudimentary folia but, histologically, the cerebellar cortex is normal. In the subcortical and deep cerebellar white matter there are numerous heterotopias of large nerve cells, the dentate nucleus is dysplastic and segmented and the roof nuclei cannot be found. In the medulla, olivary dysplasia, in the form of a C-shaped band, and anomalies of the pyramidal tracts and cranial nerve nuclei have been described. Pontoneocerebellar Hypoplasia Under this title, Brun, as part of a larger study of cerebellar anomalies, described microcephaly and severe mental retardation in two children of 11 months and 15 months who showed rudimentary cerebellar hemispheres with relatively well-preserved palaeocerebellum, a peculiar segmentation of the dentate nucleus, severely hypoplastic nuclei pontis, absent arcuate nuclei and hypoplastic inferior olives. Microcephaly is notable in most of these patients and may be profound,870 although there are no corresponding histological abnormalities. Even so, the hindbrain is disproportionately small, often 3 per cent or less of the total weight, on account of the slender brain stem (particularly the pons) and extremely small cerebellar hemispheres. Histologically, the cortex, associated white matter and roof nuclei of the vermis and archicerebellum are normal. The dentate nuclei in all these cases are grossly disorganized, lacking their normal undulating ribbon, hilum or proper amiculum. Midsagittal section showing small cerebellum and shrinkage of the superior vermis. Note the rudimentary dentate nucleus and larger grey matter heterotopias as well as (b) olivary dysplasia in the medulla. Atrophy of the granule cell layer and preservation of the Purkinje cells, many of which are present in the molecular layer. The superior and middle cerebellar peduncles are thin and poorly myelinated, whereas the restiform bodies are usually better preserved. Clinical abnormality is present from birth, with microcephaly, severe psychomotor retardation, feeding difficulties, choreiform and other abnormal movements, myoclonic jerks and seizures. The dentate nuclei may be simplified, but not segmented, and the olives dysplastic. A sibship of three affected children suggests autosomal recessive inheritance,397 but all other cases have been sporadic.

The wall of the small artery (arrow) is thickened by the deposited plasma proteins pain treatment meridian ms purchase artane on line amex. The lumen of the larger artery is filled by thrombus and there has been leakage of plasma proteins into the surrounding cortical parenchyma (anti-fibrinogen antibody and haematoxylin counterstain) best pain medication for old dogs artane 2 mg generic. At these sites the basal lamina under the damaged or regenerated endothelial cells becomes thickened or reduplicated pain treatment clinic order artane 2 mg on-line. First pain research treatment journal purchase generic artane canada, it aggravates atherosclerotic changes in extracranial and intracranial larger arteries period pain treatment uk buy artane 2 mg visa. The leptomeningeal arteries over the convexities are usually spared in normotensive atherosclerotic subjects, whereas in hypertensive patients they stand out as hardened, non-collapsed, yellowish blood vessels. Lesions similar to those in large vessel atherosclerosis may develop in arterioles down to 100 m in diameter (see later). Since they were first reported648 the pathogenesis of lacunar infarcts has been a topic of intensive research. The tunica media of the smaller arteriole shows hyperplasia, whereas in the larger arteriole there is an irregular degeneration of smooth muscle cells (b) and accumulation of collagen type I (c). Small cerebral arteries and arterioles may be affected by many other diseases, such as hereditary angiopathies, inflammatory and infective vasculitides and toxic disorders (see later). The pathogenesis of atherosclerosis in the small vessels does not differ substantially from that in larger vessels. The homogeneous eosinophilia in haematoxylin- and eosin (H&E)-stained sections may result from either fibrinoid change or collagenous fibrosis. Arteriolosclerosis tends to be associated with ischaemic white matter disease and vascular dementia rather than lacunar infarcts. The significance of micro-aneurysms in hypertensive haemorrhage has been questioned. However, definitive identification of microaneurysms in routine diagnostic analysis is very rare. Venous Collagenosis Venous collagenosis is mostly seen in older brains and increases in tandem with white matter disease. In some respects, atherosclerosis also has some features of an inflammatory disease (see earlier). The American College of Rheumatology has published clinical diagnostic criteria for several vasculitides. Deciphering the micro-aneurysms According to the traditional view, Charcot­Bouchard or miliary micro-aneurysms arise in the context of hypertension, at weakened sites in vessel walls. Inset shows the distinction between the actual length and straight distance between two points along the vessel. Periventricular venous collagenosis is invariably present in older subjects, although the extent and severity vary. There is no single generally accepted classification of vasculitides, but they are often categorized according to the aetiology or presumed pathogenesis, and by the site and type of affected blood vessels (Box 2. Revascularization of the obstructed carotid arteries can cause a marked transient hyperperfusion syndrome. There is multifocal destruction of elastic lamellae in the aorta and of smooth muscle cells in the carotid arteries. In rare fatal cases, it has been possible to analyze the topography of the inflammation in detail. The inflammation fades as the affected arteries perforate the dura, at which point the amount of elastic in the arterial wall is also markedly diminished. The key symptom is headache, and a serious sequel is blindness: transient amaurosis fugax in about 10­12 per cent of patients and permanent blindness in about 8 per cent. The blindness is usually due to extension of the disease into the ocular, most commonly, or the ophthalmic arteries or their branches but can also be caused by occipital infarction, probably as a result of emboli from thrombosed vertebral arteries. The inflammation affects primarily the tunica media, causing destruction of the elastic lamellae and inducing the formation of foreign body giant cells, a common finding wherever elastic tissue is destroyed by inflammation. Secondary fibrosis of all layers causes thickening and loss of compliance of the blood vessel walls, resulting in characteristic loss of carotid pulsations. The affected arteries are finally transformed into Diseases Affecting the Blood Vessels (a) (b) 103 2 (c) 2. The inflammatory changes may extend along the length of the artery but are often focal. Marked proliferation of intimal cells has thickened the intima and severely narrowed the lumen. At later stages, the intima is markedly thickened and the internal elastic lamina and the media largely destroyed, and the media and adventitia may become fibrotic and thickened, with blurring of their interface. The vasculitis may also induce local thrombosis; if located in an anatomically critical blood vessel, this may serve as a source of small emboli to the intracerebral arteries and be a rare cause of an infarct. There is also infiltration of the walls of several arterioles by lymphocytes and epithelioid macrophages. The most common clinical features are headaches, confusion, memory impairment, hallucinations, seizures and multifocal neurological deficits. In a minority of patients, neuroimaging reveals infarcts, haemorrhages or white matter lesions. A biopsy sample that includes leptomeninges and a wedge of cortex is best for diagnosis, particularly if it can safely be obtained from a region that shows abnormalities on imaging. The non-granulomatous form may manifest as polyarteritistype necrotizing inflammation or as a simple lymphocytic vasculitis. A can often be identified within macrophages and giant cells in the inflammatory infiltrate. White matter oedema or discrete white matter lesions are present in about two-thirds of cases. Primary small vessel inflammatory vasculopathy is considered the main cause of infarction by some, whereas others emphasize thrombotic and thromboembolic mechanisms and ascribe minor significance to vasculitis. Proponents of the former view have reported fibrinoid necrosis, mononuclear inflammatory infiltrates and fibrotic thickening of the vessel walls, resembling changes to the renal vasculature, whereas those who support the latter view have found only limited vascular pathology. Deposition of immunoglobulins and complement in blood vessel walls can be demonstrated in biopsies from extracranial, more easily available tissues but studies on intracranial blood vessels are scarce. These show a 10-fold higher disease concordance in monozygotic than dizygotic twins or siblings. Its aetiology and pathogenesis have not been established definitively, but the mechanism most commonly implicated is an immune complex-mediated vasculitis. Various antigens are implicated,793 including microorganisms, autoantigens and drugs. Most lesions are less than 1 mm in length and the vasculitis does not necessarily affect the whole circumference of the artery. Active lesions characteristically show fibrinoid necrosis, often with complete destruction of the blood vessel wall. In healed vessels, all layers of the artery show fibrous scarring and any residual inflammation is lymphocytic. The vasculitis may also involve extracerebral and intracerebral cranial blood vessels, causing ischaemic stroke, haemorrhage or encephalopathy with or without seizures. Manifestations include fever, mucosal inflammation with ulceration, nonsuppurative lymphadenopathy, oedema of hands and feet, a polymorphous rash and ischaemic cardiac symptoms. Increased concentrations of antibodies against phosphatidylserine and ribosomal phosphoproteins have been described but the pathogenesis is unclear. Perivascular infiltration by lymphocytes, macrophages and neutrophils is common, whereas involvement of the blood vessels is variable. Diseases Affecting the Blood Vessels 109 Drug-Induced Vasculitis Vasculitis is one of the pathogenetic mechanisms purported to explain the increased incidence of stroke among drug abusers. The inflammatory infiltrate is mainly lymphocytic, and some patients respond to immunosuppressive therapy. The end result of healed syphilitic vasculitis may be indistinguishable from an atherosclerotic fibrous plaque. The spirochaete seems to bind to connective tissue molecules in the blood vessel wall and induces vasculitis. Inflammatory alterations in the cerebral blood vessel walls have been reported, particularly in patients infected with the herpes viruses, notably varicella-zoster virus (see Chapter 19). Although small arteries are often affected, in rare cases involvement of large arteries. This is thought to represent an overactive response of a reconstituted immune system to various infection-related antigens (see Chapter 19, Viral Infections). Fungi of otherwise low pathogenicity are amongst the more common infective agents in such patients. A necrotic blood vessel is seen next to an intracerebral lobar haematoma of clinically undetermined origin from a 27-year-old abuser of multiple hard drugs. Fungi associated with infective cerebral vasculitis include Aspergillus, Candida, Coccidioides and Mucor species. Ruptured intracranial aneurysms are responsible for about 85 per cent of cases of subarachnoid haemorrhage. Intracranial aneurysms have been classified according to a range of features including aetiology (congenital, acquired, dissecting, infectious, tumourous), size, shape (fusiform, saccular) or association with a specific branch of a vessel. Two to five per cent of the population worldwide are estimated to develop intracranial aneurysms. The overall prevalence of aneurysms is higher in women than men (ratio 3:2) but this female preponderance does not manifest until after the fifth decade; in younger age groups, males predominate. In about 12­15 per cent of patients with saccular aneurysms there is an autosomal dominant pattern of inheritance;23 these patients tend to be younger (by about 5 years). There are two focal enhancing lesions, which disappeared with antibiotic therapy, but recurrences similarly responsive to antibiotics occurred three times in different locations. The underlying parenchyma was slightly oedematous, with minimal astrocytic reaction. Several studies have indicated that hypertension, hypercholesterolemia and cigarette smoking are risk factors. Genetic factors are important contributors to early-onset familial saccular aneurysms and subarachnoid haemorrhage. Several environmental factors have been implicated in the pathogenesis of saccular aneurysms. A risk locus associated with intracranial aneurysms was shown to be associated with elevated systolic blood pressure. Fungal hyphae of phycomycosis (mucormycosis) attached to and invading the wall of an intracerebral artery of a 52-year-old male patient, who developed cerebro­rhino­ocular phycomycosis in the context of ketoacidotic diabetes mellitus. The reported frequencies of multiple aneurysms in patients with subarachnoid haemorrhage vary from 8. A large proportion (30­40 per cent) of saccular aneurysms in children is of giant size. The walls of some aneurysms are thin and translucent and tend to collapse at autopsy. Some aneurysms have opaque walls due to fibrous thickening or atherosclerosis, and protrude as rigid sacs from their site of origin. Large aneurysms also often contain lamellated thrombus, which may seed thromboemboli into distal arteries. Small thin-walled aneurysms may be destroyed as they bleed, and only the torn edges may remain of larger aneurysms. Ruptured aneurysms are often obscured by large amounts of surrounding subarachnoid or intracerebral blood clot. Particularly if the location of the aneurysm has not been established previously by angiography or brain imaging, it is advisable to wash away the blood clot and to conduct a thorough search for the aneurysm before fixation of the brain. Dissection of fixed blood is tedious and the aneurysm may be difficult to identify within the clot. In the absence of recent bleeding, a site of previous haemorrhage is often marked by orange-brown discolouration of the pial surface and arachnoid. A more elaborate method for post-mortem 114 Chapter 2 Vascular Disease, Hypoxia and Related Conditions visualization of ruptured aneurysms or malpositioned clips has been developed for use in forensic cases. Even the endothelium may be incomplete, and blood clot may line the luminal surface. The aneurysm wall often includes atheroma, the severity of which tends to parallel the size of the aneurysm. The pads appear as flattened areas that have lost the rugose pattern of the vessel wall. The aneurysm had ruptured and caused both intracerebral haemorrhage (into the right temporal lobe) and subarachnoid haemorrhage. The elastic lamina (black) stops at the arrows, and the wall of the dilated aneurysm is composed of connective tissue with some atherosclerotic intimal thickening. The wall thins out towards the apex of the aneurysm on the right but the rupture itself is not visible. Scanning electron microscopic picture of a small, thin-walled aneurysm (A) at the bifurcation of a middle cerebral artery. A pad of vessel wall thickening (P) is seen proximal to the bifurcation, and the rugose pattern of the normal vessel wall is disturbed. A silicone rubber angiographic X-ray of a brain after an accidental kinking of the right anterior cerebral artery against the clip after ligating an aneurysm of the anterior communicating artery. As a consequence, the territory of the right anterior cerebral artery has remained unfilled by the contrast medium. Diseases Affecting the Blood Vessels 115 recent rupture, the frayed remnants of the wall show necrosis and infiltration by inflammatory cells. This may be accompanied by deposition of glycosaminoglycans, accumulation of macrophages, calcification and haemosiderin deposits. Immunohistochemical studies have shown reduced smooth muscle actin, consistent with the atrophy of the media. Abnormalities of components of the extracellular matrix, including collagens and elastin, have also been demonstrated. In a minority of cases, patients may present with clinical manifestations of focal nerve or parenchymal compression.

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Patients are instructed to relax the diaphragm and increase anterolateral abdominal muscle contraction under visual control pain treatment centers ocala fl discount artane 2 mg buy. Early results indicate that biofeedback achieves a gratifying amelioration of the sensation of abdominal distension and a reduction in abdominal perimeter treating pain after shingles buy generic artane on line. Mechanisms of intestinal gas retention in humans: impaired propulsion versus obstructed evacuation knee pain treatment running artane 2 mg mastercard. Impaired reflex control of intestinal gas transit in patients with abdominal bloating neck pain treatment guidelines order artane online pills. Mechanisms of postprandial abdominal bloating and distension in functional dyspepsia treatment for pain related to shingles buy discount artane 2 mg line. Abdominal accommodation: a coordinated adaptation of the abdominal walls to its content. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference. Abdominal accommodation induced by meal ingestion: differential responses to gastric and colonic volume loads. Accommodation of the abdomen to its content: integrated abdominothoracic response. Mechanisms of abdominal distension in severe intestinal dysmotility: abdomino-thoracic response to gut retention. New insight into intestinal motor function via non-invasive endoluminal image analysis. Impaired intestinal gas propulsion in manometrically proven dysmotility and in irritable bowel syndrome. Anal gas evacuation and colonic microbiota in patients with flatulence: effect of diet. Chronic intestinal pseudoobstruction is a syndrome characterized by recurrent symptoms of intestinal obstruction with associated radiographic evidence of small bowel dilatation but in the absence of obvious mechanical obstruction. It is essential to make a timely and accurate diagnosis and to identify the cause. It is associated with visceral myopathy of the smooth muscle or visceral neuropathy of the enteric nervous system. Sporadic cases of visceral neuropathies, such as localized Hirschsprung disease or diffuse intestinal dysplasia, occur mostly in infants and children. Scleroderma, a generalized connective tissue disorder of the small arteries with associated fibrosis, can affect multiple organs. Neuromuscular disorders can affect the motor neurons, peripheral nerves, neuromuscular junctions, and muscles. Amyloidosis is caused by the deposition of insoluble fibrin proteins that are resistant to proteolysis. The small bowel myenteric plexus itself is usually intact histologically, but can be involved in some cases. An idiopathic inflammatory neuropathy has been described with neuronal and axonal degeneration associated with lymphocytic ganglionitis with neuronal degeneration. At first, patients are suspected of having either partial or complete small bowel obstruction because of their presenting symptoms; however, mechanical obstruction cannot be identified on radiologic testing. Symptoms are quite variable, ranging from mild postprandial distress to persistent abdominal distension associated with abdominal pain, malnutrition, and an inability to eat. Patients who have undergone a subtotal colectomy or whose ileocecal valve has been resected can present with abdominal distension due to ascending coliform bacteria, but the presence of diffusely dilated small bowel likely represents an unrecognized diffuse motility disorder prior to surgery. Raynaud, arthralgia, Chronic Intestinal Pseudo-obstruction173 174Chapter 14 digit swelling, muscle pain, and proximal muscle weakness may identify patients with an underlying connective tissue disorder. Back pain, proteinuria, and an elevated globulin-to-albumin ratio occur in secondary amyloidosis associated with multiple myeloma. Main physical examination findings typically include abdominal distention with tenderness and a succession splash. Enteric dysmotility describes a subgroup of patients without evidence of dilated lumen. A complete metabolic panel, along with thyroid-stimulating hormone, vitamin B12, complete blood count, and inflammatory markers (eg, erythrocyte sedimentation rate and C-reactive protein), should be obtained. Identification of antineuronal nuclear antibodies (eg, anti-Hu, anti-Ri, anti-Purkinje cell) should be pursued in patients at risk for paraneoplastic syndrome. Other autoantibodies have been identified, but they are often absent in most patients. Testing for lactic acid, thymidine phosphorylase levels, nucleotide concentrations, and genetic analysis can be obtained in patients with systemic manifestations of mitochondrial disorders. Presence of small intestinal diverticulosis and pneumotosis intestinalis should be identified. Intraluminal or extraluminal occlusion may be identified, especially in patients with duodenal and proximal jejunal dilation. Mucosal biopsies of the proximal small bowel may detect amyloidosis by Congo red stain, but rectal biopsy and fat pad aspiration are more sensitive for amyloidosis. Viral cultures should be obtained in individuals at risk for cytomegalovirus and herpes simplex virus. The small bowel appears diffusely dilated, and retained food is seen in the stomach. Overgrowth of coliform bacteria is an indication of small bowel peristaltic failure. Motility Studies Although not available in most centers, scintigraphy allows for the evaluation of gastric, small bowel, and colonic transit. Wireless motility capsule measures small bowel transit based on changes in pH when entering the duodenum (rise in pH) and when traversing the ileocecal junction (fall in pH). Abnormal esophageal manometry has been suggested as a surrogate marker for small bowel dysmotility. The pressure profile within the small bowel can be evaluated using either standard or 24-hour ambulatory antroduodenal manometry. The normal 3 phases during the fasting period should be identified based on the frequency and amplitude of contractions. Phase I is a Chronic Intestinal Pseudo-obstruction177 quiescent phase with only minimal spontaneous contractile activity. Visceral myopathy is typically associated with hypomotility with low-amplitude contractions (< 10 mm Hg) in the small bowel. Autonomic testing should be considered if there is evidence of a vagal neuropathy with abnormal postprandial response on antroduodenal manometry and there is no known underlying neurologic disorder. Advances in minimally invasive surgical approaches make surgical biopsy an acceptable approach. For these cases, it is essential to obtain a full-thickness biopsy during surgery in patients without an identifiable mechanical obstruction. Our recommendations for histologic and immunohistochemical evaluation are provided in Tables 14-3 and 14-4. Findings can be reported for the outer and inner smooth muscle layers and for the myenteric plexus. Although current therapeutic approaches are suboptimal, recent refinements in nutritional support, pharmacological therapy, and transplant options have helped improve the management of the disease. Patients should be managed by a multidisciplinary team including a neurogastroenterologist, nutritionist, and transplant surgeon. Small and frequent meals consisting of liquid or homogenized foods that are low fat and low residue are better tolerated than solids in those with adequate intestinal absorption. Fat-soluble vitamins A, D, E, and K, as well as B12 and folic acid, should be checked and, if necessary, supplemented. A nasojejunal feeding trial can be performed in malnourished patients to test the ability of the small bowel to tolerate direct nutritional supplementation. Low-flow enteral feedings (eg, 25 to 50 mL/hr) with higher caloric concentrations (eg, 2 cal/mL) can be utilized. Furthermore, medication administration can be accomplished through the jejunostomy tube. Of note, neither metoclopramide 182Chapter 14 nor domperidone affect intestinal motility beyond the proximal jejunum. In a small, open-label study, erythromycin, a motilin agonist, was shown to be effective during acute exacerbations of intestinal pseudoobstruction. Lower doses of erythromycin in liquid formulation (50 to 125 mg 3 times per day) may help to minimize tachyphylaxis. Neostigmine is a reversible acetylcholinesterase inhibitor that stimulates muscarinic parasympathetic receptors, resulting in increased colonic motor activity. Case reports have suggested its efficacy in managing acute exacerbations of intestinal pseudoobstruction (0. However, efficacy of pyridostigmine for small bowel motility disorders is unknown. Nonabsorbable antibiotics like rifaximin can be given for 10 to 14 days, but the excessive cost commonly limits their use. Other options are metronidazole, ciprofloxacin, neomycin, tetracycline, and doxycycline. To keep the regimen simple for the patient, a selected antibiotic can be used for 2 weeks on the first day of the month, followed by an antibiotic-free interval for the rest of the month. A different antibiotic is used on the first day of next month for 2 weeks and again followed by an antibiotic-free interval. Immunosuppressive therapies (eg, prednisone, rituximab, cyclophosphamide) have been shown in a few case reports to be beneficial in patients demonstrating an inflammatory enteric neuropathy or myopathy. However, the efficacy of surgery is limited due to the progressive nature of the underlying gut dysfunction. Surgery is often required if patients develop acute volvulus of the small bowel and cecum due to a dilated lumen. Both children and adults are affected; however, the true prevalence and incidence are unknown. Nutritional support is essential in patients with frequent vomiting and suboptimal oral intake. Isolated or multivisceral transplantation is reserved for patients who are unable to tolerate long-term parenteral nutrition. Diagnosis and treatment of chronic intestinal pseudo-obstruction in children: report of consensus workshop. Clinical and morphofunctional features of idiopathic myenteric ganglionitis underlying severe intestinal motor dysfunction: a study of three cases. Clinical features and long-term survival in chronic intestinal pseudoobstruction and enteric dysmotility. Epidemiology and clinical experience of chronic intestinal pseudo-obstruction in Japan: a nationwide epidemiologic survey. Generalized transit delay on wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. Prognostic yield of esophageal manometry in chronic intestinal pseudoobstruction: a retrospective cohort of 116 adult patients. The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group. Full-thickness biopsy findings in chronic intestinal pseudo-obstruction and enteric dysmotility. Clinical-histological associations in gastroparesis: results from the Gastroparesis Clinical Research Consortium. Quantitation of cellular components of the enteric nervous system in the normal human gastrointestinal tract: report on behalf of the Gastro 2009 International Working Group. Long-term outcome of chronic intestinal pseudoobstruction adult patients requiring home parenteral nutrition. Chronic intestinal pseudoobstruction syndrome: clinical analysis, outcome, and prognosis in 105 children. Erythromycin for the treatment of chronic intestinal pseudo-obstruction: description of six cases with a positive response. Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudoobstruction. Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction: a double-blind, placebo-controlled, cross-over, multiple n=1 study. Non-transplantation surgical approach for chronic intestinal pseudo-obstruction: analysis of 63 adult consecutive cases. Isolated intestinal transplant for chronic intestinal pseudo-obstruction in adults: long-term outcome. Second, alterations in small bowel microbiota may have clinical and physiological manifestations beyond maldigestion and malabsorption. These may include alterations in metabolic functions secondary to abnormal intraluminal fermentation, intestinal barrier, and immune functions. Thus, while the bacterial load is relatively low at the proximal small bowel (~ 100 to 103), it increases significantly at the distal jejunum and ileum (~ 106 to 109) and particularly in the large intestine (~ 1010 to 1012). Furthermore, the composition of the bacterial communities also changes from mainly aerobic bacteria in the proximal small bowel to a mix of aerobes and anaerobes in the distal segments of the small bowel and to primarily anaerobes in the large intestine. Our current understanding of the intestinal microbiota is based on data generated from studies done primarily on luminal content (eg, fecal samples or duodenal aspirates). However, it is important to recognize that this approach provides a limited perspective and that our current knowledge on the microbial composition, function, and clinical relevance of the luminal versus mucosal mucous microbial microenvironments is still under intensive investigation. Physiological Protecting Mechanisms and Predisposing Factors Several physiological mechanisms help prevent overgrowth of bacteria in the small bowel. The stomach has a protecting barrier role against intestinal invasion of bacteria from the outside environment, since, with the exception of Helicobacter pylori and a few other acid-resistant bacterial strains, its highly acidic environment is not favorable for bacterial colonization.

The staircase is considerably flattened on Mount Everest and in the most hypoxic patients treatment guidelines for back pain buy artane mastercard. Hypoxic response mechanisms 83 Hyperventilation: occurring almost immediately and accompanied by a respiratory alkalosis bayhealth pain treatment center buy genuine artane on line. Oxygen extraction from blood: oxyhaemoglobin dissociation curve shifts to the right the pain treatment & wellness center hempfield boulevard greensburg pa buy artane overnight delivery, decreasing affinity for O2 with the ultimate consequence of decreasing brain tissue pO2 knee pain treatment video discount artane. Capillary density: hypoxic brain neovascularization is important for adaptation over time midsouth pain treatment center cordova discount artane online american express. Highaltitude pulmonary oedema results from the grossly hyperdynamic pulmonary circulation at altitude. A paradoxical increase in O2-derived free-radical generation may play a role in both cerebral and pulmonary oedema at high-altitude. A plethora of other neurological conditions can occur at altitude,95 not all necessarily due to hypoxia. Even an experienced mountaineer may lose accrued climbing wisdom, show clear errors of judgement and make poor decisions at high altitudes. However, the syndrome reverses on return to low altitudes and permanent deficits are not detectable on neuropsychological testing. These include expansion of 84 Chapter 2 Vascular Disease, Hypoxia and Related Conditions presynaptic terminals containing multilamellar bodies, aggregated or clumped synaptic vesicles and various tubular arrays and profiles. Similar ultrastructural changes can be seen in other elements of the brain, including neuronal perikarya, glia and vascular cells. Although ganglioside breakdown has been found in human infant brains exposed to hypoxia,820 adult brains do not show change in free fatty acids but only small changes in prostaglandins and eicosanoids. Lactate begins to increase when the oxygen content of inspired air drops to 12 per cent, corresponding to a saturation of O2 (SaO2) of 50 per cent. A new steady state is achieved in hypoxia, with upregulation of mainly regulatory genes whereas in ischaemia there is mass activation of genes, in association with tissue destruction (see earlier). Many classes of genes are differentially induced and regulated by hypoxia and ischaemia. Some genes have adaptive value when stimulated,233,525,1107 whereas others may be harmful. Even physiological stimuli and neurotransmitter (acetylcholine) release can activate genes such as the transcriptional regulator c-fos. In hypoxaemia, one of the first genes to be upregulated is that for erythropoeitin. In hypoxaemia, only delivery of O2 is impaired, not removal of products of metabolism. If a grave prognosis is spuriously ascribed to a coma accompanying a pure hypoxic insult, then treatment could be withdrawn from a patient who has not suffered widespread brain necrosis. In medicolegal review, it is important to determine whether cardiorespiratory arrest or only respiratory arrest neurotransmission failure and energy failure In the hypoxic brain, neurotransmission ceases before energy failure. The prognosis is very different if cardiac arrest has not occurred and blood pressure has been maintained. Total cerebral ischaemia of only 2 minutes can cause neuronal necrosis957 whereas even profound arterial hypoxia, without cardiac arrest or hypotension, does not. Mostly young people demonstrate this syndrome of respiratory failure without heart arrest. This pathophysiological and pathological distinction between hypoxia and ischaemia is thus important for the pathologist as well as the clinician. In the special case of hanging, the weight of the individual is used to tighten a constricting band or rope around the neck. The temporary inability to breathe due to chest wall compression during a vertex delivery is normal if the umbilical cord is supplying oxygenated blood, as are physiological decelerations in fetal heart rate. Breech delivery, with the umbilical cord pressed against the pelvic rim until delivery of the aftercoming head, initially seems a plausible risk factor for cerebral ischaemia, cerebral necrosis and cerebral palsy. Large studies of breech deliveries, however, have shown no risk associated with vaginal delivery versus caesarean section for the development of subsequent neurological deficits. The generally litigious climate attributing cerebral palsy to obstetric or neonatal paediatric malpractice is based on spurious claims. These include low birth weight, disorders of coagulation and intrauterine exposure to infection or inflammation, all of which show a positive association with cerebral palsy. Forensic analysis distinguishes three causes: (i) suffocation, (ii) strangulation and (iii) chemical asphyxia. Although suffocation and strangulation are discussed here, more detailed analysis is available in textbooks of forensic neuropathology. Sulphide, Cyanide and azide Exposure to sulphide is seen clinically in a number of circumstances. Cyanide exposure occurs industrially, and in suicide and homicide attempts, because the chemical is easily available. The admixture with acid produced free cyanide gas, lethal at 300 parts per million (ppm). Although azide is an important industrial chemical, used also in rocket fuels and as a herbicide, insecticide and molluscicide, it is no longer used as a fumigating agent in buildings. Historically, there was widespread use of both cyanide and azide to rid ships, buildings, rooms and apparatuses of both infection and infestation by insects. Sometimes, the fumigator perished because of the action of these agents, in a manner similar to workers exposed to natural gas or sewers that contains H2S. Gaseous sulphide smells of rotten eggs, and cyanide smells of apricot seeds or bitter almonds. Exposure to any of these three agents causes brain damage, but heart failure always supervenes in sulphide-,8 cyanide-405 and azide-related670 injury. Exposure to low to moderate ambient concentrations of H2S at 20­50 ppm causes eye and lung irritation. Higher concentrations of H2S paralyse the olfactory nerves and sense of smell, making it impossible to recognize the signal rotten-egg odour. The mechanism of immediate death is too fast to be accounted for by necrosis of cells due to cytochrome binding. Inhalation of 500 ppm sulphide causes immediate apnoea, related to hyperpolarization of neurons in the medulla oblongata that control breathing. The immediate death often leads to a scenario in which a missing person exposed to H2S is sought after by rescue workers, who are themselves then overcome by the gas. Whether necrosis is due to direct histotoxicity, cardiac hypotension or standstill is not clear in these physiologically uncontrolled human observations. Experimental work suggests that the cerebral necrosis relates to the potent and immediate depression of blood pressure by cyanide or sulphide. Exposure to even very high (supra-lethal without ventilation) concentrations of these agents is incapable of producing cerebral necrosis unless hypotension supervenes. In one series, a single ventilated animal that received a very high dose of sulphide (a supra-lethal dose in the unventilated animal) showed cerebral necrosis;84 physiological monitoring of this animal had revealed persistent hypotension to <4. Animals that do show necrosis in studies of both cyanide and sulphide encephalopathy do so in a distribution resembling that after global ischaemia. Target organs in decompression sickness include the spinal cord,162 as well as the skin, bone, retina807 and ear. Air embolism also plays a role in the neurological damage that can be seen after cardiac bypass surgery. Air introduced into the cardiac chambers during open-heart surgery can embolize to the brain. The yellow colour of necrosis is absent and the walls of the cysts are smooth, unlike foci of necrosis. This post-mortem alteration is due to somatic death being noninstantaneous, with hypotensive shock redistributing blood flow away from an ischaemic bowel while preserving that to the heart and brain. Ischaemic bowel is a rich source of bacteria and anaerobes characteristically find their way into the blood stream just before death. When the heart fails, it pumps bacteria that seed the brain, normally a sterile organ, in a transient peri-mortem septicaemia before death and cardiac standstill. If images of the cells can be lightened by photographic or computerized image analysis, the preservation of cellular substructure is evident. Recovery of dark neurons can be demonstrated through serial study over time, with reversal of the appearance of cytoplasmic condensation,72 the organelles and cell membranes. Dark neurons occur in the early stages of neuronal injury due to ischaemia,227 hypoglycaemia72 and epilepsy. They have plagued the interpretation of tissue sections since their early observation165 and their profiles can occasionally be seen in normal tissue. This alteration is easily mistaken by the uninitiated for cystic infarcts, especially if the cavities are few in number. The gross appearance (a) results from gas-forming anaerobic bacteria, which seed the brain peri-mortem. The cysts are smooth (a, b), with no hint of yellow colour or ragged edge, as in necrosis. Gram-positive bacilli (c) can be demonstrated in the parenchyma and in the walls of the cysts. Smoking one pack of cigarettes per day leads to carboxyhaemoglobin levels of 2­3 per cent. Smokers of more than two packs per day can have carboxyhaemoglobin levels of up to 6­7 per cent. Signs and symptoms are diverse and may include headache, dizziness, nausea, vomiting, syncope, seizures, coma, dysrhythmias and cardiac ischaemia. Two capillaries cross the microscopic field, which includes both dark and normal neurons. Acutely, the brain is pink because of the appearance of the bright-red carboxyhaemoglobin. Neurons seem very sensitive to the perturbation that causes the cellular contraction at the time of fixation. Neuroimaging techniques allow visualization of the pallidal lesion more easily than of the nigral lesion during life. Cardiac arrest can give rise to metabolic and structural lesions focally in the globus pallidus or the substantia nigra. A prominent role for hypotension in the pathogenesis of brain damage generally is further suggested by cyanide poisoning, another form of histotoxic hypoxia marked by cardiac failure. Neuroimaging reveals more subtle abnormalities in the globus pallidus than seen in classical pan-necrosis. The association of partial necrosis of the pallidum with a psychiatric syndrome is in line with new concepts of basal ganglia function that extend beyond motor control. Basal ganglia neuronal loops are not limited to the motor cortex but also connect with the posterior parietal, premotor and prefrontal cortex,513 and with the medial and lateral temporal lobes, hippocampus, anterior cingulate and orbitofrontal cortex. It is difficult to commit suicide with a modern, well-maintained car999 but this is not widely known by the public, accounting for the increasing prevalence of incomplete globus pallidus necrosis and psychic akinesia. Incomplete pallidal necrosis and psychic akinesia are illustrated by the case of a 52-year-old attorney, who presented with a long history of drug abuse. He required hospitalization and requested increasing doses of narcotics during his hospital stay. In a legal action, hypotension was alleged to have occurred but this could not be substantiated from his hospital course. The occurrence of white matter lesions in hypoxic states seems to be favoured by less severe insults. Such disorders frequently damage the endothelium or produce factors that activate platelets and the clotting cascade and cause thrombosis. It develops slowly and often begins in childhood, although a small minority escapes it until the ninth or tenth decade. Atherosclerosis is a disease of the whole arterial network, although marked regional variations exist. The carotid arteries are one of the most often affected extracranial sites and the progression of atheroma is similar to that in the aorta and coronary arteries. The characteristics of the fibrous caps in plaques seem to play a major role in the development of complications. Some generalizations about the risk factors have been made: high serum lipids and blood pressure are associated with a high prevalence of atherosclerosis in both the extracranial and intracranial arteries, whereas low or normal lipids and high blood pressure levels are associated mainly with intracranial and intracerebral arterial disease. The latter are removed by endothelial lipoprotein lipase in adipose tissue and skeletal muscle, and the remnants are taken up by hepatocytes, within which endogenous synthesis of cholesterol is adjusted according to the amount of exogenous cholesterol. Cholesterol, phospholipids and triglycerides are delivered from the liver to the body tissues by the apolipoproteins to ensure solubility of the lipids in the serum. In spite of the marked structural changes in the arterial walls, the atherosclerosis had not caused overt cerebrovascular symptoms. Note also the dilation (dolichoectasia) of the internal carotid arteries (arrows). The plaque impinges on the lumen, but luminal decreases of this magnitude should still allow adequate flow. There is organizing thrombotic occlusion of the left M1 after plaque rupture at autopsy. Images (d­f) kindly provided by J Ogata, National Cerebral and Cardiovascular Disease Centre, Osaka, Japan. The serial changes that occur within the intimal layer during progression of atherosclerosis are shown from left to right. The initial steps include adhesion of blood leukocytes to the activated endothelial monolayer, directed migration of the bound leukocytes into the intima, maturation of monocytes into macrophages and their uptake of lipid, yielding foam cells. Extracellular lipid derived from dead and dying cells accumulates in the central region of the plaque, often denoted the lipid or necrotic core.

In some cases pain treatment center riverbend calgary discount artane 2 mg on-line, linear radiating fracture lines extend from the central depressed fracture site pain treatment center albany ky 2 mg artane mastercard. In severe cases pain medication for cancer in dogs safe artane 2 mg, there may be a comminuted fracture back pain treatment yahoo answers generic artane 2 mg mastercard, in which part of the skull has been fractured into multiple pieces pain medication for dogs at home buy discount artane 2 mg on line. Comminuted fractures are frequently associated with parenchymal damage and are seen in high-velocity impacts, as might result from being struck by a moving vehicle or a fall from a height, or an assault with multiple blunt force impacts. These are depressed smooth fractures, their name reflecting the similarity in appearance to the defect produced when pushing into a ping-pong ball. They are not associated with a break in the inner table of the skull and are rarely associated with underlying parenchymal damage. Growing fractures may occur when dural and arachnoid tissue is trapped between the edges of the fracture, preventing it from healing. In diastatic fractures, the fracture line extends along and separates one or more sutures in the skull. However, it is likely that these lesions represent penumbral changes around typical haemorrhagic contusions. Contusions typically involve the crests of gyri and are often superficial, involving the grey matter only. The contusions that occur as a result of impact with acceleration or deceleration, such as a fall, may occur underneath the point of impact (coup injuries) or distant from the point of impact (contrecoup injuries). In forwardfall coup contusions, scalp bruising is over the forehead, with the contusions involving the frontal and temporal lobes. It has been suggested that the pattern of contusional injury gives information as to the direction and magnitude of the force applied,175 although more detailed studies4,7 do not support these observations. By definition, the pia mater is intact overlying contusions but torn in lacerations. Both types of injury typically involve the frontal poles, the inferior aspect of the frontal lobe including the gyrus rectus and the medial and lateral orbital gyri; the temporal poles and the lateral and inferior aspects of the temporal lobes; and the cortex above and below the Sylvian fissure. Fracture contusions may be seen at atypical sites in direct relationship to a skull fracture; the damaged bone ends become displaced and directly damage the underlying brain tissue. Contusions involving the occipital lobes and cerebellum are rare7 because of the smooth inner surface of the posterior fossa of the skull (compare with the bony ridges of the anterior and middle fossae); when seen, they are usually associated with an adjacent skull fracture and result from direct contact to the head by an object. Contusions may be non-haemorrhagic, although these are mostly described within the radiological literature. This example is of a burst left temporal lobe in a chronic alcoholic who sustained a simple fall and associated skull fracture. Pathology Associated with Fatal Head Injury 645 Contusions are dynamic lesions that evolve with time. One current theory is that post-traumatic coagulopathy results in continued or delayed microvascular haemorrhage; another, that the forces associated with the primary injury do not produce frank rupture of the microvessels at the time of injury but initiate molecular changes that result in subsequent structural failure. Small haemorrhages are resorbed over 2­3 weeks, whereas larger haemorrhages may take significantly longer. Old contusions are a not-infrequent incidental autopsy finding, particularly in at-risk groups, such as chronic alcoholics. They can be differentiated from old ischaemic lesions in that contusions are superficial and ischaemic lesions are typically found more deeply within the depths of sulci. Histologically, acute contusions are haemorrhagic, the haemorrhage being predominantly perivascular. Vascular margination is evident by 24 hours, and by 3­5 days there is predominantly T-lymphocyte and monocyte infiltration and both microglial and astrocytic activation. Macrophages phagocytose the degenerating red blood cells, the breakdown of haemoglobin giving rise to haemosiderin, which can be easily demonstrated with appropriate tinctorial stains. Haemosiderin-containing macrophages have been described within the haemorrhagic areas by 76 hours, and in surrounding cortex by 100 hours. A coronal section through the parasagittal frontal lesion (b) shows small haemorrhages which, in this case, are mostly limited to the cortical ribbon. There is degeneration of the cortical tissue and golden brown/orange discolouration of the surrounding parenchyma. An injury sector score between 0 and 116 can be derived for each case, providing a detailed overview of the anatomical distribution of all haemorrhagic injuries, including contusional injury. Both of these systems are research tools and rarely used in routine diagnostic practice. The clinical complications associated with a haematoma are related to the size/volume of the lesion, the anatomical location, and the rapidity with which the haematoma develops. The complications associated with a mass lesion are described later in this chapter. These form part of the spectrum of severe rotational injury and are most commonly seen in the frontal region. This example was from a road traffic accident, in a patient with a very short survival period. Parasagittal white matter haemorrhage is typically seen in road traffic accidents and is not associated with skull fractures or lucid intervals. A more rigorous method for assessing the extent of contusions in autopsy specimens was developed by Adams et al. Because the dura is tightly adherent to the inner aspect of the skull, the haematoma accumulates slowly, and lucid intervals are more common. There may be little discernible damage to the underlying brain to the naked eye, although microscopic examination frequently demonstrates at least focal ischaemic injury in fatal cases. It has been suggested that blood entering the extradural space can leave via veins, forming an arteriovenous shunt, and that this shunt delays haemostasis and clinical symptoms, contributing to the lucid interval. They are typically associated with heat-related fissuring of the skull, although the actual mechanism of their formation is unknown. There has been considerable discussion around the anatomical basis of the subdural space. Haines and colleagues179,180 demonstrated that there is no space or potential space, but rather that blood collects within a fissure that develops in the dural border cell layer. The dural border cell layer is the cell layer at the deep junction of the dura with the arachnoid. That bridging veins can rupture to produce subdural bleeding has been disputed,269 although anatomical,180 biomechanical,93 post-mortem424 and clinical observations233 offer strong support for this mechanism. Bridging veins have a consistent wall thickness as they pass across the subarachnoid space, but show marked variation in wall thickness as they enter the dural tissues along with increased circumferential, as opposed to longitudinal, collagen fibres. The haematoma is well circumscribed because of the tight adherence of the dura to the skull. However, it has been hypothesized that subdural and subarachnoid blood with associated mass effect may result in decreased blood flow in the affected hemisphere. This two-year-old presented with an acute subdural haematoma and underwent cranial decompression to decrease risk of subfalcine herniation. The sinusoids formed by neovascularization are fragile and are considered liable to rebleed, and occasional case reports support this contention. The blood has extended through the fissure created in the dural arachnoid border area, covering much of the underlying hemisphere. The gyral pattern is accentuated on the side of the haematoma, whereas the contralateral hemisphere shows flattening of the gyri. The haematomas are encapsulated and contain blood clot at various stages of organization. They have a central core of altered blood with a liquid component, surrounded by an inner and an outer membrane. The membrane adjacent to the dura has a thickened fibroblastic layer, and vascular sinusoids extend from this region into the blood clot. Current evidence suggests that fragile new blood vessels within the evolving haematoma are susceptible to bleeding, resulting in repeated episodes of haemorrhage that enlarge the overall lesion. The fluid may contain blood or blood-breakdown products, such that the fluid may be blood-stained or xanthochromic. The fissure (space) may develop as a result of mild trauma or meningeal infection or after neurosurgical procedures. Subdural hygroma is seen in infants and children and in the elderly, particularly where there is brain atrophy. Trauma is the most common cause, and subdural hygroma accounts for 5­20 per cent of post-traumatic mass lesions,242 although it may be more appropriate to consider them space-filling lesions because they typically do not cause an increase in pressure as assessed by lumbar puncture. The hygromas are commonly bilateral428 and usually within the frontal and temporal regions; posterior fossa examples are rare. The haemtomas are encapsulated and contain blood clot at various stages of organization. In one study, 478 patients were identified over a seven-year period with this diagnosis, and all had a good outcome, none requiring neurosurgical intervention. The haemorrhage is usually secondary to damage to the vertebral arteries but rarely may involve other vessels, such as the internal carotid382 or basilar artery. Hyperextension of the neck315 and a rapid increase in intra-arterial pressure caused by a blow441 have been suggested. The outcome for patients with traumatic basal ganglia haemorrhages is poor, with 59 per cent dying and only 16 per cent making a favourable recovery. A recent study showed 60 per cent to be due to road traffic accidents and 40 per cent due to falls, and confirmed the poor outcome, with 35 per cent of patients dying. A study of traumatic basal ganglia haematomas in children found that 52 per cent were due to high-velocity trauma and 38 per cent secondary to a fall from a height, with assault accounting for the remaining cases. This definition excludes contusions and the haemorrhagic progression in contusions that was discussed previously. Such lesions are typically seen in the setting of a high-velocity rotational head injury, in this case resulting from a road traffic accident. There was an increase in parasagittal white matter haemorrhages and diffuse traumatic axonal injury in these cases, all of these pathologies being associated with angular acceleration. The haemorrhage begins immediately, but the haematoma may increase in size over 30­60 minutes post injury, the duration of bleeding being determined by blood pressure and any underlying coagulopathy. Although this arrangement is of great value in protecting the soft parenchyma of the brain from injury, the design allows little opportunity to accommodate enlarging mass lesions, such as expanding haematomas, within the cranial cavity. The increasing volume may be secondary to a diffuse process, such as brain swelling, or may be caused by a unilateral expanding mass lesion, such as a haematoma or contusion. Acute prolonged pressure greater than 20 mmHg is abnormal, greater than 40 mmHg is associated with neurological dysfunction and compromised cerebral circulation and above 60 mmHg is virtually always fatal. Brain herniation may extend under the falx cerebri, damaging the cingulate gyrus (subfalcine or supracallosal hernia); under the tentorium cerebelli, damaging the parahippocampal gyrus/medial temporal lobe (tentorial or uncal hernia); or through the foramen magnum, damaging the tonsils of the cerebellum (tonsillar hernia) and the brain stem. In some cases, it represented the extension of a parenchymal haematoma into the ventricle or retrograde spread of subarachnoid blood from the infratentorial structures, although in a significant proportion haemorrhage was from structures in the periventricular region, including ruptured fornix/septum pellucidum, subependymal veins in the ventricular walls, choroid plexus or damaged corpus callosum. Subfalcine Herniation A subfalcine hernia develops as a result of a supratentorial mass lesion. A subfalcine hernia may obstruct flow within the pericallosal artery (anterior cerebral circulation) resulting in infarction in the corpus callosum and cingulate gyrus. It can be difficult to differentiate between the haemorrhagic lesion associated with diffuse traumatic axonal 10. The forniceal structures are torn, and the haemorrhage may have arisen from small vessels within the septum pellucidum. A wedge of necrosis usually develops in the inferior part of the temporal lobe at the point where it is in contact with the free edge of the tentorium cerebelli. The ipsilateral oculomotor nerve may be damaged and, when involved, appears kinked and discoloured. Branches of the ipsilateral posterior cerebral artery may be compromised by the tentorial hernia, resulting in infarction within the territory supplied by this artery, particularly involving the inferior part of the temporal lobe and medial occipital cortex. Bilateral tentorial herniation is typically seen in cases of global brain swelling. This pathology is common in fatal traumatic brain injury cases with significant acute subdural or extradural haematomas. The haemorrhages are most likely a consequence of vascular congestion within the brain stem parenchyma, and rupture of paramedian pontine branches of the basilar artery. True Duret haemorrhages are due to axial displacement, with forces pushing down from above. However, brain stem haemorrhages can be seen 654 Chapter 10 Trauma (a) (b) macroscopically. There is necrosis of the tonsils, and often ischaemic damage is seen in the medulla. The combination of pressure and ischaemia on the medulla results in cardiorespiratory collapse. Assessment of tonsillar herniation can be difficult in the absence of necrosis, although usually at least microscopic haemorrhage can be identified. She had transient diabetes insipidus, related to forces through the anterior skull base and pituitary stalk, which resolved. The patient is an average student attending regular school classes, but has some attention deficits. At autopsy Duret haemorrhages can be large, resulting in extensive damage to the midbrain and pons, such that in some cases the midbrain is replaced by a necrotic, haemorrhagic mass. The midline distribution should be differentiated from the dorsolateral distribution of haemorrhages in diffuse traumatic axonal injury, although often it can be difficult to differentiate between these two entities 10. Blunt Force Head Injury; Diffuse Injury 655 often produce herniation of the superior part of the cerebellar hemispheres upward through the tentorium cerebelli. This may be associated with superior cerebellar artery territory infarction in the superior part of the cerebellar hemispheres. Early stabilization of patients reduces the incidence of hypotensive brain injury, but not of diffuse ischaemic injury. Diffuse ischaemic injury can develop as a consequence of reduced perfusion or metabolic mismatch.

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References

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