COVID19

A review of the literature: cytokine storm in COVID-19 and novel treatments and trials

Virginia Thornley, M.D.
Neurologist
April 13, 2020

Neurologybuzz.com
http://virginiathornleymd.com/

Introduction
COVID-19 is now a global pandemic. The world is in the midst of a virus that is still an unknown entity. Here, we look at the published research of what we know so far.

Cytokine storm
COVID-19 or the coronavirus is thought to incite a cytokine storm. On review of the literature for severe influenza, a cytokine storm refers to the release of cytokine factors triggered by infection or drugs. It is caused by the breakdown of infected white blood cells through apoptosis causing the release of cytokine factors that lead to a release of even more white blood cells. First, there are infected white blood cells then pro-inflammatory cytokines react. These lead to increased expression of anti-viral, proinflammatory apoptotic genes resulting in tissue damage. There are simultaneous regenerative processes occurring. Usually, the repair is complete. In some cases, it results in severe tissue damage and excess inflammatory responses resulting in alveolar damage. The excessive cytokine-induced inflammation can leak systemically resulting in widespread organ failure (1).

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photo credit: CDC through Unsplash

Therapies including IL-6 inhibitors and convalescent plasma
In one report, there is some treatment targeting the cytokine storm which is thought to make some progress including interleukin-6 (IL-6) antibody inhibitors, stem cell therapy as well as transfusion of plasma in convalescence(2). Currently, there are clinical trials at Mount Sinai Hospital in New York City to look into the use of convalescent plasma. There are ongoing trials for interleukin-6 inhibitors by drug companies Sanofi and Regeneron.

Chloroquine
While chloroquine is recommended by expert Chinese consensus after extensive discussion, there are, however, no large human randomized controlled clinical trials yet in COVID-19 showing sufficient scientific evidence that it definitively works(3). Many clinical studies for drugs are ongoing at the time of this writing.

NSAIDs and COVID-19
While there are no studies specifically on the effect of non-steroidal anti-inflammatory drugs on COVID-19, however, there are suggestions it could potentially blunt the immune system from fighting the virus (4). In a UK publication in the BMJ 2020, doctors and scientists believe that NSAIDs in the setting of respiratory failure in COVID-19 could potentially lengthen the time of recovery. Thoughts are that the respiratory illness may be prolonged with the use of NSAIDs. This stemmed from a comment made by an infectious disease doctor in the south of France where 4 individuals with COVID-19 appeared to worsen with the inclusion of NSAIDs in the treatment protocol. Ibuprofen was deleted from treatment protocols in patients with infections in France as of 2019 with paracetamol used in its place. This was supported by expert figures in the UK (4).

Hydroxychloroquine and azithromycin
One small study of 20 patients was recently published showing some improvement of patients on a combination of hydroxychloroquine and azithromycin (5).

Summary
Because this is a novel virus, research is still ongoing and fluid. Larger human studies are needed. There are larger trials ongoing for various drugs. So far most of the research that has been published is in a small number of patients.

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Disclaimer: This is information only not advice, please consult with your physician

References
1. Liu, Q., Zhou, Y. & Yang, Z. The cytokine storm of severe influenza and the development of immunomodulatory therapy. Cell Mol Immunol 13, 3–10 (2016). https://doi.org/10.1038/cmi.2015.74
2.Chen, C., Zheng, X.R., Ju, Z.Y., He, WF. Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies. Zhonghua Shao Shang Za Zhi. 2020 Mar. 1;36(0):E005
3.Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185-188. doi: 10.3760/cma.j.issn.1001-0939.2020.03.009.
4. BMJ 2020;368:m1086 doi: 10.1136/bmj.m1086
5. Gautret, P., Lagier, J., Parola, P., Hoang, V.T., Meddeb, L., Mailhe, M., Doudier, B., Courion, J., Giordanengo, V., Viera, V., Dupont, H., Honore, S., Colson, P., Chabriere, E.,La Scola, B., Rolain, J., Brouqui, P., Raoult, D. Hydroxychloroquine and azithromycin as a treatment of COVD-19: results of an open-label non-randomized clinical trial, Int. J. Antimicrobi Agents. 2020, Mar 20doi: 10.1016/j.ijantimicag.2020.105949 [Epub ahead of print]

Disclaimer: This is information only not advice, please consult with your physician

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COVID19

Review of literature: introduction and clinical presentations of COVID19

Review of literature: introduction to the COVID19 and clinical presentations

credit: photo by CDC by Unsplash

Virginia Thornley, M.D.
Neurologist
April 2, 2020

Introduction
A new virus emerged in Wuhun, China in December 2019. But the information is still emerging on how to treat it and the exact pathophysiology.

The coronavirus is a type of virus that can infect both animals and humans.
It was named COVID19 for corona virus disease 2019 and renamed SARS-CoV2 which was discovered in the epithelium of the respiratory system of patients from Wuhun, China (1).

COVID-19
COVID19 first occurred December 7, 2019 in the markets of Wuhun, China. The pathogen is the SAR-CoV2. The intermediate host is thought to be the Pangolin. It is a type of RNA virus. The original host is an animal but it jumped to humans. The species pathogen is the B-corona virus. The latency period is about 2-7 days infecting people who have never been exposed to it before(1).

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Clinical presentation
The infection is classified as mild, moderate, severe and critical. Mild cases present with fever, respiratory symptoms and no pneumonia on imaging studies. Moderate is described as those with fever, respiratory symptoms and pneumonia on imaging studies. Severe cases present with respiratory failure with a respiratory rate greater than 30/minute, oxygen saturation or O2 saturation of less than or equal to 93mmHg, PaO2/FiO2 of less than 300mmHg. Critical cases include one of the following: need for mechanical ventilation, shock or organ failure requiring ICU admission. There can be dyspnea leading to acute respiratory distress syndrome (ARDS), metabolic abnormalities that are refractory to correction, shock and thrombosis(3).

Epidemiology
The SARS epidemic which occurred in 2003 affecting China extending to other other Southeast Asian countries, by contrast, lasted 7 months affecting 8096 people resulting in 774 deaths. There was a high mortality rate among hospital personnel of about 21% (1). The COVID19 started December 7, 2019 and is still ongoing at the time of this writing. At the time of this writing, there are 1,040617 affected with 55,188 deaths(2). The numbers continue to climb. It was declared a pandemic by the WHO. Most clinical cases are elderly, however, the coronavirus could be seen in those with diabetes mellitus and hepatitis B. An immunocompromised state is also a risk factor. Male to female ratio based on studies in China is 2.7:1. Mortality rate is 2.1%

References:
1. Xu, J., Zhao, S., Teng, T., Abdalla, A.E., Zhu, W., XIE, L., Wang, Y., Guo, X. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses. 2020, Feb. 22;12(2).
2. Worldometer, Coronavurus pandemic 2019
3. Feng, Y., Liu, N., Hu, J., Wu, l., Su, G., Zhong, N., Zheng, Z. 4S Respiratory rehabilitation guidelines for patients with pneumonia infected by new Coronavirus. Chinese Journal of Tuberculosis and Respiratory Diseases, 2020, 43: Pre-published online. DOI: 10.3760 / cma.j.issn.1001-0939.2020.0004

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Essential tremor, Uncategorized

Deep brain stimulation and essential tremor

Virginia Thornley, M.D.
Neurologist, Epileptologist
November 6, 2019
Essential tremor is now treated with implantation of a deep brain stimulating device. It has been approved for treatment for Parkinson’s disease, essential tremor, dystonic tremor and obsessive compulsive disorder (1).
Basically, within the brain, there is a recurrent loop that is not inhibited by the correct feedback inhibition resulting in repetitive actions. In obsessive-compulsive disorders, there are repetitive thoughts and actions since this loop is not controlled.
In one study, the ventral intermediate nucleus (VIM) was stimulated in 98 patients with Parkinson’s disease, essential tremor and dystonic tremor with sustained improvement. There was significant long-term improvement even after 10 years(2).
The mechanism is unclear. However, certain nuclei stimulated were found to result in side effects. Thalamic stimulation resulted in fatigue. Subthalamic nuclear implantation was found to give rise to depression and suicidality(3).
Neurologybuzz.com
References
  1. Naestromm, M., Blomstedt, P., Hariz, M., Bodjund, O., Deep brain stimulation for obsessive-compulsive disorder: knowledge and concerns among psychiatrists, psychotherapists and patients,  Surg. Neurol Int. 2017; 8:298 
  2. Cury, R.G., Fraix, V., Castrioto, A.,Perez-Fernandez, M.A., Krack, P., Chabardes, S., Seigneuret, E., Alho, E.J., Benabid, A.L., Moro, E. Thalamic deep brain stimulation in Parkinson disease, essential tremor and dystonia. Neurology. 2017 Sep 26;89(13):1416-1423
  3. Zarzycki, M.Z., Domitrz, I., Stimulation-induced side effects after deep brain stimulation-a systematic review. Acta Neuropsychiatr. 2019, Aug 27:1-24
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multiple sclerosis, Uncategorized

The impact of immunomodulating agents used in multiple sclerosis on the risk of cancer

Virginia Thornley, M.D., Neurologist, Epileptologist
June 14, 2019
Introduction
Multiple sclerosis is already an illness where the immune system recognizes the nervous system specifically the white matter tracts as foreign and attacks it. The complex cascade of mechanisms make adequate treatment challenging. Many treatments focus on the inflammatory mechanism with little attention on the degenerative mechanism involved.
Presentation of symptoms come in a wide variety depending on the the location of the multiple sclerosis plaque in the brain.
Patients may have concomitant morbidities which may make treatment challenging.
 
Immunomodulating agents and its impact on cancer
Many of the newer treatments for multiple sclerosis work at the level of the immune system through immunosuppression, the newer ones tend to be very potent. With greater efficacy comes greater risks including the risk of cancer.
Some of the newer medications can potentially increase the risk of cancer. Higher risk of cancer was found in many reports to occur with use of cyclophosphamide, azathioprine and mitoxanthrone. Fingolimod, natalizumab and alemtuzamab  can potentially increase the risk of cancer, these agents lack long-term data and work through the immune system. Dimethyl fumarate, terifluonimide, ocrelizumab, daclizumab and cladribine merit mandatory risk management plans to detect cancer before its use.
Reference
  1. Lebrun, C., Rocher, F., Cancer risk in patients with multiple sclerosis: potential impact of disease-modifying drugs. CNS Drugs. 2018, Oct. 32(10):939-949 doi:10.1007/s40263-018-0564-y
Disclaimer: This is medical information only not medical advice. Please consult your physician
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cluster headache

Mechanism and novel approaches to treatment of cluster headache

Virginia Thornley, M.D., Neurologist
January 2, 2019
Cluster headache is a debilitating neurological condition which may be difficult to control. Novel approaches to treatment have been explored because of its refractory response to treatment.
Mechanisms involved in cluster headache
The pathophysiology involves the trigeminovascular pathway. This involves innervation to the  cerebral blood vessels and trigeminal complex including the nerves and ganglion. The ganglion has connections with the blood vessels of the cerebrum, the trigeminocervical complex and the dorsal horns of the C1 and C2 levels. In cluster headaches, certain chemicals are found to be increased during an attack  including calcitonin gene-related peptide and neurokinins which are neuropeptide vasodilators (1).
Calcitonin gene-related peptide antibody therapies
Some of the new anti-CGRP (calcitonin gene-related peptide antibody) therapies recently introduced to migraine patients have been applied to patients with cluster headache, including fremazunab and galcanezumab (2). it has been found that CGRP is released from the trigeminal ganglion and its transcription is increased when there are conditions that mimic those of migraine which includes an neurogenic inflammatory state (3).
There has been some success in its treatment although its application is not yet indicated for these drugs (2).
Botulinum toxin injection
Injection of onabotulinum toxin into the sphenopalatine ganglion was studied in 7 patients with chronic cluster headache. Of these, 3 dropped out. The patients were followed 24 months. There was a 50% reduction in occurrence of pain, after repeated injections. Due to the small size results should be interpreted with caution, however, because of repeated injections, its effectiveness may be significantly underestimated. This is a small pilot observational study. Larger studies are needed (4).
 
Vagal nerve stimulation
Vagal nerve stimulation was employed in 30 patients and a mean reduction of 26 attacks/week to 9.5 over a 3-6 month period was seen. Mean attack duration was 51.9 to 29.5 minutes. Larger studies are needed (5).
In summary 
Several new novel approaches include vagal nerve stimulation and botulinum toxin injections. Anti-CGRP antibodies are another novel treatment but have not yet been submitted for an indication. Larger studies are needed.
@VThornley_MD
Reference
  1. Goadsby, P.J., Edvinson, L., Human in vivo evidence for trigeminovascular activation in cluster headache.Neuropeptude chanes and effects of acute attackes therapies. Brain. 1994 Jun; 117 (Pt 3):427-34
  2. Ashehoug, I., Bratbak, D.F., Tronvik, E.A. Long-term outcome of patients with intractable chronic cluster headache treated with injection of onabotulinumtoxin A toward the sphenopalatine ganglion – an observational study. Headache, 2018, Nov; 58(10):1519-1529
  3. P.L. Durham, Calcitonin gene-related peptide and migraine. 2006, Jun. 46 (Suppl 1):S3-S8
  4. Tepper, S.J. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018
  5. Marin, J., Giffin, N., Consiglio, E., mcClure, C., Liebler, E., Davies, B. Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience. J. Headache Pain. 2018, Nov. 23; 19

Disclaimer: This is for informational purposes only and is not medical advice. Please see your physician. Reading this does not constitute a physician-patient relationship.

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Parkinson's disaese

Parkinson’s disease: a look at a novel biomarker, immunogenetic & mitochondrial studies

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Virginia Thornley, M.D., Neurologist, Epileptologist
December 17, 2018
Introduction
Parkinson’s disease is typically diagnosed through clinical evaluation. At times, it may be difficult to differentiate from other disorders if all cardinal features are not present. This looks at the literature to review biomarkers that may be helpful in evaluation of the diagnosis of Parkinson’s disease.
 
Novel serum marker LAG-3
One study correlates the serum marker LAG-3 lymphocyte activation gene 3  (LAG-3). It is thought to be related to the transmission of alpha-synuclein which could be connected to the degenerative process in Parkinson’s disease. Serum LAG-3 was found to be higher in the serum levels compared to patients with essential tremors and a control group that was sex and age matched. LAG-3 can potentially serve as a biomarker when the diagnosis is in question (1).
 
Immunogenicity
As the population ages, there is a proliferation of neurodegenerative disorders. Familial disorders account for a small portion of these about 5-10%. It is thought that there are genetic and environmental component to the familial types of neurodegenerative diseases. Gene variants are found on HLA (human leukocyte antigen) which code for MHL II (major histocompatibility complex class II) which is found in microglia which has an immunologic component. Microglia phagocytizes unnecessary proteins but also produces an inflammatory response. How the immune system responds to environmental factors resulting in neurodegenerative disease is a subject of research and needs to be elucidated further (2). 
 
The role of the mitochondrial dysfunction in Parkinson’s disease
Mitochondrial dysfunction and oxidative damage is found in the cells of patients with Parkinson’s disease. Mitochondrial abnormalities have been hypothesized to correlate with the pathophysiology of Parkinsons disease. Recent research has shown a tying of both genetic and environmental factors in relation to the pathophysiology of Parkinson’s disease. The PINK1 and Parkin gene are related to mitochondrial function and are present in Parkinson’s disease and the pathways involved with the  quality control in the mitochondrion. When oxidative stress is present and the cells cannot detoxify this can affect mitochondrial functioning which is the powerhouse of cells producing ATP or the energy source (3).
Reference
  1. Cui, S., Du, J.J., Liu, S.H., Meng, J., Lin, Y.Q., Li, G., He, Y.X., Zhang, P.C., Chen, S., Wang, G., Serm soluble lymphocyte activation gene-3 as a diagnostic biomarker in Parkinson’s disease: a pilot multicenter study,” Mov Disord 2018, Nov. doi:10.1002/mds.27569 (epub ahead of print)
  2. Aliseychik, M.P., Andreeva, T.V., Rogaev, E.I., “Immunogenetic factors of neurodegenerative diseases: the role of HLA Class II,” Biochemistry, 2018, Sep. 83(9):1104-1116
  3. Sato, S., Hattori, N., “Genetic mutations and mitochondrial toxins shed new light on the pathogenesis of Parkinson’s disease.” Parkinsons Dis. 2011; 2011:979231
 
 
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