Nicholas J. Patronas

Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison

BACKGROUND Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke. METHODS We did a single-centre, prospective, blind comparison of non-contrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by four experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging. RESULTS 356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischaemic or haemorrhagic), acute ischaemic stroke, and chronic haemorrhage more frequently than did CT (p<0.0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial haemorrhage. MRI detected acute ischaemic stroke in 164 of 356 patients (46%; 95% CI 41-51%), compared with CT in 35 of 356 patients (10%; 7-14%). In the subset of patients scanned within 3 h of symptom onset, MRI detected acute ischaemic stroke in 41 of 90 patients (46%; 35-56%); CT in 6 of 90 (7%; 3-14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78-88%) and CT of 26% (56 of 217; 20-32%) for the diagnosis of any acute stroke. INTERPRETATION MRI is better than CT for detection of acute ischaemia, and can detect acute and chronic haemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because our patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, our results are directly applicable to clinical practice.

Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography

Positron emission tomography was used to measure local cerebral glucose utilization by the 2-[18F]fluoro-2-deoxy-D-glucose technique in 23 patients with cerebral gliomas. All 10 high-grade (III and IV) astrocytomas demonstrated a region of high activity with a glucose consumption of 7.4 ± 3.5 (SD) mg/100 gm per minute. The 13 low-grade (I and II) gliomas had a glucose metabolic rate of 4.0 ± 1.8 mg/100 gm per minute, with no distinctly visible hot spot. Thus, we found a correlation between rate of glycolysis and malignancy in primary cerebral tumors. Cerebral cortical glucose utilization was often depressed in areas adjacent to or neurally connected to the tumor site, and there was focal irregular delta wave EEG activity in these areas.

Comparison of MRI and CT for Detection of Acute Intracerebral Hemorrhage

CONTEXT Noncontrast computed tomography (CT) is the standard brain imaging study for the initial evaluation of patients with acute stroke symptoms. Multimodal magnetic resonance imaging (MRI) has been proposed as an alternative to CT in the emergency stroke setting. However, the accuracy of MRI relative to CT for the detection of hyperacute intracerebral hemorrhage has not been demonstrated. OBJECTIVE To compare the accuracy of MRI and CT for detection of acute intracerebral hemorrhage in patients presenting with acute focal stroke symptoms. DESIGN, SETTING, AND PATIENTS A prospective, multicenter study was performed at 2 stroke centers (UCLA Medical Center and Suburban Hospital, Bethesda, Md), between October 2000 and February 2003. Patients presenting with focal stroke symptoms within 6 hours of onset underwent brain MRI followed by noncontrast CT. MAIN OUTCOME MEASURES Acute intracerebral hemorrhage and any intracerebral hemorrhage diagnosed on gradient recalled echo (GRE) MRI and CT scans by a consensus of 4 blinded readers. RESULTS The study was stopped early, after 200 patients were enrolled, when it became apparent at the time of an unplanned interim analysis that MRI was detecting cases of hemorrhagic transformation not detected by CT. For the diagnosis of any hemorrhage, MRI was positive in 71 patients with CT positive in 29 (P<.001). For the diagnosis of acute hemorrhage, MRI and CT were equivalent (96% concordance). Acute hemorrhage was diagnosed in 25 patients on both MRI and CT. In 4 other patients, acute hemorrhage was present on MRI but not on the corresponding CT--each of these 4 cases was interpreted as hemorrhagic transformation of an ischemic infarct. In 3 patients, regions interpreted as acute hemorrhage on CT were interpreted as chronic hemorrhage on MRI. In 1 patient, subarachnoid hemorrhage was diagnosed on CT but not on MRI. In 49 patients, chronic hemorrhage, most often microbleeds, was visualized on MRI but not on CT. CONCLUSION MRI may be as accurate as CT for the detection of acute hemorrhage in patients presenting with acute focal stroke symptoms and is more accurate than CT for the detection of chronic intracerebral hemorrhage.

Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population.

Magnetic resonance imaging (MRI) at 1.5 tesla, combined with the use of the paramagnetic contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), enhances the capacity to visualize the pituitary gland and to screen patients for pituitary adenomas. However, in autopsy series of unselected humans, the prevalence of silent pituitary adenomas was estimated to be 3% to 27% [1-5]. If there is a substantial prevalence of occult pituitary adenomas detected by MRI in the general population, the usefulness of MRI as a screening test or as a method to confirm the pituitary cause of endocrinopathy is compromised. To determine the prevalence of focal pituitary lesions compatible with the diagnosis of a pituitary adenoma in humans with normal endocrine function, we did MRI scans of the pituitary gland before and after administration of Gd-DTPA in 100 volunteers. Methods Seventy women and 30 men, 18 to 60 years old, were recruited from the general population and the normal-volunteers office of the National Institutes of Health. The volunteers had normal physical examinations and were selected by age and sex to correspond to the distribution of patients with symptomatic pituitary adenomas [6, 7]. Fifty-eight of the women (83%) were between 20 and 45 years old, and 27 of the men (90%) were between 30 and 60 years old. Random basal values of serum prolactin and -subunit, plasma growth hormone, thyroid-stimulating hormone, thyroxine, triiodothyronine, free thyroxine, and thyroxine-binding globulin were measured. Young women selected for the study had normal menstrual cycles. Persons with previous or current endocrine disturbances were excluded. The protocol was approved by the Investigational Review Board of the National Institute of Neurological Disorders and Stroke, and all participants gave informed consent. Magnetic Resonance Imaging All scans were obtained with a 1.5-T scanner (Sigma, General Electric; Milwaukee, Wisconsin). T1-weighted coronal and sagittal images of the pituitary fossa were obtained with a repetition time (TR) of 600 ms and an echo time (TE) of 15 ms (TR/TE = 600/15). In the coronal plane, interleaved sections 3 mm in thickness without intersection gap were obtained with two repetitions and a 16-cm field of view. The acquisition matrix was 256 192. Gadolinium-DTPA (0.1 mmol/kg body weight) was administered intravenously over 2 minutes, and the T1-weighted coronal images were repeated immediately (Figure 1). Figure 1. Pituitary magnetic resonance scan of a normal volunteer. Left. Right. Evaluation of Pituitary Glands Magnetic resonance scans were interpreted independently by three experienced reviewers. The scans of the normal volunteers were randomly mixed with scans of 57 patients with surgically confirmed Cushing disease. The reviewers were aware that the scans of the patients had been intermingled with those of the volunteers. Identifying information for patients and volunteers was masked. Reviewers evaluated the pituitary gland before and after the administration of Gd-DTPA by appraising gland and sellar size, stalk deviation, gland convexity, and position and size of focal pituitary abnormalities. Measurements were made with hand-held calipers. The readers also provided a summary interpretation of each MRI scan. The diagnosis of a pituitary abnormality, including the presence of an adenoma, was accepted only when the same area of the gland was independently interpreted as similarly abnormal by at least two of the three reviewers. Results Pituitary Gland Magnetic Resonance Scans in Normal Volunteers Pituitary Size and Shape The mean gland height in the 100 volunteers was 6.9 0.1 mm. It was greater in women (7.1 1.3 mm; mean SD) than in men (6.6 1.2 mm; P = 0.008). On coronal scans, the superior surface of the gland was convex upward in 33 persons (29 women). Upward convexity of the superior surface of the gland was limited to one side in 21 persons (12 right, 10 left) and occurred centrally in 11. The posterior pituitary gland was identified as a small focus of high-signal intensity in the posterior sella by at least two reviewers in 92 persons (by three reviewers in 77). One participant was considered to have an enlarged sella. Fifty-nine volunteers were interpreted by all three reviewers as having a normal pituitary gland. In 3, cerebrospinal fluid filled the superior portion of the sella (partially empty sella). Focal Pituitary Abnormalities Before Gd-DTPA was administered, 22 sites of focal abnormal signal intensity in the pituitary were detected by at least one reviewer in 21 volunteers (Table 1). All three reviewers considered the same site as an adenoma (by the presence of an area of low-signal intensity) in 1 person. Seven (6 women, 1 man) had focal areas of decreased signal, which were interpreted by at least two of the three reviewers as adenomas. Fourteen sites in 13 persons were considered abnormal by a single reviewer. Table 1. Pituitary Magnetic Resonance Imaging in 100 Normal Women and Men After Gd-DPTA was administered, 41 different sites of abnormal signal intensity in the pituitary gland were detected in 34 volunteers. Ten of them (7 women, 3 men) had focal areas of decreased signal intensity that were interpreted as pituitary adenomas by at least two reviewers. All three reviewers considered the same site as an adenoma in 2 persons. Six of the 7 women were 25 to 45 years old (1 was 48 years old) and the men were 22, 35, and 53 years old. The lesions were 3 3 mm to 6 6 mm in diameter (coronal plane). Thirty-two sites in 23 participants were considered abnormal by a single reviewer. The scan of only 1 volunteer interpreted as having an adenoma had stalk deviation. An upward convex shape of the superior surface of the pituitary gland occurred in 8 of the 10 volunteers considered to have an adenoma. However, in only five of these studies was the elevation on the side of the lesion. Endocrine Screening Tests The endocrine studies done were normal in the 10 persons with an abnormal MRI scan. In the 90 volunteers whose MRI scans were interpreted as normal, 3 (1 woman, 41 years old; 2 men, 37 and 48 years old) had evidence of mild primary hypothyroidism. Three women (33, 34, and 44 years old) had elevated growth hormone levels (>10 g/L; single random sample). Pituitary Gland Magnetic Resonance Scans in Patients with Cushing Disease Cushing disease was confirmed by adrenocorticotropin staining of an adenoma or by remission of hypercortisolism after selective adenomectomy or hemihypophysectomy. Five macroadenomas and 45 microadenomas were identified at surgery in the 57 patients with Cushing disease. In the 50 patients with adenomas identified at surgery, 56% (all patients with macroadenomas and 51% of 45 patients with microadenomas) had areas of focal low-signal intensity after administration of Gd-DTPA that were diagnosed by at least two reviewers as adenomas. However, in 4 of the 23 patients with microadenomas and a focal pituitary MRI abnormality, the position of the adenoma in the gland was incorrect as read on the MRI scan. In two patients, the MRI scan indicated a lateral tumor, but the tumor was found in the midline at surgery. In the third patient the reverse occurred, and in the fourth the tumor was found on the opposite side of the gland. Thus, 26 of 45 (58%) of the 45 microadenomas that were large enough to be found and selectively excised at surgery were not detected by MRI. The size of the tumors that were not detected (6 2 mm) did not differ significantly from the size of those that were (5 2 mm). Discussion The configuration of the pituitary gland is influenced by age and sex, the location of the carotid arteries, the shape of the pituitary fossa, transmission of cerebrospinal fluid pulsation into the sella turcica permitted by an incompetent diaphragma sella, and the presence of an intrasellar mass [8-12]. The results of our study of the size and shape of the normal pituitary gland confirm the findings of other studies using computed tomography (CT) or MRI scanning without Gd-DPTA enhancement [11, 12]. A convex contour of the superior surface of the pituitary gland was once considered to be unusual or abnormal [3, 11, 12]. (However), recent studies using CT or MRI scanning found that convex superior contours occur in as many as 35% to 44% of women of childbearing age [9, 12, 13]. An upward convex shape of the superior surface of the pituitary gland occurred in 34% of our 70 women. Deviation of the pituitary stalk also has been suggested as an indirect sign of the presence and site of an adenoma. However, rates of stalk deviation as high as 46% have been reported in normal persons [14]. Stalk deviation occurred in 13% of our volunteers. The 4% incidence of an empty sella in our volunteers agrees with the 3% to 4% prevalence reported by others using CT [3, 12] and MRI [13]. Autopsy series estimate the prevalence of asymptomatic pituitary adenomas to be 1.5% to 27% [1-6]. Microscopic examination of the pituitary gland at autopsy is much more sensitive than contrast-enhanced MRI scanning for detecting adenomas, and immunohistochemical techniques allow direct hormonal assessment of the tissue. However, the prevalence of asymptomatic adenomas in a young adult cohort is unknown because autopsy series do not accurately reflect this population. Young women, the group in which symptomatic pituitary tumors occur most frequently, are under-represented in autopsy studies. Previous imaging techniques, such as plain roentgenography, polytomography, and pneumoencephalography, were unreliable for detecting pituitary microadenomas [1]. Shortly after its introduction, CT scanning became the diagnostic procedure of choice for examining the pituitary gland because it was noninvasive, offered improved resolution, and, for the first time, permitted direct visualization of the pituitary gland. By high-resolution, contrast-enhanced CT scanning, Wolpert and colleagues [12] identified p

Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship.

Patients with the rare genetic disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS) have defects in DNA nucleotide excision repair (NER). The NER pathway involves at least 28 genes. Three NER genes are also part of the basal transcription factor, TFIIH. Mutations in 11 NER genes have been associated with clinical diseases with at least eight overlapping phenotypes. The clinical features of these patients have some similarities but also have marked differences. NER is involved in protection against sunlight-induced DNA damage. While XP patients have 1000-fold increase in susceptibility to skin cancer, TTD and CS patients have normal skin cancer risk. Several of the genes involved in NER also affect somatic growth and development. Some patients have short stature and immature sexual development. TTD patients have sulfur deficient brittle hair. Progressive sensorineural deafness is an early feature of XP and CS. Many of these clinical diseases are associated with developmental delay and progressive neurological degeneration. The main neuropathology of XP is a primary neuronal degeneration. In contrast, CS and TTD patients have reduced myelination of the brain. These complex neurological abnormalities are not related to sunlight exposure but may be caused by developmental defects as well as faulty repair of DNA damage to neuronal cells induced by oxidative metabolism or other endogenous processes.

MR color mapping of myelin fiber orientation.

Diffusion of water in brain white matter has been shown to be anisotropic: Water mobility is lower when measured perpendicular to the fiber direction rather than parallel to it. This feature was used to produce images of the myelin fiber orientation. Coronal and sagittal MR diffusion images were obtained in volunteers using an echo-planar imaging sequence sensitized to molecular diffusion in perpendicular directions. Color-coded images of myelin orientation were then generated by combining these images together. The orientation of the white matter tracts was found to be in excellent agreement with known anatomy. Myelin fiber orientation mapping may offer a new perspective to evaluate white matter disorders.

Early-onset stroke and vasculopathy associated with mutations in ADA2

BACKGROUND We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because the disorder presented in early childhood. METHODS We performed whole-exome sequencing in the initial three patients and their unaffected parents and candidate-gene sequencing in three patients with a similar phenotype, as well as two young siblings with polyarteritis nodosa and one patient with small-vessel vasculitis. Enzyme assays, immunoblotting, immunohistochemical testing, flow cytometry, and cytokine profiling were performed on samples from the patients. To study protein function, we used morpholino-mediated knockdowns in zebrafish and short hairpin RNA knockdowns in U937 cells cultured with human dermal endothelial cells. RESULTS All nine patients carried recessively inherited mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), encoding adenosine deaminase 2 (ADA2), that were predicted to be deleterious; these mutations were rare or absent in healthy controls. Six patients were compound heterozygous for eight CECR1 mutations, whereas the three patients with polyarteritis nodosa or small-vessel vasculitis were homozygous for the p.Gly47Arg mutation. Patients had a marked reduction in the levels of ADA2 and ADA2-specific enzyme activity in the blood. Skin, liver, and brain biopsies revealed vasculopathic changes characterized by compromised endothelial integrity, endothelial cellular activation, and inflammation. Knockdown of a zebrafish ADA2 homologue caused intracranial hemorrhages and neutropenia - phenotypes that were prevented by coinjection with nonmutated (but not with mutated) human CECR1. Monocytes from patients induced damage in cocultured endothelial-cell layers. CONCLUSIONS Loss-of-function mutations in CECR1 were associated with a spectrum of vascular and inflammatory phenotypes, ranging from early-onset recurrent stroke to systemic vasculopathy or vasculitis. (Funded by the National Institutes of Health Intramural Research Programs and others.).

Endolymphatic Sac Tumors: A Source of Morbid Hearing Loss in von Hippel-Lindau Disease

OBJECTIVES Isolated reports suggest a possible association of endolymphatic sac tumors (ELSTs), which are extremely rare in the general population, with von Hippel-Lindau disease (VHL). To determine if hearing loss and ELSTs are a component of VHL, we examined prevalence, clinical presentation, and natural history of hearing loss and ELSTs in VHL. DESIGN Brain magnetic resonance images (MRIs) from 374 patients screened for VHL were reviewed for evidence of ELSTs. The VHL patients with MRI evidence suggestive of ELSTs or a history of hearing loss, tinnitus, or vertigo underwent additional radiologic and audiologic evaluations. To further assess prevalence of hearing loss and ELST in VHL, the next 66 patients screened in the VHL clinic (49 with proven VHL, 17 at risk for VHL) received MRI and audiologic assessment. SETTING Referral center. PARTICIPANTS Study subjects comprised 374 persons screened for VHL, 66 consecutive patients with VHL or at risk for VHL, 4 patients with 6 ELSTs, and 13 previously reported patients with VHL and invasive tumors of the temporal bone. INTERVENTION Magnetic resonance image and computed tomographic (CT) scan of the posterior fossa and audiologic assessment. MAIN OUTCOME MEASURES Any ELST visible on MRI or CT and hearing loss compatible with ELST. RESULTS Magnetic resonance imaging revealed evidence of 15 ELSTs in 13 (11%) of 121 patients with VHL, but in none of the 253 patients without evidence of VHL (P<.001). Clinical findings in these 13 patients included hearing loss (13), tinnitus (12), vertigo (8), and facial paresis (1). Mean age at onset of hearing loss was 22 years (range, 12-50 years). Hearing for pure tones was abnormal in all affected ears and in 6 of the 11 additional, allegedly unaffected ears. In 8 patients (62%), hearing loss was the first manifestation of VHL. Presence or absence of hearing loss was associated with duration of symptoms (P<.002) and with tumor size (P<.01). Further, 43 (65%) of the 66 patients from the VHL clinic had pure tone threshold abnormalities, abnormalities that occurred bilaterally in 23 (54%) of the 43 affected subjects; however, evidence is lacking for a definitive association with ELST (3 [6%] of 49 patients with proven VHL had ELST evident on MRI). CONCLUSIONS Hearing loss and ELSTs are frequently associated with VHL syndrome and should be considered when screening individuals at risk for VHL and when monitoring patients with an established diagnosis of VHL. Many patients with VHL have hearing loss without radiographic evidence of an ELST. Whether it is caused by an ELST that is too small to be detected by MRI or is produced by some other etiology is still unknown. Audiologic evaluation and MRI should allow early detection and enhance management of hearing loss in these patients.

Neonatal Diagnosis and Treatment of Menkes Disease

BACKGROUND Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but presymptomatic detection is hindered by the inadequate sensitivity and specificity of diagnostic tests. Exploiting the deficiency of a copper enzyme, dopamine-beta-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes. METHODS Between May 1997 and July 2005, we measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in 81 infants at risk. In 12 newborns who met the eligibility criteria and began copper-replacement therapy within 22 days after birth, we tracked survival and neurodevelopment longitudinally for 1.5 to 8 years. We characterized ATP7A mutations using yeast complementation, reverse-transcriptase-polymerase-chain-reaction analysis, and immunohistochemical analysis. RESULTS Of 81 infants at risk, 46 had abnormal neurochemical findings indicating low dopamine-beta-hydroxylase activity. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting disease. Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination; 1 of these patients had a mutation that complemented a Saccharomyces cerevisiae copper-transport mutation, indicating partial ATPase activity, and the other had a mutation that allowed some correct ATP7A splicing. CONCLUSIONS Neonatal diagnosis of Menkes disease by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment. (ClinicalTrials.gov number, NCT00001262.)

Quantitative analysis of cerebral vasculopathy in patients with Fabry disease

Objective This studys purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. Background Fabry disease is an X-linked recessive disorder due to a-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. Methods A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. Results On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. Conclusion These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.