Limitations of T2*-Gradient Recalled-Echo and Susceptibility-Weighted Imaging in Characterizing Chronic Subdural Hemorrhage in Infant Survivors of Abusive Head Trauma.

A possible misconception among radiologists is that chronic subdural hemorrhage should show some degree of blooming on T2*-gradient recalled-echo or susceptibility-weighted sequences such as SWI and susceptibility-weighted angiography, which is not necessarily true. We present 5 cases of chronic subdural hemorrhages in infants, demonstrating intensity near or greater than that of CSF with variable amounts of hemosiderin staining along the neomembranes. We review the physiology and MR imaging physics behind the appearance of a chronic subdural hemorrhage, highlighting that the absence of a BBB can allow hemosiderin to be completely removed from the subdural compartment. Finally, we stress the importance of reviewing all multiplanar sequences for the presence of neomembranes, which can be quite subtle in the absence of hemosiderin staining and are critical for making the diagnosis of chronic subdural hemorrhage.

Parenchymal Brain Laceration as a Predictor of Abusive Head Trauma.

BACKGROUND AND PURPOSE: Accurate differentiation of abusive head trauma and accidental head injury in infants and young children is critical and impacts clinical care, patient prognosis, forensic investigations, and medicolegal proceedings. No specific finding seen on cross-sectional brain imaging has been reported to distinguish abusive head trauma from accidental injury. Our study investigated whether a specific imaging finding, parenchymal brain laceration, is unique to children diagnosed with abusive head trauma. MATERIALS AND METHODS: We retrospectively identified 137 patients with abusive head trauma and 28 patients who incurred moderate to severe accidental brain injury. Brain MR imaging represented the imaging standard for characterizing intracranial injuries. RESULTS: Among the abusive head trauma cohort, parenchymal brain lacerations were identified in 18 patients, while none were identified in any patients with accidental injury. CONCLUSIONS: Our findings are in concurrence with the existing forensic, pathology, and imaging literature, which suggests that parenchymal brain lacerations may be related to abusive injury mechanisms.

Does intracranial venous thrombosis cause subdural hemorrhage in the pediatric population?

Unexplained SDH in infants and children is an accepted marker for AHT. It has been proposed that IVT may be the initiating event leading to the development of acute SDH, mimicking the appearance of traumatic SDH. Our study aims to investigate if nontraumatic IVT causes SDH in the pediatric population. We retrospectively identified 36 patients with IVT and reviewed neuroimaging studies for the concurrent presence of SDH. In our 36 patients with IVT, no associated SDH was observed. Even with extensive IVT, no SDH was present. Three false-positive diagnoses of IVT were identified in the setting of mastoiditis and traumatic SDH, demonstrating pitfalls in imaging. In conclusion, our findings do not support the previous AHT literature stating that IVT is associated with, or leads to, SDH in neonates, infants, or children.

Cerebellar leukoencephalopathy: most likely histiocytosis-related.

BACKGROUND: Histiocytosis, both Langerhans and non-Langerhans cell type, can be associated with cerebellar white matter abnormalities, thought to be paraneoplastic. The associated clinical picture consists of ataxia, spasticity, and cognitive decline. Hormonal dysfunction is frequent. MRI shows cerebellar white matter abnormalities, as well as brainstem and basal ganglia abnormalities. This so-called "neurodegenerative syndrome" may occur years before or during manifest histiocytosis and also years after cure. We discovered similar MRI abnormalities in 13 patients and wondered whether they could have the same syndrome. METHODS: We reviewed the clinical and laboratory information of these 13 patients and evaluated their brain MRIs. Seven patients underwent spinal cord MRI. RESULTS: All patients were isolated cases; 10 were male. They had signs of cerebellar and pyramidal dysfunction, behavioral problems, and cognitive decline. MRI showed abnormalities of the cerebellar white matter, brainstem, basal ganglia, and, to a lesser extent, cerebral white matter. Three patients had spinal cord lesions. Three patients had laboratory evidence of hormonal dysfunction. No evidence was found of an underlying metabolic defect. In two patients biopsy of nodular brain lesions revealed histiocytic infiltrates. CONCLUSIONS: Considering the striking clinical and MRI similarities between our patients and the patients with this neurodegenerative syndrome in the context of proven histiocytosis, it is likely that they share the same paraneoplastic syndrome, although we cannot exclude a genetic disorder with certainty. The fact that we found histiocytic lesions in two patients substantiates our conclusion. Patients with cerebellar white matter abnormalities should be monitored for histiocytosis.

Pilomyxoid astrocytoma: expanding the imaging spectrum.

BACKGROUND AND PURPOSE: Pilomyxoid astrocytoma (PMA) is a recently described variant of pilocytic astrocytoma (PA) with unique clinical and histopathologic characteristics. Because the histopathology of PMA is distinct from that of PA, we hypothesized that PMAs would display distinctive imaging characteristics. We retrospectively reviewed the imaging findings in a large number of patients with PMA to identify these characteristics. MATERIALS AND METHODS: CT and MR images, pathology reports, and clinical information from 21 patients with pathology-confirmed PMA from 7 institutions were retrospectively reviewed. CT and MR imaging findings, including location, size, signal intensity, hemorrhage, and enhancement pattern, were tabulated. RESULTS: Patients ranged in age from 9 months to 46 years at initial diagnosis. Sex ratio was 12:9 (M/F). Twelve of 21 (57%) tumors were located in the hypothalamic/chiasmatic/third ventricular region. Nine (43%) occurred in other locations, including the parietal lobe (2/21), temporal lobe (2/21), cerebellum (2/21), basal ganglia (2/21), and fourth ventricle (1/21). Ten (48%) tumors showed heterogeneous rim enhancement, 9 (43%) showed uniform enhancement, and 2 (9%) showed no enhancement. Five (24%) masses demonstrated intratumoral hemorrhage. CONCLUSION: This series expands the clinical and imaging spectrum of PMA and identifies characteristics that should suggest consideration of this uncommon diagnosis. One third of patients were older children and adults. Almost half of all tumors were located outside the typical hypothalamic/chiasmatic region. Intratumoral hemorrhage occurred in one quarter of patients. PMA remains a histologic diagnosis without definitive imaging findings that distinguish it from PA.

A phase II study of a 5T4 oncofoetal antigen tumour-targeted superantigen (ABR-214936) therapy in patients with advanced renal cell carcinoma.

In a phase II study, 43 renal cell carcinoma patients were treated with individualised doses of ABR-214936; a fusion of a Fab recognising the antigen 5T4, and Staphylococcal enterotoxin A. Drug was given intravenously on 4 consecutive days, treatment was repeated 1 month later. Treatment was associated with moderate fever and nausea, but well tolerated. Of 40 evaluable patients, 28 had disease control at 2 months, and at 4 months, one patient showed partial response (PR) and 16 patients stable disease. Median survival, with minimum follow-up of 26 months was 19.7 months with 13 patients alive to date. Stratification by the Motzer's prognostic criteria highlights prolonged survival compared to published expectation. Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected, whereas the low-exposure patients survived as expected. Sustained interleukin-2 (IL-2) production after a repeated injection appears to be a biomarker for clinical effect, as the induced-IL-2 level on the day 2 of treatment correlated with survival. The high degree of disease control and the prolonged survival suggest that this treatment can be effective. These findings will be used in the trial design for the next generation of drug, with reduced antigenicity and toxicity.

Absent semicircular canals in CHARGE syndrome: radiologic spectrum of findings.

BACKGROUND AND PURPOSE: This paper describes the CT findings that characterize the middle and inner ear anomalies in coloboma, heart defects, choanal atresia, mental retardation, genitourinary, and ear anomalies (CHARGE) syndrome. With this information, neuroradiologists will be better prepared to provide clinically relevant information to their referring physicians regarding this rare syndrome. MATERIALS AND METHODS: CT studies from 13 patients were reviewed by 2 neuroradiologists with Certificate of Additional Qualification. Each ear was counted separately for a total of 26 ears. Middle and inner ear anomalies associated with CHARGE syndrome were categorized. Investigational review board approval was obtained. RESULTS: Twenty of 26 (77%) ears demonstrated cochlear aperture atresia. Four of these ears were evaluated with MR imaging and were found to lack a cochlear nerve. Twenty-one of 26 (81%) cochlea had some form of dysplasia. Six of 26 (23%) round windows were aplastic. Three of 26 (12%) round windows were hypoplastic. Twenty-one of 26 (81%) oval windows were atretic or aplastic. Fifteen of 26 (58%) vestibules were hypoplastic or dysplastic. There were 5 of 26 (19%) enlarged vestibular aqueducts. Twelve of 26 (46%) vestibular aqueducts had an anomalous course. All cases demonstrated absent semicircular canals. Twenty-three of 26 (88%) facial nerve canals had an anomalous course. Four of 26 (15%) tympanic segments were prolapsed. Three of 26 (12%) temporal bones had an anomalous emissary vein referred to as a petrosquamosal sinus. Twenty-one of 26 (81%) middle ear cavities were small. Twenty-three of 26 (93%) ossicles were dysplastic with ankylosis. Three of 26 (12%) internal auditory canals were small. CONCLUSION: The CT findings that correlate to the anomalies of CHARGE syndrome affect conductive as well as sensorineural hearing. Stenosis of the aperture for the cochlear nerve aperture on CT is suggestive of hypoplasia or absence of the cochlear nerve, which has been demonstrated in some cases by MR. Absence of the cochlear nerve would be a contraindication to cochlear implantation.

Linomide and antibody-targeted superantigen therapy abolishes formation of liver metastases in mice.

Hematogenous spread of tumor cells and metastasis formation in the liver are insidious aspects of cancer progression and are not frequently amenable to curative treatment. We examined the effect of Linomide and antibody-targeted therapy against the formation of hepatic metastases in vivo. For this purpose, syngenic B16 melanoma cells transfected with GA733-2 (a human colon cancer cell surface antigen) were injected into a mesenteric vein of C57/Bl6 mice. To test bacterial superantigen (Sag) targeting for immunotherapy of liver metastases, we used genetically fused proteins consisting of SEA and a Fab moiety of a GA733-2 tumor-reactive antibody (C215Fab-SEA). Linomide dose-dependently reduced hepatic metastases, and at 300 mg/kg this reduction was more than 80%. Treatment with C215Fab-SEA decreased metastases formation by 49% and the combination of Linomide and C215Fab-SEA was found to completely abolish liver metastases (>99% reduction). Taken together, our novel data suggest that Linomide and antibody-targeted superantigen therapy individually markedly reduce and together abolish liver metastases. Considering that current therapy of hepatic metastases is mainly limited to surgical resection in a subgroup of patients, these findings indicate that Linomide alone or in combination with antibody-targeted superantigen may provide a novel approach against liver metastases.

Systemic immune response of young chickens orally immunized with bovine serum albumin.

The efficacy of oral immunization, with and without commercial adjuvants, to mount a systemic immune response in young chickens was studied. Bovine serum albumin (BSA) mixed with a pegylated C8/C10 mono/di-glyceride, (Softigen), or Cholera toxin B-subunit (CTB), administered orally by gavage to 15-day-old chickens resulted in circulating immunospecific anti-BSA IgG, IgM and IgA antibodies. Continuous 5-day oral administration of BSA without adjuvant also resulted in immunospecific IgM and IgA antibodies in the circulation of chickens first immunized at 15 days of age; and immunospecific antibodies of all three classes in chickens first immunized when they were 22 days old. IgG and IgM serum concentrations were more than 4 to 10 times higher, respectively, in CTB- and Softigen-treated chickens as compared to chickens immunized without adjuvants. The IgA response in the orally immunized chickens seemed unaffected by CTB and Softigen. The antibody concentrations in chickens immunized subcutaneously with BSA emulsified in Freund's Incomplete Adjuvant (FIA) were approximately 10 times higher than those of the chickens orally immunized using CTB and Softigen.

Roquinimex inhibits dextran sodium sulfate-induced murine colitis.

OBJECTIVE: Roquinimex is a modulator of the immune system and has been shown to attenuate induction of several inflammatory and autoimmune diseases. The objective of the present study was to determine the efficacy of roquinimex in a model of murine colitis. MATERIALS AND METHODS: For this purpose, Balb/c mice were exposed to 5% dextran sodium sulfate (DSS) in the drinking water for five to six days. Roquinimex (300 mg kg(-1) day(-1)) was administered by subcutaneous (s.c.) injection 3 days prior to and throughout the treatment period with DSS. In separate experiments, 300 mg kg(-1) day(-1) of roquinimex was given therapeutically after initiation of DSS challenge. RESULTS: DSS provoked clinical signs of colitis, reduced crypt height (CH) and increased mucosal damage score (MDS) as analyzed by histology. In addition, challenge with DSS increased the colonic content of myeloperoxidase (MPO). Prophylactic administration of DSS-treated mice with roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity. CONCLUSIONS: These findings suggest that roquinimex strongly inhibits murine colitis and may provide a novel pharmacological approach to treat inflammatory bowel disease.

Fetal antigen 1 (FA1) in the adult rat adrenal gland, ovary and pituitary gland.

Fetal antigen 1 (FA1) is a circulating glycoprotein containing six epidermal growth factor (EGF)-like repeats. FA1's larger membrane-bound precursor is defined by the cDNAs referred to as either human delta-like (dlk) or human adrenal specific cDNA, pG2. In rodents FA1 has also been studied under the names of preadipocyte factor 1 (Pref-1), and zona glomerulosa-specific factor (ZOG). FA1 is abundantly expressed in fetal tissues, but in the mature cells of the adult organism the tissue presence of the protein seems to be restricted to neuroendocrine tissues. The present study demonstrates FA1 localisation in endocrine tissues of the adult female rat in which the protein was found present in the medulla and the zona glomerulosa of the cortex of the adrenal glands, in the pars distalis of the adenohypophysis, and in the ovarian granulosa lutein cells. No staining was found in the pancreas, which is in contrast to what has been described in the human.

Suppression of experimental autoimmune neuritis by ABR-215062 is associated with altered Th1/Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue.

The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man. In previous studies, we reported that Linomide suppressed the clinical EAN and myelin antigen-reactive T and B cell responses. Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180-199 and Freund's complete adjuvant was strongly suppressed by ABR-215062 administered daily subcutaneously from the day of inoculation. ABR-215062 dose-dependently reduced the incidence of EAN, ameliorated clinical signs and inhibited P0 peptide 180-199-specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves. The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines IFN-gamma and TNF-alpha, as well as the enhancement of anti-inflammatory cytokine IL-4 in lymph node cells and periphery nerve tissues, respectively, in a dose-dependent manner. These effects indicate that ABR-215062 may mediate its effects by regulation of Th1/Th2 cytokine balance and suggest that ABR-215062 is potentially a new chemical entity for effective treatment of autoimmune diseases.

Oral immunisation of chickens using cholera toxin B subunit and Softigen as adjuvants results in high antibody titre in the egg yolk.

Oral immunisation by gavage of laying hens with human immunoglobulin G (IgG) combined with a number of potential adjuvants was performed. The resulting immunospecific egg yolk (IgY) antibodies were quantified by ELISA. The following adjuvants were tested: A Poly(lactide-co-glycolide) (PLG) microspheres, Cholera toxin B-subunit (CTB), CTB conjugated with glutaraldehyde, Dimethyl dioctadecyl ammonium bromide (DDA), and Softigen (pegylated C8/C10 mono/di glyceride). Hens in a positive control group were immunised with human IgG in saline emulsified with an equal volume of Freund's Incomplete Adjuvant. High titres of immunospecific IgY antibodies against human IgG were recorded in the eggs from the chickens immunised orally with the antigen combined with glutaraldehyde conjugated CTB and in the chickens immunised with the antigen combined with Softigen. The present results show that invasive technique related stress could be eliminated/reduced in polyclonal antibody producing animals.

Effects of Linomide on immune cells and cytokines inhibit autoimmune pathologies of the central and peripheral nervous system.

Linomide (roquinimex, LS 2616) is a quinoline-3-carboxamide with pleiotropic immune modulating capacity and it has therapeutic effects in several experimental animal models of autoimmune diseases. Linomide has been evaluated in clinical trials for multiple sclerosis, and was indeed shown to have disease inhibitory effects. However, due to unexpected side effects recorded in patients treated with Linomide, premature termination of clinical trials was required. The basic mechanism(s) of action of Linomide in inducing beneficial effects in autoimmune diseases is still elusive. Some experimental evidence indicates that Linomide influences the regulation of the cytokine profile, resulting in the inhibition of autoimmune and inflammation pathologies. This review focuses on Linomide applied in models for autoimmune and inflammation pathologies of the central and the peripheral nervous system, and summarises its very encouraging disease inhibitory effects and their potential pharmacological basis. The beneficial effects recorded with Linomide in both experimental and clinical trials emphasise the possible value of substances with Linomide-like activity for clinical use in autoimmune and inflammation pathologies in the near future.

The immunomodulator Linomide: role in treatment and prevention of autoimmune diabetes mellitus.

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disorder characterized by destruction of the pancreatic beta-cells by auto-reacting lymphocytes. An attractive therapeutic approach to this disease would be to abrogate the autoimmune process at an early stage, thus preserving a critical mass of pancreatic beta-cells necessary for maintenance of normal glucose tolerance. Linomide (quinoline-3-carboxamide, Roquinimex, LS 2616), is a novel, orally absorbed, immunomodulatory drug that has been shown to be effective in various models of autoimmunity without causing non-specific immunosuppression. In this review, we describe the efficacy of Linomide for ameliorating the autoimmune process and diabetes in the non-obese diabetic (NOD) model of IDDM when administered at early stages of the disease. We also show that advanced disease in the NOD mouse can be treated effectively by combining Linomide with therapeutic modalities designed to increase pancreatic beta-cell mass. Subsequent clinical studies have shown that Linomide preserves beta-cell function in individuals with new-onset IDDM. Based on these data, Linomide or derivatives thereof might be useful for treatment of human IDDM.

Linomide abolishes leukocyte adhesion and extravascular recruitment induced by tumor necrosis factor alpha in vivo.

The immunomodulator Linomide (roquinimex) ameliorates the development of numerous inflammatory and immunological diseases, including sepsis, arthritis, and encephalomyelitis. However, the mechanism underlying this protective effect of Linomide remains unclear. In this study, we wanted to evaluate the effect of Linomide treatment on the different steps in the extravasation process of leukocytes stimulated by tumor necrosis factor alpha (TNF-alpha) in vivo. For this purpose, we used intravital microscopy in the mouse cremaster muscle microcirculation. We found that pretreatment with Linomide dose-dependently (3-300 mg/kg) reduced TNF-alpha-induced leukocyte adhesion and tissue recruitment. Notably, at 300 mg/kg response to TNF-alpha was nearly abolished, i.e. leukocyte adhesion was decreased by 83% and recruitment by 86%. In fact, the anti-inflammatory effect of this dose of Linomide corresponded in magnitude to the potency of 10 mg/kg of dexamethasone. Moreover, administration of Linomide did not alter the systemic leukocyte counts. On the other hand, 1-10 mg/kg of dexamethasone decreased the circulating number of mononuclear leukocytes by 77%. Taken together, our novel findings demonstrate that Linomide is a potent inhibitor of leukocyte adhesion and recruitment in cytokine-activated tissues. These data may help explain the documented protection provided by Linomide in inflammatory diseases characterized by cytokine and leukocyte accumulation.

Inhibition of autoimmune disease by the immunomodulator linomide correlates with the ability to activate macrophages.

Linomide is a potent immunomodulator that has been shown to inhibit autoimmunity in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE). Linomide's mechanism of action is unknown, however, it has been suggested to modulate the function of antigen presenting cells (APC) and that this may account for the inhibition of autoimmune disease. In this study we have been able to show that Linomide treatment of SJL/N mice upregulates the cell surface expression of several activation markers on macrophages and B cells. Thus, we found the following markers, expressed as a % of control, to be significantly upregulated following Linomide treatment; MHC class II (260%), Ly-6A/E (520%), CD11a (280%), CD54 (190%) and CD80 (200%) on macrophages and Ly-6A/E (250%) and CD11a (150%) on B cells. The duration and dosage of Linomide required to obtain these effects is similar to those required for EAE inhibition. Several Linomide analogues were made by the introduction of structural modifications into the Linomide molecule, resulting in a number of compounds with varying effects on EAE. We found a linear relationship between the compound's ability to inhibit EAE and its ability to upregulate MHC class II on macrophages (p<0.001), such that compounds which were able to inhibit EAE also upregulated MHC class II expression, whereas those that did not inhibit EAE were unable to do so. These results suggest that drug-mediated activation of distinct APC functions may be protective in autoimmunity.

CT, MRI and MRS of Epstein-Barr virus infection: case report.

We report MRI and proton MR spectroscopy (MRS) findings in a 12-month-old girl with Epstein-Barr virus encephalitis. CT and MRI showed focal lesions in the basal ganglia. MRS of the lesions showed decreased N-acetyl aspartate and elevation of some amino acids, indicating an infectious rather than ischemic etiology. This case illustrates the use of MRS to narrow differential diagnosis.