Edward R. Laws

Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.

Glial cell line–derived neurotrophic factor (GDNF) exerts potent trophic influence on midbrain dopaminergic neurons. This randomized controlled clinical trial was designed to confirm initial clinical benefits observed in a small, open‐label trial using intraputamenal (Ipu) infusion of recombinant human GDNF (liatermin).

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD

Objective: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. Background: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. Methods: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 μg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 μg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson’s Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. Results: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. “On” and “off” total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 μg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 μg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. Conclusions: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues—putamen and substantia nigra.

Guidelines for acromegaly management: An update

OBJECTIVE The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. PARTICIPANTS The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. CONCLUSIONS The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.

Acromegaly: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to formulate clinical practice guidelines for acromegaly. PARTICIPANTS The Task Force included a chair selected by the Endocrine Society Clinical Guidelines Subcommittee (CGS), five experts in the field, and a methodologist. The authors received no corporate funding or remuneration. This guideline is cosponsored by the European Society of Endocrinology. EVIDENCE This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. The Task Force reviewed primary evidence and commissioned two additional systematic reviews. CONSENSUS PROCESS One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of the Endocrine Society and the European Society of Endocrinology reviewed drafts of the guidelines. CONCLUSIONS Using an evidence-based approach, this acromegaly guideline addresses important clinical issues regarding the evaluation and management of acromegaly, including the appropriate biochemical assessment, a therapeutic algorithm, including use of medical monotherapy or combination therapy, and management during pregnancy.

SEIZURES AFTER HEAD TRAUMA: A POPULATION STUDY

A cohort of 2747 patients with head injuries was followed for 28,176 person-years to determine the magnitude and duration of the risk of posttxaumatic seizures. Injuries were classified as severe (brain contusion, intracerebral or intracranial hematoma, or 24 hours of either unconsciousness or amnesia), moderate (skull fracture or 30 minutes to 24 hours of unconsciousness or amnesia), and mild (briefer unconsciousness or amnesia). The risk of posttraumatic seizures after severe injury was 7.1% within 1 year and 11.5% in 5 years, after moderate injury the risk was 0.7 and 1.6%, and after mild injury the risk was 0.1 and 0.6%. The incidence of seizures after mild head injuries was not significantly greater than in the general population.

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

Proliferative Activity and Invasiveness among Pituitary Adenomas and Carcinomas: An Analysis Using the MIB-1 Antibody

Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

Brain tumor survival: Results from the National Cancer Data Base

Hospital-based data reported to the National Cancer Data Base (NCDB) were available for over 60,000 patients with a primary brain tumor diagnosed from 1985–1988 and 1990–1992. The most common histologies were glioblastomas, astrocytomas and meningiomas. Five-year survival rates for these tumors were 2%, 30% and 70% respectively. Histology, age at diagnosis, behavior, and location were important variables in estimating survival. Comparisons with population-based registry data suggest that the malignant tumors are well represented in NCDB, but the benign histologies are under-reported. Survival estimates for the malignant tumors are comparable to previously reported studies. The NCDB provides recent information on brain tumor distribution and survival patterns not available in other large databases.

The incidence, causes, and secular trends of head trauma in Olmsted County, Minnesota, 1935–1974

Records in the Mayo Clinic linkage system were reviewed to determine the incidence of head trauma in Olmsted County, Minnesota, from 1935–1974. Minimum criteria for inclusion—loss of consciousness, posttraumatic amnesia, or skull fracture—were met by 3587 cases. During the decade from 1965–1974, the age-adjusted incidence rates per 100,000 population were 270 in males and 116 in females. The rate was highest—658—in males aged 15 to 24, but it was at least 50 in all age and sex groups. Major causes of head injury were automobile accidents (37%) and falls (2%). The incidence of head injuries related to automobiles and recreation has been increasing, whereas most other categories have remained stable or have declined. Of all cases, 446 were fatal, the average annual incidence being 32 per 100,000 in males and 9 per 100,000 in females. Among the groups at high risk of head trauma are those who have had head trauma previously.

A retrospective analysis of pituitary apoplexy.

Thirty-seven patients with pituitary apoplexy were analyzed with an emphasis on clinical presentation and visual outcome. Their mean age was 56.6 years, with a male to female ratio of 2:1. Presenting symptoms included headache (95%), vomiting (69%), ocular paresis (78%), and reduction in visual fields (64%) or acuities (52%). Computed tomographic scanning correctly identified pituitary hemorrhage in only 46% of those scanned. Thirty-six patients underwent transsphenoidal decompression. By immunostaining criteria, null-cell adenomas were the most frequent tumor type (50%). Long-term steroid or thyroid hormone replacement therapy was necessary in 82% and 89% of patients, respectively. Long-term desmopressin therapy was required in 11%, and 64% of the male patients required testosterone replacement therapy. Surgery resulted in improvement in visual acuity deficits in 88%, visual field deficits in 95%, and ocular paresis in 100%. Analysis of the degree of improvement in preoperative visual deficits with the timing of the surgery demonstrated that those who underwent surgery within a week of apoplexy had significant recovery in their visual acuities. In the stable, conscious patient with residual vision in each eye, surgical decompression should be performed as soon as possible, because delays beyond 1 week may retard the return of visual function.