High-Dose Bapineuzumab Puts Some Alzheimer Patients At Risk for Vasogenic Cerebral Edema

Dr. Stephen Salloway (pictured) reported at the recent American Academy of Neurology annual meeting on the much ballyhooed bapineuzumab study for Alzheimer patients. I take a particular interest in this topic: my own 89-year-old father was a subject in the study, but was removed from it due to the development of some kind of MRI changes. Salloway, Brown University neurologists and one of the study's lead investigators, reported that patients on the 2.0 mg/kg dose of bapineuzumab (the highest dose level in the study) had a significantly increased risk of developing vasogenic cerebral edema. Because it is a double-blinded study, I do not know what dose my dad was on (or if he was given a placebo). Bapineuzumab is an anti-beta-amyloid monoclonal antibody. It is thought that the antibody may have compromised cerebral blood vessel walls by attaching to mural amyloid, which tends to accumulate in Alzheimer patients. Investigators decided that "continued development of the highest dose was not advisable," said Carlos Paya, MD, PhD, president of the biotech firm Elan, which is working with Wyeth Pharmaceuticals to develop the antibody for clinical use. That being said, the antibody continues to show promise in slowing cognitive decline among patient who do not harbor a apolipoprotein E4 allele and will continue to accrue patients for the phase 3 study at lower doses.

Source: Neurology Today (May 21, 2009), page 4.

A 75-year-old man with a large, subretinal mass requiring enucleation

The patient is a 75-year-old male who reported to his ophthalmologist complaining of failing vision as well as intermittent “flashes of light” in his left eye over the previous four months. Examination of the left eye revealed markedly elevated intraocular pressure. Fundiscopic examination revealed a large grayish brown subretinal mass with surrounding retinal folds in the superior portion of the eye. The eye was subsequently enucleated. Here is a picture of the bisected eyeball:

The following is a whole mount of the globe with optic nerve on left and iris on right:

This is a photomicrograph of the anterior chamber angle, which is involved by tumor:

Here is a sampling of different regions within the tumor:

Discussion:

This is a uveal malignant melanoma, mixed cell type. Although the retina harbors a pigmented epithelium, melanomas do not arise from the retina but rather from the melanocytes inhabiting the uveal tract. The uvea is a continuous entity comprised of the iris, ciliary body, and choroid. Melanomas can arise anywhere along the uveal tract. In this case, the melanoma is arising in the choroid and extends into the ciliary body. Tumoral involvement of the irido-corneal angle led to blockage of aqueous humor reabsorption in this patient, resulting in increased intraocular pressure (glaucoma). Three cell types are seen in uveal melanomas: spindle A, spindle B, and epithelioid. Spindle A cells have markedly elongated nuclei and uncommonly have mitotic figures. Spindle B cells share with A-type cells an elongated profile, but spindle B cells have larger, more ovoid nuclei harboring a more prominent nucleolus. Epithelioid melanoma cells are rounder and more anaplastic in appearance, tend to be discohesive, and are occasionally multinucleated. The current case contains a mixture of spindle B and epithelioid type cells. The presence of epithelioid cells confers a worse prognosis. Tumor size is another prognostically significant feature. In contrast to cutaneous melanomas, however, the lateral extent of the tumor is a more significant prognostic feature than is depth. Other prognostically adverse histopathologic features include: high mitotic count; ciliary or choroidal location (iris melanomas fare better); optic nerve extension; intrascleral extension; necrosis; lymphocytic infiltration; neovascularization; and nucleolar prominence. Since there are no lymphatics within the eye, metastasis of uveal neoplasms take an exclusively hematogenous route, with seeding to the liver outnumbering other sites by a very wide margin. Although enucleation is the treatment of choice for larger choroidal melanomas (basal diameter >15 mm and height >10 mm), new precision radiotherapies such as proton beam irradiation and plaque brachytherapy can provide eye-sparing treatments for smaller lesions. As a result, pathologists today see far fewer enucleation specimens secondary to melanoma than in the past. Nevertheless, approximately 10-15% of eyes treated with precision radiotherapy ultimately require enucleation due to subsequent local recurrence or procedure-related glaucoma.

References:

1. Folberg R. “Chapter 29: The Eye” in Robbins and Cotran Pathologic Basis of Disease, 7^th ed. (Kumar, Abbas, Fausto, editors) Elsevier, 2005;1434.

2. Stallard HB. “Chapter 43: Diseases of the Choroid” in The Eye and Its Diseases, 2^nd ed. (Berens C, editor). WB Saunders: 1949;560-563.

3. Rosai J. “Chapter 30: Eye and Ocular Adnexa” in Rosai and Ackerman’s Surgical Pathology, 9^th ed. Elsevier: 2004;2751-2757.