RESUMO
PURPOSE: The purpose of this paper is to describe the venous anatomy of the insula using conventional MR brain imaging and confocal reconstructions in cases with glioma induced venous dilatation (venous gliography). METHODS: Routine clinical MRI brain scans that included thin cut (1.5-2â¯mm) post contrast T1 weighted imaging were retrospectively reviewed to assess the insular venous anatomy in 19 cases (11 males and 8 females) with insular gliomas. Reconstruction techniques (Anatom-e and Osirix) were used to improve understanding of the venous anatomy. RESULTS: We identified the following insular and peri-insular veins on MRI: the superficial middle cerebral vein (SMCV), peri-insular sulcus vein, vein of the anterior limiting sulcus, the precentral, central, and posterior sulcus veins of the insula, the communicating veins and deep MCV. CONCLUSIONS: We concluded that venous anatomy of insula is complicated and is often overlooked by radiologists on MR brain imaging. Use of confocal imaging in different planes helped us to identify the superficial and deep middle cerebral veins and their relationship to the insula. The understanding of the insular venous architecture is also useful to distinguish these vessels from insular arteries. This knowledge may be helpful for presurgical planning prior to insular glioma resection.
Assuntos
Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Imageamento por Ressonância Magnética , Adulto , Idoso , Variação Biológica Individual , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/patologia , Veias Cerebrais/anatomia & histologia , Veias Cerebrais/patologia , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/cirurgia , Humanos , Hiperemia/diagnóstico por imagem , Hiperemia/patologia , Processamento de Imagem Assistida por Computador , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Transient contrast enhancing lesions can be seen with CT in patients with MS, particularly during acute exacerbations. Conventional 40 gm iodine enhancement technique followed by immediate postinfusion scanning was compared with high dose (80 gm iodine) enhancement technique followed by a 1-hour delayed CT scan; delayed high dose technique (DHD) in nine exacerbations. New lesions, totaling 36 in all, were observed in each case with the DHD technique. With time, the borders expanded in 98% of lesions, thus confirming in vivo that a defective blood-brain barrier (BBB) underlies this phenomenon.
Assuntos
Esclerose Múltipla/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Feminino , Humanos , Infusões Parenterais , Iodo , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
In a kindred of 122 individuals we found 5 individuals with cerebral vascular malformation, 3 representing typical cavernous angiomas. The condition was inherited as an autosomal dominant trait with variable expressivity. Forty-three relatives were examined prospectively by cranial computed tomography (CCT) and lesions were found in 15; 7 were followed prospectively with CCT scans for 5 years. Angiography in 5 of these cases failed to demonstrate the lesion. In 3 patients with previously normal CCT scans a change in blood volume or membrane permeability allowed visualization of the lesion on contrast scans. In 2 individuals, both parents of affected children, a normal CCT scan was found. This emphasizes the limitations of CCT in detecting this disorder. Biochemical and red blood cell immunological genetic linkage studies were done in 36 persons. No linkage was found with any of the markers. The natural history of this disorder, characterized by marked clinical and radiographic variation in site of lesion, and the timing and severity of intracranial hemorrhage, make it a useful model for investigating contributing factors and consequences of intracranial hemorrhage in general. For at-risk and affected patients early and sequential CCTs are necessary. Familial cavernous angioma should be included in the differential diagnosis of all young persons presenting with cerebrovascular impairment, seizures, intracranial calcifications or hemorrhage.
Assuntos
Neoplasias Encefálicas/genética , Hemangioma Cavernoso/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Hemorragia Cerebral/etiologia , Feminino , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Hemangioma Cavernoso/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
The pharmacokinetics of diatrizoate contrast media were determined following low- (0.7 g I/kg) and high- (1.5 g I/kg) dose intravenous administration. The higher dose of contrast media produced plasma concentrations of iodine which remained approximately twice as high as conventional doses for one hour following infusion. This finding may explain the improved CT images obtained after infusion of higher doses of iodine contrast media. There was no significant long-term change in plasma osmolality noted in venous blood after either dose.
Assuntos
Diatrizoato de Meglumina/administração & dosagem , Diatrizoato/análogos & derivados , Adulto , Feminino , Humanos , Injeções Intravenosas , Iodo/sangue , Cinética , Masculino , Concentração Osmolar , PlasmaRESUMO
A technique for alleviating artifacts in excision of cadaver spines for computed tomographic (CT) study is described. It maintains distension of the thecal sac by filling the spinal subarachnoid space with gelatin containing iodinated contrast media. The excision, handling, and storage procedures described prevent all but minute amounts of air from entering the specimen and producing artifacts which can degrade the CT images. The frozen specimen can be sectioned with a band saw in any plane and correlated with the CT images. This technique allows CT-anatomic correlation of not only bony and extrathecal soft tissues of the spine, but also the intrathecal neural elements.
Assuntos
Cadáver , Dissecação/métodos , Coluna Vertebral/diagnóstico por imagem , Preservação de Tecido/métodos , Tomografia Computadorizada por Raios X , Humanos , Vértebras Lombares/diagnóstico por imagemRESUMO
The rates at which the paramagnetic compounds deoxyhemoglobin (Hb) and methemoglobin (MHb) form in vivo within an area of hemorrhage are unknown. The present experiment establishes the baseline concentrations and rates of change in paramagnetic hemoglobin concentrations, as well as the pH in normal heparinized and clotted human blood maintained in vitro at 37 degrees C under anaerobic conditions over 30 hours. There was a moderate increase in Hb concentration in normal heparinized blood (average increase was 15.5%, rate = 0.50%/hour) and a slight increase in MHb concentration in the heparinized blood and clots (average increase was 1.4%, rate = 0.044%/hour). A second experiment was done to verify the activity of the RBC systems responsible for maintaining the hemoglobin molecule in the reduced state. Conversion of MHb to Hb in these samples proceeded at a rate of 5.6%/hour. In a third experiment, blood from 11 normal subjects maintained at 4 degrees C 25 degrees C was analyzed for MHb concentration over the course of 28 days. The level of MHb formation remained in the range of normal for at least 11 days in all subjects. The authors conclude that at basal conditions created in vitro, the blood levels of both Hb and MHb remain at relatively low levels. Therefore, if the accumulation of Hb and/or MHb occurs in acute in vivo hematomas it must be driven by intrinsic tissue factors.
Assuntos
Hemorragia Cerebral/sangue , Hemoglobinas/análise , Humanos , Concentração de Íons de Hidrogênio , Metemoglobina/análise , Oxirredução , Oxiemoglobinas/análiseRESUMO
Magnetic resonance (MR) imaging and computed tomography (CT) are routinely performed with the use of contrast materials in the diagnosis of neuro-ophthalmologic disease. Iodinated agents are commonly used in CT scanning and femoral contrast arteriography, and gadolinium is used in MR imaging. While contrast materials contribute greatly to diagnostic accuracy, they may also be responsible for adverse effects, ranging in severity from mild discomfort to death. The most frequent and severe side effects are associated with ionic iodinated contrast agents, while the rate of adverse reactions is less with use of nonionic iodinated contrast agents. Side effects and adverse reactions to gadolinium are uncommon, but they do occur. In neuro-ophthalmologic diagnosis, MR imaging is generally preferred over CT scanning, partly because of its greater ability to delineate soft tissue intracranial structures, but also because of the relative safety of gadolinium as a contrast agent. Properties of contrast agents are discussed in the context of specific imaging techniques and tissues investigated. Types and severity of adverse effects as well as risk factors for incurring such effects are summarized.
Assuntos
Meios de Contraste/farmacologia , Imageamento por Ressonância Magnética/métodos , Oftalmologia/métodos , Tomografia Computadorizada por Raios X/métodos , Oftalmopatias/diagnóstico , Humanos , Doenças do Sistema Nervoso/diagnóstico , Reprodutibilidade dos TestesRESUMO
This report describes a patient with a headache and a bitemporal hemianopsia immediately following endoscopic ethmoid and sphenoid sinus surgery. Computed tomographic imaging revealed tension pneumocephalus caused by surgical interruption of the boundaries between the sinus(es) and the anterior cranial cavity. The delineation of the central chiasmal injury required follow-up magnetic resonance imaging.
Assuntos
Lesões Encefálicas/diagnóstico , Endoscopia/efeitos adversos , Quiasma Óptico/lesões , Pneumocefalia/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Adulto , Lesões Encefálicas/etiologia , Feminino , Cefaleia/etiologia , Hemianopsia/etiologia , Humanos , Imageamento por Ressonância Magnética , Pólipos Nasais/cirurgia , Pneumocefalia/etiologia , Complicações Pós-Operatórias/etiologia , Sinusite/cirurgia , Tomografia Computadorizada por Raios X , Campos VisuaisRESUMO
This report presents a patient who sustained closed head injury with chiasmal trauma. This uncommon injury may not be apparent on routine imaging studies. It is significant, not only from the visual standpoint, but also because of the association with serious conditions, such as panhypopituitarism, traumatic carotid aneurysm, carotid cavernous fistulae, and meningitis associated with leakage of cerebrospinal fluid. This report demonstrates that magnetic resonance imaging (MRI) is the best method for identifying chiasmal abnormalities.
Assuntos
Imageamento por Ressonância Magnética , Quiasma Óptico/lesões , Acidentes de Trânsito , Adolescente , Lesões Encefálicas/complicações , Lesões Encefálicas/diagnóstico , Diplopia/etiologia , Humanos , Masculino , Quiasma Óptico/patologia , Fraturas Cranianas/complicações , Tomografia Computadorizada por Raios X , Transtornos da Visão/etiologiaRESUMO
MR scans were obtained at 0.5 and 1.0 T in 40 patients with 46 intracerebral hematomas categorized as hyperacute (0-2 days), acute (3-7 days), subacute (8-14 days), and chronic (15 days to 6 years). In a retrospective review, the signal intensity of the lesions was compared with that of normal white matter of the brain on spin-density, T1-, and T2-weighted spin-echo and T1-weighted gradient-echo sequences. The classic appearance and evolution of hematomas described in the literature at 1.5 T were not found in a significant number of the cases reviewed. In the hyperacute group, only five of eight hematomas had signal intensities that were hypointense relative to brain on T2-weighted images. Two of eight hyperacute hematomas were hyperintense relative to brain on the T1-weighted spin-echo images. However, T1-weighted gradient-echo images reliably demonstrated a hypointense signal in some portion of the hematoma in 45 of 46 cases. We conclude that while there is no constant temporal pattern on spin-echo or gradient-echo sequences, there are signal-intensity changes suggestive of hemorrhage in nearly all hematomas imaged at 0.5 and 1.0 T. Although the inconsistency may be frustrating from a diagnostic standpoint, this variability may reveal important individual differences in hematomas and the brain that surrounds them, and thus be clinically significant. Before these data can be mechanistically analyzed, the reason for contrast on MR scans of hematoma must be better understood.
Assuntos
Hemorragia Cerebral/diagnóstico , Hematoma/diagnóstico , Imageamento por Ressonância Magnética/métodos , Hemorragia Cerebral/epidemiologia , Hematoma/epidemiologia , Humanos , Estudos RetrospectivosRESUMO
Forty-three patients with cerebral vascular malformation were studied with precontrast, immediate contrast, and 1 hr delayed high dose contrast computed tomography (CT) scans. The precontrast scans were abnormal in 81% of patients. The delayed high dose scans demonstrated one angiographically occult, thrombosed arteriovenous malformation not seen on pre- or immediate contrast scans, four cases with additional zones of encapsulated hemorrhage or infarction not seen on pre- or immediate contrast CT, and two cases of venous angiomas seen on immediate contrast scans but not on delayed high dose scans. In 50% of patients, large vessels surrounding the malformation faded on the delayed dose scans which were less specific for vascular malformation than immediate contrast CT. We conclude that: (1) delayed high dose scans offer no significant advantage in patients with symptoms suggesting vascular malformation of the brain; and (2) while less specific than immediate contrast CT, these scans do not preclude detection of vascular malformations of the brain. Therefore, delayed high dose CT can be used in patients with suspected blood-brain barrier lesions without fear of missing vascular malformations.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Meios de Contraste , Hemangioma/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Criança , Pré-Escolar , Hemangioma Cavernoso/diagnóstico por imagem , Humanos , Lactente , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
PURPOSE: To describe the in vivo CT appearance of acute intracerebral blood clots formed from anemic platelet-depleted blood. METHODS: Three patients with intracerebral hemorrhage secondary only to thrombocytopenia were examined with CT within 2 1/2 hours after the onset of clinical symptoms. RESULTS: There were no unusual CT features found in the intracerebral hemorrhages of patients with only thrombocytopenia. Specifically, a hyperdense zone(s) surrounded by areas of decreased density was identified. CONCLUSION: Clot retraction (which cannot occur in patients with severe thrombocytopenia) is not necessary for the CT appearance of acute intracerebral hemorrhage.
Assuntos
Hemorragia Cerebral/diagnóstico por imagem , Retração do Coágulo , Trombocitopenia/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Hemorragia Cerebral/sangue , Feminino , Hemoglobinometria , Humanos , Pessoa de Meia-Idade , Contagem de Plaquetas , Trombocitopenia/sangueRESUMO
This case illustrates that a large zone of signal void can be produced on short relaxation time MR images when gadopentate dimeglumine is injected through an infiltrated intravenous catheter. The authors consider the physics behind this paradoxical decrease in signal intensity where there are high concentrations of gadopentate dimeglumine.
Assuntos
Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico , Imageamento por Ressonância Magnética , Compostos Organometálicos/efeitos adversos , Ácido Pentético/efeitos adversos , Meios de Contraste/administração & dosagem , Gadolínio DTPA , Humanos , Injeções Intravenosas , Veias Jugulares , Masculino , Pessoa de Meia-Idade , Pescoço/patologia , Compostos Organometálicos/administração & dosagem , Ácido Pentético/administração & dosagemRESUMO
PURPOSE: To investigate the effect of the MR environment on vital signs of term neonates. METHODS: We retrospectively analyzed physiological monitoring data obtained from seven term infants (20 to 22 days old) undergoing a clinically indicated MR examination. They were monitored for heart rate, blood pressure, and oxygen saturation while sedated and physically quiet. Six control infants were monitored while sedated and resting in the magnet. RESULTS: All of the test infants exhibited substantial changes in blood pressure, heart rate, and/or oxygen saturation during the MR examination. No such changes were observed in the control infants. CONCLUSION: These preliminary results suggest that undergoing an MR examination may alter the vital signs of term newborn infants.
Assuntos
Pressão Sanguínea/fisiologia , Frequência Cardíaca/fisiologia , Recém-Nascido/fisiologia , Imageamento por Ressonância Magnética , Oxigênio/sangue , Malformação de Arnold-Chiari/diagnóstico , Encéfalo/patologia , Hemorragia Cerebral/diagnóstico , Síndrome de Dandy-Walker/diagnóstico , Feminino , Humanos , Imageamento por Ressonância Magnética/instrumentação , Masculino , Monitorização Fisiológica , Valores de ReferênciaRESUMO
A multicenter prospective study was performed in 49 patients with 77 regions of cerebral infarction. Each patient was evaluated in the acute (0-5 days) and subacute (6-17 days) phases by (1) clinical neurologic examination, (2) CT scans, and (3) N-isopropyl-p-123I-iodoamphetamine (123IMP) single-photon emission CT (SPECT) scans. The abilities of the scans to (1) detect a lesion and (2) predict the clinical outcome were assessed. For lesion detection, 123IMP-SPECT was superior to CT in the first 2 days, but the scans were equally effective 3-5 days after onset. In the subacute phase, IV contrast-enhanced CT was superior to 123IMP-SPECT and unenhanced CT. The clinical outcome was only mildly correlated with the results of the acute and subacute 123IMP-SPECT and the acute CT scans. Reduction in lesion size on the subacute scans did not correlate with clinical improvement. We conclude that the parameters measured by CT and 123IMP-SPECT in patients with acute cerebral infarction cannot reliably be used to predict clinical outcome. 124I contamination of 123IMP and the use of low-energy collimators may have decreased lesion detectability.
Assuntos
Infarto Cerebral/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Infarto Cerebral/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prognóstico , Estudos Prospectivos , Fatores de TempoRESUMO
PURPOSE: To characterize the imaging features of intracerebral hemorrhages in coagulopathies that alter prothrombin time or partial thromboplastin time. METHODS: A fluid-blood level was defined as a horizontal interface between hypodense bloody serum layered above hyperdense settled blood. The prevalence of fluid-blood levels in acute intracerebral hemorrhages was determined on third-generation CT scans in 32 patients with elevation in prothrombin time or partial thromboplastin time. This was compared with the frequency of fluid-blood levels in 185 patients with intracerebral hemorrhage in which there was no laboratory evidence of coagulopathy. RESULTS: The probability of finding a fluid-blood level in an intracerebral hemorrhage of a patient with abnormal prothrombin time or partial thromboplastin time was 59% (sensitivity). The probability that there will be no fluid-blood level in a patient with a normal prothrombin time and partial thromboplastin time was 98% (specificity). CONCLUSION: Fluid-blood levels in acute intracerebral hemorrhage are moderately sensitive to the presence of coagulopathy (ie, abnormal prothrombin time and partial thromboplastin time) and highly specific for this condition. Thus, an intracerebral hemorrhage with a fluid-blood level should prompt a thorough search for coagulopathy because early treatment of this condition may improve the 40% mortality in these patients. Caution should be used to distinguish the horizontal interface of a fluid-blood level from a clot with a flat top. A decubitus CT is useful in these rare instances.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico por imagem , Barreira Hematoencefálica/fisiologia , Hemorragia Cerebral/diagnóstico por imagem , Hematoma/diagnóstico por imagem , Imageamento por Ressonância Magnética , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/induzido quimicamente , Testes de Coagulação Sanguínea , Hemorragia Cerebral/sangue , Hemorragia Cerebral/induzido quimicamente , Feminino , Hematoma/sangue , Hematoma/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
The effect of an intravenous bolus of 4.3 ml/kg of 60% meglumine diatrizoate on the blood-brain barrier (BBB) was studied in five adult unanesthetized dogs. Intravenous 3% Evans blue dye (4 ml/kg) was used as an indicator of BBB disruption. The animals were observed for signs of neurotoxicity for 1 hr after contrast-medium injection and then sacrificed. Their brains were removed and sectioned. None of the dogs displayed clinical evidence of neurotoxicity, and none of the brain specimens showed evidence of BBB disruption. The authors concluded that there is a statistically significant lack of correlation between the intravenous administration of 4.3 ml/kg of 60% meglumine diatrizoate and BBB disruption (p less than 0.05 with a probability of 90%). A previous publication reported focal BBB disruption in anesthetized dogs with dosages of 4 ml/kg and 6 ml/kg of 60% intravenous contrast agent given as an initial bolus followed by a drip infusion. The present study duplicated this prior experiment using the 6 ml/kg dose followed by infusion in three additional unanesthetized dogs and failed to substantiate the previous findings. This discrepancy leads to the assumption that the BBB damage noted in the previous experiment was somehow related to a factor(s) other than the intravenous contrast-medium injection. The BBB cannot be disrupted in the unanesthetized dog with intravenous doses of 60% contrast media of even 6 ml/kg.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Diatrizoato de Meglumina/toxicidade , Diatrizoato/análogos & derivados , Animais , Encéfalo/efeitos dos fármacos , Estado de Consciência , Diatrizoato de Meglumina/administração & dosagem , Cães , Azul Evans , Injeções Intravenosas , Permeabilidade , Coloração e Rotulagem , Fatores de TempoRESUMO
We reviewed the current literature and theories pertaining to the appearance of hemorrhage on MR images. New theories were formulated to explain the etiology of spin-echo (SE) and gradient-echo contrast on clinical MR images of hematomas at low and intermediate field strengths. It is our hope that these theories will prompt further experiments to prove or disprove their validity. The discussion of SE contrast focuses on the powerful MR effects mediated by changes in protein concentration. These changes are postulated to occur as a result of (1) clot matrix formation; (2) settling of RBCs, which increases the number of RBCs per unit volume and the total protein concentration; and (3) alterations in intracellular protein concentration caused by changes in RBC hydration. The contribution of acid methemoglobin to image contrast via the proton electron dipole-dipole mechanism is also included. The discussion of gradient-echo contrast focuses on the inhomogeneity that may be present within voxels that contain a blood clot. This inhomogeneity results when the voxel contains regions with different magnetic susceptibilities (i.e., clumped RBCs and serum). Two temporally arranged schemata for T2-weighted and T1-weighted SE scans are presented that illustrate how these factors might interact to explain the diverse appearance of hematomas on clinical SE images. The signal intensity on T2-weighted SE scans appears to be dependent primarily on the state of hydration of the RBC. This factor and the presence or absence of methemoglobin appear to be the major factors that govern contrast on T1-weighted SE images.
Assuntos
Hemorragia Cerebral/diagnóstico , Imageamento por Ressonância Magnética , Doença Aguda , Humanos , Modelos Cardiovasculares , Modelos Neurológicos , Concentração Osmolar , Proteínas/metabolismoRESUMO
The pathophysiology of iodine-enhanced computed tomography (CT) patterns produced by embolic arterial cerebral infarction in the baboon is reported. The appearance of iodine patterns in zones of nonperfusion, blood-brain barrier damage, loss of autoregulation, and neovascularity is demonstrated. The iodine CT patterns were correlated with stable xenon CT flow studies, regional cerebral blood flow studies, clinical course, and pathology.
Assuntos
Angiografia Cerebral , Infarto Cerebral/diagnóstico por imagem , Diatrizoato de Meglumina , Diatrizoato/análogos & derivados , Tomografia Computadorizada por Raios X/métodos , Animais , Barreira Hematoencefálica , Infarto Cerebral/fisiopatologia , Circulação Cerebrovascular , Modelos Animais de Doenças , PapioRESUMO
Responses to intrathecal metrizamide in dogs were found to be age-related: Adult dogs had seizures; 7-week-old dogs appeared stuporous; 6-day-old dogs were clinically unaffected. The brain metrizamide concentrations 4, 6, and 20 hr after intrathecal injection correlated directly with the occurrence and severity of neurotoxic symptoms. Age-related differences in brain metrizamide concentration may be explained by two factors. The first is the failure of current clinical guidelines to adjust the recommended dosage of metrizamide to reflect differences among age groups in brain weight rather than body weight. This error resulted in lower doses/gram of brain weight being given to the puppies. However, the large differences in brain metrizamide concentrations among the three groups of dogs could not be explained solely by differences in the dose. A second factor, physiologic age-related differences in brain penetration, is believed to be operative. The precise nature of these differences is unclear.