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A 3-year-old boy presented with acute onset of prolonged right sided focal seizures with secondary generalisation. The investigation findings were suggestive of a neoplastic process more than an inflammatory process. Decision to perform brain biopsy from the lesion to establish the precise nature of lesion was undertaken.

UVOD: Robotski sustav RONNA je robotski sustav za stereotaktičku navigaciju koji je konstruiran u suradnji s Fakultetom strojarstva i brodogradnje i Kliničkom bolnicom Dubrava. Donosimo prospektivnu studiju robotskih biopsija izvedenih robotskim sustavom RONNA s detaljnom analizom točnosti primjene i usporedbom s drugim robotskim sustavima iz literature i stereotaktičkim biopsijama izvedenim Leksell okvirom. Donosimo i rezultate in vitro testiranja robotskoga sustava RONNA na antropomorfnom fantomu u robotskom laboratoriju. MATERIJALI I METODE: Svaka skupina se sastoji od 32 pacijenta, u jednoj skupini su obavljene biopsije bez okvira robotskim sustavom RONNA, a u drugoj skupini obavljene su biopsije Leksellovim okvirom. Grupa koja je operirana robotskim sustavom RONNA uključivala je 32 uzastopna bolesnika i to 11 žena (34,38%) i 21 muškarca (65,62%); prosječna dob u skupini žena bila je 68 ± 12,91 godina (raspon 40 - 83 godine), dok je prosječna dob u skupini muškaraca bila 64 ± 12,68 godina (raspon 34 - 79 godina). Skupinu bolesnika kojima je učinjena stereotaktička biopsija pomoću Leksellovog okvira čine 32 bolesnika, 12 žena (37,5%) i 20 muškaraca (62,5%); prosječna dob u skupini žena bila je 60 ± 10,10 godina (raspon 50 - 80 godina), dok je prosječna dob u skupini muškaraca bila 62,5 ± 15,49 godina (raspon 24 - 79 godina). Postoperativni CT i MR pregledi snimljeni su i korišteni za precizno mjerenje i izračunavanje pogreške ciljne točke (GCT) i pogreške ulazne točke (GUT) za robotske biopsije. Obje su skupine uspoređivane prema svim relevantnim antropološkim i kliničkim značajkama, kao što su spol, dob, trajanje bolesti, lokacija tumora, boravak u bolnici, PHD dijagnoza, komplikacije. Također, za robotske biopsije analizirano je trajanje postupaka i utjecaj kuta putanje bioptičke sonde na kost lubanje na točnost. REZULTATI: Nije bilo postoperativnog mortaliteta, morbiditeta ili infekcija. U skupini bolesnika koji su operirani robotskim sustavom RONNA trajanje operacije iznosilo je 57,5 ± 19,1 (raspon 41 - 128 min), dok je prosječni boravak bolesnika u bolnici bio 4 ± 1,08 dana (raspon 3 - 6 dana). U skupini bolesnika kod kojih je učinjena stereotaktička biopsija pomoću Leksell okvira trajanje operativnog zahvata, odnosno vrijeme od trenutka ulaska bolesnika u operacijsku salu do završetka operativnog zahvata iznosilo je 38 ± 12,28 (raspon 21 - 57 min), dok je prosječni boravak bolesnika u bolnici bio 7 ± 6,46 dana (raspon 2 - 30 dana). U obje skupine rezultati samo jedne patohistološke dijagnoze bili su nejasni, stoga je dijagnostička točnost robotskog sustava RONNA i okvira Leksell 96,87% (31/32). Pogreška ciljne točke (GCT), pogreška ulazne točke (GUT), kut putanje u odnosu na površinsku kost i duljina putanje temeljito su analizirani za robotske biopsije. Prosječna vrijednost GCT je 1,95 ± 1,11 (raspon 0,39 - 5,58 mm), prosječna vrijednost GUT je 1,42 ± 0,74 (raspon 0,35 - 3,36 mm), prosječni kut prema površini kosti je 15,30 ± 9,60° (raspon 2,70 - 38,10), dok je prosječna duljina putanje 45,73 ± 17,41 mm (raspon 15,50 – 86,10). Linearna regresija pokazala je statističku značajnost između GCT i GUT i kuta putanje na kosti lubanje. Trajanje postupka za robotske biopsije smanjivalo se s vremenom (p, INTRODUCTION: We bring a prospective study of robotic biopsies performed with RONNA robotic system compared to biopsies performed with the Leksell frame. MATERIALS AND METHODS: Patients are divided into two groups of 32 patients, in one group frameless biopsies with RONNA robotic system were performed and in another group framebased biopsies with Leksell frame were performed. Post-operative CT and MRI scans were assessed to precisely measure and calculate target point error (TPE) and entry point error (EPE) for robotic biopsies. Both groups were compared by all relevant anthropological and clinical features. RESULTS: There was no postoperative mortality, morbidity or infections. In both groups the results of only one pathohistological diagnosis were unclear, therefore the diagnostic accuracy of the RONNA robotic system and Leksell frame is 96.87% (31/32, The average value of TPE is 1.95 ± 1.11 (range 0.39 - 5.58 min), the average value of EPE is 1.42 ± 0.74 (range 0.35 - 3.36 min), the average angle to the bone surface is 15.30 ± 9.60° (range 2.70 - 38.10), while the average length of trajectory is 45.73 ± 17.41 mm (range 15.50 – 86.10). Linear regression showed statistical significance between the TPE and EPE and the angle of the trajectory on the skull bone. The duration of the procedure showed statistical significance between the first ten and the last ten performed operations (p = 0.0007). CONCLUSION: The RONNA G4 robotic system is a precise and highly accurate autonomous neurosurgical assistant for performing frameless brain biopsies.

Background and purpose: An accurate histopathological examination with minimal neuronal damage is essential for optimizing treatment strategies of central nervous system lesions. We investigated the feasibility and safety of CT and 3-tesla (3 T) MR-guided freehand brain aspiration biopsies with 18/20-gauge coaxial needles in performing a single imaging unit. Materials and methods: We reviewed CT and 3 T-MR guided freehand aspiration biopsies with 18/20-gauge coaxial needles of 33 patients (11-female and 22-male, mean and median ages: 53 years, min–max 21–79 years) in our tertiary hospital within an 8-year-period were included in this retrospective study. Lesion sizes, diagnostic yield, morbidity, and mortality rates of these biopsies without a scalp incision, surgical burr-hole, or stereotactic-instrumentation/neuro-navigation guidance were assessed. All biopsies were performed with local anesthesia and sedation within a single imaging unit of our radiology department. All free-hand biopsies were done as in-patient procedures and the patients were closely observed after the biopsies. Results: The mean diameter of the lesions was 27 mm (median 25; range 15–46 mm). The diagnostic yield of all free-hand brain biopsies was 88% [one inconclusive result (90%) for 3 T-MR; three inconclusive results (87%) for CT]. There was no major hemorrhage or hematoma, no clinical deterioration, or no infection in our patients on early- and late-phase examinations. Postprocedural minor hemorrhage with a ≤ 2 cm diameter was observed in two patients. The morbidity rate of the study population is 6%. There was no procedure-related infection or mortality in the post-procedural 3 weeks. Conclusions: Freehand CT or 3 T-MR guided aspiration biopsy was a safe and feasible method for pathological diagnosis of intracranial lesions. Biopsy workflow was simplified with this technique. It could be considered a valuable alternative for stereotaxic biopsies, especially for centers that do not have stereotaxic equipment or experience. © 2022, The Author(s) under exclusive licence to Japan Radiological Society.

OBJECTIVE The literature shows discrepancies in stereotactic brain biopsy complication rates, severities, and outcomes. Little is known about the timeline of postbiopsy complications. This study aimed to analyze 1) complications following brain biopsies, using a graded severity scale, and 2) a timeline of complication occurrence. The secondary objectives were to determine factors associated with an increased risk of complications and to assess complication-related management and extra costs. METHODS The authors retrospectively examined 1500 consecutive stereotactic brain biopsies performed in adult patients at their tertiary medical center between April 2009 and April 2019. RESULTS Three hundred eighty-one biopsies (25.4%) were followed by a complication, including 88.2% of asymptomatic hemorrhages. Symptomatic complications involved 3.0% of the biopsies, and 0.8% of the biopsies were fatal. The severity grading scale had a 97.6% interobserver reproducibility. Twenty-three (51.1%) of the 45 symptomatic complications occurred within the 1st hour following the biopsy, while 75.6% occurred within the first 6 hours. Age ≥ 65 years, second biopsy procedures, gadolinium-enhanced lesions, glioblastomas, and lymphomas were predictors of biopsy-related complications. Brainstem biopsy-targeted lesions and cerebral toxoplasmosis were predictive of mortality. Asymptomatic hemorrhage was associated with delayed (> 6 hours) symptomatic complications. Symptomatic complications led to extended hospitalization in 86.7% of patients. The average extra cost for management of a patient with postbiopsy symptomatic complication was $35,702. CONCLUSIONS Symptomatic complications from brain biopsies are infrequent but associated with substantial adverse effects and cost implications for the healthcare system. The use of a severity grading scale, as the authors propose in this article, helps to classify complications according to the therapeutic consequences and the patient’s outcome. Because this study indicates that most complications occur within the first few hours following the biopsy, postbiopsy monitoring can be tailored accordingly. The authors therefore recommend systematic monitoring for 2 hours in the recovery unit and a CT scan 2 hours after the end of the biopsy procedure. In addition, they propose a modern algorithm for optimal postoperative management of patients undergoing stereotactic biopsy.

OBJECTIVE The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors’ a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies. METHODS The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality. RESULTS Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23–88 years). The median follow-up was 8.5 months (range 0.1–231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months. CONCLUSIONS Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.

Purpose To report a case of bilateral ocular ischemia caused by intravascular lymphoma with presence of bilateral Triangular Sign of Amalric. Observations A 67-year-old female was admitted to our hospital for progressive paraplegia and a 6-month history of acute painless vision loss OD. Initial exam showed vision of CF OD and 20/20 OS with normal anterior exam. Fundus exam revealed a likely previous CRAO OD with pale nerve and attenuated vessels. Both fundi had triangular regions of pigmentary change known as the Triangular Sign of Amalric, indicative of choroidal ischemia. However, the left eye was asymptomatic. Neuro-imaging revealed multifocal enhancing lesions throughout the central nervous system of unclear etiology. An extensive neurologic and systemic workup was unrevealing, including a brain biopsy, and empiric treatment for an unspecified inflammatory condition with IV corticosteroids was initiated. During her hospitalization, she developed acute painless vision loss OS, and exam showed NLP vision OU with signs of acute retinal and choroidal ischemia OS. A subsequent brain biopsy revealed intravascular lymphoma. Conclusions and Importance: Triangular pigmentary changes indicate choroidal ischemia, and can be seen in many conditions. This patient presented with the Triangular Sign of Amalric in both eyes, including her asymptomatic left eye. Intravascular lymphoma should be considered in cases of concomitant inflammatory brain lesions and chorio-retinal ischemia.

Introduction: The Covid-19 pandemic has resulted in a spark in interest in the subject given the high exposure rate to viral antigens in the form of infections and vaccines. It is expected that acute disseminated encephalomyelitis (ADEM) cases see a rise in incidence during this period. Given the plethora of Covid-19-related central nervous system (CNS) involvement, it is important to be aware of the varied presentations of ADEM. Case reports: In this paper, we report 3 cases of ADEM following Covid-19 infection. Patients presented with polyfocal neurological symptoms 6 to 18 days after respiratory symptoms onset. The diagnosis of Covid-19 was made based on nasal swab reverse transcriptase-polymerase chain reaction (RT-PCR) and chest computerized tomography (CT). Discussion: These cases illustrate both classic and atypical presentations requiring exclusion of a spectrum of CNS conditions to be able to retain the diagnosis of ADEM. Consequently, we stress the importance of context, clinical examination and MRI findings in the differentials. In addition, we discuss workup, and particularly, the indication of brain biopsy. Also, the paper discusses options in therapy and the prognosis. The prognosis of covid-associated ADEM is dependent on the extent of pathology intrinsic to ADEM and the intrication of the prognosis of Covid-19 infection. Conclusion: The key message in these 3 cases is that clinicians should have a low threshold of suspicion of ADEM in the Covid-19 context, adopt appropriate workup strategies, and initiate adequate treatment for better outcomes.

Objective new-onset refractory status epilepticus (NORSE) is defined as de novo refractory seizures occurring in previously healthy adults, without a clear underlying etiology. Due to refractory seizures and insufficient understanding of pathophysiology, management of these patients remains challenging and often leads to poor clinical outcomes. Various infectious and autoimmune mechanisms have been proposed but have not been validated and a large number of patients are thus labeled ‘cryptogenic’. Moreover, histopathological findings have rarely been described in NORSE and are usually autopsy evaluations. In this paper, we describe the clinical correlates and histopathological findings in patients presenting with NORSE. Methods A case series of five patients with NORSE who underwent neurosurgical intervention and had histopathological examination during their acute clinical course. Results In all patients,status epileptics was refractory to treatment with antiseizure drugs (ASDs) and anesthetic agents. Autoimmune work-up revealed elevated titer of anti-GAD antibody in one patient but was unremarkable in others. Empiric use of immunomodulation therapy in three patients did not lead to cessation of status epilepticus (SE). Due to failure of prolonged medical management, three patients underwent palliative surgery for resection of epileptogenic tissue whereas the other two had diagnostic brain biopsy. Histopathology obtained during biopsy revealed evidence of vasculitis in one and necrotizing vasculopathy in another. The patient with anti-GAD antibodies had evidence of lymphocytic infiltration in limbic structures. The remaining two had nonspecific histopathological findings. Significance Although our findings are limited by a small number of patients, it adds to the growing premise of NORSE being related to an underlying autoimmune process. Additional studies, especially with histopathological data are needed to better understand this devastating disorder.

Here, we report two cases showing tumor-like white matter lesions; one case was diagnosed as having inflammatory disease, and the other was diagnosed as having astrocytoma. Their outcomes were completely distinct despite similar pathology. Prior to biopsy, perfusion computed tomography (CT) and magnetic resonance imaging (MRI) were conducted. The two mass-forming lesions were distinct in edema level and vascularity patterns on CT and MRI. However, pathological examination of brain biopsy specimens revealed commonalities, including (1) proliferation of glial cells, (2) perivascular lymphocytic infiltration, and (3) appearance of numerous macrophages. Although atypical astrocytes proliferated in both cases, nuclear atypia was more distinct in case 2 than in case 1. The immunohistochemical results were the same for both cases: isocitrate dehydrogenase 1 (IDH1) R132H mutation was negative, and alpha thalassaemia mental retardation X-linked (ATRX) was retained. Faint immunoreactivity for p53 was observed in a few glial cells, and Ki-67 immunoreactive cells were markedly reduced in numbers (< 1%). Inflammatory reactions were evident in both cases: T cells dominantly infiltrated over B cells in the perivascular area in case 1, whereas both T and B cells infiltrated in case 2. Molecular analysis revealed wild-type IDH1 and IDH2 in both cases. However, a telomerase reverse transcriptase (TERT) sequence mutation was detected in case 2 but not in case 1. Eventually, case 1 was diagnosed as having inflammatory lesions, whereas case 2 was diagnosed as having diffuse astrocytoma associated with inflammatory reactions. The prognosis was favorable for case 1, whereas case 2 died 10 months following biopsy. These data indicated the diagnostic value of molecular analysis, for example, a TERT mutation, in association with the radiological findings. Although in case 2, histopathological evidence did not suggest high-grade glioma, the case met the new diagnostic criteria: "diffuse astrocytic glioma, IDH wild-type, with molecular features of glioblastoma, World Health Organization (WHO) grade IV," according to cIMPACT-NOW, update 3. Thus, interdisciplinary approaches are essential for accurate diagnosis of newly categorized white matter diseases.

Background We aimed to investigate the detection rate of body CT or PET/CT for sites of extracranial disease in patients with a new pathological diagnosis of CNS DLBCL and to identify factors associated with sites of extracranial disease. Methods An international multicenter cohort study of consecutive immunocompetent patients with a new diagnosis of CNS DLBCL confirmed by brain biopsy who underwent CT and/or PET/CT to evaluate for sites of extracranial disease between 1998 and 2019. The primary outcome was the detection rate of extracranial lymphoma by CT or PET/CT. Subgroup analyses according to age and EBV status were also performed. Logistic regression analyses were performed to determine factors related to sites of extracranial disease. Detection rates of CT and PET/CT were compared. Results One thousand and forty-three patients were included. The overall detection rate of CT or PET/CT was 2.6% (27/1043). The treatment approach was adjusted in 74% of these patients. Multivariable analysis demonstrated that age >61 years (OR, 3.10; P = .016) and EBV positivity (OR, 3.78; P = .045) were associated with greater odds of extracranial lymphoma. There was no statistically significant difference in detection rate between CT and PET/CT (P = .802). In patients ≤61 years old, the false-referral rates were significantly higher than the detection rates (P < .001). Conclusion Our results showed increased odds of extracranial lymphoma in patients with older age or EBV-positive lymphoma. Treatment was adjusted in a majority of patients diagnosed with extracranial lymphoma, thereby supporting the current guidelines for the use of contrast-enhanced body CT or PET/CT in patients with newly diagnosed CNS DLBCL.

Intraocular lymphomas are among the rare malignancies that present with a wide variety of clinical manifestations. Differential diagnosis can be very troublesome due to its mimicking nature, insidious disease onset, and partial treatment response to steroids. The most important step in diagnosis is a high index of suspicion. Signs of the disease are now easier to detect using multimodal imaging techniques. In this case series, we reviewed the clinical characteristics of two women aged 70 and 71 years and a 72-year-old man with intraocular lymphoma and described their multimodal imaging findings in detail. Bilateral eye involvement was present in all three cases at our first ophthalmological examination. While the disease first presented with ocular involvement in two of the three cases, ocular involvement was detected seven years after initial heart involvement in one patient. All three patients had diffuse large B-cell lymphomas (one diagnosed with retinal biopsy, one with conjunctival biopsy, and the remaining with stereotactic brain biopsy). Intraocular lymphoma should be diagnosed and treated using a multidisciplinary approach, and we share our experience in this case series.

This article reports a rare case of Brain Mucormycosis in a 12 year-old girl who presented with relapse Acute Lymphoblastic Leukemia (ALL). On the 12th day of chemotherapy, although there was no CNS symptoms, the second Lumbar Puncture (LP) revealedmthe CNS relapse which developed to Into brain abscess presenting with right side hemiparesis. The brain magnetic resonance imaging (MRI) and the brain biopsy revealed small, multifocal necrosis and acute inflammation with septal fungal hyphae branching, which was proven to be caued by Mucormycosis according to Polymerase Chain Reaction (PCR). The patient responded to treatment with intravenous liposomal Amohotericin B and Caspofungin after two months, suggesting that Brain Mucormycosis in ALL cases can be managed with sequential therapy by antifungals.

During minimally-invasive surgery, endoscopes and other surgical tools enter the body of the patient through small openings, allowing the operations to be performed with less post-operative pain and faster recovery for the patient, as well as less wound complications. Although great advantages are achieved from the patient’s point-of-view, several difficulties have still to be handled by the surgeons. First, the limited field of view of the endoscope makes target-area localizations and related identifications complex. Second, surgeons should still match mentally the medical images for the surgical planning with the current patient anatomy. These difficulties can be addressed by using computer vision technologies for guiding surgical procedures. More specifically, this thesis aims at the following three points, the first two for neurosurgery, and the third for perfusion assessment during surgery. The challenges for this dissertation are partitioned in two primary aspects. The first point aims at the fusion of medical images on the endoscopic view, in order to develop an augmented reality system. The second point is based on hyperspectral imaging (HSI), which is compared with diffuse reflectance spectroscopy (DRS), to improve brain tissue classification for neurosurgery. The third point exploits the PPG imaging (iPPG) technique and its potential use is evaluated for peripheral arterial disease (PAD) and organ perfusion assessment during surgery. To address the first point, a new neurosurgical application is implemented on the already existing Philips Augmented Reality (AR) surgical navigation system, designed for spinal surgery. This navigation system incorporates an optical tracking system (OTS) with four video cameras embedded in the flat detector of the motorized C-arm. A hand-eye camera calibration algorithm for the fusion of medical images on the endoscopic view is implemented and integrated into the AR system. This technology is validated for endo-nasal surgery, a neurosurgical procedure for the removal of tumors located at the skull base, such as pituitary tumors. Intra-operative Cone Beam Computed Tomography (CBCT) images are fused with the view of the surgical field obtained by the endoscope camera. The accuracy of CBCT image co-registration is tested, using a custom-made grid with incorporated 3D spheres. The system achieves a sub-millimeter accuracy of image overlay of 0.55 mm, measured as mean target registration error (TRE), with a standard deviation of 0.24 mm. Afterwards, an anatomically realistic head phantom is developed, with materials chosen to achieve both X-ray attenuation and mechanical properties, similar to the real tissue. Using the phantom, a proof of concept of the skull-base surgical simulation is provided, then the accuracy and efficacy of the AR system are evaluated for the insertion of biopsy needles, which is a common neurosurgical procedure that requires high precision. Several 2-mm spherical biopsy targets are inserted inside the brain of the brain phantom. The obtained mean accuracy of the biopsy needle insertions (n=30) is 0.8±0.43 mm, with a mean device insertion time of 155±43 seconds. These experiments demonstrate that a high accuracy is obtained during neurosurgery with the proposed methods and one phantom. For the second point, a near-infrared (NIR) hyperspectral imaging (HSI) sensor is mounted on an endoscope, to explore contactless brain-tissue classification and HSI is compared with diffuse reflectance spectroscopy (DRS), which is an alternative optical technique that requires a probe in contact with the tissue. The classification is performed on ex-vivo porcine brain tissue, which is analyzed and classified in white and gray matter. The HSI reaches a sensitivity of 95% and specificity of 93%, whereas DRS reaches sensitivity and specificity of 96%. The results show that the spectral signature of the tissue in the NIR range contains sufficient information to discriminate brain tissue in white/ gray matter. Further investigation on ex-vivo tumor sample data is required prior to the clinical validation of HSI. The third part concentrates on exploring PPG imaging for extracting perfusion information on tissue. By using an off-the-shelf camera and a light source, the dynamic changes in blood volume are remotely detected beneath the skin and a map is derived correlated to the blood perfusion. After evaluating PPG imaging for local and temporal perfusion-change detections, it is employed for Peripheral Arterial Diseases (PAD) assessment. Reduced blood flow is simulated on 21 volunteers and iPPG is compared with ultrasound and Laser Speckle Contrast Analysis. These experiments show that iPPG can detect reduced perfusion levels and correlates well with the other measurement systems. Finally, this technology is deployed for organ perfusion assessment during intestine surgery. The experiments demonstrate that PPG imaging can be successfully used for extracting perfusion maps from the organ surface, even for detecting perturbations and perfusion changes during several stages of the surgery. The results of this dissertation contribute with novel techniques and approaches to add value to endoscopic and navigation technology systems, as well as to tissue classification and perfusion monitoring, during minimally-invasive surgery. The three main explored research points and their proposed techniques, namely image fusion with the endoscopic view, tissue classification via HSI and PPG imaging for perfusion assessment, can be potentially implemented and combined into a single endoscopic platform, resulting into a new multi-modal endoscopic system. Moreover, the thesis shows that the proposed techniques and algorithms increase the quality of the decision-making process and have the potential to improve the patient surgical outcome.

During minimally-invasive surgery, endoscopes and other surgical tools enter the body of the patient through small openings, allowing the operations to be performed with less post-operative pain and faster recovery for the patient, as well as less wound complications. Although great advantages are achieved from the patient’s point-of-view, several difficulties have still to be handled by the surgeons. First, the limited field of view of the endoscope makes target-area localizations and related identifications complex. Second, surgeons should still match mentally the medical images for the surgical planning with the current patient anatomy. These difficulties can be addressed by using computer vision technologies for guiding surgical procedures. More specifically, this thesis aims at the following three points, the first two for neurosurgery, and the third for perfusion assessment during surgery. The challenges for this dissertation are partitioned in two primary aspects. The first point aims at the fusion of medical images on the endoscopic view, in order to develop an augmented reality system. The second point is based on hyperspectral imaging (HSI), which is compared with diffuse reflectance spectroscopy (DRS), to improve brain tissue classification for neurosurgery. The third point exploits the PPG imaging (iPPG) technique and its potential use is evaluated for peripheral arterial disease (PAD) and organ perfusion assessment during surgery. To address the first point, a new neurosurgical application is implemented on the already existing Philips Augmented Reality (AR) surgical navigation system, designed for spinal surgery. This navigation system incorporates an optical tracking system (OTS) with four video cameras embedded in the flat detector of the motorized C-arm. A hand-eye camera calibration algorithm for the fusion of medical images on the endoscopic view is implemented and integrated into the AR system. This technology is validated for endo-nasal surgery, a neurosurgical procedure for the removal of tumors located at the skull base, such as pituitary tumors. Intra-operative Cone Beam Computed Tomography (CBCT) images are fused with the view of the surgical field obtained by the endoscope camera. The accuracy of CBCT image co-registration is tested, using a custom-made grid with incorporated 3D spheres. The system achieves a sub-millimeter accuracy of image overlay of 0.55 mm, measured as mean target registration error (TRE), with a standard deviation of 0.24 mm. Afterwards, an anatomically realistic head phantom is developed, with materials chosen to achieve both X-ray attenuation and mechanical properties, similar to the real tissue. Using the phantom, a proof of concept of the skull-base surgical simulation is provided, then the accuracy and efficacy of the AR system are evaluated for the insertion of biopsy needles, which is a common neurosurgical procedure that requires high precision. Several 2-mm spherical biopsy targets are inserted inside the brain of the brain phantom. The obtained mean accuracy of the biopsy needle insertions (n=30) is 0.8±0.43 mm, with a mean device insertion time of 155±43 seconds. These experiments demonstrate that a high accuracy is obtained during neurosurgery with the proposed methods and one phantom. For the second point, a near-infrared (NIR) hyperspectral imaging (HSI) sensor is mounted on an endoscope, to explore contactless brain-tissue classification and HSI is compared with diffuse reflectance spectroscopy (DRS), which is an alternative optical technique that requires a probe in contact with the tissue. The classification is performed on ex-vivo porcine brain tissue, which is analyzed and classified in white and gray matter. The HSI reaches a sensitivity of 95% and specificity of 93%, whereas DRS reaches sensitivity and specificity of 96%. The results show that the spectral signature of the tissue in the NIR range contains sufficient information to discriminate brain tissue in white/ gray matter. Further investigation on ex-vivo tumor sample data is required prior to the clinical validation of HSI. The third part concentrates on exploring PPG imaging for extracting perfusion information on tissue. By using an off-the-shelf camera and a light source, the dynamic changes in blood volume are remotely detected beneath the skin and a map is derived correlated to the blood perfusion. After evaluating PPG imaging for local and temporal perfusion-change detections, it is employed for Peripheral Arterial Diseases (PAD) assessment. Reduced blood flow is simulated on 21 volunteers and iPPG is compared with ultrasound and Laser Speckle Contrast Analysis. These experiments show that iPPG can detect reduced perfusion levels and correlates well with the other measurement systems. Finally, this technology is deployed for organ perfusion assessment during intestine surgery. The experiments demonstrate that PPG imaging can be successfully used for extracting perfusion maps from the organ surface, even for detecting perturbations and perfusion changes during several stages of the surgery. The results of this dissertation contribute with novel techniques and approaches to add value to endoscopic and navigation technology systems, as well as to tissue classification and perfusion monitoring, during minimally-invasive surgery. The three main explored research points and their proposed techniques, namely image fusion with the endoscopic view, tissue classification via HSI and PPG imaging for perfusion assessment, can be potentially implemented and combined into a single endoscopic platform, resulting into a new multi-modal endoscopic system. Moreover, the thesis shows that the proposed techniques and algorithms increase the quality of the decision-making process and have the potential to improve the patient surgical outcome.

During minimally-invasive surgery, endoscopes and other surgical tools enter the body of the patient through small openings, allowing the operations to be performed with less post-operative pain and faster recovery for the patient, as well as less wound complications. Although great advantages are achieved from the patient’s point-of-view, several difficulties have still to be handled by the surgeons. First, the limited field of view of the endoscope makes target-area localizations and related identifications complex. Second, surgeons should still match mentally the medical images for the surgical planning with the current patient anatomy. These difficulties can be addressed by using computer vision technologies for guiding surgical procedures. More specifically, this thesis aims at the following three points, the first two for neurosurgery, and the third for perfusion assessment during surgery. The challenges for this dissertation are partitioned in two primary aspects. The first point aims at the fusion of medical images on the endoscopic view, in order to develop an augmented reality system. The second point is based on hyperspectral imaging (HSI), which is compared with diffuse reflectance spectroscopy (DRS), to improve brain tissue classification for neurosurgery. The third point exploits the PPG imaging (iPPG) technique and its potential use is evaluated for peripheral arterial disease (PAD) and organ perfusion assessment during surgery. To address the first point, a new neurosurgical application is implemented on the already existing Philips Augmented Reality (AR) surgical navigation system, designed for spinal surgery. This navigation system incorporates an optical tracking system (OTS) with four video cameras embedded in the flat detector of the motorized C-arm. A hand-eye camera calibration algorithm for the fusion of medical images on the endoscopic view is implemented and integrated into the AR system. This technology is validated for endo-nasal surgery, a neurosurgical procedure for the removal of tumors located at the skull base, such as pituitary tumors. Intra-operative Cone Beam Computed Tomography (CBCT) images are fused with the view of the surgical field obtained by the endoscope camera. The accuracy of CBCT image co-registration is tested, using a custom-made grid with incorporated 3D spheres. The system achieves a sub-millimeter accuracy of image overlay of 0.55 mm, measured as mean target registration error (TRE), with a standard deviation of 0.24 mm. Afterwards, an anatomically realistic head phantom is developed, with materials chosen to achieve both X-ray attenuation and mechanical properties, similar to the real tissue. Using the phantom, a proof of concept of the skull-base surgical simulation is provided, then the accuracy and efficacy of the AR system are evaluated for the insertion of biopsy needles, which is a common neurosurgical procedure that requires high precision. Several 2-mm spherical biopsy targets are inserted inside the brain of the brain phantom. The obtained mean accuracy of the biopsy needle insertions (n=30) is 0.8±0.43 mm, with a mean device insertion time of 155±43 seconds. These experiments demonstrate that a high accuracy is obtained during neurosurgery with the proposed methods and one phantom. For the second point, a near-infrared (NIR) hyperspectral imaging (HSI) sensor is mounted on an endoscope, to explore contactless brain-tissue classification and HSI is compared with diffuse reflectance spectroscopy (DRS), which is an alternative optical technique that requires a probe in contact with the tissue. The classification is performed on ex-vivo porcine brain tissue, which is analyzed and classified in white and gray matter. The HSI reaches a sensitivity of 95% and specificity of 93%, whereas DRS reaches sensitivity and specificity of 96%. The results show that the spectral signature of the tissue in the NIR range contains sufficient information to discriminate brain tissue in white/ gray matter. Further investigation on ex-vivo tumor sample data is required prior to the clinical validation of HSI. The third part concentrates on exploring PPG imaging for extracting perfusion information on tissue. By using an off-the-shelf camera and a light source, the dynamic changes in blood volume are remotely detected beneath the skin and a map is derived correlated to the blood perfusion. After evaluating PPG imaging for local and temporal perfusion-change detections, it is employed for Peripheral Arterial Diseases (PAD) assessment. Reduced blood flow is simulated on 21 volunteers and iPPG is compared with ultrasound and Laser Speckle Contrast Analysis. These experiments show that iPPG can detect reduced perfusion levels and correlates well with the other measurement systems. Finally, this technology is deployed for organ perfusion assessment during intestine surgery. The experiments demonstrate that PPG imaging can be successfully used for extracting perfusion maps from the organ surface, even for detecting perturbations and perfusion changes during several stages of the surgery. The results of this dissertation contribute with novel techniques and approaches to add value to endoscopic and navigation technology systems, as well as to tissue classification and perfusion monitoring, during minimally-invasive surgery. The three main explored research points and their proposed techniques, namely image fusion with the endoscopic view, tissue classification via HSI and PPG imaging for perfusion assessment, can be potentially implemented and combined into a single endoscopic platform, resulting into a new multi-modal endoscopic system. Moreover, the thesis shows that the proposed techniques and algorithms increase the quality of the decision-making process and have the potential to improve the patient surgical outcome.

Glioblastoma (GBM) is the most common adult malignant glioma (MG) variant, and the median survival of persons with GBM is about 2 years, even with aggressive treatments. Dogs and humans are the only species in which brain tumors commonly develop spontaneously, with an estimated post-mortem frequency of primary brain tumors approximating 2% in both species. Gliomas represent about 35% of all canine primary brain tumors, with high-grade oligodendroglioma and astrocytoma phenotypes accounting for about 70% of all canine gliomas. Canine gliomas are also treated using surgical, radiotherapeutic, and chemotherapeutic regimens similar to those used in humans. The efficacy of these therapies in dogs with MG is also poor, with median survival times ranging from 3-8 months, which closely mirrors the dismal prognosis associated with human GBM. Thus, treatment of MG represents a current and critically unmet need in both human and veterinary medicine. In this work, we investigate minimally invasive methods to access the brain for the purposes of ultimately improving the diagnosis and treatment of malignant brain tumors. Chapter 1 reviews the current clinical challenges associated with the treatment of GBM, highlights the value of using the spontaneous canine glioma model in translational brain tumor studies, and introduces High-Frequency Irreversible Electroporation (H-FIRE) and Convection Enhanced Delivery (CED), which are two novel treatment platforms for GBM being developed in our lab. In Chapter 2, we demonstrate that definitive diagnosis of brain tumors, a critical first step in patient management, can be safely and accurately performed in dogs with naturally occurring brain tumors using a stereotactic brain biopsy procedure. Chapter 3 evaluates the in vivo safety and biocompatibility of fiberoptic microneedle devices, a major technical component of our convection-enhanced thermotherapy catheter system (CETCS), chronically implanted in the rodent brain. The CETCS is a novel technology being developed and used in our laboratory to improve the delivery of drugs to brain tumors using CED. This study provides regulatory data fundamental to the commercialization of the CETCS device for brain tumor treatment by illustrating that the device did not cause clinically significant neurological complications and resulted in mild pathologic changes in brain tissue, similar to other types of devices designed and approved for use in the brain. In Chapters 4 and 5 we explore possible bystander effects of H-FIRE on glutamate metabolism in the brain. H-FIRE has been shown to be able to both ablate brain tumors as well as disrupt the blood-brain barrier (BBB). As these therapeutic effects of H-FIRE are dependent on applying electrical fields to the tissue that either reversibly permeabilize the cell membrane, allowing treated cells to survive, or permanently disrupt the structure of the cell membrane, causing cell death, we hypothesized that altering the membrane permeability with HFIRE would increase the extracellular glutamate concentrations and contribute to excitotoxic brain tissue damage. Chapters 4 used in vitro brain cell culture systems and in vivo experiments in normal and glioma-bearing rat brains to determine if glutamate release in the brain occurs as a bystander effect following H-FIRE treatment, identify concentrations of glutamate necessary to induce death of cells or BBB disruption, and characterize glutamatergic gene expression in response to H-FIRE treatment. Chapter 5 describes the use of magnetic resonance spectroscopic and spatial transcriptomic methods to further quantify the in vivo effects of H-FIRE treatment on glutamate release and metabolism in dogs with spontaneous brain tumors. The in vitro results indicated that the magnitude of glutamate release following H-FIRE is insufficient to induce cytotoxicity in normal or neoplastic brain cell lines, and also did not increase the permeability of the BBB. In our in vivo model systems, we documented significant, transient post-H-FIRE increases in glutamate to concentrations previously associated with excitotoxicty, with upregulation of the expression of genes involved with ionotropic and metabotropic glutamatergic receptor signaling. A contemporaneous upregulation of genes associated with glutamate uptake and recycling were also noted, indicating an adaptive, protective response to the glutamate release. Our work summarily demonstrates that the diagnosis and potential treatment of malignant brain tumors can be achieved through the use of minimally invasive techniques that provide local access to brain tissue. While complications will always be possible anytime the brain is manipulated surgically, and further investigations are required to characterize the spectrum and mechanisms of adverse events that can occur following CETCS CED and H-FIRE treatment, our results support the continued development of these novel therapeutic platforms for the treatment of GBM. Doctor of Philosophy Glioblastoma (GBM) is the most common adult malignant glioma (MG) variant, and the median survival of persons with GBM is about 2 years, even with aggressive treatments. Dogs and humans are the only species in which brain tumors commonly develop spontaneously, with an estimated post-mortem frequency of primary brain tumors approximating 2% in both species. Gliomas represent about 35% of all canine primary brain tumors, with high-grade oligodendroglioma and astrocytoma phenotypes accounting for about 70% of all canine gliomas. Canine gliomas are also treated using surgical, radiotherapeutic, and chemotherapeutic regimens similar to those used in humans. The efficacy of these therapies in dogs with MG is also poor, with median survival times ranging from 3-8 months, which closely mirrors the dismal prognosis associated with human GBM. Thus, treatment of MG represents a current and critically unmet need in both human and veterinary medicine. In this work, we investigate minimally invasive methods to access the brain for the purposes of ultimately improving the diagnosis and treatment of malignant brain tumors. Chapter 1 reviews the current clinical challenges associated with the treatment of GBM, highlights the value of using the spontaneous canine glioma model in translational brain tumor studies, and introduces High-Frequency Irreversible Electroporation (H-FIRE) and Convection Enhanced Delivery (CED), which are two novel treatment platforms for GBM being developed in our lab. In Chapter 2, we demonstrate that definitive diagnosis of brain tumors, a critical first step in patient management, can be safely and accurately performed in dogs with naturally occurring brain tumors using a stereotactic brain biopsy procedure. Chapter 3 evaluates the in vivo safety and biocompatibility of fiberoptic microneedle devices, a major technical component of our convection-enhanced thermotherapy catheter system (CETCS), chronically implanted in the rodent brain. The CETCS is a novel technology being developed and used in our laboratory to improve the delivery of drugs to brain tumors using CED. This study provides regulatory data fundamental to the commercialization of the CETCS device for brain tumor treatment by illustrating that the device did not cause clinically significant neurological complications and resulted in mild pathologic changes in brain tissue, similar to other types of devices designed and approved for use in the brain. In Chapters 4 and 5 we explore possible bystander effects of H-FIRE on glutamate metabolism in the brain. H-FIRE has been shown to be able to both ablate brain tumors as well as disrupt the blood-brain barrier (BBB). As these therapeutic effects of H-FIRE are dependent on applying electrical fields to the tissue that either reversibly permeabilize the cell membrane, allowing treated cells to survive, or permanently disrupt the structure of the cell membrane, causing cell death, we hypothesized that altering the membrane permeability with HFIRE would increase the extracellular glutamate concentrations and contribute to excitotoxic brain tissue damage. Chapters 4 used in vitro brain cell culture systems and in vivo experiments in normal and glioma-bearing rat brains to determine if glutamate release in the brain occurs as a bystander effect following H-FIRE treatment, identify concentrations of glutamate necessary to induce death of cells or BBB disruption, and characterize glutamatergic gene expression in response to H-FIRE treatment. Chapter 5 describes the use of magnetic resonance spectroscopic and spatial transcriptomic methods to further quantify the in vivo effects of H-FIRE treatment on glutamate release and metabolism in dogs with spontaneous brain tumors. The in vitro results indicated that the magnitude of glutamate release following H-FIRE is insufficient to induce cytotoxicity in normal or neoplastic brain cell lines, and also did not increase the permeability of the BBB. In our in vivo model systems, we documented significant, transient post-H-FIRE increases in glutamate to concentrations previously associated with excitotoxicty, with upregulation of the expression of genes involved with ionotropic and metabotropic glutamatergic receptor signaling. A contemporaneous upregulation of genes associated with glutamate uptake and recycling were also noted, indicating an adaptive, protective response to the glutamate release. Our work summarily demonstrates that the diagnosis and potential treatment of malignant brain tumors can be achieved through the use of minimally invasive techniques that provide local access to brain tissue. While complications will always be possible anytime the brain is manipulated surgically, and further investigations are required to characterize the spectrum and mechanisms of adverse events that can occur following CETCS CED and H-FIRE treatment, our results support the continued development of these novel therapeutic platforms for the treatment of GBM.