Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Mononeuritis multiplex following immune checkpoint inhibitors in malignant pleural mesothelioma.

Introduction: Mononeuritis multiplex is frequently related to vasculitic neuropathy and has been reported only sporadically as an adverse event of immune checkpoint inhibitors. Methods: Case series of three patients with mononeuritis multiplex-all with mesothelioma-identified in the databases of two French clinical networks (French Reference Center for Paraneoplastic Neurological Syndromes, Lyon; OncoNeuroTox, Paris; January 2015-October 2022) set up to collect and investigate n-irAEs on a nationwide level. Results: Three patients (male; median age 86 years; range 72-88 years) had pleural mesothelioma and received 10, 4, and 6 cycles, respectively, of first-line nivolumab plus ipilimumab combined therapy. In patient 1, the neurological symptoms involved the median nerves, and in the other two patients, there was a more diffuse distribution; the symptoms were severe (common terminology criteria for adverse events, CTCAE grade 3) in all patients. Nerve conduction studies indicated mononeuritis multiplex in all patients. Peripheral nerve biopsy demonstrated necrotizing vasculitis in patients 1 and 3 and marked IgA deposition without inflammatory lesions in patient 2. Immune checkpoint inhibitors were permanently withdrawn, and corticosteroids were administered to all patients, leading to complete symptom regression (CTCAE grade 0, patient 2) or partial improvement (CTCAE grade 2, patients 1 and 3). During steroid tapering, patient 1 experienced symptom recurrence and spreading to other nerve territories (CTCAE grade 3); he improved 3 months after rituximab and cyclophosphamide administration. Discussion: We report the occurrence of mononeuritis multiplex, a very rare adverse event of immune checkpoint inhibitors, in the three patients with mesothelioma. Clinicians must be aware of this severe, yet treatable adverse event.

Anti-Hu Antibodies in Patients With Neurologic Side Effects of Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: To clinically characterize post-immune checkpoint inhibitor (ICI) Hu antibody (Ab) neurologic disorders, we analyzed Hu-Ab-positive patients with neurologic immune-related adverse events (n-irAEs) and compared them with patients with other n-irAEs, ICI-naive patients with Hu-Ab paraneoplastic neurologic syndromes (PNSs) identified in the same study center, and those with Hu-Ab n-irAEs reported elsewhere. METHODS: Patients whose samples were sent to the French reference center for a suspicion of n-irAE (2015-2021) were identified; those with a final diagnosis of n-irAE and Hu-Ab were included. Control groups included patients with a final diagnosis of n-irAE occurring during the same period as the patients included (2018-2021) but without Hu-Ab, and ICI-naive patients with Hu-Ab PNS diagnosed during the same period; a systematic review was performed to identify previous reports. RESULTS: Eleven patients with Hu-Ab and n-irAEs were included (median age, 66 years, range 44-76 years; 73% men). Ten patients had small cell lung cancer, and 1 had lung adenocarcinoma. The median follow-up from onset was 3 months (range 0.5-18 months). Compared with those with other n-irAEs (n = 63), Hu-Ab-positive patients had more frequently co-occurring involvement of both central and peripheral nervous systems (36% vs 8%, p = 0.02) and limbic (54% vs 14%, p < 0.01), brainstem (27% vs 5%, p = 0.02), and dorsal root ganglia (45% vs 5%, p < 0.01) involvement. The proportion of patients with severe disability (modified Rankin Scale score >3) at diagnosis was higher among Hu-Ab n-irAEs (91% vs 52%, p = 0.02). Patients with Hu-Ab had also poorer outcome (100% vs 28%, p < 0.01) and higher mortality (91% vs 46%, p < 0.01). There was no significant difference in terms of clinical features between Hu-Ab n-irAEs and ICI-naive Hu-Ab PNS (n = 92), but there was a poorer outcome (56/78, 71%, p < 0.01) and higher mortality (26%, p < 0.01) among the former. No significant difference was found between the patients reported herein and those in the literature. DISCUSSION: The presence of Hu-Ab identifies a subgroup of n-irAEs that consistently reproduce the phenotypes of Hu-Ab-related PNS, supporting the hypothesis of ICI triggering or unmasking PNS. As these patients show high disability and mortality, further studies are required to investigate the underlying immunopathogenic mechanisms and to improve the outcome of Hu-Ab n-irAEs.

Mechanical Thrombectomy in Distal Residual Occlusions of the Middle Cerebral Artery after Large Vessel Recanalization in Acute Stroke: 2b or not 2b? A Pragmatic Approach in Real-Life Scenarios.

BACKGROUND /OBJECTIVE: Recent studies have suggested that a recanalization grade of modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2c is strongly related with good clinical outcome rather than the current therapeutic angiography target ≥2b. To achieve better recanalization, additional further maneuvers on distal residual vessel occlusion (RVO) may be required. The aim of this study was to evaluate the safety and efficacy of rescue treatment in RVOs after recanalization of large vessel occlusions in the anterior circulation. METHODS: A single-center retrospective review of a prospectively maintained stroke databank was performed. Patients presenting with RVOs after mechanical thrombectomy on the M1/internal carotid artery terminus were included and further divided into treated and untreated groups: the former underwent additional maneuvers on RVOs, whereas the latter did not. Baseline and posttreatment clinical, radiologic, and angiographic data were compared between the 2 groups. End points included good functional outcome (modified Rankin Scale [mRS] score ≤2) rates of hemorrhagic transformations, neurologic deterioration and mortality. RESULTS: RVOs were observed in 183/488 patients (37.5%). 74/183 (40.4%) underwent rescue treatment, showing a better outcome in terms of median 24 hours National Institutes of Health Stroke Scale score (13 vs. 18; P < 0001), 24 hours Alberta Stroke Programme Early CT Score (6 vs. 5; P < 0.001) and 3 months mRS score 0-2 (47.3% vs. 33.1%; P = 0.06). Recanalization of the superior (frontal) branch of the middle cerebral artery was particularly critical in terms of outcome. Hemorrhagic transformation was higher in the untreated group (53.6% vs. 66.6%; P = 0.1) as well as symptomatic intracranial hemorrhage (13.1% vs. 29.4%; P = 0.01). Neurologic deterioration occurred more often among untreated patients (16.2% vs. 25.7%; P = 0.1). Three complications (1.3%) occurred during rescue treatment. CONCLUSIONS: When feasible, improving mTICI score 2a-2b recanalization to mTICI 2c/3 is safe and associated with a better clinical outcome, particularly for residual occlusions involving the superior branch of bifurcation.

Neurologic manifestations associated with COVID-19: a multicentre registry.

OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Antibodies against the node of Ranvier: a real-life evaluation of incidence, clinical features and response to treatment based on a prospective analysis of 1500 sera.

INTRODUCTION: IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP. METHODS: 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department. RESULTS: IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies). CONCLUSIONS: Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.

Posterior reversible encephalopathy syndrome associated with reversible cerebral vasoconstriction syndrome in a patient presenting with postpartum eclampsia: A case report.

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction (RCVS) are rare neurological disorders with complex physiopathology which is not yet fully understood. We present here the case of a 31-year-old woman with a bi-amniotic bi-chorial pregnancy who developed immediate postpartum eclampsia after vaginal delivery, associated with RCVS and PRES. Although post-partum is a well-known precipitating factors for these diseases, to our knowledge, there are only few similar cases reported with the association of these syndromes. Repeated MRI scans were instrumental in the final diagnosis of RCVS associated with PRES, allowing us to give the patient the appropriate treatment. These two syndromes have similar symptoms but may have different treatments, thus highlighting the importance of a correct diagnosis.

Thrombectomy by Direct Cervical Access in Case of Common Carotid Occlusion with Collateral Supply to Internal Carotid Artery: Uncommon Anatomic Variant.

BACKGROUND: Mechanical thrombectomy for acute ischemic stroke recently proved its superiority to standard medical management alone. With the increasing number of procedures, practitioners are exposed to unexpected situations that may lead to failure of access and significantly worse clinical outcome. Being able to plan the procedure and use alternative techniques may be useful in case of peculiar anatomy. CASE DESCRIPTION: We report here the case of a 60-year-old man referred to our institution for an acute ischemic stroke. The patient had an initial National Institutes of Health Stroke Scale score of 19. The patient's medical history revealed an unspecified cervical treatment at the level of C5-C6 20 years previously. Magnetic resonance imaging showed a left M1 occlusion and the absence of ipsilateral common carotid. The digital subtraction angiography revealed an anastomosis through the left inferior and superior thyroid artery. Mechanical thrombectomy was performed through direct cervical access with a TICI 3 recanalization score. CONCLUSIONS: Absence of viable access to perform mechanical thrombectomy during acute ischemic stroke is a rare but pejorative event. Direct common carotid puncture, even in its distal segment, when necessary is a feasible technique to perform internal carotid catheterization.

DWI-ASPECTS (Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Scores) and DWI-FLAIR (Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery) Mismatch in Thrombectomy Candidates: An Intrarater and Interrater Agreement Study.

BACKGROUND AND PURPOSE: We aimed to study the intrarater and interrater agreement of clinicians attributing DWI-ASPECTS (Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Scores) and DWI-FLAIR (Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery) mismatch in patients with acute ischemic stroke referred for mechanical thrombectomy. METHODS: Eighteen raters independently scored anonymized magnetic resonance imaging scans of 30 participants from a multicentre thrombectomy trial, in 2 different reading sessions. Agreement was measured using Fleiss κ and Cohen κ statistics. RESULTS: Interrater agreement for DWI-ASPECTS was slight (κ=0.17 [0.14-0.21]). Four raters (22.2%) had a substantial (or higher) intrarater agreement. Dichotomization of the DWI-ASPECTS (0-5 versus 6-10 or 0-6 versus 7-10) increased the interrater agreement to a substantial level (κ=0.62 [0.48-0.75] and 0.68 [0.55-0.79], respectively) and more raters reached a substantial (or higher) intrarater agreement (17/18 raters [94.4%]). Interrater agreement for DWI-FLAIR mismatch was moderate (κ=0.43 [0.33-0.57]); 11 raters (61.1%) reached a substantial (or higher) intrarater agreement. CONCLUSIONS: Agreement between clinicians assessing DWI-ASPECTS and DWI-FLAIR mismatch may not be sufficient to make repeatable clinical decisions in mechanical thrombectomy. The dichotomization of the DWI-ASPECTS (0-5 versus 0-6 or 0-6 versus 7-10) improved interrater and intrarater agreement, however, its relevance for patients selection for mechanical thrombectomy needs to be validated in a randomized trial.

IRMA study: Prevalence of subdiaphragmatic visceral infarction in ischemic stroke and atrial fibrillation.

Background Occult atrial fibrillation (AF) may, in part, explain cryptogenic stroke. A 22% prevalence of subdiaphragmatic visceral infarction (SDVI) among patients with ischemic stroke (IS) due to AF has been reported, using abdominal MRI. We sought to assess the reproducibility of this method and to confirm that SDVI is more prevalent in cases of AF-caused IS than in IS of other etiologies. Methods In consecutive patients admitted to our hospital, we compared SDVI prevalence in three groups: patients with IS due to AF (IS+/AF+ group), patients with stroke of another determined cause (IS+/AF- group) and patients with AF without stroke (IS-/AF+ group). Results A total of 111 patients were included. The median time between inclusion and abdominal MRI was six days. SDVI was more frequent in the IS+/AF+ group ( n = 10; 21.3%), than in IS+/AF- ( n = 1; 3.3%) and IS-/AF+ ( n = 0) groups, p = 0.002. The most frequent localization was the kidney. Conclusions The prevalence of SDVI was higher among patients with AF-caused IS. In cases of cryptogenic stroke, a positive abdominal MRI may suggest occult AF as the cause and identify a high risk of AF in this subgroup of patients.

Diagnostic Yield of Venous Thrombosis and Pulmonary Embolism by Combined CT Venography and Pulmonary Angiography in Patients with Cryptogenic Stroke and Patent Foramen Ovale.

BACKGROUND: Paradoxical embolism via a patent foramen ovale (PFO) has been suggested as a potential stroke mechanism. Combined CT venography and pulmonary angiography (CVPA) is a simple, validated and accurate technique to diagnose deep venous thrombosis (DVT) or pulmonary embolism (PE). We sought to assess the prevalence of DVT or PE among patients with PFO and cryptogenic stroke (CS) by CVPA. METHODS: Patients were identified retrospectively from a clinical registry of consecutive patients with stroke admitted to our Stroke Unit. The following criteria were required for inclusion in this study: CS, PFO identified by transthoracic echography using contrast medium and CVPA performed during the hospitalization following stroke. RESULTS: A total of 114 patients with PFO underwent a CVPA within 7 days (interquartile range 4-9) from stroke symptom onset. On cerebral imaging, 11% had multiple infarcts. CVPA documented deep vein thrombosis (DVT) in 10 patients (8.8%) and PE in 5 patients (4.4%), that is, a total of 12 patients with prevalence of 10.5% (95% CI 5.5-17.7). Patients with PE-DVT had higher D-dimers and C reactive protein level than patients without PE-DVT (p < 0.05). CONCLUSION: CVPA may be used by the stroke team in the work-up of suspected paradoxical embolism among cryptogenic ischemic stroke patients with PFO.

Prior IV Thrombolysis Facilitates Mechanical Thrombectomy in Acute Ischemic Stroke.

BACKGROUND: In acute ischemic stroke (AIS), bridging therapy, including intravenous thrombolysis (IVT) and mechanical thrombectomy (MET), appears to be very promising. However, data on the impact of IVT before the endovascular procedure are limited. METHODS: To examine the impact of IVT on the MET procedure, we compared the duration of this procedure, number of passes, recanalization rate, safety issues, and outcome in consecutively recruited patients either eligible for MET alone (intravenous fibrinolysis contraindication) or receiving MET preceded by IVT for proximal middle cerebral artery (MCA) occlusion within 6 hours of stroke onset. RESULTS: From January 2011 to June 2013, 68 cases with proximal MCA occlusion were available for analysis (MET alone, 40; IVT + MET, 28). The 2 groups did not differ significantly in baseline characteristics. The median National Institutes of Health Stroke Scale score at admission was 15 (10-20) for MET and 18 (13-19) for IVT + MET groups, respectively (P = .39). The median duration of the endovascular procedure (from groin puncture to recanalization) was significantly shorter in the IVT + MET group compared with that in MET alone (35 minutes [21-60] versus 60 minutes [25-91]; P = .043). The number of passes of the thrombectomy device per patient tended to be lower in the IVT + MET group than those in the MET group (P = .080). The IVT + MET group also had a higher rate of complete recanalization and a better outcome at 3 months. CONCLUSIONS: Prior IVT may facilitate the MET procedure. Further studies on MET in AIS should assess the direct impact of IVT on the endovascular procedure.

FXTAS: new insights and the need for revised diagnostic criteria.

OBJECTIVE: Fragile X-associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS. METHODS: Clinical, morphologic (brain MRI, (123)I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women. RESULTS: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal (123)I-ioflupane SPECT. Unified Parkinson's Disease Rating Scale motor score was correlated to abnormal (123)I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04). CONCLUSIONS: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.

Partially thrombosed intracranial aneurysms: symptoms, evolution, and therapeutic management.

BACKGROUND: Partially thrombosed intracranial aneurysms (PTIAs) are different from saccular or nonthrombosed giant or large aneurysms, as they are characterized by multiple intramural thrombotic phenomena related to recurrent vessel wall dissections. METHODS: We retrospectively reviewed clinical and radiological files of 23 consecutive patients with PTIAs (mean age 49.3 years). Twenty-two lesions were studied by magnetic resonance imaging (MRI). Patients were managed by endovascular treatments, medically with steroids, or conservatively. RESULTS: Thirteen patients presented with progressive neurological symptoms. Subarachnoid hemorrhage was suspected but not proven in three. At MRI, 90.9% of PTIAs caused mass effect; perilesional T2 hypersignal compatible with edema was evident in 13.6%. Aneurysmal wall enhancement was detectable in 63.2% of the PTIAs and considered a marker of inflammatory processes. Parent artery occlusion was performed in seven patients with clinical improvement in six. Selective coiling was proposed in three patients (one improved, one remained stable, and one experienced symptoms progression). Three patients were treated with steroids and improved. Ten patients were managed conservatively: eight because spontaneous thrombosis of the lesion had been diagnosed and two because of clinical and radiological stability. CONCLUSIONS: The natural history of PTIAs is different from other aneurysms. They most commonly present with progressive neurological symptoms due to mass effect. MRI properly diagnoses PTIAs and allows precise follow-up, more accurately than angiography because it detects prominent "abluminal" features indicating inflammation and neovascularization. Spontaneous thrombosis is part of the natural history of PTIAs and it should be taken in consideration when discussing the therapeutic management.

Real-time monitoring and scale-up synthesis of concentrated gold nanorods.

The control and monitoring of gold nanorod growth are critical for maintaining the quality of gold nanorods. Through in situ spectroscopic determination of gold nanorod growth in cuvettes, we found that this growth correlates with the evolution of extinction spectra and solution colors. This spectroscopy provides a universal method for in situ observation of the chemical evolution of nano-materials using cuvettes as small reactors at ambient temperature. Synthesis of gold nanorods with high concentrations and high yields is scaled up by simply increasing the solute concentration of the growth solution. Under optimal synthetic conditions, a yield of up to 0.1 g of gold nanorods is obtained, and spectrum monitoring indicates the formation of few spherical gold nanoparticles.

Experimental evaluation of angularly variable fiber geometry for targeting depth-resolved reflectance from layered epithelial tissue phantoms.

The present study focuses on enhancing the sensitivity and specificity of spectral diagnosis in a stratified architecture that models human cervical epithelia by experimentally demonstrating the efficacy of using angularly variable fiber geometry to achieve the desired layer selection and probing depths. The morphological and biochemical features of epithelial tissue vary in accordance with tissue depths; consequently, the accuracy of spectroscopic diagnosis of epithelial dysplasia may be enhanced by probing the optical properties of this tissue. In the case of cellular dysplasia, layer-specific changes in tissue optical properties may be optimally determined by reflectance spectroscopy when specifically coupled with angularly variable fiber geometry. This study addresses the utility of using such angularly variable fiber geometry for resolving spatially specific spectra of a two-layer epithelial tissue phantom. Spectral sensitivity to the scattering particles embedded in the epithelial phantom layer is shown to significantly improve as the obliquity of the collection fibers increases from 0 to 40 deg. Conversely, the orthogonal fibers are found to be more sensitive to changes in the stromal phantom layer.

Targeting spectral signatures of progressively dysplastic stratified epithelia using angularly variable fiber geometry in reflectance Monte Carlo simulations.

A key component of accurate spectroscopic-based cancer diagnostics is the ability to differentiate spectral variations resulting from epithelial tissue dysplasia. Such measurement may be enhanced by discretely probing the optical properties of the epithelial tissue where the morphological and biochemical features vary according to tissue depths. More precisely, layer-specific changes in tissue optical properties correlated to cellular dysplasia can be determined by conventional reflectance spectroscopy when it is coupled with angularly variable fiber geometry. Thus, this study addresses how angularly variable fiber geometry can resolve spatially specific spectral signatures of tissue pathology by interpreting and analyzing the reflectance spectra of increasingly dysplastic epithelial tissue in reflectance-mode Monte Carlo simulation. Specifically, by increasing the obliquity of the collection fibers from 0 to 40 deg in the direction facing toward the illumination fiber, the spectral sensitivity to tissue abnormalities in the epithelial layer is thereby improved, whereas orthogonal fibers are more sensitive to the changes in the stromal layer.

Influence of fiber optic probe geometry on the applicability of inverse models of tissue reflectance spectroscopy: computational models and experimental measurements.

Accurate recovery of tissue optical properties from in vivo spectral measurements is crucial for improving the clinical utility of optical spectroscopic techniques. The performance of inversion algorithms can be optimized for the specific fiber optic probe illumination-collection geometry. A diffusion-theory-based inversion method has been developed for the extraction of tissue optical properties from the shape of normalized tissue diffusion reflectance spectra, specifically tuned for a fiber probe that comprises seven hexagonally close-packed fibers. The central fiber of the probe goes to the spectrometer as the detecting fiber, and the surrounding six outer fibers are connected to the white-light source as illumination fibers. The accuracy of the diffusion-based inversion algorithm has been systematically assessed against Monte Carlo (MC) simulation as a function of probe geometry and tissue optical property combinations. By use of this algorithm, the spectral absorption and scattering coefficients of normal and cancerous tissue are efficiently retrieved. Although there are significant differences between the diffusion approximation and the MC simulation at short source-detector (SD) separations, we show that with our algorithm the tissue optical properties are well retrieved within the SD separation of 0.5-3 mm that is compatible with endoscopic specifications. The presented inversion method is computationally efficient for eventual real-time in vivo tissue diagnostics application.

Depth-sensitive reflectance measurements using obliquely oriented fiber probes.

Computer simulation is used to facilitate the design of fiber-probe geometries that enable enhanced detection of optical signals arising from specific tissue depths. Obtaining understanding of the relationship between fiber-probe design and tissue interrogation is critical when developing strategies for optical detection of epithelial precancers that originate at known depths from the tissue surface. The accuracy of spectroscopic diagnostics may be enhanced by discretely probing the optical properties of epithelium and underlying stroma, within which the morphological and biochemical features vary as a function of depth. While previous studies have investigated controlling tissue-probing depth for fluorescence-based modalities, in this study we focus on the detection of reflected light scattered by tissue. We investigate how the depth of optical interrogation may be controlled through combinations of collection angles, source-detector separations, and numerical apertures. We find that increasing the obliquity of collection fibers at a given source-detector separation can effectively enhance the detection of superficially scattered signals. Fiber numerical aperture provides additional depth selectivity; however, the perturbations in sampling depth achieved through this means are modest relative to the changes generated by modifying the angle of collection and source-detection separation.