The outcome of tibial diaphyseal fractures in the elderly.

We describe the outcome of tibial diaphyseal fractures in the elderly (≥ 65 years of age). We prospectively followed 233 fractures in 225 elderly patients over a minimum ten-year period. Demographic and descriptive data were acquired from a prospective trauma database. Mortality status was obtained from the General Register Office database for Scotland. Diaphyseal fractures of the tibia in the elderly occurred predominantly in women (73%) and after a fall (61%). During the study period the incidence of these fractures decreased, nearly halving in number. The 120-day and one-year unadjusted mortality rates were 17% and 27%, respectively, and were significantly greater in patients with an open fracture (p < 0.001). The overall standardised mortality ratio (SMR) was significantly increased (SMR 4.4, p < 0.001) relative to the population at risk, and was greatest for elderly women (SMR 8.1, p < 0.001). These frailer patients had more severe injuries, with an increased rate of open fractures (30%), and suffered a greater rate of nonunion (10%). Tibial diaphyseal fractures in the elderly are most common in women after a fall, are more likely to be open than in the rest of the population, and are associated with a high incidence of nonunion and mortality.

High frequency of missense mutations in glycogen storage disease type VI.

Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen. Six mutations of the PYGL gene, which encodes the liver isoform of the enzyme, have been identified in the literature. We have characterized eight patients from seven families with GSD type VI and identified 11 novel PYGL gene defects. The majority of the mutations were missense, resulting in the substitution of highly conserved residues. These could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H). Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC]. Only 7 of the 23 (30%) reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease. There was heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis. We conclude that deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.

Perfusion-weighted MRI as a marker of response to treatment in acute and subacute stroke.

We carried out baseline and short-term follow-up MRI, including perfusion-weighted imaging (PWI) and tests of neurologic and cognitive function on 15 consecutive patients with large-vessel ischemic stroke who showed a persistent large perfusion-diffusion mismatch at enrollment up to seven days after the onset of symptoms. Of these, ten underwent induced blood pressure elevation with phenylephrine and oral medications (in eight) or intravenous fluids (in two) with the goal of improving perfusion; five had no such treatment. Significant functional improvement was defined by a reduction of 3 or more points on the NIH stroke scale (NIHSS). Significant improvement in perfusion was defined by a reduction in the volume of hypoperfused brain by 30 cc on PWI using time-to-peak (TTP) maps, without enlargement of the infarct. There was a strong, statistically significant association between improved function and improved perfusion: six (75%) of eight patients who improved in function, but none of the seven who did not, showed a reduction in volume of hypoperfused brain. All six patients who met the perfusion goal, and only two (22%) of nine who did not showed significant functional improvement (Fisher's exact: P < 0.01). There were no differences between patients who improved functionally and those who did not with respect to age, initial volume of abnormality on DWI or PWI, initial NIHSS, or changes on DWI. These findings indicate that reduction in volume of hypoperfused brain on PWI is a marker of response to treatment to improve perfusion even in subacute stroke and that partial reperfusion of regions of salvageable but dysfunctional tissue is a mechanism of improved function associated with induced blood pressure elevation.

A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke.

BACKGROUND: Small, unrandomized studies have indicated that pharmacologically induced blood pressure elevation may improve function in ischemic stroke, presumably by improving blood flow to ischemic, but noninfarcted tissue (which may be indicated by diffusion-perfusion mismatch on MRI). We conducted a pilot, randomized trial to evaluate effects of pharmacologically induced blood pressure elevation on function and perfusion in acute stroke. METHODS: Consecutive series of patients with large diffusion-perfusion mismatch were randomly assigned to induced blood pressure elevation ('treated' patients, n = 9) or conventional management ('untreated' patients, n = 6). RESULTS: There were no significant differences between groups at baseline. NIH Stroke Scale (NIHSS) scores were lower (better) in treated versus untreated patients at day 3 (mean 5.6 vs. 12.3; p = 0.01) and week 6-8 (mean 2.8 vs. 9.7; p < 0.04). Treated (but not untreated) patients showed significant improvement from day 1 to day 3 in NIHSS score (from mean 10.2 to 5.6; p < 0.002), cognitive score (from mean 58.7 to 27.9% errors; p < 0.002), and volume of hypoperfused tissue (mean 132 to 58 ml; p < 0.02). High Pearson correlations between the mean arterial pressure (MAP) and accuracy on daily cognitive tests indicated that functional changes were due to changes in MAP. CONCLUSION: Results warrant a full-scale, double-blind clinical trial to evaluate the efficacy and risk of induced blood pressure elevation in selective patients with acute/subacute stroke.

MRI and proton MRSI in women heterozygous for X-linked adrenoleukodystrophy.

OBJECTIVE: To utilize neuroimaging procedures to assess the extent of cerebral involvement in female subjects heterozygous for X-linked adrenoleukodystrophy (X-ALD). METHODS: Brain MRI studies were performed in 76 female subjects heterozygous for X-ALD (mean age 43 years, range 8 to 75 years). Sixty-five had clinical evidence of spinal cord involvement resembling that in males with adrenomyeloneuropathy (AMN), two had clinical evidence of cerebral involvement, and nine showed no neurologic abnormality. Readers blinded to clinical findings further analyzed abnormal MRI studies. In eight women whose MRI results were normal, four-slice long echo time MRS imaging (MRSI) studies were performed and compared to those of eight age-matched controls. RESULTS: MRI results were normal in 65 subjects and abnormal in 11. In eight of the latter group, the MRI changes were judged to be due to causes other than X-ALD. Lesions were attributed to X-ALD in the remaining three. Two of these patients had lesions that resembled those in male patients with cerebral X-ALD. In one patient with a mild AMN-like syndrome, brain MRI abnormalities were confined to the corticospinal tract. When compared to those of controls, MRSI studies in eight female patients with normal results on brain MRI showed a significant reduction of N-acetylaspartate/creatine and N-acetylaspartate/choline ratios in the internal capsule and corticospinal projection fibers. The N-acetylaspartate/choline ratio was significantly reduced in the parieto-occipital white matter and the choline/creatine ratio was significantly increased in the frontal white matter. CONCLUSION: Brain involvement demonstrable by MRI is rare in female subjects heterozygous for X-ALD, including those who have clinical evidence of spinal cord involvement. Nevertheless, N-acetylaspartate levels are reduced in the corticospinal projection fibers in female subjects with normal results on MRI, suggesting axonal dysfunction.

Subcortical aphasia and neglect in acute stroke: the role of cortical hypoperfusion.

We have hypothesized that most cases of aphasia or hemispatial neglect due to acute, subcortical infarct can be accounted for by concurrent cortical hypoperfusion. To test this hypothesis, we demonstrate: (i) that pure subcortical infarctions are associated with cortical hypoperfusion in subjects with aphasia/neglect; (ii) that reversal of cortical hypoperfusion is associated with resolution of the aphasia; and (iii) that aphasia/neglect strongly predicts cortical ischaemia and/or hypoperfusion. We prospectively evaluated a consecutive series of 115 patients who presented within 24 h of onset or progression of stroke symptoms, with MRI sequences including diffusion weighted imaging (DWI) and perfusion weighted imaging (PWI), and detailed testing for aphasia or hemispatial neglect. The association between aphasia or neglect and cortical infarct (or dense ischaemia) on DWI and cortical hypoperfusion indicated by PWI, was evaluated with chi-squared analyses. Fisher exact tests were used for analyses with small samples. Cases of DWI lesion restricted to subcortical white matter and/or grey matter structures (n = 44) were examined for the presence of aphasia or neglect, and for the presence of cortical hypoperfusion. In addition, subjects who received intervention to restore perfusion were evaluated with DWI, PWI, and cognitive tests before and after intervention. Finally, the positive predictive value of the cognitive deficits for identifying cortical abnormalities on DWI and PWI were calculated from all patients. Of the subjects with only subcortical lesions on DWI in this study (n = 44), all those who had aphasia or neglect showed concurrent cortical hypoperfusion. Among the patients who received intervention that successfully restored cortical perfusion, 100% (six out of six) showed immediate resolution of aphasia. In the 115 patients, aphasia and neglect were much more strongly associated with cortical hypoperfusion (chi(2) = 57.3 for aphasia; chi(2) = 28.7 for neglect; d.f. = 1; P < 0.000001 for each), than with cortical infarct/ischaemia on DWI (chi(2) = 8.5 for aphasia; chi(2) = 9.7 for neglect; d.f. = 1; P < 0.005 for each). Aphasia showed a much higher positive predictive value for cortical abnormality on PWI (95%) than on DWI (62%), as did neglect (100% positive predictive value for PWI versus 74% for DWI). From these data we conclude that aphasia and neglect due to acute subcortical stroke can be largely explained by cortical hypoperfusion.

Hypoperfusion of Wernicke's area predicts severity of semantic deficit in acute stroke.

Based on earlier findings that the presence of word comprehension impairment (a deficit in the meaning of words, or lexical semantics) in acute stroke was strongly associated with the presence of hypoperfusion or infarct in Wernicke's area, we tested the hypothesis that the severity of word comprehension impairment was correlated with the magnitude of delay in perfusion of Wernicke's area on magnetic resonance perfusion-weighted imaging. Eighty patients were prospectively studied within 24 hours of onset or progression of acute left hemisphere stroke symptoms, with diffusion-weighted imaging, perfusion-weighted imaging, and detailed language tests. For 50 patients without infarct in Wernicke's area, we found a strong Pearson correlation between the rate of errors on a word comprehension test and the mean number of seconds of delay in time-to-peak concentration of contrast in Wernicke's area, relative to the homologous region on the right. These results add further evidence for the crucial role of Wernicke's area (Brodmann's area 22) in word comprehension and indicate that the magnitude of delay on PWI may be a gross indicator of tissue dysfunction.

Vascular compression by a ventricular shunt catheter: clinical value of volume-rendered CT angiography.

One of the strongest advantages of CT angiography (CTA) lies in its unique ability to display simultaneously the anatomy of the vascular system and the topographic relationships existing between the vessels and the neighboring structures. The case we report, a 76-year-old man who underwent an intraventricular shunt placement complicated by a stroke, shows how this topographic assessment also provides important diagnostic information when vascular lesions resulting from an extrinsic compression mechanism are suspected.

Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study.

OBJECTIVE: To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis. SUBJECTS AND METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations. RESULTS: One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected. CONCLUSIONS: These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.

Restoring blood pressure reperfused Wernicke's area and improved language.

Longitudinal clinical and imaging data from a patient who sustained a left frontal-temporal stroke with hypoperfusion of the adjacent Wernicke's area are reported. His language deficits were partially ameliorated by pharmacologically increasing his blood pressure, and were exacerbated when blood pressure dropped. There was a striking temporal and statistical correlation between mean arterial pressure and language accuracy. MR perfusion imaging showed that language gains were accompanied by improved perfusion of Wernicke's area when mean arterial pressure was increased.

Reperfusion of specific brain regions by raising blood pressure restores selective language functions in subacute stroke.

We report a series of six single subject studies examining the effects of pharmacological blood pressure elevation on regional brain perfusion and language function. Previous reports indicate that hypoperfusion of specific brain regions, as delineated by magnetic resonance perfusion weighted imaging (PWI), is associated with disruption of selective lexical functions. On this basis, we hypothesized that reperfusion of the same regions, in the absence of infarct in that region, would restore the associated lexical function. We present five patients with impaired lexical-semantics associated with poor perfusion, but not infarction, of Brodmann's area 22 (BA 22), and one patient with impaired lexical-semantics and a superimposed deficit in retrieving the phonological representations of words, associated with poor perfusion Brodmann's area 37 (BA 37) as well as BA 22. Each patient was treated with induced blood pressure elevation to increase perfusion of the ischemic and dysfunctional tissue. Daily testing of naming and comprehension, with stimulus sets matched for frequency, familiarity, and length, showed improved lexical-semantics in the patients who showed reperfusion of BA 22 and improved oral naming (but not lexical-semantics) in the patient who showed reperfusion of BA 37. These cases illustrate that loss of function with hypoperfusion of a circumscribed area of the brain, and recovery of the same function with improved perfusion of that brain region, can reveal brain/language relationships prior to reorganization after brain injury.

Reversible posterior leukoencephalopathy occurring during resection of a posterior fossa tumor: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: Our goal was to present a clinically and radiographically documented case of reversible posterior leukoencephalopathy (RPL) that occurred during resection of a posterior fossa tumor. Although RPL has been previously described in multiple nonsurgical settings, we hope that this case description makes RPL more clinically and radiographically recognizable to neurosurgeons. CLINICAL PRESENTATION: RPL is the clinical syndrome of headaches, altered mental status, seizures, and visual loss, with radiographic findings of reversible parieto-occipital changes on cerebral computed tomographic and magnetic resonance imaging scans. It has been previously reported in the settings of malignant hypertension, renal disease, eclampsia, and immunosuppression. To our knowledge, the patient presented represents the first clinically and radiographically documented case of RPL occurring during resection of a posterior fossa tumor. The patient intraoperatively exhibited wide fluctuations in blood pressure and awoke with clinical and radiographic findings consistent with RPL. INTERVENTION: Aggressive intraoperative and postoperative management of the patient's blood pressure, supportive intensive care, rehabilitation, and close radiographic follow-up were performed. CONCLUSION: RPL can occur as a result of intraoperative variations in blood pressure, even among young, previously healthy individuals. With the aforementioned interventions, the patient experienced significant clinical and radiographic recovery.

Computed tomography in the diagnosis and prognosis of open-globe injuries.

OBJECTIVE: Determine sensitivity, specificity, and prognostic signs of orbital and ocular computed tomography (CT) in diagnosing patients with open globe injury. DESIGN: Randomized masked review of computed tomograms and retrospective clinical correlation of patients with ocular trauma. PARTICIPANTS: Two hundred patients who underwent CT evaluation for ocular trauma between 1989 and 1993. METHODS: CTs were read by three masked observers; findings were tabulated and compared for variability among observers; sensitivity and specificity were calculated and CT findings were grouped according to visual outcome retrieved from record review. RESULTS: In the absence of clinical information, sensitivity and specificity were 75% and 93%, respectively. The positive predictive value ranged from 88% to 97%, with a calculated overall positive predictive value of 95%. Patients who had a poor visual outcome (visual acuity <2/200) or who underwent enucleation had significantly more CT findings than patients with a good visual outcome. Vitreous hemorrhage, absence of lens, and severe distortion of vitreous space are among the most common CT findings associated with poor visual outcome. CONCLUSIONS: CT is not sensitive enough to be solely relied upon for diagnosis of all open globe injuries. CT findings only complement clinical findings, increasing the clinician's overall ability to make an accurate diagnosis of open globe injury, and may provide useful prognostic information regarding visual outcome.

Reversible leukoencephalopathy associated with re-infusion of DMSO preserved stem cells.

We report a case of posterior reversible leuko- encephalopathy (PRL) following the infusion of dimethylsulfoxide (DMSO) cryopreserved autologous stem cells in the setting of myeloablative chemotherapy in a patient with recurrent Ewing's sarcoma. Magnetic resonance (MR) imaging revealed white matter changes which resolved over the next 2 months. Bone Marrow Transplantation (2000) 26, 797-800.

MR perfusion imaging reveals regions of hypoperfusion associated with aphasia and neglect.

OBJECTIVE: To evaluate diffusion-weighted imaging (DWI) and MR perfusion imaging (MRPI) as tools for identifying regions of infarct and hypoperfusion associated with aphasia and neglect in hyperacute stroke. Secondary goal: to establish a functional correlate of a radiologically defined "ischemic penumbra." METHODS: Forty subjects underwent DWI, MRPI, and standardized tests for lexical deficits or hemispatial neglect within 24 hours of stroke onset or progression. Ten patients had repeat DWI, MRPI, and cognitive testing after 3 days (in some cases after reperfusion therapy). Pearson correlations between error rate on cognitive testing and volume of abnormality on DWI versus MRPI were determined at each time period, and regions of hypoperfusion corresponding to specific cognitive deficits were identified. RESULTS: Error rate was more strongly correlated with volume of hypoperfused tissue on MRPI (r = 0.65 to 0.93; p < 0.01 to p < 0.0003) than with volume of lesion on DWI (r = 0.54 to 0.75; p = 0.14 to p < 0.01) for dominant and nondominant hemisphere stroke, at each time point. Forty-eight percent of aphasic patients and 67% of those with hemispatial neglect had either no infarct or only small subcortical infarct on DWI, but had focal cortical hypoperfusion. Patients who had successful reperfusion therapy showed resolution of the hypoperfused territory beyond the infarction on repeat MRPI and showed resolution of corresponding deficits. CONCLUSIONS: MRPI shows regions of hypoperfused cortex associated with lexical deficits or hemispatial neglect, even when DWI shows no infarct or only small subcortical infarct. MRPI-DWI mismatch indicates regions of functionally salvageable tissue.

Major structural defects in the antithrombin gene in four families with type I antithrombin deficiency--partial/complete deletions and rearrangement of the antithrombin gene.

The molecular basis of quantitative antithrombin deficiency was investigated in four families predicted to have major antithrombin gene rearrangements. A 1,442 bp deletion and insertion of the sequence 5'T(n = 38-40)GAGACG was characterised in one case. Sequence surrounding the breakpoints contained two perfect, and one imperfect, inverted repeats which may have mediated formation of a stem loop structure on one strand during DNA replication potentiating the deletion. A 9,219 bp deletion spanning introns 2 to 5 was identified in a second family. The identical 6 bp sequence was upstream of each breakpoint and the 5' breakpoint was located in a sequence of the Alu 3 repeat predicted to be susceptible to strand breakage during transcription. This may have promoted misalignment, and deletion, of one of the repeats and the intervening DNA. A novel 1.8 kb antithrombin gene fragment was present in DNA digests from affected members of the third family suggesting a partial antithrombin gene duplication event while in the remaining family, evidence supporting a complete gene deletion was obtained.

Diagnostic evaluation of stroke.

Diagnostic testing in patients with ischemic stroke serves many purposes, including confirmation of the diagnosis and providing clues as to possible causes. Evaluation of the cerebral vasculature, the heart, the blood coagulation system, and selected other diagnostic tests may point to a mechanism of stroke which helps determine treatment and prognosis. With the recent advent of acute interventions for ischemic stroke, diagnostic testing is now an important component in the emergency management of stroke. In this article, the authors will review the standard approach to diagnostic testing for patients with ischemic stroke or transient ischemic attack, and new developments in neuro-imaging and their use in acute stroke assessment.

Diffusion-weighted MRI and proton MR spectroscopic imaging in the study of secondary neuronal injury after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Cerebral ischemia has been proposed as contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). Possible tools for investigating this hypothesis are diffusion-weighted (DWI) and proton magnetic resonance spectroscopic imaging ((1)H-MRSI). However, magnetic field inhomogeneity induced by paramagnetic blood products may prohibit the application of such techniques on perihematoma tissue. We report on the feasibility of DWI and (1)H-MRSI in the study of human ICH and present preliminary data on their contribution to understanding perihematoma tissue functional and metabolic profiles. METHODS: Patients with acute supratentorial ICH were prospectively evaluated using DWI and (1)H-MRSI. Obscuration of perihematoma tissue with both sequences was assessed. Obtainable apparent diffusion coefficient (Dav) and lactate spectra in perihematoma brain tissue were recorded and analyzed. RESULTS: Nine patients with mean age of 63.4 (36 to 87) years were enrolled. Mean time from symptom onset to initial MRI was 3.4 (1 to 9) days; mean hematoma volume was 35.4 (5 to 80) cm(3). Perihematoma diffusion values were attainable in 9 of 9 patients, and (1)H-MRSI measures were obtainable in 5 of 9 cases. Dav in perihematoma regions was 172.5 (120.0 to 302.5)x10(-5) mm(2)/s and 87.6 (76.5 to 102.1)x10(-5) mm(2)/s in contralateral corresponding regions of interest (P=0.002). One patient showed an additional area of reduced Dav with normal T(2) intensity, which suggests ischemia. (1)H-MRSI revealed lactate surrounding the hematoma in 2 patients. CONCLUSIONS: DWI and (1)H-MRSI can be used in the study of ICH patients. Our preliminary data are inconsistent with ischemia as the primary mechanism for perihematoma tissue injury. Further investigation with advanced MRI techniques will give a clearer understanding of the role that ischemia plays in tissue injury after ICH.