Photoreceptor loss in age-related macular degeneration

PURPOSE: The authors showed previously that parafoveal rods, but not cones, decrease during the course of adulthood in donor eyes that were screened to exclude the grossly visible macular drusen and pigmentary disturbances typical of age-related macular degeneration (AMD). Because AMD begins in the parafovea, this selective loss of rods actually may be subclinical AMD not yet visible in the fundus. If so, AMD must have a predilection for rods over cones. The authors tested this hypothesis by determining the relative numbers of cones and rods in donor eyes with mid-to late-stage AMD and in age-matched controls. METHODS: Thirteen eyes (from seven donors) with grossly visible macular drusen and pigmentary disturbances were either wholemounted for photoreceptor counts or sectioned through the fovea for histopathology and carbonic anhydrase histochemistry to label red-green cones. Eyes were assigned to AMD or control groups on the basis of histopathology and clinical history. RESULTS: Five nonexudative AMD (NE-AMD) eyes from three donors showed sparing of foveal cones and loss of rods and cones in the parafovea. In two donors, rod loss exceeded cone loss at most parafoveal locations, and in one donor, rod density was normal and cone density was reduced. In eight exudative AMD (EX-AMD) eyes from five donors, photoreceptors surviving along the margins of and overlying disciform scars were largely cones. CONCLUSIONS: Photoreceptors are lost in NE-AMD as well as in the more severe exudative form, consistent with functional and clinical studies. The authors propose that rods die in older eyes without evidence of overt retinal pigment epithelial disease. In persons susceptible to AMD, the retinal pigment epithelium becomes dysfunctional. Secondarily, rod loss continues and cones begin to degenerate. Eventually, only degenerate cones remain; ultimately, all photoreceptors may disappear.     

Cigarette smoking and age-related macular degeneration

BACKGROUND: Age-related macular degeneration (ARMD) is one of the leading causes of severe visual impairment among older Americans. Several hypotheses have been proposed regarding the pathogenesis of ARMD. The possible association of cigarette smoking and ARMD remains controversial. METHODS: Studies concerning the relationship between cigarette smoking and ARMD are identified through the use of Vision Articles Online and PubMed. Articles published since 1970 are reviewed. RESULTS: The literature reviewed strongly supports a link between smoking and ARMD. CONCLUSIONS: The identification of smoking as a risk factor can lead to early intervention. Such intervention may lessen visual loss from this disease, which has limited medical treatment options.     

Radiotherapy of exudative senile macular degeneration. A prospective controlled study

Despite the successful therapy of subretinal neovascular membranes by laserphotocoagulation there are many problems to be overcome. In the case of subfoveolar neovascularization, photocoagulation leads to a sudden decrease in visual acuity. Recently radiotherapy is considered as an alternative. Complications and effectivity were evaluated in this prospective and randomized trial. The initial results are presented. PATIENTS AND METHODS: There are 76 patients (51 women, 25 men, average age 77.7 +/- 8.6 years) included in the prospective randomized study. All of them show subfoveolar neovascular membranes in FLA and a decrease in visual acuity between 0.05 and 0.5. They were randomly assigned to either the radiotherapy or the control group. Radiotherapy was done within 6 days by 6 x 2 Gy (6 MV photons). The follow-up was at 4 weeks, after 3 months, after 6 months and then every 6 months after the end of radiotherapy. On average the follow-up is at 15.1 months. RESULTS: Concerning age and visual acuity before therapy, the control group and the radiotherapy group were not significantly different. At 4 weeks after radiotherapy, visual acuity was 0.13 +/- 0.46 (LogMAR). After 12 months, visual acuity at a distance was 0.11 +/- 0.30 in the therapy group and 0.09 +/- 0.13 (P = 0.838) in the control group. Patients with a preoperative visual acuity better than 0.2 improved more after radiotherapy. Metamorphopsy improved in 75% of the therapy group. The following complications could be observed: In the control group 3 patients suffered subretinal bleeding, in the radiotherapy group 3 patients, respectively. CONCLUSIONS: At present, the follow-up is too short to recommend radiotherapy as a standard procedure in the case of subfoveolar neovascularization. The results in patients with a better preoperative visual acuity encourage us to continue this study.     

Advanced glycation end products in age-related macular degeneration

OBJECTIVE: To investigate the localization of N epsilon-(carboxymethyl)lysine (CML), a component and major immunologic epitope of advanced glycation end products, in aged eyes and choroidal neovascular membranes (CNVMs) surgically excised from eyes with age-related macular degeneration. METHODS: Immunohistochemistry for CML was performed using 8 snap-frozen, surgically excised CNVMs. Twelve eyes from patients aged 69 to 82 years and 2 donor eyes, 1 each from a 23-week-old fetus and 21-year-old patient, without age-related macular degeneration or diabetic retinopathy were also examined. To determine if retinal pigment epithelial cells in CNVMs accumulate advanced glycation end products, cytokeratin and CML were stained in paired serial sections. RESULTS: Soft, macular drusen and/or basal laminar and basal linear deposits were observed in 8 of 12 aged eyes. Each case showed CML accumulation, while overlying retinal pigment epithelial cells showed no accumulation in all 12 eyes. In CNVMs, however, retinal pigment epithelial cells showed CML accumulation in their cytoplasm. CONCLUSION: The additional accumulation of advanced glycation end products in soft, macular drusen and/or retinal pigment epithelial cells may play a role in the pathogenesis of CNVM formation in age-related macular degeneration. CLINICAL RELEVANCE: Recently, advanced glycation end products have been found to play a role both in aging changes and neovascularization. Localization of advanced glycation end products in the above-mentioned tissue may lead to a better understanding of the pathogenesis of age-related macular degeneration.     

Slow photostress recovery and disease severity in age-related macular degeneration

SETTING: The Matiben Chest Clinic at the West Algiers University Teaching Hospital, and 3 outpatient clinics specializing in tuberculosis and lung disease in Algiers. OBJECTIVE: To determine the tolerance and efficacy of a fixed proportion combination of 3 antituberculosis drugs (per tablet: 50 mg isoniazid + 120 mg rifampicin + 300 mg pyrazinamide) given during the first 2 months of a daily 6-month chemotherapy regimen. DESIGN: Random prospective treatment trial comparing a group of 124 patients receiving the triple combination with another group of 126 patients receiving the 3 drugs separately during the initial treatment phase. The continuation phase was identical for the 2 groups. Comparison of tolerance in the first 2 months, and of the failure and relapse rates (respectively at the end of treatment and 24 months after the end of treatment). RESULTS: During the first 2 months side-effects were significantly more common in the group receiving the drugs separately. At the end of treatment and during the following 24 months there were no significant differences in the cumulative rates of observed failures and relapses (2% and 1%). CONCLUSION: The triple combination studied could replace the separate drugs in the initial treatment phase in countries where the bioavailability of the drugs used has been proven.     

Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group

AIM: A case-control study was initiated to determine the risk factors for the development of age related macular degeneration (AMD). METHODS: Study participants, who were all white, aged 50-85 years, and were recruited from private ophthalmology practices. Each practitioner enrolled patients with bilateral AMD, who were then matched with controls for sex and age. Environmental factors and systemic and ocular histories were screened. All patients had bilateral red-free fundus photographs and fluorescein angiography. Photographs were classified into pigment epithelium alterations, drusen, geographic atrophy, and exudative AMD. Statistical analysis included the identification of risk factors for AMD. A multivariate analysis was performed at the end of the study. Analysis included the entire study population and was carried out for each stage of AMD. RESULTS: 1844 controls were compared with 1844 patients with AMD. Mean age was 71 years for controls and 72 for cases. Logistic regression identified six major risk factors for AMD (whole population): arterial hypertension (odds ratio (OR) = 1.28), coronary disease (OR = 1.31), hyperopia (OR = 1.33), light coloured irises (OR = 1.22), and lens opacities or previous cataract surgery (OR = 1.55). The significance of vascular risk factors was increased for late stages of AMD, especially the atrophic forms (coronary disease, OR = 3.19). CONCLUSIONS: This large case-control study confirms some of the risk factors previously identified and may contribute to the determination of methods for prevention of AMD.     

The clinical significance of senile cardiac amyloidosis: a prospective clinico-pathological study

The heart was screened for amyloid deposits in an unselected post-mortem series of 244 patients over 60 who had been admitted to a geriatric department. Cardiac amyloidosis was found in 121 cases (49-6 per cent) but was limited to minor atrial involvement in 55 (22-5 per cent). The prevalence and severity of cardiac amyloidosis were significantly related to age and sex, females having the higher prevalence (56 per cent compared with 37 1/2 per cent). Cardiac amyloidosis was also significantly correlated with the occurrence of atrial fibrillation and of cardiac failure during the period of admission to hospital. Cardiac amyloidosis showed no significant correlations with other factors studied which included ECG evidence of left ventricular hypertrophy, ischaemia and bundle branch block, pathological evidence of cardiac enlargement or ischaemia, diagnosis of malignant disease, generalized wasting and the occurrence of digitalis toxicity.     

Photocoagulation of well-defined choroidal neovascularization in age-related macular degeneration: clinicopathologic correlation

PURPOSE: To present the clinicopathologic features of the eyes of a patient with age-related macular degeneration (ARMD): the right eye was treated for well-defined extrafoveal choroidal neovascularization (CNV), and the left eye had an untreated disciform scar. METHODS: The patient was studied ophthalmoscopically and by fluorescein angiography at the time of presentation and on follow-up examinations up to 54 days after laser treatment, when he died. The posterior portions of both eyes (obtained postmortem), including the macula and optic nerve head, were sectioned serially for light microscopy. Tissue sections from both eyes were removed from glass slides and studied by transmission electron microscopy. RESULTS: Histopathologic study of the right eye disclosed a thin layer of basal laminar deposit throughout the posterior pole. Two defects in Bruch's membrane without CNV were present within the area of laser photocoagulation located superior to the fovea. No CNV was present in the scar. Eleven areas of early CNV were present in the posterior pole. Histopathologic study of the left eye showed a prominent basal laminar deposit throughout the posterior pole. A 2.6 x 2.7 mm disciform scar was present that was located mostly in the subretinal space. Four sources of CNV were present. CONCLUSIONS: The clinicopathologic features of a treated eye with well-defined extrafoveal CNV, and the fellow eye with a disciform scar, both associated with ARMD, are presented. Although laser treatment obliterated a choroidal neovascular membrane, 11 additional areas of early, subclinical CNV were present.     

The short-wavelength mechanisms of Stiles in age-related macular degeneration

Clinical measurements by the increment-threshold technique of W.S. Stiles are reported in five cases of age-related macular degeneration. Measurements were made on a modified Tübingen perimeter using 1 degree, short-wavelength targets presented on a red field.     

Laser photocoagulation of neovascular lesions in senile macular degeneration

Eighty-four eyes with aging macular degeneration were included in this five-year retrospective study (1989-1994). Sixty-four eyes were treated with laser, whereas in 20 eyes photocoagulation was not performed because these patients refused laser treatment. The latter served as a control group. Out of 64 laser-treated eyes, 48 (75%) eyes had extramacular choroidal, and 15 (25%) juxtafoveal neovascular membrane. A comparable percentage and alterations were recorded in the control group of eyes. At the beginning of the study, the mean visual acuity distribution was 0.5 in both the treated and untreated group of eyes, which was not statistically significant (p > 0.16). Recurrent neovascularization developed in 33 (52%) out of 64 eyes at the end of the first and in the second year after photocoagulation, being the main cause of severe vision impairment. At the beginning of the second year, the risk of severe vision loss by six or more Snellen's lines was recorded in 14 (41%) out of 33 eyes with the vision of 0.15, and after five years in 22 (73%) out of 33 eyes with the vision of 0.08. A the end of the study, unchanged or slightly deteriorated visual acuity (0.5-0.4) was found in 27 (42.1%) out of 64 laser-treated eyes, and in only 2 (10%) out of 20 untreated eyes. At the end of the five-year study, total risk of severe vision loss by six or more Snellen's lines was present in 30 (52.8%) out of 64 laser-treated eyes, and in 15 (74%) out of 20 untreated eyes. Study results showed laser treatment of neovascular aging macular degeneration to be absolutely useful in decreasing visual acuity reduction as compared to the untreated control group.     

Age-related macular degeneration and smoking. The Rotterdam Study

OBJECTIVE: To assess the relation between cigarette smoking and age-related macular degeneration (AMD) in a population of elderly persons. DESIGN: A cross-sectional, community-based study. SETTING: City district of Rotterdam, the Netherlands. PARTICIPANTS: A total of 6174 persons 55 years and older who participated in the Rotterdam Study. In 36 persons atrophic AMD and in 65 persons neovascular AMD were diagnosed. MAIN OUTCOME MEASURES: Age-related macular degeneration was diagnosed by evaluating fundus transparencies, smoking behavior was identified by interviewing subjects, and the presence of atherosclerosis was assessed by the ankle-arm systolic blood pressure index. Relative risks and 95% confidence intervals (CIs) were calculated using multivariate logistic regression analysis. RESULTS: In subjects younger than 85 years, current smokers had a 6.6-fold increased risk of neovascular AMD vs those who had never smoked (95% CI, 2.8-15.9). Former smokers had a 3.2-fold increased risk of neovascular AMD vs nonsmokers in this age group (95% CI, 1.4-7.4). These associations were not observed in subjects 85 years or older. Smoking was not associated with atrophic AMD. A strong increased risk of neovascular AMD was present in those who had smoked more than 10 pack-years (relative risk, 6.5; 95% CI, 2.9-14.8). Adjusting the results for atherosclerosis did not change the association. Persons who had quit smoking 20 or more years before the eye examination had no increased risk. CONCLUSIONS: The results provide evidence for a dose-response relationship between smoking and AMD, particularly in persons with the neovascular form of the disease.     

Retinal projections in cyprinid fishes: a degeneration and radioautographic study

The retinal projections of three species of cyprinid fish (Cyprinus macrolepidotus, Cyprinus carpio, Rutilus rutilus) were examined with Nauta and Fink-Heimer methods following enucleation and with radioautography following intraocular injection of [3H]-L-proline. Optic tract axons cross completely in the optic chiasma and are distributed to the hypothalamus (nucleus opticus hypothalamicus pars magnocellularis), the thalamo-pretectal region (11 distinct primary optic centers), and the tectum opticum (stratum fibrosum et griseum superficiale, stratum griseum centrale and stratum album centrale). No accessory optic tract was found. The experimental studies on visual projection of various teleosts are reviewed and discussed.     

Central neurocytoma: clinico-pathological study of 5 cases and review of the literature

Five cases of central neurocytoma, confirmed by immunohistochemical and electron microscopy studies, are reported and 127 cases from the literature are reviewed. Central neurocytomas are more frequent than previously thought, and will be diagnosed with increasing frequency in the future, if intraventricular tumors with histological aspect of oligodendroglioma or ependymoma will be routinely studied by immunohistochemistry and electron microscopy. The occurrence of an intraventricular tumor with a typical MR aspect in a young patient should suggest preoperatively the diagnosis of neurocytoma. The positivity for synaptophysin and neuron specific enolase, the negativity for neurofilament protein and glial fibrillary acid protein, and the finding of elements of neuronal differentiation on electron microscopy, are the main pathological features of these tumors. Complete removal of the tumor mass without radiotherapy is the treatment of choice. The prognosis is usually favorable without recurrence.     

The photon therapy of subfoveal choroidal neovascularization in age-dependent macular degeneration. The results of a prospective study in 40 patients

AIM: To determine the effect of external beam radiotherapy on subfoveal choroidal neovascularization in age-related macular degeneration. PATIENTS AND METHODS: Between September 1995 and July 1996, 40 patients (9 males and 31 females; mean age 74 years, range 61 to 83 years) were included in a prospective study. Eight patients had classic, well-defined neovascularisations, 32 patients had occult lesions. Complete ophthalmic investigations included visual acuity contrast sensitivity as well as fluorescein and indocyanine green angiographic examinations prior to treatment and 1, 3, 6, and 12 months after radiotherapy. External beam radiotherapy (8-MV photons) was delivered with a total dose of 14.4 Gy in 8 fractions of 1.8 Gy per day (Figures 1 and 2). The field size averaged 5.5 x 4.5 cm. RESULTS: No treatment related morbidity during or after treatment was obtained. After 6 months follow-up the visual acuity was improved in 2 (5%) patients and maintained at pretreatment level in 17 (42%) patients. However, 12 months post treatment a stable situation was found in 6 (15%) patients and a decrease in visual acuity in 34 (85%) patients (Table 1). The central visual fields deteriorated significantly from 16.5 decibel (dB) to 12.4 dB. The enlargement of exudates and neovascular membranes increased 5- to 7-fold. At 12 months after treatment, 3 (7.5%) patients stated that they had improved vision subjectively, 12 (30%) patients had no change and 25 (62.5%) patients suffered from subjective decrease in visual acuity. CONCLUSIONS: Using a total dose of 14.4 Gy/1.8 Gy no difference concerning visual acuity and exudative changes in comparison to the natural history on age-related macular degeneration was obtained after 12 months. However, the results of multicenter studies are to be awaited.     

Artificial light and early-life exposure in age-related macular degeneration and in cataractogenic phototoxicity

Cryptosporidium has received increasing attention as a pathogen in normal as well as immunocompromised persons. We report a case of cryptosporidiosis occurred in a 18-months-old-girl who was treated with spiramycin for 8 days with complete resolution of diarrhea within the first days of therapy; follow-up stool examination was negative for the protozoan. The incidence of diarrhea due to Cryptosporidium seems to be higher than it was reported before: so fecal samples, when negative for other etiological agents, should be examined for Cryptosporidium oocysts. Spiramycin seems to be an effective and well-tolerated drug: treatment is recommended in children with prolonged and/or severe diarrhea when Cryptosporidium seems to be the etiological cause of the disease.     

Activation and degeneration during aging: a morphometric study of the human hypothalamus

During the course of aging both activation and degenerative changes are found in the human hypothalamus. Degeneration may start around middle-age in some neurotransmitter- or neuromodulator-containing neurons. For instance, a decreased number of vasoactive intestinal polypeptide (VIP) neurons was observed in the suprachiasmatic nucleus (SCN) of middle-aged males. The normal circadian fluctuations seen in the number of vasopressin (AVP) neurons in the SCN of young subjects diminished in subjects older than 50 years. Moreover, a sharp decline in cell number was found in the sexually dimorphic nucleus (SDN) after 50 years in males. On the other hand, many hypothalamic systems remain perfectly intact during aging like the oxytocin (OXT) neurons in the paraventricular nucleus (PVN). The AVP neurons in the PVN are activated during aging as appears from their increasing cell number. Also the corticotrophin-releasing hormone (CRH) neurons of the PVN are activated in the course of aging, as indicated by their increased number and their increased AVP coexpression. Part of the infundibular nucleus, the subventricular nucleus, contains hypertrophic neurokinin B neurons in postmenopausal women. It can be concluded that a multitude of changes in the various hypothalamic nuclei may be the biological basis for many functional changes in aging, i.e., both endocrine and central alterations, and that only a minority of the possible human hypothalamic changes have so far been studied.