The Severe Mini-Mental State Examination: a new neuropsychologic instrument for the bedside assessment of severely impaired patients with Alzheimer disease.

The bedside and office assessment of cognitive abilities in moderately to severely impaired patients with Alzheimer disease could be enhanced by a well-standardized instrument. The authors' group has developed such an instrument (i.e., Severe Mini-Mental State Examination; SMMSE) to assess this population. Based on the Folstein Mini-Mental State Examination (MMSE), the SMMSE, which totals 30 points, was designed to briefly assess cognitive domains relatively preserved in moderate to severe Alzheimer disease. One hundred eighty-two patients with possible or probable Alzheimer disease were administered both the MMSE and SMMSE. Performances on the SMMSE and MMSE were found to correlate significantly only when MMSE fell below 9 points (p < 0.0001). However, as performance on the MMSE approached floor levels, patients continued to score at half maximal levels on the SMMSE. Functional staging with the Clinical Dementia Rating Scale and the Global Deterioration Scale also were found to significantly correlate with performance on the SMMSE (p < 0.001). Test-retest performance on both the SMMSE and MMSE was relatively stable over a period of 5 months. Inter-rater reliability of the SMMSE was excellent. These results suggest that the SMMSE has both construct and criterion validity for assessing severely impaired Alzheimer disease patients. Our results also suggest that the SMMSE may be a useful instrument for assessing severely impaired patients at the bedside and in the office.

Laser ablation of burns: initial clinical trial.

BACKGROUND: Scanning, high-powered carbon dioxide laser ablation of eschar may facilitate blood conservation in patients with burns. METHODS: Twenty-one children with full-thickness burns that required serial excisions were enrolled in a Human Studies Committee approved protocol in which a full-thickness wound was ablated with a rapidly scanned continuous wave carbon dioxide laser system. A control wound was sharply excised, and both wounds were immediately autografted. End points were engraftment at 7 days and serial Vancouver scar scores. RESULTS: The children had an average age of 8.3 +/- 1.2 years, weight of 36.3 +/- 4.9 kg, and burn size of 40% +/- 5.1%. The study wounds were ablated with an average energy of 99.2 +/- 5.7 W; there was no bleeding from 19 successfully ablated wounds. Initial engraftment averaged 94.7% +/- 3.5% in the control sites and 94.7% +/- 3.3% in the study sites (P = 1.0). There was no significant difference in Vancouver scar scores at an average follow-up of 32.0 +/- 5.2 weeks. CONCLUSIONS: This pilot study follows a successful trial of this concept in a porcine model and demonstrates the technical feasibility of laser vaporization of burn eschar in humans with immediate autografting. Further refinement of the technique is required before it can be generally recommended.

Consensus workshop on the toxic effects of long-term PUVA therapy.

The possibility that there is an increased risk of melanoma in patients with psoriasis treated with psoralen-UV-A (PUVA) therapy has raised concern on the part of physicians and patients about the long-term safety of this treatment. In response to this concern, the National Psoriasis Foundation sponsored a workshop at which invited participants with expertise in PUVA therapy, psoriasis treatment, melanoma and nonmelanoma skin cancer, and epidemiological and clinical trials were asked to develop a consensus on the following 3 issues: the risk of long-term adverse effects of PUVA therapy with emphasis on nonmelanoma and melanoma skin cancer; the guidelines for physicians and patients for selection and use of PUVA therapy with consideration of the risk-benefit ratio of this treatment compared with the risk-benefit ratios of alternative treatments; and the directions for further evaluation of the long-term effects Of PUVA therapy.

The substitution of digital images for dermatologic physical examination.

OBJECTIVE: To investigate the diagnostic accuracy of clinicians viewing a patient's history and static digital image set compared with clinicians who conducted office-based physical examinations of the same patients. DESIGN: Observational study. SETTING AND PATIENTS: One hundred sixteen adult patients presenting with dermatologic symptoms in a university-based practice who consented to have their skin conditions documented with a still digital camera according to a standardized protocol. MAIN OUTCOME MEASURES: Concordance between office-based dermatologists' diagnoses and 2 remote clinicians' diagnoses using still digital images (resolution, 92 dots per inch) and identical medical history data to render diagnoses. RESULTS: When photographic quality was high and office-based clinician certainty was high, remote clinicians were in agreement more than 75% of the time. Office-based and remote clinicians were in agreement 61% to 64% of the time for all cases. No specific disease category appeared to be more or less amenable to diagnosis based on still digital imagery. The diagnostic certainty of the office-based clinician (reported from 0-10) had the most impact on agreement. When cases with office-based clinician certainty of no more than 7 were compared with cases with certainty of at least 9, agreement increased 54% for remote clinician 1 and 111% for remote clinician 2. As an isolated variable, photographic quality had a modest impact on agreement. CONCLUSIONS: Still digital images can substitute for the dermatologic physical examination in up to 83% of cases. This study provides validation of the store-and-forward concept of telemedicine as applied to dermatology. These results serve as the foundation for field testing of the concept in primary care settings.

Treatment of vasospasm with a 480-nm pulsed-dye laser.

Laser energy at a wavelength of 480 nm was applied in 1-microseconds pulses of 3 to 10 mJ to two models of vasospasm. Rabbit common carotid arteries (CCA's) were constricted chronically by the application of human blood within a silicone sheath. Peak vasospasm developed 24 to 48 hours later, and persisted for up to 6 days. Endovascular laser treatment was delivered to 40 CCA's via a 200-microns diameter silica quartz fiber introduced through the femoral artery. The CCA caliber increased from 60% of the pre-vasospasm control diameter to a minimum post-laser diameter of 83% of control. No instances of laser-induced perforation or of arterial thrombosis were observed for up to 60 days after treatment. Prophylactic laser application to nine normal vessels was able to attenuate the development of vasospasm if blood was applied immediately thereafter (88% vs. 59% of control diameter, p less than 0.02), but not if blood was applied 7 days later. Studies in 16 normal CCA's established that there was a considerable margin between the laser energy required to induce dilatation and that which caused perforation, providing that the fiber remained relatively central within the artery. Morphological examination demonstrated focal loss of endothelial cells immediately after laser application, followed approximately 7 days later by the development of areas of intimal hyperplasia. Only minimal changes were observed in the medial or adventitial layers. In a second study, the basilar artery of seven dogs was constricted chronically by two intracisternal injections of autologous blood 3 days apart. Five dogs received endovascular laser treatment 7 or 10 days after the first injection, when basilar artery diameter was reduced to a mean of 61% and 77% of control, respectively. Immediately following treatment, basilar artery diameter increased to 104% and 102% of resting diameter, respectively. Both untreated and laser-treated arteries were smaller than the control diameter at 30 days (80% and 82%, respectively), but in each group the vasodilatory response to hypercapnia was preserved. These findings indicate that 1-microsecond laser pulses are well tolerated by systemic and cerebral arteries in two different animal models, and suggest that the 480-nm pulsed-dye laser may have an application for the treatment or prophylaxis of cerebral vasospasm.

Application of the 1-microsecond pulsed-dye laser to the treatment of experimental cerebral vasospasm.

Laser energy of 480 nm was applied in 1-microsecond pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-microns fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood. 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-microsecond pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

Current and future trends in laser medicine.

In this overview, a number of the major current, and possible future developments in laser medicine are explored. In therapeutic applications, particular emphasis is given to obtaining selectivity in tissue targets and interaction mechanisms in order to achieve specific biological effects. This includes spatial confinement of thermal damage by pulsed laser irradiation and targetting by exogenous photothermal or photochemical chromophores. The potential for diagnostic applications of lasers in medicine is illustrated primarily by various in vivo spectroscopic techniques. Both therapeutic and diagnostic applications will rely increasingly on the development of total systems in which lasers will form only one, albeit an essential, part. Numerous scientific and technical problems need to be solved in order to realize the full clinical potential of the many new concepts in laser medicine. The impetus for such progress will come from integrated, multidisciplinary collaborations between medical, scientific and industrial groups.

Dohi memorial lecture. Laser medicine and laser dermatology.

As laser devices become smaller, more reliable, and less expensive, dermatology will benefit from new laser-based therapeutic and diagnostic methods. Already there are simple, non-scarring, and relatively painless techniques for removal of pigmented lesions, tattoos, and vascular lesions. Because much of the basic and applied research in photobiology is grounded in dermatology research, dermatology will continue to be a major contributor to advances in laser medicine and photomedicine. An increase in understanding and ability to manipulate laser-tissue interactions will add greatly to the future of medicine and surgery, especially in applications utilizing pulsed lasers. We are learning how to: 1) vary wavelength, pulse duration, and energy to influence the nature of microscopic injury and host response in order to achieve a net therapeutic benefit; 2) utilize exogenous chromophores to increase the selection of targets for laser radiation; and 3) capture optical technology developed for industrial and military use, in order to benefit mankind with new medical and surgical techniques.

Longwave ultraviolet radiation (UVA, 320-400 nm)-induced tan protects human skin against further UVA injury.

The protective effect of a UVA (320-400 nm) induced tan against cutaneous injury by further UVA-irradiation was studied by evaluating the histopathologic changes in tanned and untanned normal human buttock skin 24 h after exposure to 2 and 4 minimal erythema doses of UVA. In each subject there were fewer polymorphonuclear leukocytes and less endothelial cell prominence and vessel wall necrosis in the UVA tanned skin than in the untanned UVA-irradiated skin. In the tanned control and tanned UVA-irradiated skin there was a prominent mononuclear cell inflammatory infiltrate that was much greater than in untanned skin. In immunoperoxidase stained tissue sections, the mononuclear cells were predominantly T cells, and in all of the specimens the number of phenotypic helper/inducer cells exceeded the phenotypic cytotoxic/suppressor cells. This demonstrates that a UVA tan provides photoprotection against acute UVA exposure. In addition, tanning, with or without further UVA-irradiation, was associated with a mononuclear cell inflammatory infiltrate.

Enhancing the carotenoid content of atherosclerotic plaque: implications for laser therapy.

Selective laser ablation of human atherosclerotic plaque is possible because endogenous carotenoid pigments found in atherosclerotic plaque confer a twofold preferential absorption of laser radiation at 450 to 500 nm. In this study, patients with carotid endarterectomy were pretreated with oral beta carotene to determine if the carotenoid content and therefore laser selectivity of plaque could be increased in vivo. Beta carotene-treated patients had a significant, nearly twofold increase in their plaque carotenoid concentration, which increased from 0.22 to 0.40 microgram beta carotene/mg cholesterol. These results suggest that selective ablation of atherosclerotic plaque may be enhanced by pretreating patients with doses of oral beta carotene for short periods of time.

Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical trial. 1977.

Extensive psoriasis in 1,308 patients has been treated two or three times a week with oral 8-methoxypsoralen followed by high intensity, long-wave ultraviolet light (PUVA). Excluding 169 patients still under early treatment, psoriasis cleared in 88% and failed to clear in 3%. One percent dropped out due to complications of treatment, and 8% for other reasons. The twice-a-week schedule was superior for patients with lighter skin types. Once a remission was induced, there was no difference in its maintenance when patients were treated once a week, once every other week, or once every third week. Each of these schedules was superior to no maintenance treatment. Immediate side effects of the 45,000 treatments administered in the first 18 months of this study were uncommon, temporary, and generally mild. No clinically significant changes in laboratory screening or eye examinations attributable to PUVA have been uncovered.

Visible action spectrum for melanin-specific selective photothermolysis.

The skin of black and albino guinea pigs was irradiated with single, 750 nsec-long laser pulses at 435, 488, 530, and 560 nm in order to determine an action spectrum for the gross threshold response of immediate epidermal whitening. In addition, the immediate and delayed gross and histologic changes induced at, above, and below the threshold radiant exposures at all four wavelengths were studied. The action spectrum in the black guinea pigs was consistent with the reported absorption spectrum of DOPA-melanin. Histologically, there was epidermal damage immediately after radiant exposures at and above threshold at all four wavelengths. In addition, radiant exposures greater than threshold caused an immediate decrease in stainable epidermal pigment that was most marked at 435 and 488 nm. The healing response was also wavelength- and dose-dependent. Seven days after above-threshold exposures, there was little epidermal pigment in the 435 nm specimens. As wavelength increased, there was progressively more pigment, and in the 560 nm specimens, the epidermal pigment was equivalent to that seen in nonirradiated black guinea pig control specimens. Seven days after subthreshold radiant exposures, there was increased epidermal pigmentation and melanocytes at all four wavelengths. This was the most pronounced in the 435 nm specimens. There was no observable epidermal damage in albino guinea pig skin.

Pigmented guinea pig skin irradiated with Q-switched ruby laser pulses. Morphologic and histologic findings.

Q-switched ruby laser pulses cause selective damage to cutaneous pigmented cells. Repair of this selective damage has not been well described. Therefore, using epilated pigmented and albino guinea pig skin, we studied the acute injury and tissue repair caused by 40-ns, Q-switched ruby laser pulses. Gross observation and light and electron microscopy were performed. No specific changes were evident in the albino guinea pigs. In pigmented animals, with radiant exposures of 0.4 J/cm2 or greater, white spots confined to the 2.5-mm exposure sites developed immediately and faded over 20 minutes. Delayed depigmentation occurred at seven to ten days, followed by full repigmentation by four to eight weeks. Regrowing hairs in sites irradiated at and above 0.4 J/cm2 remained white for at least four months. Histologically, vacuolation of pigment-laden cells was seen immediately in the epidermis and the follicular epithelium at exposures of 0.3 J/cm2 and greater. Melanosomal disruption was seen immediately by electron microscopy at and above 0.3 J/cm2. Over the next seven days, epidermal necrosis was followed by regeneration of a depigmented epidermis. By four months, melanosomes and melanin pigmentation had returned; however, hair follicles remained depigmented and devoid of melanocytes. This study demonstrates that selective melanosomal disruption caused by Q-switched ruby laser pulses leads to transient cutaneous depigmentation and persistent follicular depigmentation. Potential exists for selective treatment of pigmented epidermal and dermal lesions with this modality.

Pulsed photothermal radiometry in turbid media: internal reflection of backscattered radiation strongly influences optical dosimetry.

The integrated irradiance (energy fluence rate) within tissue can exceed the incident irradiance due to backscattered and multiply reflected light near the sample surface. This was studied quantitatively using pulsed photothermal radiometry, which measures blackbody radiation emitted by a sample during and after absorption of an optical pulse. Aqueous gels containing absorbing dye with or without various scattering materials were studied using a fast sensitive IR detector system and 1-micros tunable pulsed dye laser. For nonscattering samples, the temperature transient (T-jump) due to absorption of a laser pulse was consistent with Beer's law for homogeneous absorbing media. When scattering was present, increases of up to almost an order of magnitude in the T-jump were observed. For a given absorption coefficient, there was a proportional relationship between the increase in the T-jump and the sample's diffuse reflectance. A model describing the reflectance of diffuse radiation at the sample boundary was derived to explain this result. To test the model, the refractive index was varied with air as the external medium and was also matched to that of BaF(2) as the externalmedium. The subsurface fluence is, to areasonable approximation, given by E congruent with E(0)(l + 2bR),where E(0) is the incident fluence of an infinitely wide collimated beam, b is a coefficient strongly dependent on only the refractive index, and R is the measured diffuse reflectance of the sample. This study shows that irradiance within tissues can greatly exceed the irradiance of incident collimated light, an effect that should be accounted for in photomedical dosimetry or research.

Effect of hypoxia on sunburn cell formation and inflammation induced by ultraviolet radiation.

Oxygen intermediates are responsible for a number of ultraviolet (UV) radiation effects. To test the hypothesis that UV-induced formation of sunburn cells and skin edema (ear swelling) result from oxidative damage, we examined the effect of hypoxia tissue responses to UV in the mouse ear. Hypoxia resulting from vascular occlusion by ear clamping, either before or after UVB exposure, decreased formation of sunburn cells. Ear clamping alone caused significant ear swelling, which was enhanced when combined with UVB exposure. Using topical 8-methoxypsoralen + UVA (PUVA), increased sunburn cells were observed when ears were clamped for 10 min prior to UVA exposure, but not following exposure. Ear swelling caused by PUVA was also enhanced when ears were clamped during exposure. These results suggest that induction of sunburn cells by UVB is dependent on oxygen, and that UVB and PUVA induce sunburn cell formation by distinct mechanisms.

Selective vascular coagulation of rabbit colon using a flashlamp-excited dye laser operating at 577 nanometers.

Previous studies have demonstrated that brief pulses of selectively absorbed optical radiation can be used to confine thermal injury to pigmented targets within tissues. We performed studies in rabbits to assess the usefulness of this technique for selectively coagulating the colonic vasculature. By measuring the optical absorbance of rabbit colon with a spectrophotometer, it was determined that hemoglobin exhibits strong absorption relative to the rabbit colon at a wavelength of 577 nm. Because light must be absorbed to affect tissue, it was hypothesized that laser pulses of this wavelength would selectively damage blood vessels. This hypothesis was tested by examining the effect of 300-microseconds-long 577-nm laser pulses on rabbit colon in vivo. For delivered radiant exposures between 4 and 8 J/cm2, selective coagulation of the colonic vasculature could be produced without damage to the surrounding colon. At greater radiant exposures, vessel hemorrhage was occasionally noted but no transmural thermal injury was produced with delivered radiant exposures as high as 22 J/cm2. This technique may form the basis of a safe and simple treatment of vascular lesions of the colon such as angiodysplasia.

Selective laser ablation of venous thrombus: implications for a new approach in the treatment of pulmonary embolus.

Laser radiation was employed to ablate venous thrombus or emboli with parameters that would not injure endovascular tissues. Output from a 482-nm, 1-microsec pulsed dye laser was delivered through a 320-microns-diameter fiber to in vitro samples of fresh thrombus (T), venous or pulmonary emboli (VE), inferior vena cava (IVC), pulmonary artery (PA), pulmonary valve, and endocardium (atrial and ventricular). The mean threshold fluences for ablation of T and VE were 1.1 and 5.1 J/cm2, respectively. In contrast, the mean threshold fluences for IVC and PA were significantly higher (P less than 0.0001), at 120 and 124 J/cm2, respectively. Ablation efficiency of thrombus was in excess of 100 mg/J, under conditions that caused no histologic injury to the pulmonary artery. To correlate ablation studies with optical absorption by the tissues, optical properties of fresh T, VE, IVC, and PA were studied. Hemoglobin species accounted for the more than 10 times higher 482-nm absorption by T and VE compared to IVC and PA. This explains the differences in ablation thresholds and, thus, the selectivity encountered. These observations demonstrate, more than any other study in the vascular system, that with pulsed optical radiation, efficient laser ablation of venous thrombus is feasible with a wide margin of safety, and without damage to the surrounding vascular tissue.

Laser lithotripsy: animal studies of safety and efficacy.

The safety and efficacy of pulsed tunable dye laser fragmentation of common bile duct stones was assessed in pigs. Laser pulses were conducted through a flexible quartz fiber that was in direct contact with stones that had been surgically implanted into the common bile duct. All calculi were rapidly fragmented into small pieces without significant damage to the common bile duct. The immediate and delayed effects of pulsed lasers on the common bile duct were also evaluated. The common bile duct demonstrated a high tolerance to laser-induced damage even when the laser was discharged directly into the bile duct wall. These results suggest that laser lithotripsy can be performed in humans with a high degree of safety and efficacy.