The diagnosis of acromegaly: value of inferior petrosal sinus sampling

The early diagnosis of acromegaly may be difficult when serum levels of growth hormone are minimally elevated and imaging of the pituitary gland fails to show an adenoma. However, transsphenoidal surgery has the greatest chance of cure at this stage. We therefore investigated the value of sampling petrosal sinuses for measurement of growth hormone in this group of patients. Simultaneous bilateral sampling of the inferior petrosal sinuses to measure serum concentrations of growth hormone was performed in five patients suspected of having acromegaly but with nondiagnostic CT scans (n = 5) and MR images (n = 3) of the pituitary gland. Levels of growth hormone from the petrosal sinuses were five to 36 times greater than levels in the peripheral veins in all five patients, and three of four showed a marked response to growth hormone-releasing hormone. During transsphenoidal surgery, growth hormone-producing microadenomas were resected completely in four patients. In the fifth patient, a left-sided microadenoma had invaded the cavernous sinus and could not be resected completely. Lateralization of the adenomas within the pituitary gland on the basis of differences in levels of growth hormone between the two petrosal sinuses was not completely reliable. Elevated levels of growth hormone in selective samples from the inferior petrosal sinuses can help support an early diagnosis of acromegaly when peripheral growth hormone levels and imaging are not diagnostic.     

Meningeal Gd-DTPA enhancement in patients with malignancies

Nineteen patients with malignant diseases and pathologically enhancing meninges were studied by pre- and postcontrast (Gd-diethylene-triamine pentaacetic acid) magnetic resonance (MR) scans. Two patterns of enhancement were recognized: the dural (14 patients) and the leptomeningeal (mainly pial) (5 patients). Positive cytology was found in only 3 of the 14 patients with dural enhancement (21%), whereas in the remaining 11 patients we noted either nonspecific CSF findings such as elevated protein, high white blood cell count, and low glucose or entirely normal CSF. Four patients (80%) in the group with leptomeningeal enhancement showed positive cytology and one had normal CSF analysis. We conclude that meningeal enhancement as seen on MR imaging is a nonspecific finding and correlates well with positive cytology only when the more rare form of leptomeningeal enhancement is encountered.     

Cushing's disease presenting with avascular necrosis of the hip: an orthopedic emergency.

Nontraumatic avascular necrosis (AVN) of the hip is commonly caused by exogenous glucocorticoid administration, whereas it has rarely been associated with endogenous hypercortisolism. We report a 30-yr-old woman with Cushing's disease whose presenting manifestation was early AVN of the hip. Although plain x-ray was negative, magnetic resonance imaging (MRI) of the hip showed stage 2 AVN. Her orthopedic disease was considered an emergency, and thus, it was treated with core decompression before the diagnosis of Cushing's syndrome (CS) was pursued further. The femur recovered fully, as demonstrated by her improved clinical picture and a subsequent MRI. AVN carries a poor prognosis, if not treated early. The diagnostic procedure of choice is MRI, because plain radiographs are falsely negative in early stages. This case illustrates that AVN can be the presenting manifestation of CS; to prevent irreversible effects on the femoral head, core decompression should not be delayed for the purpose of evaluation and treatment of CS.     

Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma.

Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas. IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters. No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free > 18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL.     

Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis: implications for clinical trials and natural history.

Six patients with early, mild, relapsing-remitting multiple sclerosis were studied with monthly gadolinium-enhanced magnetic resonance imaging scans for 8 to 11 months. Numerous enhancing lesions were observed irrespective of clinical activity. Four of the 6 patients had one or more enhancing lesions present on each examination. The other 2 patients had enhancing lesions noted in 7 and 9 of 11 months. In contrast, only two clinical exacerbations were observed during the study period. Neither the exacerbations nor other changes in symptoms or signs correlated with occurrence of the enhancing lesions. Enhancement generally persisted for less than 1 month. The opening of the blood-brain barrier as reflected by gadolinium enhancement on magnetic resonance imaging may represent ongoing disease activity in patients with mild, relapsing-remitting multiple sclerosis who are clinically stable. The frequency of these lesions appears to be sufficient to use as an outcome measure in clinical trials testing clinical efficacy in patients with early, relapsing-remitting multiple sclerosis.     

Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease

Context  Endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau disease and cause irreversible sensorineural hearing loss (SNHL) and vestibulopathy. The underlying mechanisms of audiovestibular morbidity remain unclear and optimal timing of treatment is not known. Objective  To define the mechanisms underlying audiovestibular pathophysiology associated with ELSTs. Design, Setting, and Patients  Prospective and serial evaluation of patients with von Hippel-Lindau disease and ELSTs at the National Institutes of Health between May 1990 and December 2006. Main Outcome Measures  Clinical findings and audiologic data were correlated with serial magnetic resonance imaging and computed tomography imaging studies to determine mechanisms underlying audiovestibular dysfunction. Results  Thirty-five patients with von Hippel-Lindau disease and ELSTs in 38 ears (3 bilateral ELSTs) were identified. Tumor invasion of the otic capsule was associated with larger tumors (P = .01) and occurred in 7 ears (18%) causing SNHL (100%). No evidence of otic capsule invasion was present in the remaining 31 ears (82%). SNHL developed in 27 of these 31 ears (87%) either suddenly (14 ears; 52%) or gradually (13 ears; 48%) and 4 ears had normal hearing. Intralabyrinthine hemorrhage was found in 11 of 14 ears with sudden SNHL (79%; P < .001) but occurred in none of the 17 ears with gradual SNHL or normal hearing. Tumor size was not related to SNHL (P = .23) or vestibulopathy (P = .83). Conclusions  ELST-associated SNHL and vestibulopathy may occur suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms occur with small tumors that are not associated with otic capsule invasion.      

Treatment of autoimmune premature ovarian failure.

There is no known immunosuppressive therapy for autoimmune premature ovarian failure that has been proven safe and effective by prospective randomized placebo-controlled study. Nevertheless, immunosuppression using corticosteroids has been used on an empirical basis for this condition. Here we present two cases of young women with premature ovarian failure who were treated with glucocorticoids in the hopes of restoring fertility. The first case illustrates the potential benefit of such therapy, and the second case illustrates a potential risk. The first patient with histologically proven autoimmune oophoritis was treated with alternate day glucocorticoid treatment. She had return of menstrual bleeding six times and ovulatory progesterone concentrations four times over a 16 week period. The second patient with presumed but unconfirmed autoimmune ovarian failure was referred to us after having been treated with a 9 month course of corticosteroids. During that treatment her menses did not resume. The corticosteroid treatment was complicated by iatrogenic Cushing syndrome and osteonecrosis of the knee. Identifying patients with autoimmune premature ovarian failure presents the opportunity to restore ovarian function by treating these patients with the proper immune modulation therapy. On the other hand, potent immune modulation therapy can have major complications. Corticosteroid therapy for autoimmune premature ovarian failure should be limited to use in placebo-controlled trials designed to evaluate the safety and efficacy of such treatment.     

Automated detection and volume measurement of plexiform neurofibromas in neurofibromatosis 1 using magnetic resonance imaging.

An automated technique for segmentation and volumetric measurement of plexiform neurofibromas (PN) in neurofibromatosis 1 using short T1-inversion recovery magnetic resonance images is presented. The algorithm described implements heuristics derived from human-based recognition of lesions. This technique combines region-based with boundary-based segmentation. Two observers, who performed semi-automated volume calculations and manual tracings to estimate tumor volume, validated this method on 9 PNs of different size and location. This automated method was reproducible (coefficient of variation 0.6-5.6%), yielded similar results to manual tumor tracings (R = 0.999) and will likely improve the ability to measure PNs in ongoing clinical trials.