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Objectives Diagnostic programs and second opinion clinics have grown and evolved in the recent years to help patients with rare, puzzling, and complex conditions who often suffer prolonged diagnostic journeys, but there is a paucity of literature on the clinical characteristics of these patients and the efficacy of these diagnostic programs. This study aims to characterize the diagnostic journey, case features, and diagnostic outcomes of patients referred to a team-based second opinion clinic at Stanford. Methods Retrospective chart review was performed for 237 patients evaluated for diagnostic second opinion in the Stanford Consultative Medicine Clinic over a 5 year period. Descriptive case features and diagnostic outcomes were assessed, and correlation between the two was analyzed. Results Sixty-three percent of our patients were women. 49% of patients had a potential precipitating event within about a month prior to the start of their illness, such as medication change, infection, or medical procedure. A single clear diagnosis was determined in 33% of cases, whereas the remaining cases were assessed to have multifactorial contributors/diagnoses (20%) or remained unclear despite extensive evaluation (47%). Shorter duration of illness, fewer prior specialties seen, and single chief symptom were associated with higher likelihood of achieving a single clear diagnosis. Conclusions A single-site academic consultative service can offer additional diagnostic insights for about half of all patients evaluated for puzzling conditions. Better understanding of the clinical patterns and patient experiences gained from this study helps inform strategies to shorten their diagnostic odysseys.

NIH Public Access Author Manuscript J Invest Dermatol. Author manuscript; available in PMC 2012 November 09. Published in final edited form as: J Invest Dermatol. 2008 February ; 128(2): 485–488. doi:10.1038/sj.jid.5700991. The Importance of Long-Term Monitoring to Evaluate the Microvascular Response to Light-Based Therapies $watermark-text Bernard Choi 1,2 , Wangcun Jia 1 , Jennifer Channual 1 , Kristen M. Kelly 1,3 , and Justin Lotfi 1 Bernard Choi: choib@uci.edu 1 Beckman Laser Institute and Medical Clinic, University of California, Irvine, California, USA 2 Department of Biomedical Engineering, University of California, Irvine, California, USA 3 Department of Dermatology, University of California, Irvine, California, USA TO THE EDITOR $watermark-text Optimization of laser therapy for disfiguring vascular birthmarks is one specific clinical application (Kelly et al ., 2005). Current treatment protocols involve the use of high-power pulsed laser irradiation with parameters chosen to induce selective photocoagulation of the targeted blood vessels, a method known as selective photothermolysis (Anderson and Parrish, 1983). Protocol design is based largely on results from numerical modeling studies (van Gemert et al ., 1997), which are designed to predict the laser light distribution within the skin and subsequent photothermal response leading toward selective photocoagulation. However, current modeling methods do not incorporate adequately the complex dynamics associated with changes in light absorption due to conversion of hemoglobin to methemoglobin (Barton et al ., 2001; Kimel et al ., 2005) and convective mixing of blood during pulsed laser irradiation (Kimel et al ., 2003), limiting their overall predictive capability. Furthermore, these models do not consider the chronic, biological response of the microvasculature to therapeutic laser intervention, which remains a poorly researched field. Knowledge of the biological response is critical to understand the repair processes initiated with photothermal injury and to assess the ultimate efficacy of the treatment. $watermark-text Animal models used as a platform to study light-based, microvascular-targeted therapies include the chick chorioallantoic membrane (Kimel et al ., 1994, 2003), hamster cheek pouch (Suthamjariya et al ., 2004), and rodent dorsal window chamber (Barton et al ., 1998, 1999, 2001; Choi et al ., 2004; Babilas et al ., 2005; Smith et al ., 2006). Optical imaging modalities used to evaluate noninvasively therapeutic outcome include video imaging, fluorescence microscopy, Doppler optical coherence tomography, and laser speckle imaging. Typically, short-term ( 24 hour after intervention) monitoring periods usually are not performed with nontumor-bearing window chambers, presumably due to the reduced clarity of the chamber imposed by poor maintenance of window integrity secondary to infection. However, we hypothesized that the short-term response of the microvasculature is a poor predictor of the long-term response. With emphasis on aseptic methods, we have been able to maintain clear window chamber preparations for as long as 45 days after intervention. CONFLICT OF INTEREST The authors state no conflict of interest.

The rodent dorsal window chamber is a widely used in vivo model of the microvasculature. The model consists of a 1cm region of exposed microvasculature in the rodent dorsal skin that is immobilized by surgically implanted titanium frames, allowing the skin microvasculature to be visualized. We describe a detailed protocol for surgical implantation of the dorsal window chamber which enables researchers to perform the window chamber implantation surgery. We further describe subsequent wide-field functional imaging of the chamber to obtain hemodynamic information in the form of blood oxygenation and blood flow on a cm size region of interest. Optical imaging techniques, such as intravital microscopy, have been applied extensively to the dorsal window chamber to study microvascular-related disease and conditions. Due to the limited field of view of intravital microscopy, detailed hemodynamic information typically is acquired from small regions of interest, typically on the order of hundreds of μm. The wide-field imaging techniques described herein complement intravital microscopy, allowing researchers to obtain hemodynamic information at both microscopic and macroscopic spatial scales. Compared with intravital microscopy, wide-field functional imaging requires simple instrumentation, is inexpensive, and can give detailed metabolic information over a wide field of view.

Background and Objective: Pulsed dye laser (PDL) treatment of cutaneous vascular lesions is associated with variable and unpredictable efficacy. Thus, alternative treatment modalities are needed. Previous in vitro and in vivo studies have demonstrated enhanced selective vascular destruction with benzoporphyrin derivative (BPD) monoacid ring A photodynamic therapy (PDT) followed immediately by PDL irradiation (PDT+PDL). Here, we evaluate PDT alone, PDL alone, and PDT+PDL protocols using an optimized in vivo rodent dorsal window chamber model. Study Design/Materials and Methods: A dorsal window chamber was surgically installed on male Golden Syrian hamsters. BPD solution was administered intravenously via a jugular venous catheter. Evaluated interventions included: (1) Control (no BPD, no light); (2) Control (BPD, no light); (3) PDT alone (λ = 576 nm; 25, 50, 75, or 96 J/cm2radiant exposure; 15 minutes post-BPD injection); (4) PDL alone at 7 J/cm2(585 nm, 1.5 milliseconds pulse duration, 7 mm spot); and (5) PDT (25 or 75 J/cm2)+PDL (7 J/cm2). Laser speckle imaging was used to monitor blood flow dynamics before, immediately after, and 1, 3, and 5 days post-intervention. Results: Perfusion reduction on day 1 post-intervention was achieved with PDT>50 J/cm2, PDL alone, and PDT+PDL. However, by day 5 post-intervention, recovery of flow was observed with PDT alone at 50 J/cm2(-15.1%) and PDL alone (+215%). PDT (75 J/cm2)+PDL resulted in the greatest prolonged reduction in vascular perfusion (-99.8%). Conclusions: Our in vivo data suggest that the PDT+PDL therapeutic protocol can result in enhanced and persistent vascular shutdown compared to PDT or PDL alone. The PDT+PDL approach has potential for considerable superficial vascular destruction and should be considered as a treatment modality for cutaneous vascular lesions. Monitoring of blood flow changes for as long as possible is crucial for accurate assessment of light-based vascular interventions. © 2008 Wiley-Liss, Inc.

Background and Objectives: Presently, cutaneous vascular lesions are treated using a single cryogen spurt and single laser pulse (SCS-SLP), which do not necessarily produce complete lesion removal in the majority of patients. In this study, the feasibility of applying multiple cryogen spurts intermittently with multiple two-wavelength laser pulses (MCS-MTWLP) was studied using numerical and animal models. Study Design/Materials and Methods: Two treatment procedures were simulated: (1) SCSþ532 nm SLP; and (2) MCSþ532/1064 nm MTWLP. Light transport and heat diffusion in human skin were simulated with the Monte Carlo method and finite element model, respectively. Possible epidermal damage and blood vessel photocoagulation were evaluated with an Arrhenius-type kinetic model. Blood vessels in the rodent window chamber model (RWCM) were irradiated with either SLP or MTWLP. Laser-induced structural and functional changes in the vessels were documented by digital photography and laser speckle imaging (LSI). Results: The numerical results show that the MCSMTWLP approach can provide sufficient epidermal protection while simultaneously achieving photocoagulation of larger blood vessels as compared to SCS-SLP. Animal studies show that MTWLP has significant advantages over SLP by inducing irreversible damage to larger blood vessels without adverse effects. Conclusions: MCS-MTWLP may be a promising approach to improve therapeutic outcome for patients with cutaneous vascular lesions featuring large blood vessels. Lasers Surg. Med. 39:494–503, 2007. 2007 Wiley-Liss, Inc.

We employ speckle imaging and window chamber models to study vascular remodeling processes after light-based therapies. Our data demonstrate that the response involves substantial remodeling over a monitoring period of up to 30 days post-intervention.

Noninvasive blood flow characterization is essential to assess the health status of biological tissue and to evaluate the efficacy of therapies which target the microvasculature. Optimization of laser therapy for disfiguring vascular birthmarks is one specific clinical application. Current treatment protocols involve the use of high-power pulsed laser irradiation with parameters selected to induce selective photocoagulation of the targeted blood vessels. Protocol design is based largely on results from numerical modeling studies, which have predictive capability of the laser light distribution within the skin and subsequent photothermal response leading towards selective photocoagulation. However, the biological response of the microvasculature to therapeutic laser intervention remains a poorly-researched field. We hypothesize that the acute photothermal response of the microvasculature is a poor predictor of the chronic response, due to vascular remodeling processes which are not included in current modeling studies. To test this hypothesis, we employ an optical imaging method to assess blood flow dynamics in response to therapeutic intervention.

Background and Objectives: Hypervascular skin lesions (HVSL) are treated with medical lasers characterized by a variety of parameters such as wavelengthl, pulse duration tp, and radiant exposure E that can be adjusted for different pathology and blood vessel size. Treatment parameters have been optimized assuming constant optical properties of blood during laser photocoagulation. However, recent studies suggest that this assumption may not always be true. Our objective was to quantify thermally induced changes in blood that occur during irradiation using standard laser parameters. Study Design/Materials and Methods: Glass capillary tubes (diameter D ¼ 100, 200, and 337 mm) filled with fresh or hemolyzed rabbit blood were irradiated once at l ¼ 585, 595, or 600 nm, tp ¼ 1.5 milliseconds; and also atl ¼ 585 nm, tp ¼ 0.45 milliseconds. E was increased until blood ablation caused formation of permanent gas bubbles. In a corroborative study, human blood was heated at 508C and absorbance spectra were measured as a function of time. Results: Threshold radiant exposure, Ethresh, for gas bubble formation was found not to depend on l, which might be surprising in view of the 10-fold lower absorption coefficient at 600 nm as compared to 585 nm. The spectroscopic study revealed heat-induced changes in blood constituent composition of hemoglobins (Hb) from initially 100% oxyhemoglobin (HbO2) to deoxyhemoglobin (HHb) and, ultimately, methemoglobin (metHb) as the major constituent. Model calculations of Ethresh(l,D) based on changing constituent blood composition during heating with milliseconds lasers were found to correlate with experimental results. Conclusions: For laser treatment of HVSL it appears thatl is of secondary importance and that the choice of tp is a more important factor. Lasers Surg. Med. 36:281–288, 2005. 2005 Wiley-Liss, Inc.

Noninvasive blood flow imaging can provide critical information on the state of biological tissue and the efficacy of approaches to treat disease. With laser speckle imaging (LSI), relative changes in blood flow are typically reported, with the assumption that the measured values are on a linear scale. A linear relationship between the measured and actual flow rate values has been suggested. The actual flow rate range, over which this linear relationship is valid, is unknown. Herein we report the linear response range and velocity dynamic range (VDR) of our LSI instrument at two relevant camera integration times. For integration times of 1 and 10 ms, the best case VDR was 80 and 60 dB, respectively, and the worst case VDR was 20 and 50 dB. The best case VDR values were similar to those reported in the literature for optical Doppler tomography. We also demonstrate the potential of LSI for monitoring blood flow dynamics in the rodent dorsal skinfold chamber model. These findings imply that LSI can provide accurate wide-field maps of microvascular blood flow rate dynamics and highlight heterogeneities in flow response to the application of exogenous agents. © 2006 Society of Photo-Optical Instrumentation Engineers.