Diffusion tensor imaging in multiple sclerosis at different final outcomes.

OBJECTIVES: Methods to evaluate the relative contributions of demyelination vs axonal degeneration over the long-term course of MS are urgently needed. We used magnetic resonance diffusion tensor imaging (DTI) to estimate degrees of demyelination and axonal degeneration in the corpus callosum (CC) in cases of MS with different final outcomes. MATERIALS AND METHODS: We determined DTI measures mean diffusivity (MD), fractional anisotropy (FA), and axial (AD) and radial (RD) diffusivities in the CC of 31 MS patients, of whom 13 presented a secondary progressive course, 11 a non-progressive course, and seven a monophasic course. The study participants were survivors from an incidence cohort of 254 attack-onset MS patients with 50 years of longitudinal follow-up. As reference, we included five healthy individuals without significant morbidity. RESULTS: In patients with secondary progression, compared to all other groups, the corpus callosum showed increased RD and reduced FA, but no change in AD. None of the parameters exhibited differences among non-progressive and monophasic course groups and controls. CONCLUSION: Increased RD was observed in secondary progressive MS, indicating significant myelin loss. Normal RD values observed in the clinically isolated syndrome and non-progressive groups confirm their benign nature. AD was not a characterizing parameter for long-term outcome. Demyelination revealed by increased RD is a distinguishing trait for secondary progression.

Clinically isolated syndromes with no further disease activity suggestive of multiple sclerosis at the age of population life expectancy.

The proportion of patients with clinically isolated syndrome (CIS) reported to convert to clinically definite multiple sclerosis varied between 30 and 75%. We studied the lifetime probability of remaining in the "CIS only" condition. The study was based on the longitudinally followed Gothenburg 1950-1964 incidence cohort (n = 306). Survival analysis revealed that 17.8% of 236 attack onset patients remained "CIS only". Patients with afferent (optic and sensory) symptoms had a better prognosis with approximately 30% of these patients remaining "CIS only". Patients who had experienced no relapse during the first 25 years remained "CIS only" for the subsequent 25 years of follow-up.

Update of the original HDLS kindred: divergent clinical courses.

BACKGROUND: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first identified among a Swedish kindred with 17 cases. The average age of onset was 36 years. Autopsy in four cases revealed the presence of axonal spheroids. The causative gene is unknown. METHODS: We performed genealogical and longitudinal observations of the original kindred. Forty members were examined, five telephone-interviewed, and one of the original HDLS cases from 1984 was neuropathologically examined. The clinical course was documented. The cerebrospinal fluid (CSF) findings of two recently affected cases were examined, and one of those autopsied. RESULTS: Of those examined, two developed HDLS during our survey and 38 were healthy. Those interviewed by telephone were healthy. One had symptoms suggestive of HDLS in 1984, but autopsy during our survey showed no spheroids. This patient, two relatives healthy at our examination and one without symptoms at telephone interview had HDLS diagnoses in the 1984 report. Thus, four HDLS diagnoses were unconfirmed. The number of identified patients amounts to 15 among 75 individuals in four generations, including two recent cases who demonstrated a subacute multisystem encephalopathy in Case 1 and an insidious course in Case 2. CSF showed signs of neurodegeneration without inflammation, and autopsy verified HDLS in Case 1. CONCLUSIONS: Some HDLS cases were misdiagnosed with unspecified psychiatric diagnoses in affected relatives from the original 1984 publication. However, HDLS is an encephalopathy dominated by a frontal lobe syndrome with an inexorably progressive and fatal course, where the different symptomatology in two recent cases confirmed the existence of acute and chronic variants.

Augmented reality glasses as a new tele-rehabilitation tool for home use: patients' perception and expectations.

MATERIALS AND METHODS: A qualitative approach was employed to track perspectives from a range of patients with chronic lung and/or heart diseases. COPD, IPF and MI outpatients from Denmark and Finland were invited to participate. Data were collected through focus group and semi-structured in-depth interviews. Qualitative analysis was performed using standard thematic analytical approaches. A topic guide was used to explore experiences and perceptions of the ARG telerehabilitation device among participants. RESULTS: Thirteen patients (4 MI, 2 IPF and 7 COPD), 3 women and 10 men aged 56 to 75 years (mean age 63.3 years) were allocated into one focus group (9 patients) and 4 interviews (4 patients). Twelve patients reported the added value of ARG and suggested constructive changes such as the adjustable screen/brightness, robust head fixation for exercise performance, easy to navigate interface and supported feedback based on exercise performance. CONCLUSION: Patients with chronic heart or lung diseases described the added value in an ARG telerehabilitation programme. Improvements for a future version of the ARG were suggested.IMPLICATIONS FOR REHABILITATIONPatients with chronic pulmonary and heart diseases have difficulties to change behaviour to a more active and healthy lifestyle, offers from the health sector to participate in rehabilitation programmes at the hospital are feasible and improves quality of life and exercise capacity. Not all the patients are capable of participating in such rehabilitation programmes due to frailty and long distance to the hospital. Telerehabilitation seems to be a potential treatment to cope with the needs expressed above.Patient involvement in the development of a telerehabilitation solution to empower chronic pulmonary and heart patients to train, ensures a positive contribution to the design of the expected augmented reality software and hardware envisioned solution for telerehabilitation.The development of a user-centered telerehabilitation platform responding to the preferences of patients with chronic disease will remove barriers that limit use and compliance and improve empowerment in future research projects.

Regulation of G(1) cyclin-dependent kinases in the mammalian cell cycle.

Cyclin-dependent kinases are the key regulators of cell-cycle transitions. In mammalian cells, Cdk2, Cdk4, Cdk6 and associated cyclins control the G(1) to S phase transition. Because proper regulation of this transition is critical for an organism's survival, these protein kinases are exquisitely regulated at different mechanistic levels and in response to a large variety of intrinsic and extrinsic signals.

White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings.

BACKGROUND: Leukoencephalopathies are a heterogeneous group of severe encephalopathy syndromes with myelin, axonal or vascular pathology, typically with extensive white matter lesions on MRI T2-FSE and/or -FLAIR sequences. OBJECTIVES: This review is restricted to leukoencephalopathies with onset in adult age and a dominant inheritance. These diseases are generally severe and often lethal and present with an exacerbating or insidiously progressive course. MATERIAL AND METHODS: The focus is on four syndromes with pure leukoencephalopathies, however, leukoencephalopathies with associated clinical features are included. RESULTS: T2 weighted MR imaging often show features common for leukoencephalopathies, yet shows distinguishing features in transthyretin amyloidosis. CONCLUSION: The diagnosis within the group of leukoencephalopathies thus characterized by MRI relies mainly upon clinical and genetic analysis. The differential diagnosis against treatable leukoencephalopathies is increasingly relevant.

White matter diffusion is higher in Binswanger disease than in idiopathic normal pressure hydrocephalus.

OBJECTIVES: To explore diagnostic differences in periventricular white matter (PWM) and deep white matter (DWM) diffusion patterns in patients diagnosed with Binswanger disease (BD) and in patients diagnosed with probable idiopathic normal pressure hydrocephalus (INPH) using diffusion-weighted imaging (DWI). MATERIALS AND METHODS: Apparent diffusion coefficient (ADC) values were calculated in the PWM and DWM in patients with INPH (n = 14) and BD (n = 9) and in controls (n = 10) using an spin echo echo planar imaging single-shot diffusion sequence and region of interest (ROI) analysis. RESULTS: Patients with BD had higher ADC values than patients with INPH in the PWM and DWM in the frontal and occipital regions (P < 0.05) and higher values than controls in the frontal PWM and DWM (P < 0.01). After shunt surgery, ADC values were reduced in the frontal PWM in patients with INPH (P < 0.05). CONCLUSIONS: Increased diffusion in the PWM and DWM in patients with BD may reflect irreversible breakdown of axonal integrity caused by the subcortical ischaemic vascular disease. By contrast, the normal white matter diffusion in patients with INPH indicates structurally intact axons, compatible with the reversibility of this disorder. DWI may be an important non-invasive diagnostic tool for differentiating between INPH and BD and identifying shunt responders and reversible brain damage in patients with INPH. However, the overlap between patients with INPH and BD in this study restricts the predictive value of the method.

Small baseline volume of left hippocampus is associated with subsequent conversion of MCI into dementia: the Göteborg MCI study.

BACKGROUND: Earlier studies have reported that hippocampal atrophy can to some extent predict which patients with mild cognitive impairment (MCI) will subsequently convert to dementia, and that converters have an enhanced rate of hippocampal volume loss. OBJECTIVE: To further validate the hypothesis that hippocampal atrophy predicts conversion from MCI to dementia, to relate baseline hippocampal volume to different forms of dementia, and to investigate the role of hippocampal side differences and rate of volume loss over time. PATIENTS: The subjects (N=68) include patients with MCI at baseline and progression to dementia at the two-year follow-up (N=21), stable MCI patients (N=21), and controls (N=26). Among the progressing patients, 13 were diagnosed as having AD. METHODS: The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually on the MRI investigations at baseline and at the two-year follow-up. RESULTS: Hippocampal volumetry could predict conversion to dementia in both the AD and the non-AD subgroup of converters. Left hippocampal volume in particular discriminated between converting and stable MCI. Cut off points for individual discrimination were shown to be potentially useful. The converting MCI group had a significantly higher rate of hippocampal volume loss as compared to the stable MCI group. CONCLUSIONS: In MCI patients, hippocampal volumetry at baseline gives prognostic information about possible development of AD and non-AD dementia. Contrary to earlier studies, we found that left hippocampal volume has the best predictive power. Reliable predictions appear to be possible in many individual cases.

Unmyelinated tactile afferents signal touch and project to insular cortex.

There is dual tactile innervation of the human hairy skin: in addition to fast-conducting myelinated afferent fibers, there is a system of slow-conducting unmyelinated (C) afferents that respond to light touch. In a unique patient lacking large myelinated afferents, we found that activation of C tactile (CT) afferents produced a faint sensation of pleasant touch. Functional magnetic resonance imaging (fMRI) analysis during CT stimulation showed activation of the insular region, but not of somatosensory areas S1 and S2. These findings identify CT as a system for limbic touch that may underlie emotional, hormonal and affiliative responses to caress-like, skin-to-skin contact between individuals.

Accumulation of cyclin E is not a prerequisite for passage through the restriction point.

The restriction point (R) is defined as the point in G(1) after which cells can complete a division cycle without growth factors and divides G(1) into two physiologically different intervals in cycling cells, G(1)-pm (a postmitotic interval with a constant length of 3 to 4 h) and G(1)-ps (a pre-DNA-synthetic interval with a variable length of 1 to 10 h). Cyclin E is a G(1) regulatory protein whose accumulation has been suggested to be critical for passage through R. We have studied cyclin E protein levels in individual cells of asynchronously growing cell populations, with respect to both passage through R and entry into S phase. We found that the postmitotic G(1) cells that had not yet reached R were negative for cyclin E accumulation. On the other hand, cells that had passed R were found to accumulate cyclin E at variable times (1 to 8 h) after passage through R and 2 to 5 h before entry into S. These kinetic data rule out the hypothesis that passage through R is dependent on the accumulation of cyclin E but suggest, instead, the converse, that passage through R is a prerequisite for cyclin E accumulation. Furthermore, we found that most of the cyclin E protein is downregulated within 1 to 2 h after entry into S.

Effects of number of diffusion gradient directions on derived diffusion tensor imaging indices in human brain.

BACKGROUND AND PURPOSE: The effects of a number of diffusion-encoding gradient directions (NDGD) on diffusion tensor imaging (DTI) indices have been studied previously with theoretic analysis and numeric simulations. In this study, we made in vivo measurements in the human brain to compare different clinical scan protocols and to evaluate their effects on the calculated DTI indices. METHODS: Fifteen healthy volunteers were scanned with a 1.5T MR scanner. Single-shot DTI images were acquired using 3 protocols different in NDGD and number of excitations (NEX) for each direction (NDGD/NEX = 6/10, 21/3, 31/2). Means and standard error of mean (SEM) were calculated and compared in 6 regions of interest (ROIs) for mean diffusivity (D), fractional anisotropy (FA), diffusion tensor eigenvalues (lambda(1), lambda(2), and lambda(3)), and correlation coefficients (r) of these indices among the 3 DTI protocols. RESULTS: At the ROI level, no significant differences were found for the mean and SEM of D and FA among protocols (P > .05). The 6-NDGD protocol, however, yielded higher values for lambda(1) and lambda(2) and lower values for lambda(3) in most ROIs (P < .05) compared with the other protocols. At the voxel level, the correlation between the protocols r(21-31) were higher than r(6-21) and r(6-31) in most ROIs. The correlation of FA among 3 protocols also increased with increasing anisotropy. CONCLUSION: For ROI analyses, different NDGDs lead to similar values of FA and D but different eigenvalues. However, different NDGDs at the voxel level provide varying values. The selection of the NDGD, therefore, should depend on the focus of different DTI applications.

Linomide reduces the rate of active lesions in relapsing-remitting multiple sclerosis.

The synthetic immunomodulator Linomide, a quinoline-3-carboxamide, has a profound inhibitory influence in several experimental autoimmune diseases, including acute and chronic experimental allergic encephalomyelitis. In a double-blind trial, 31 patients with relapsing-remitting multiple sclerosis were randomized to oral doses of 2.5 mg Linomide or placebo once a day for six months. Fourteen patients receiving Linomide and 14 receiving placebo completed the trial, and the results were based on this population. The mean number of active (new and enlarged T2 weighted) lesions per monthly MRI scan was 1.37 in the patients receiving Linomide and 4.22 in the patients receiving placebo (p = 0.043). The percentage of scans with active MRI lesions was lower in the Linomide-treated group (p = 0.0064). When neurologic deficit was assessed by the Regional Functional Scoring System (RFSS), the Linomide group showed an improvement of 1% of the maximal RFSS range and the placebo group a deterioration of 0.2% (p = 0.14). There were three patients with relapses in the Linomide-treated group and six in the placebo group (p = 0.22). A slightly decreased proportion of natural killer cells in cerebrospinal fluid and peripheral blood was noted in the Linomide group. A severe adverse event of pleuropericarditis occurred in one of the Linomide-treated patients. The most frequent adverse event was musculoskeletal pain, of mild to severe degree, which tended to diminish after three months on Linomide therapy.

A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS.

OBJECTIVE: To evaluate the effect of treatment with the antiherpes drug valacyclovir on MRI-evident lesions in patients with relapsing-remitting MS in a phase 2, randomized, double-blind, placebo-controlled study. BACKGROUND: It has been postulated from virologic studies that herpesvirus infection could play a role in the progression of MS. METHODS: Patients were eligible for the study if they had had two or more MS relapses in the 2-year period before enrollment. Seventy patients with Expanded Disability Status Scale scores of 0 to 5.5 were randomly assigned to receive 1 gram of valacyclovir (n = 36) or placebo (n = 34) three times daily for 24 weeks. Patients underwent MRI every fourth week for 32 weeks: twice during pretreatment, six times during treatment, and once after treatment. Scoring of neurologic disability was performed at the start and end of the treatment period. The primary endpoint was the number of new active MRI-evident lesions over 24 weeks of treatment. Secondary endpoints included other MRI measures and clinical endpoints. RESULTS: The mean number of new active lesions +/- SD per patient during 24 weeks of treatment with valacyclovir was 11.9 +/- 17.6 and that during placebo treatment was 14.5 +/- 21.4. A protocol-planned exploratory analysis stratified patients according to baseline activity; this analysis showed that patients with high levels of disease activity in the valacyclovir treatment group (n = 17) developed fewer new active lesions per scan than did those in the placebo treatment group (n = 11). The median number (Q(1), Q(3) range) of active lesions was 2.0 (1.38, 3.96) in the valacyclovir treatment group and 6.5 (2.63, 9.0) in the placebo treatment group. CONCLUSIONS: Valacyclovir treatment did not reduce the formation of active lesions in patients with relapsing-remitting MS who had two or more relapses during the previous 2-year period. In a subgroup of patients with high levels of disease activity who had more than one active MRI-evident lesion during 4 weeks, valacyclovir treatment was associated with a reduced number of new active MRI-evident lesions and with an increase in the number of scans free of new active lesions. The results of the exploratory subgroup analysis provide support for further studies of antiherpes therapy for patients with MS and high levels of MRI-evident disease activity.

Adverse effects of brain irradiation correlated with MR and CT imaging.

Forty-one patients treated for primary malignancies of the brain at the University of Rochester Cancer Center since 1970 were assessed for adverse effects of irradiation clinically, and by computerized tomography (CT) and magnetic resonance (MR) imaging. At diagnosis, patients ranged in age from 1-65 years (median 19 years) and the most common tumor (in 30) was astrocytoma. Radiation doses ranged from 45 to 81.3 Gy (median 56.8 Gy). White matter changes visible on MR were graded on a scale of 1-4, with grades 1-2 known to occur in some normal patients. Areas of increased signal intensity not associated with the tumor or surgery were visible in all patients (gr 1 = 37%, gr 2 = 32%, gr 3 = 17%, gr 4 = 15%) whereas only 35% had regions of abnormality (hypodensity) on CT. Sulci enlargement and ventricular abnormalities (asymmetry or dilatation) were present in approximately 50% of patients by each technique. Higher grade MR lesions were associated with radiation to large volumes and high doses. For the 36 patients treated with 1.5-2.0 Gy daily fractions, the mean radiation dose by grade was as follows: gr 1 = 55.1 Gy, gr 2 = 58.8 Gy, gr 3 = 60.0 Gy, gr 4 = 63.5 Gy. All 5 patients treated on a hyperfractionated schedule had gr 1-2 changes despite receiving greater than 70 Gy. Fifty percent of patients treated to the whole brain (+/- boost) had gr 3-4 changes, compared with 14% treated with local fields (peak dose regions similar in both groups). Among the children (less than or equal to 13 years), 20% had gr 3-4 changes compared with 56% of adults (excluding hyperfractionated patients). This finding may be due entirely or in part to the lower radiation doses used for children (mean 54.4 Gy vs. 63.7 Gy in adults). Clinical abnormalities attributable to irradiation included an impairment in mental functioning in 7 adults, and learning disabilities in 5 children. Five of these adults (71%) had gr 3-4 changes on MR as compared to gr 3-4 changes in 29% of the remaining adult group. Five patients developed seizure disorders. We conclude that adverse effects of brain irradiation are more sensitively imaged by MR than CT and that these abnormalities are associated with larger treatment volumes and either (or both) higher doses or older age. Conversely, some patients treated with high radiation doses have unremarkable changes on MR, and others have severe white matter changes which are not clinically expressed.(ABSTRACT TRUNCATED AT 400 WORDS)

Iohexol vs. metrizamide in studies of glucose metabolism. A survey.

Nonionic contrast media represent a significant advance for myelography due to their substantially lower neurotoxicity. Some side effects have been noted with metrizamide, however. Origins of adverse effects have not been clearly defined. Studies reviewed here investigated the effects of two nonionic contrast media, metrizamide and iohexol, on glucose metabolism in neural tissue cells in vitro using rat hippocampal tissue slices. Isotonic metrizamide produced metabolic disturbances that may partially explain some clinical adverse effects. It was hypothesized that iohexol, which, unlike metrizamide, does not contain a 2-deoxy-D-glucose component, would not have this effect. A series of in vitro experiments compared the two media. Results showed no evidence that iohexol caused metabolic disturbances, but in vitro there was a depressive effect on metabolism from hypertonicity. In vivo water will rapidly diffuse toward hypertonic areas, thus neutralizing the osmotic effect. The lesser metabolic effect suggests that iohexol would be safer than metrizamide for subarachnoid examinations.

Effects of radiopaque contrast media on calcium uptake and phosphatidylinositol metabolism in rat brain synaptosomes.

Radiographic contrast media (RCM) used in the subarachnoid space are associated with occasional adverse reactions. This study examines the possibility that RCM reactions are caused by interactions with the plasma membrane phosphatidylinositol (PI) second messenger system. Isolated nerve endings, known as synaptosomes, were produced from rat brain homogenates. The synaptosomes were then incubated with RCM to determine if 32Pi labeling of the PIs or the uptake of 45Ca were influenced in a manner consistent with known mechanisms. The RCM metrizamide, iopamidol, iodixanol, and iotrol (but not iohexol) increased the 32Pi labeling. Hyperosmolality produced large increases in phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol-4, 5,-bisphosphate (PIP2) labeling. In the non-depolarized state iodixanol, but not metrizamide or iohexol, caused a time-dependent increase in 45Ca uptake. Iodixanol, iohexol, and metrizamide also augmented the veratrine-stimulated uptake of calcium, but none of the RCM affected the uptake of Ca resulting from potassium depolarization. The increased 32Pi labeling of the PIs caused by RCM is not directly related to Ca uptake, because the direction of change is wrong. RCM perturbations of the plasma membrane may cause an inhibition of other membrane components and systems. Hyperosmolality also may cause inhibition of membrane components. It is not known if these effects are important in clinically observed RCM toxicity.

The effects of gadolinium-DTPA and -DOTA on neural tissue metabolism.

Gadolinium DTPA and DOTA are being used extensively for imaging blood-brain barrier lesions. This study was performed to determine clinically relevant blood, cerebrospinal fluid (CSF), and neural tissue concentrations of these agents, and to determine if they alter neural tissue glucose metabolism. Bolus injections of 0.2 mmol Gd-DTPA/kg were made in rabbits, and blood, CSF, and neural tissue Gd concentrations were measured using atomic emission. Rat hippocampus slices were incubated for 6 hours in solutions of Gd-DTPA and Gd-DOTA, and effects on the production of carbon-14-labeled CO2 from glucose determined. Plasma concentrations reached a peak of 2.46 mmol at 1 minute postinjection, and dropped to 50% of peak in 6 minutes. The highest CSF concentration observed was approximately 0.1 mmol, and the mean lumbar cord concentration was approximately 8.5 mumol/g. Gd-DTPA and Gd-DOTA concentrations greater than 1.0 mmol caused significant increases in CO2 production. In areas of blood-brain barrier lesions, Gd-DTPA and Gd-DOTA may cause changes in tissue metabolism; however, in other areas it is much less likely.

Iopamidol and neural tissue metabolism. A comparative in vitro study.

Metrizamide was the first water-soluble contrast medium with a neurotoxicity low enough to allow it to be used routinely in the entire subarachnoid space. However, neurologic complications are still observed in some patients following the use of metrizamide. The cause of this toxicity has not been established, but existing evidence suggests an interference with glucose metabolism. In previous studies, a depression in CO2 production in neural tissue slices was demonstrated when isotonic metrizamide was added but not isotonic iohexol. In addition to iohexol, there is another new, nonionic, monomeric, water-soluble CM, iopamidol, soon to be released for clinical use in the United States. Iopamidol, like iohexol, has shown fewer adverse reactions and seems to be safer for myelography than metrizamide. Direct comparative studies of iopamidol and iohexol are sparse and the cause of their toxicity is not yet understood. This study was performed to determine the effect of iopamidol on neural tissue glucose metabolism as compared with the effects of iohexol and metrizamide. Metrizamide decreased CO2 production in neural tissue slices by 23%. Iopamidol and iohexol did not produce significant depression. Moreover, this model could not demonstrate any significant difference between iopamidol and iohexol in direct comparisons. The new monomeric contrast media, iopamidol and iohexol, thus do not appear to interfere with glucose metabolism. Adverse reactions to these new media are most likely caused by other mechanisms.

The effect of iohexol on glucose metabolism compared with metrizamide.

In a previous in vitro study we demonstrated reduced CO2 production in rat hippocampal tissue when metrizamide was added. This metabolic depression is believed to be a result of the 2-deoxy-D-glucose (2-DG) portion of the metrizamide molecule since 2-DG is a known competitive inhibitor of glucose metabolism. This competitive inhibition probably occurs at the cell membrane since it has never been shown that metrizamide penetrates neural cells. Further the inhibition is most likely related to competition for the membrane glucose carrier. A new nonionic contrast medium, iohexol, does not contain a 2-DG component and if the hypothesis for the metabolic inhibition is valid we should not expect metabolic inhibition with iohexol. This hypothesis was tested using the rat hippocampus model previously used for metrizamide. We compared iohexol with metrizamide in isotonic concentrations and also examined the effect of hypertonicity. These experiments did not demonstrate inhibition of CO2 production with iohexol at near physiologic osmolalities, however, there was a marked depressive effect with increasing osmolality. This effect from hypertonicity is, however, probably of less importance in vivo where water will rapidly diffuse toward the hypertonic areas. The apparent lack of interference of the iohexol molecule on glucose metabolism should therefore make iohexol a more suitable contrast medium, for subarachnoid investigations than metrizamide.

Further support for the glucose hypothesis of metrizamide toxicity. The effect of metrizamide and glucose analogue-free contrast media on hexokinase.

Metrizamide neurotoxicity has been hypothesized to be caused by an inhibitory effect of the drug on glucose metabolism. Metrizamide contains a glucose side chain, and glucose analogues including metrizamide have been shown to be inhibitors of hexokinase, an enzyme that is central to cerebral glucose metabolism. We studied the effect of the nonionic contrast agents iohexol, iotrol, and iopamidol, and the ionic contrast meglumine diatrizoate, on hexokinase in vitro. Although metrizamide reproducibly caused competitive inhibition of the reaction, the nonglucose contrast agents had no significant effect on the enzyme. These results add further support for the glucose hypothesis of metrizamide neurotoxicity.