Friday, December 24, 2021

2021 MEDTECH REVIEW: TRANSCRANIAL DOPPLER ULTRASOUND IMAGING

Written by:  Dr. Robert L. Bard  |  Lennard M. Gettz, Ed.D |  Noelle Cutter, PhD   

Since the advent of ultrasound scanning in the 1950's, the global movement to develop and expand its diagnostic features continue in its appeal with the medical community today.  The ultrasound design use of sound waves and echo reflection became widely accepted for being the safe (non-radiation), inexpensive, repeatable and non-invasive alternative in medical imaging.  Early clinical upgrades included the development of the pulse Doppler paradigm (1966) to enable scanning layers of the heart via blood flow. This offered diagnostic advantages to its application in the mid-seventies for live-action scans of the human fetus. These qualities earned its place as the standard in pediatric use while continuing to earn the confidence of radiologists and imaging specialists for a wide range of diagnostic applications from emergency critical care to supplemental cancer screening. 



THE SCIENCE OF BLOOD FLOW AND DOPPLER TECHNOLOGY
Hemodynamics is defined as the study of blood flow in relation to the status of the circulatory system and homeostatic mechanisms of autoregulation.   Through the monitoring of blood flow, diagnostic analysis can provide many answers to the health and physiological status of the target area scanned as well as cell-level metabolism, the regulation of the pH, osmotic pressure and temperature of the whole body, and the protection from microbial and mechanical harm.[1]   Assessing injuries, inflammation or mutative growths (like cancer tumors), assessment of blood flow provides diagnostic answers about the severity of tissue disorders or tumor malignancy.

The expansion of ultrasound research and development broke new ground in 1982 when Dr. Rune Aaslid (Norwegian Neurosurgical researcher) first introduced Cerebral Hemodynamics with the implementation of Transcranial Doppler science to offer noninvasive transcranial recorded imaging of flow velocity in basal cerebral arteries.  His report detailed that placing an accurately configured Doppler ultrasound transducer in the temporal area (just above the zygomatic arch)offers quantitative data of the blood flow velocity in the middle, proximal anterior and posterior cerebral arteries.[1.2] This scan is critical for detecting vasospasms and for reviewing circulation in the brain for potential disease of the carotid and vertebral arteries. [1.5] 

In 1989, Dr. Aaslid published the first study on dynamic cerebral autoregulation in humans - a biological and metabolic function dedicated to stabilizing cerebral blood flow. TCD detects the slightest change in perfusion-- the volumetric measure at which blood is delivered to tissue, or volume of blood per unit time per unit tissue mass. Alongside the study of blood pressure, Cerebral Autoregulation is vital to maintaining life as it supports proper delivery of adequate oxygen (in the blood) and nutrients to the brain and the removal of CO2 & other waste products.[2]  As Dr Aaslid used the TCD by scanning through the transtemporal approach, others explored the intracranial arteries through the orbital (eye socket) window. By the early 90's, the next generation of development teams (Spencer, Seidel, Dobson & Moehring) improved on the Doppler innovation to detect microemboli and hemodynamic physiology. Today, TCD is widely accepted and utilized for an expanding set of clinical and research applications including  ischemic stroke, sickle cell disease, subarachnoid hemorrhage and vasospasm. 

According to cancer diagnostic imaging expert Dr. Robert Bard, the introduction of 4D Doppler technology aligned with the ultrasound's base design concept of providing instantaneous, real time readings.  "Let's take the case of breast cancer screening, the technician simply puts the probe on the breast, finds the area, pinpoints it, presses a button and seconds later you have the map showing the types of vessels, volumetric arterial density and spatial location of the vessels in relation to the adjacent organs. You have functions that give you a vessel density measurement which shows how aggressive this is. Instead of genetic markers (which are very popular), visually displaying tumor aggression  performed in a matter of seconds to show cancer vessel invasion is a game-changer for any early detection or monitoring facility. Tumor aggression by blood flow evaluation is used worldwide in nuclear medicine, CT scans and MRI technology, however, one of the simplest and most cost-effective alternatives is the non‐invasive 3D Doppler breast procedure."


INTRACRANIAL SCANNING WITH DOPPLER ULTRASOUND
In 1982, continued advancement led to the Transcranial Doppler (TCD) ultrasonography for outpatient and inpatient settings. By integrating the ability to study BLOOD FLOW into a low-frequency transducer, placing the probe on the temporal area measures the cerebral arteries to detect and quantify cerebrovascular activities, diseases and brain injuries.   Other applications include the diagnoses of vasospasm (VSP) after an aneurysm rupture, hemorrhage or hemodynamic changes after ischemic or cryptogenic stroke. It also enables the study of cranial pressure fluctuations.  TCD also offers significant clinical benefits in the monitoring of sickle-cell disease by scanning brain stem death and elevated raised intracranial pressure (ICP).  Added features allow for surgical and post-op monitoring of vasomotor functions as well as detecting critical disorders like a microembolism.

SUMMARY OF TARGET CONDITIONS FOR TCD APPLICATIONS 
•    Vasospasm /aneurysm
•    Sickle cell anemia, to determine a patient's stroke risk
•    Ischemic stroke
•    Intracranial stenosis/ blockage of the blood vessels
•    Cerebral microemboli


PART 2: VERIFYING SIGNS OF COVID-19 STROKE THROUGH IMAGING

By: Robert L. Bard, MD  and Dr. Pierre Kory, MD

Early detection and prevention of arterial and venous disease is key to minimizing the effects of arterial obstruction & hemorrhage, brain aneurysms, and strokes from venous thrombosis.  The association of trauma to PTSD is now followed by advanced Doppler ultrasound and functional MRI. This abnormal physiology may also manifest as arterial dissection, collagen disease, inflammatory arthritis, dermatitis, ocular disorders, GI disturbances, limb pain, aneurysms of the brain and aorta. Devastating strokes in the Covid-19 era occur in the younger age group and the Latin population who are at higher risk.


INTRODUCTION
Interest in arteritis was elevated with the study of Tayakasu’s disease in the 1970's when advances in contrast arteriography diagnosed diffuse vascular involvement causing strokes and aneurysms in multiple sites. While this arterial inflammation is more common in Asians, in the US, blacks are nearly three times more likely to have a stroke at age 45 than whites. The pediatric population seems to be at higher risk for this arteritis as evidenced by their unusual rate of Covid-19 affliction affecting the vasculature and called “MULTIPLE ACUTE INFLAMMATORY SYNDROME“.  Birth control pills is a distinct cause of such disease in younger women while cancer, alcoholism and obesity raise the incidence at all ages. [3]

We have learned over the last century that blockages of coronary arteries to the heart and carotid arteries to the brain are precipitated by inflammation of the inner walls of the vessel, called the “intima”


While thickening of the interior wall of vessels gradually occurs over time and is aggravated by diet, stress and hypertension (high blood pressure), the acutely disabling event occurs when there is an abrupt tear of the overlying plaque which ruptures debris which then forms a blood clot which blocks blood flow or the clot travels deeper into the brain and blocks blood flow. Similarly, abnormal heart rhythms such as “atrial fibrillation”, causes the pooling of blood in the heart which predisposes to clot formation and the clots can then travel into the brain causing a stroke. In Covid-19, the virus causing severe inflammation in the blood which then promotes clot formation which can travel through the vascular system and affect almost every organ system in the human body, with the brain and lungs being the most vulnerable. An article in September NEUROLOGY reported by Medscape documented the incidence of large artery stroke as the presenting symptom of COVId-19 was highest in men under the age of 50 years.  [4]

HISTORY
A medical research team at Metropolitan Hospital in New York first noticed unusual neurologic symptoms in young and middle aged patients in the late 1960s. As a division of the NY Medical College system, they were fortunate to have an active interventional radiology department specializing in neuroimaging and arteriography. The observation of distortion and occlusion of arteries supplying the brain, kidneys, GI tract and lower limbs to various degrees from single to multiple locations was closely linked to the Japanese disorder known as Tayakasu’s arteritis at the time and recently renamed “arteritis.” A clinical finding of this arterial inflammation in the abdominal aorta was pain in the upper abdomen by the great vessels by palpation. Astute physicians were successfully treating this with commonly available “aspirin.”

However, the chronic and diffuse nature of arteritis often weakened the vessel wall producing aneurysmal dilation and rupture. Today we find sophisticated non-invasive or minimally invasive modalities to be the first line of interrogation of vasculitis. [5]


COVID AND STROKE
COVID-19 was rapidly understood as a disease caused by severe and widespread inflammation and “hypercoagulability” (a tendency to spontaneously form clots in the blood vessels.) Autopsies have revealed extensive small vessel strokes, with such strokes often occurring despite aggressive blood thinner treatment and regardless of the timing of the disease course, suggesting that it plays a role very early in the disease process. In one autopsy series, there was a widespread presence of small clots with acute stroke observed in over 25%. In a recent review of the incidence of stroke in COVID-19, almost 2% of all hospital patients suffered a stroke, which is 8x higher than in patients with influenza. More worrisome is that this is almost definitely a gross underestimate given the many likely missed strokes in patients who died on ventilators who were too ill to obtain imaging, the general restrictions on and lack of autopsies, and the well-recognized decrease in the number of patients with acute stroke symptoms seeking medical attention in the COVID-19 era.  Another worrisome finding from a recent study of COVID-19 cases found that 45.5% of patients reported neurologic symptoms [6,7]. This under-recognized epidemic of neurological symptoms and strokes in COVId-19 highlights the need for more intensive imaging and investigation to achieve not only earlier recognition and improved treatment of patients but in furthering understanding of COVID-19 effects on brain function.


DIAGNOSIS BY IMAGING
Blood flow abnormalities in the arterial system are best study by Doppler imaging like the weather Doppler showing tornadoes. Multiple options exist for blood flow analysis including:

- Carotid Sonogram
- Carotid Doppler
- Eye Sonography
- Transorbital Doppler
- Contrast Enhanced Ultrasound
- Transcranial Doppler
- Hybrid Imaging
- 3D/4D Vessel Density Histogram
- Endoarterial 3D Doppler
- Retinal OCT
- Soft Tissue OCT
- Reflectance Confocal Microscopy
- Small Coil MRI
- 7 Tesla MRI

CAROTID SONOGRAM: While cerebrovascular disease is often diagnosed ex post facto after a catastrophic episode with MRI and CT, the non invasive Doppler analysis of the vascularity is generally checked with ultrasound for plaque and obstruction. A useful measure of the risk of coronary and cerebrovascular disorder is the carotid intimal thickness (CIMT). Standard depth of the inner wall thickness is a measure best obtained by high resolution sonograms since a reading over 0.9mm indicates increased risk. The newer sonogram units have depth resolution of 0.02mm making this a preferred non invasive option.







DOPPLER IMAGING TECHNOLOGIES

- COLOR DOPPLER - most common application where red is flow towards the probe and blue is flow away from the probe
- POWER DOPPLER - higher spatial resolution without directional flow correlation
3D POWER DOPPLER - allows volumetric analysis of vessel density used in treatment correlation where more vessels means increased neovascularity and fewer vessels correlates with clinical improvement
- ANGIODOPPLER – similar to color Doppler with higher spatial resolution
MICROVASCULAR DOPPLER-images capillary flow
B-FLOW DOPPLER-not true flow technology but observes motion of red blood cells directly

CAROTID DOPPLER: Flow abnormalities of turbulence and absence are commonly evaluated with this modality. Plaque forms more readily in aberrant flow patterns and high velocity regions accompanying narrowing.

EYE SONOGRAPHY: Sonofluoroscopy of the orbital soft tissues and eyes is performed in multiple scan planes with varying transducer configurations and frequencies. Power and color Doppler use angle 0 and PRF at 0.9 at optic nerve head. 3D imaging of optic nerve and carotid, central retinal arteries and superficial posterior ciliary arteries performed in erect position before and after verbal communication. Retinal arterial flow is measured. Optic nerve head bulging is checked as increased intracranial pressure may be demonstrable.

TRANSORBITAL DOPPLER: R/L ciliary arteries have normal Doppler flows of 10cm/s which is symmetric.

CONTRAST ENHANCED ULTRASOUND: Widely used European nonionic contrast injection allows imaging capillary size vessels and perfusion characteristics

TRANSCRANIAL DOPPLER: This measures the flow in the anterior, middle and posterior cerebral arteries as well as Circle of Willis.

3D/4D VESSEL DENSITY HISTOGRAM: Multiple image restoration and reconstruction shows retinal vessel density of 25% at the optic nerve head and adjacent region with quantitative accuracy.[8]

ENDOARTERIAL 3D DOPPLER: Microcatheters inserted into the arterial or venous system provide measurement of wall thickness and presence of inflammatory vessels inside the intima.

RETINAL OCT: Subtraction techniques done with OCT optical coherence tomography may show changes in the caliber of the retinal vessels with verbal ideation.

SOFT TISSUE OCT: The depth of penetration may be extended to 2-3mm allowing for analysis of vascular changes in erythematous or erythropoor dermal areas. Thrombosis may be observed.

REFLECTANCE CONFOCAL MICROSCOPY: This microscopic analysis of the cells also quantifies microvascular pathology and is a potential modality for studying vasculitis.

SMALL COIL MRI: High resolution systems used for animal study and superficial organs can image the intra-arterial anatomy including dynamic contrast imaging on standard 1.5T and 3T units.

7 TESLA MRI: High field systems analyze signal abnormalites rapidly with high resolution.

HYBRID IMAGING: Hybrid imaging refers to combining diagnostic modalities to assess disease and monitor therapy. 







REFERENCES

1) Hemodynamics: https://en.wikipedia.org/wiki/Hemodynamics

2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224659/

3). Hassani SN, Bard RL: Ultrasonic Diagnosis of  Aortic Aneurysms. J. Natl. Med. Assoc. 66:298-299, July 1974

4). Lande A, Bard RL: Arteriography of Pedunculated Splenic Cysts. Angiology 25:617-621, October 1974

5). Lande A, Bard RL, Rossi P: Takayasu's Arteritis: A World Entity. N.Y. State J. Med. 76:1477-1482, Sep 1976

6). Helbick Eur Radiol 30:5536-5538, 2020

7). Mao l  JAMA Neurol 2020 77:683-690

8). Bard RL , Gettz L, van der Bent S etal: Proceedings of the 4th Inflammatory Disease Summit at NY Academy of Medicine  Nov 2021


Thursday, December 16, 2021

MEDTECH REVIEW: Fluorescence Imaging for Inflammation and Infection (official)

Written by: Dr. Robert L. Bard

Upon review of all the imaging technologies available, clinicians are constantly in search for what provides us the most accurate quantitative data from the standpoint of non‐invasive safety. In the case of diagnosing cancers and bacterial infections, we are now exploring the potential of the intelligence behind bioluminescence and fluorescence (or autofluorescence) probes.

From a 2019 study (by Raizman et al) about use of this technology (MolecuLight i:X) with debridement, scans of 22 wounds were conducted under standard and violet light in patients after debridement. Scans, performed non-invasively at the point-of-care, demonstrated remaining bacteria/biofilm signal in 100% of wounds after sharp debridement, triggering additional removal of tissue. [1] 

Re-scanning demonstrated a marked decrease or complete removal of bacteria in most wounds, yet a subset showed persistent or increased bacterial signals post debridement. The authors, aided by the knowledge gained from this technology,  proposed “the subgroup with persistent bacterial fluorescence post-debridement was at increased risk of deep compartment infection and required more frequent debridement and/or antibiotics.” [1]. See example of this in figure 2 (tissue in green, bacteria in red). Others have demonstrated ability to markedly decrease antibiotic usage using this technology, showing great potential for stewardship efforts [2].

Currently, the technology can take direct images of the skin or mucosal surface to indicate bacteria on the tongue or oral lining. Exploratory reviews of this imaging device also shows possible benefits in scanning potential biopsy material with violet light at the tissue and see if it's suggestive for cancer or inflammatory disease. 




SCAN 1: The Test Drive

Autofluorescence has been proven and used worldwide to show inflammatory changes and bacterial infection. It's used to find both Gram‐negative bacteria and Gram‐positive bacteria, aerobic and anaerobic. (Fig‐1) The illustrated scan shows the normal skinfolds as green and the skin image is homogeneous (there's nothing dark). (Fig‐2) The scan of the finger on the opposite hand which the patient expressed chronic irritation. Upon initial observationit appears that Autofluorescence may detect inflammation through the upper dermis, a change documented visually and by ultrasound imaging as minimal epidermal thickening associated with inflammatory skin disease (mild type). When we turned on the fluorescence scan, the exact one centimeter area of redness on the skin corresponded to the one centimeter darkened area on the finger.


SCAN 2: IMAGING VALIDATION WITH ULTRASOUND 
(Fig-3) For my diagnostic research projects in dermal lesions and infections, one of my "weapons of choice" is the doppler ultrasound.  From tumors to traumas, radiologists and clinicians rely on feature-rich computerized systems that provided remarkable patient data for its non‐invasive and real-time view of inflammatory disease to align with our study of the Autofluorescence for its work on atopic dermatitis and other viral diseases (ie. Covid-19) which may affect the skin and be sampled with this noninvasive technology. Since it hasn't been clinically documented in the dermal tissues, this is an opportunity to form a new type of imaging that is non-invasive to consider avoiding biopsies on children.

In the case of Fig-3, I used a high-frequency setting on a popular handheld point of care ultrasound probe to recognize a 0.3cm depth scan of the same area of the finger that was previously scanned by the fluorescence device. The top right arrow (1a) shows the enlarging dark stripe indicating inflammatory thickening or the epidermis. The middle grey area (arrow 1b) represents subdermal inflammation of subcutaneous tissue or mild inflammatory skin disease -  confirming the prior evaluation.

EXPANSION POTENTIAL: RESEARCH 
Fluorescence imaging is proven to have a four‐millimeter depth of diagnostic accuracy in the tongue or mucous membranes‐ similar to the cervix or the vagina or the intestine lining. There is a rich literature of its use in skin wounds and wound infection. However, it's use in skin diseases has not been fully explored‐ so this is a beta test to see if and how it will work in non‐invasive diagnosis of inflammatory skin disease, especially in children. Exploring this technology is of great importance because dermatitis is recognized as a major pediatric disorder. Also disabling inflammatory chronic skin disease (psoriasis, rosacea) are a major focus of successful treatment by pharmacology companies.


AUTOFLUORESCENCE FIELD TEST   
 
by: Randall Weisel, DDS (Excerpt from Journal of Dentistry and Oral Sciences/ "Auto Fluorescence Allows Us to Detect Early Signs of Oral Cancer and Much More")

Review of autofluorescence enables us to objectively examine the oral cavity for inflammation and infection. Many systemic diseases are perpetuated by microorganisms that colonize in the oral environment. They enter the cardiovascular system by enzymatic processes that open the oral mucosa to allow their entry. A majority of the microbes are anaerobes and/or facultative anaerobes. When they enter the host, they metabolize blood. Their waste by products contains iron elements within a compound called porphyrin. Porphyrin will fluoresce when exposed to certain wavelengths of light. Healthcare providers can utilize this natural occurring process to objectively see these harmful pathogens. This may indicate that the host has a Sleep Related Breathing Disorder (SRBD). Sleep apnea is a primary disorder of SRBD’s. This technology offers medical and dental fields a screening tool for a pandemic healthcare problem.

Pathogenic microbial presences and the size of the colony (the bioload) can be relatively determined [19]. Fluorescence visualization of red-orange means bacterial pathogens are present. Presence of bluish green/bright white indicates presence of Pseudomonas [19]. The conditions for these pathogens to exist can occur within individuals with Sleep Related Breathing Disorders (SRBD). Sleep Apnea is the most prevalent of these disorders [20]. Researchers should focus their attention to the dorsum of the tongue ecosystem. Autofluorescence, performed with technology that utilizes electromagnetic spectral ranges and special filters that are components of the Velscope, allows visualization of pathogenic microbes. Scientific research demonstrates that oral pathogens (Pg, Aa, and Fn) may be direct and/or indirect causative agents of systemic diseases. These oral pathogens cause inflammation and infection.



SPECIAL THANKS to Dr. Monique Rennie, Director of Scientific Affairs and Global Engagement at Moleculight for her generous technical support and assistance greatly added  to the quality and integrity of this feature article. 


REFERENCES:

1) Raizman R et al. Use of a bacterial fluorescence imaging device: wound measurement, bacterial detection and targeted debridement. J Wound Care (2019). https://pubmed.ncbi.nlm.nih.gov/31825778/

2) Price N. Routine fluorescence imaging to detect wound bacteria reduces antibiotic use and antimicrobial dressing expenditure while improving healing rates: retrospective analysis of 229 foot ulcers. Diagnostics 2020;10:927.

19) Le, L.; Baer, M.; Briggs, P.; Bullock, N.; Cole, W.; DiMarco, D.; Hamil, R.; Harrell, K.; Kasper, M.; Li, W.; et al. Diagnostic Accuracy of Point-of-Care Fluorescence Imaging for the Detection of Bacterial Burden in Wounds: Results from the 350-Patient Fluorescence Imaging Assessment and Guidance Trial. Advances in Wound Care. 2021. https://pubmed.ncbi.nlm.nih.gov/32870774/

20) Sleep-Disordered Breathing.chapter 23.Thoracic.org. 237-247. Boillot A, Demmer RT, Mallat Z, Sacco RL, Jacobs DR, Benessiano J, et al. Periodontal microbiota and phospholipases: the oral infections and vascular disease epidemiology study (INVEST). Atherosclerosis. 2015;242(2):418-23. PubMed | CrossRef

21) Bale BF, Doneen AL, Vigerust DJ. High-risk periodontal pathogens contribute to the pathogenesis of atherosclerosis. Postgrad Med J. 2017;93(1098):215-20. PubMed | CrossRef

22. Boillot A, Demmer RT, Mallat Z, Sacco RL, Jacobs DR, Benessiano J, et al. Periodontal microbiota and phospholipases: the oral infections and vascular disease epidemiology study (INVEST). Atherosclerosis. 2015;242(2):418-23. PubMed | CrossRef

23) Desvarieux M, Demmer RT, Jacobs Jr DR, Rundek T, Boden-Albala B, Sacco RL, et al. Periodontal bacteria and hypertension: the oral infections and vascular disease epidemiology study (INVEST). J Hypertens. 2010;28(7):1413. PubMed | CrossRef


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