Chiari malformation: CSF flow dynamics in the craniocervical junction and syrinx.

BACKGROUND: A CSF flow study in patients with Chiari malformation (ChM) who undergo craniocervical junction decompression (CCJD). METHODS: Using spatial modulation of magnetization (SPAMM), cerebrospinal fluid (CSF) flow velocities were measured at the prepontine (PP), anterior cervical (AC), and posterior cervical (PC) subarachnoid spaces (SAS) in healthy subjects (n = 11) and patients with Chiari malformation (ChM) before and/or after CCJD (n = 15). In the syringes, the intrasyrigeal pulsatile CSF motion was estimated qualitatively as present or absent. FINDINGS: In normal subjects, the mean CSF velocities were 2.4 +/- 0.2 cm/s (PP), 2.8 +/- 0.3 cm/s (AC), and 2.4 +/- 0.2 cm/s (PC). Velocities were significantly lower than normal in patients with ChM prior to CCJD, reduced by 38%, 25%, and 79% in the 3 regions, respectively (P<0.001). Post-CCJD, velocities were 20% (PP), 100% (AC), and 40% (PC) greater than preoperatively (P<0.001). CONCLUSIONS: In ChM, the posterior cervical CSF flow velocity was low, increased minimally after CCJD and, by itself, had limited predictive value. Post-CCJD, an increase of the sum of anterior and posterior cervical CSF flow velocities by more than 20% consistently preceded or coincided with marked headache improvement. After CCJD, the finding that the intrasyringeal CSF pulsatile motion had become absent was an earlier and more sensitive predictor of motor or sensory improvement than a reduction in syrinx's size. SPAMM can be used to assess whether CCJD has restored CSF flow, predict outcome and provide pathophysiological insights in ChM and syringomyelia.

Inflicted head injury in infants.

There is scant neuropathological information in the child abuse literature; even the best reviews include assumptions based on the findings of a few inadequate early studies. Our recent series of 53 fatal cases (Brain 124 (2001) 1290, 1299 [1,2]) demonstrated age-related patterns of brain injury and showed the substrate of severe encephalopathy in the infants to be hypoxic brain damage, not diffuse traumatic axonal injury ('DAI'), as had previously been thought. About one-third had craniocervical injuries, particularly in the brain stem, suggestive of stretch injury to the neuraxis. Our interpretation was that this finding implied a mechanism of injury--brain stem damage from stretch injury to the neck with resultant apnoea--that could account for the clinical scenario in many cases, and for which violence would not necessarily be required. Since publishing this study we have turned our attention to the subgroup of infants who die without objective signs of injury, such as skull fracture or impact, whose carers are accused of abuse, usually, "violent shaking", on the pathologic findings alone. Given the striking discrepancy that there often is in such cases between the relatively trivial findings in the brain and the accusations of violence, we have been looking at the pathogenesis of the typical intracranial bleeding. A histologic study of dura from 50 paediatric autopsies, none of whom had suffered a head injury, has led us to propose that the subdural and retinal bleeding in such cases may well have a physiological aetiology, rather than being caused directly by trauma.

Violence is not necessary to produce subdural and retinal haemorrhage: a reply to Punt et al.

In this article we reply to the recent critique by Punt et al. in Pediatric Rehabilitation. Our hypothesis about the pathogenesis of intracranial bleeding in infants has three important implications. First, in the case of an infant with a swollen brain, subdural and retinal haemorrhage but no objective evidence of trauma, the findings by themselves are not certain evidence of abuse; second, violence is not necessary to produce subdural and retinal haemorrhage; and lastly, non-traumatic events producing apnoea with a catastrophic rise in intracranial pressure could produce a clinical picture identical to that seen in trauma.

Dural haemorrhage in non-traumatic infant deaths: does it explain the bleeding in 'shaken baby syndrome'?

A histological review of dura mater taken from a post-mortem series of 50 paediatric cases aged up to 5 months revealed fresh bleeding in the dura in 36/50, the bleeding ranging from small perivascular haemorrhages to extensive haemorrhage which had ruptured onto the surface of the dura. Severe hypoxia had been documented clinically in 27 of the 36 cases (75%). In a similar review of three infants presenting with classical 'shaken baby syndrome', intradural haemorrhage was also found, in addition to subdural bleeding, and we believe that our findings may have relevance to the pathogenesis of some infantile subdural haemorrhage. Recent work has shown that, in a proportion of infants with fatal head injury, there is little traumatic brain damage and that the significant finding is craniocervical injury, which causes respiratory abnormalities, severe global hypoxia and brain swelling, with raised intracranial pressure. We propose that, in such infants, a combination of severe hypoxia, brain swelling and raised central venous pressure causes blood to leak from intracranial veins into the subdural space, and that the cause of the subdural bleeding in some cases of infant head injury is therefore not traumatic rupture of bridging veins, but a phenomenon of immaturity. Hypoxia with brain swelling would also account for retinal haemorrhages, and so provide a unified hypothesis for the clinical and neuropathological findings in cases of infant head injury, without impact or considerable force being necessary.

Neuropathology of inflicted head injury in children. I. Patterns of brain damage.

Fifty-three cases of non-accidental head injury in children were subjected to detailed neuropathological study, which included immunocytochemistry for microscopic damage. Clinical details were available for all the cases. There were 37 infants, age at head injury ranging from 20 days to 9 months, and 16 children (range 13 months to 8 years). The most common injuries were skull fractures (36% of cases), acute subdural bleeding (72%) and retinal haemorrhages (71%); the most usual cause of death was raised intracranial pressure secondary to brain swelling (82%). On microscopy, severe hypoxic brain damage was present in 77% of cases. While vascular axonal damage was found in 21 out of 53 cases, diffuse traumatic axonal injury was present in only three. Eleven additional cases, all of them infants, showed evidence of localized axonal injury to the craniocervical junction or the cervical cord. When the data were analysed by median age at head injury, statistically significant patterns of age-related damage emerged. Our study shows that infants of 2-3 months typically present with a history of apnoea or other breathing abnormalities, show axonal damage at the craniocervical junction, and tend also to have a skull fracture, a thin film of subdural haemorrhage, but lack extracranial injury. Children over 1 year are more likely to suffer severe extracranial, particularly abdominal, injuries. They tend to have larger subdural haemorrhages, and where traumatic axonal injury is present, show patterns of hemispheric white matter damage more akin to those reported in adults. Diffuse axonal injury is an uncommon sequel of inflicted head injury in children.

Neuropathology of inflicted head injury in children. II. Microscopic brain injury in infants.

There are very few reports in the literature dealing with the neuropathology of infant head injury, and the question of whether diffuse traumatic brain damage [diffuse axonal injury (DAI)] occurs in such children has not yet been reliably established by detailed neuropathological studies. We report the findings in the brains of a series of 37 infants aged 9 months or less, all of whom died from inflicted head injuries, and 14 control infants who died of other causes. Axonal damage was identified using immunohistochemistry for beta-amyloid precursor protein. Full clinical details were available for each case, the most constant of which in the study cohort was an episode of significant apnoea at presentation, found to have been recorded in 75% of cases. Global hypoxic damage was the most common histological finding. Widespread axonal damage, interpreted as vascular, was present in 13 cases, but widespread traumatic axonal injury was found in only two children, both of whom had severe head injuries with multiple skull fractures. Epidural cervical haemorrhage and focal axonal damage to the brainstem and the spinal nerve roots, found in 11 cases but not in controls, indicate that the craniocervical junction is vulnerable in infant head injury, the neuropathology being that of stretch injury from cervical hyperextension/flexion. Damage to this region could account for the observed apnoea, which could in turn lead to hypoxic damage and brain swelling. The observation that the predominant histological abnormality in cases of inflicted head injury in the very young is diffuse hypoxic brain damage, not DAI, can be explained in one of two ways: either the unmyelinated axon of the immature cerebral hemispheres is relatively resistant to traumatic damage, or in shaking-type injuries the brain is not exposed to the forces necessary to produce DAI.

Traumatic axonal injury: practical issues for diagnosis in medicolegal cases.

In the 25 years or so after the first clinicopathological descriptions of diffuse axonal injury (DAI), the criterion for diagnosing recent traumatic white matter damage was the identification of swollen axons ('bulbs') on routine or silver stains, in the appropriate clinical setting. In the last decade, however, experimental work has given us greater understanding of the cellular events initiated by trauma to axons, and this in turn has led to the adoption of immunocytochemical methods to detect markers of axonal damage in both routine and experimental work. These methods have shown that traumatic axonal injury (TAI) is much more common than previously realized, and that what was originally described as DAI occupies only the most severe end of a spectrum of diffuse trauma-induced brain injury. They have also revealed a whole field of previously unrecognized white matter pathology, in which axons are diffusely damaged by processes other than head injury; this in turn has led to some terminological confusion in the literature. Neuropathologists are often asked to assess head injuries in a forensic setting: the diagnostic challenge is to sort out whether the axonal damage detected in a brain is indeed traumatic, and if so, to decide what - if anything - can be inferred from it. The lack of correlation between well-documented histories and neuropathological findings means that in the interpretation of assault cases at least, a diagnosis of 'TAI' or 'DAI' is likely to be of limited use for medicolegal purposes.

Compound anterior cranial base fractures: classification using computerized tomography scanning as a basis for selection of patients for dural repair.

OBJECT: A classification is proposed to organize anterior cranial base fractures systematically according to their location and size. The goal of this study was to determine whether these two variables, irrespective of cerebrospinal fluid (CSF) rhinorrhea, are related to the long-term risk of posttraumatic meningitis and, hence, to standardize decision making concerning surgical repair of associated CSF fistulas. METHODS: With the aid of high-resolution thin-section coronal computerized tomography (CT) scanning, anterior cranial base fractures were classified into the following four major types: I, cribriform; II, frontoethmoidal; III, lateral frontal; and IV, complex (any combination of the other three types). Fractures with a maximum bone displacement that extended farther than 1 cm in any plane were classified as "large" and those less than 1 cm as "small." The authors used this classification in a study of 48 patients who were treated by conservative (20 patients) or surgical (28 patients) means. The results showed a gradation of risk: the fracture most likely to develop infection was a large cribriform (Type I) and the least likely was a small lateral frontal (Type II). Statistical analysis showed that the trend for an increased infection rate was related to the cumulative effect of three variables in the following order: 1) prolonged duration of rhinorrhea (analysis of variance [ANOVA], p = 0.017); 2) large size of fracture displacement (ANOVA, p = 0.079); and 3) fracture's proximity to the midline (ANOVA, p = 0.015). CONCLUSIONS: In this series, microsurgical repair was accompanied by a minimum complication rate. Hence, the authors recommend that patients with fractures that combine the aforementioned variables should be considered to have a high long-term risk of infection and their injury should be surgically repaired as soon as the posttraumatic edema has subsided. This applies to the following fractures: large cribriform (Type I) with transient rhinorrhea lasting 5 to 8 days and large frontoethmoidal (Type II) with prolonged rhinorrhea lasting longer than 8 days. Furthermore, the authors conclude that this classification can improve the management of posttraumatic CSF fistulas of the anterior cranial base and may provide insights into the mechanisms underlying their spontaneous repair and susceptibility to meningitis.

Syndromes of posttraumatic neurological deterioration in children with no focal lesions revealed by cerebral imaging: evidence for a trigeminovascular pathophysiology.

PURPOSE: To explain the pathophysiology of the neurological deterioration that occurs after trivial head injuries in children and that is not caused by focal structural brain damage. Symptoms and/or signs include headache, confusion, drowsiness, vomiting, hemiparesis, cortical blindness, and seizures. CONCEPT: We propose that children who are susceptible to such neurological attacks have an unstable "trigeminovascular reflex," which is activated by craniofacial trauma. RATIONALE: After posttraumatic mechanical stimulation and activation of a defective or immature "excitable" trigeminovascular system, release of perivascular vasodilatory peptides causes cerebral hyperemia, which underlies the neurological deterioration. DISCUSSION: The original assumption that underlying cerebral edema was responsible for these phenomena has been proven incorrect by computed tomography. Subsequent proposed pathophysiological mechanisms include cortical spreading depression and trauma-triggered migraine. Recent research has implicated the trigeminovascular pathways in both these conditions and documented that head trauma can be associated with noncongestive cerebral hyperemia (i.e., not causing swelling). Thus, we propose that head trauma activates trigeminal nerve endings in face, scalp, dura, or cortex and, via a reflex, causes intracranial vasodilation and cerebral hyperemia. Drugs that block trigeminovascular activation might offer a benefit.

Neurological episodes after minor head injury and trigeminovascular activation.

Children appear particularly susceptible to severe but reversible neurological symptoms and/or signs after minor head injury; these include headache, confusion, drowsiness, vomiting, hemiparesis, cortical blindness, or seizures. Significantly, these neurological episodes are not associated with any identifiable structural brain abnormality on neuro-imaging. We propose that the cause of this condition is a reactive hyperaemia, a 'benign hyperaemic encephalopathy' mediated via activation of the trigeminovascular system.

The need for specialist review of pathology in paediatric cancer.

A retrospective histopathological review of 2104 cases of solid tumour was carried out to assess the variability in diagnosis of childhood cancer. Cases were subject to three independent, concurrent opinions from a national panel of specialist pathologists. The conformity between them was analysed using the percentage of agreement and the kappa statistic (kappa), a measure of the level of agreement beyond that which could occur by chance alone, and weighted kappa (w kappa), which demonstrates the degree of variation between opinions. The major groupings of the Birch-Marsden classification were used within which tumours were assigned for kappa analysis according to the clinical significance of the differential diagnoses. The mean agreement for all tumours together was 90%; kappa = 0.82, w kappa = 0.82. Retinoblastoma achieved the highest kappa value (1.0) and lymphoma the lowest (0.66). Of the cases, 16.5% had their original diagnoses amended and the panel confirmed the original diagnosis of paediatric pathologists in 89% of cases compared with 78% for general pathologists. The varying levels of agreement between experts confirm the difficulty of diagnosis in some tumour types, suggesting justification for specialist review in most diagnoses. Specialist training in paediatric pathology is also recommended.

Perfluorochemical oxygen carriers: potential uses in neurosciences.

In this article we review recent developments in the field of "first-" and "second-generation" perfluorochemical (PFC) oxygen carriers. Particular emphasis is placed on the latest research and its implications regarding the clinical and experimental neurosciences. These compounds are ideally suited to the transportation of O2 within the vascular system. Two properties that facilitate their use in this respect are their very high solubility coefficients for O2 and CO2 and their biological inertness. Unfortunately, their widespread use has been limited by logistical difficulties associated particularly with their molecular behavior in vivo. However, advances in PFC technology have led to renewed interest. A potential role for second-generation PFCs in cerebral protection is exciting. Other possible significant applications are slowly becoming established in clinical practice. Currently under investigation are potential uses in the management of severe head injuries, radiotherapy or chemotherapy of malignant brain tumors, protection against air embolism, preservation of organs for transplantation, and as a tool in microsurgery of the retina or other parts of the CNS. Diagnostic neuroimaging applications could include the employment of PFCs as adjuncts in ultrasound, Doppler, computed tomography (CT), and magnetic resonance (MR) to achieve enhanced imaging and precise staging of inflammatory, neoplastic, and vascular disease processes. Research applications could include their use in magnetic resonance imaging and spectroscopy in assessing cerebral blood flow, local oxygen tension, and brain metabolism, in molecule-specific imaging, and as physiological markers of O2, ions, and pH.

Role of endothelial cell injury in the spectrum of azathioprine-induced liver disease after renal transplant: light microscopy and ultrastructural observations.

Three cases of azathioprine-induced complex of liver diseases are described, and their light microscopy and ultrastructural findings are detailed. It was found that the drug produces a spectrum of pathological changes that include veno-occlusive disease, peliosis hepatis, perisinusoidal (Disse space) fibrosis, and nodular regenerative hyperplasia. It is suggested that the explanation for this spectrum is the variable degree of damage to the endothelial cells lining the sinusoids and the terminal hepatic venules. This spectrum is seen almost exclusively in male patients with renal transplant.

Recurrence of meningiomas after operation.

The authors reviewed 53 consecutive patients who underwent surgical removal of a meningioma within a 10-year period. The removal was graded macroscopically as either a total removal (types I-III) or a subtotal removal (type IV). The patients were observed for an average period of 5.3 years, during which time there was a 9.5% recurrence after type I removals and an 18.4% recurrence after type II. There was regrowth in 20% of the subtotal group. There was no correlation with age or sex, but histology was important. Syncytial tumors tended to recur, and mitosis and area of focal necrosis were associated with a tendency towards recurrence. The significant features associated with recurrence are discussed.

Distribution of histocompatibility and leucocyte differentiation antigens in normal human colon and in benign and malignant colonic neoplasms.

Monoclonal antibodies (McAbs) directed against the framework determinants of Class I and Class II products of the major histocompatibility complex (MHC) and against leucocyte differentiation antigens were used in an indirect immunoperoxidase technique to study their expression in normal, benign (adenomatous polyps) and malignant disease of the colon. Class I products (detected by the McAb 2A1) were strongly expressed on all cell types in normal and benign tissues but some carcinomas exhibited a heterogenous pattern of epithelial cell staining and 4/15 were completely negative. Class II products (detected by TDR31.1) were strongly expressed on cells (mainly B lymphocytes) within the lamina propria. In carcinomas TDR31.1 staining was mainly interstitial, but in 2/15, DR + epithelial cells were also detected. In normal and benign tissues, leucocytes (reactive with 2D1) found predominantly in the lamina propria, comprised T cells mainly of the helper/inducer (OKT4) subset, DR + cells in approx. equivalent proportion and a few OKM1+ cells mostly of macrophage morphology. Occasional intraepithelial lymphocytes were of cytotoxic/suppressor (OKT8) phenotype. In malignant neoplasms, there was wide inter and intra-tumour variation in the proportion of leucocytes which were heterogeneous with respect to cell type and confined mainly to the stroma. T cells were consistently predominant, but B cells and macrophages were also present. Two neoplasms showed unequivocal evidence of a shift (relative to peripheral blood) in favour of the OKT8+ subset, but in the majority of tumours OKT4+; and OKT8+ cells were present in roughly similar proportions. Natural killer cells (monitored with Leu7, HNK1) were virtually undetectable in both normal and malignant tissues. There were no apparent correlations between the extent and type of leucocyte infiltration, tumour differentiation or expression of MHC products. Some implications for the extrapolation of in vitro data on leucocyte function to the in vivo situation are discussed.