Ischemic Strokes in Young People with COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
6/23/2020
Another week, another study on horrifying brain injuries associated with COVID-19… Let’s get started. Although I’ve mentioned reports of stroke in previous reviews of neurological symptoms in COVID, I have not yet covered the published case reports describing ischemia.
A case study came out in the New England Journal of Medicine that described cases of large-vessel stroke in young patients (<50 years old), with one of the patients being a 33 year-old woman with no previous health problems (Oxley et al., 2020). Five patients described in this study tested positive for SARS-CoV-2 and their mean National Institutes of Health Stroke Scale (NIHSS) scores were 17, consistent with ischemic stroke with large artery involvement. All five patients were treated at Mount Sinai in New York during a single two-week period. This is notable because the authors also mention that over the previous year, their service only saw an average of 0.73 patients presenting with large-vessel stroke every 2 weeks, so these COVID-19 positive cases represent a big spike in ischemia among people under 50 years old. Coagulopathy and vascular endothelial dysfunction were mentioned as potential causes, but no definitive mechanism has been identified.
So far, there have not been any studies that have identified the particular strain of virus present in the US. Because the European strain has been associated with higher prevalence of ageusia and anosmia, it has been hypothesized that the European strain may lead to higher neurological symptoms compared to the Wuhan strain (see blog post from 6/8/20). Epidemiological studies need to be conducted in order to identify the prevalence of COVID-19-related neurological symptoms across the US, as well as identify which strain of SARS-CoV-2 exists in different regions. Correlating these two pieces of information may offer a clue as to how mutations in the spike protein correlate with neurological symptom presentation in COVID-19. Further, it would be interesting to identify any common genetic or environmental risk factors amongst these young patients that present with stroke.
Reference
Oxley, T. J., Mocco, J., Majidi, S., Kellner, C. P., Shoirah, H., Singh, I. P., … & Skliut, M. (2020). Large-vessel stroke as a presenting feature of Covid-19 in the young. New England Journal of Medicine, 382(20), e60.
Acute Necrotizing Myelitis in COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
6/15/2020
Adding to the macabre menagerie of potential complications from COVID-19, a new report published in Neurology: Neuroimmunology & Neuroinflammation describes acute necrotizing myelitis (ANM) associated with SARS-CoV-2 infection. A 69-year-old female patient from Spain presented to clinic with complaints of cervical pain, imbalance, and motor weakness/numbness in her left hand, which had persisted for one week. Her symptoms were preceded by fever and cough eight days prior to the onset of her neurological symptoms.
Her initial workup was negative for infections and autoimmune diseases and she was specifically ruled out for neuromyelitis optica (NMO) with a negative AQP4 and MOG IgG. On her CSF analysis, there were no oligoclonal bands, a typical marker of MS and other inflammatory disorders. Her CSF workup was also negative for bacterial or viral infection. CSF was positive for a mild lymphocytic pleocytosis (increased cell count) and high protein (2.83 g/L). The CSF was negative for SARS-CoV-2, though the nasopharyngeal swab was positive.
On review of imaging, the patient’s brain MRI was normal, but spinal cord images displayed an extensive T2-hyperintensity from medulla oblongata to C7, with evidence of acute transverse myelitis. IV Methylprednisolone was given for 5 days and led to initial improvement, though the patient proceeded to rapidly deteriorate following cessation of methylprednisolone. She developed sensory motor deficits in her hands and paraparesis with bowel incontinence. One week after admission, a follow up MRI revealed extension of the myelitis to T6 with associated enhancement and a new focal necrotizing area at T1 with peripheral enhancement. Following her clinical deterioration, the patient was treated with plasma exchange and another course of methylprednisolone pulse for 5 days, in addition to slow oral administration of prednisone, which ultimately resulted in improvement of her motor function. The patient continued to improve over the course of the next four weeks and was able to walk with assistance as well as write and use her mobile phone (though with some difficulty). Persistent issues that did not resolve at the time of writing this paper were weakness in the left leg and lack of bowel control. An MRI done post plasmapheresis revealed a decrease in myelitis extension and enhancement, but unchanged central necrosis.
The authors diagnosed her with acute necrotizing myelitis (ANM), which is rare and has been previously associated with NMO and other inflammatory diseases. The association of ANM with COVID-19 has not been studied, but it is hypothesized that ANM appears as a result of the cytokine storm secondary to viral infection. The authors also hypothesized that these neurological symptoms could be due to the neuroinvasive potential of SARS-CoV-2, which is a topic I have described in previous blog posts. This study is also similar to case studies describing COVID-associated acute necrotizing encephalitis (ANE). So far, these cases of ANE and ANM appear to be exceedingly rare complications that affect elderly patients, but not much is known about how they develop or what aspect of aging confers higher risk of developing these frightening neurological symptoms.
References
Sotoca J, Rodríguez-Álvarez Y. COVID-19-associated acute necrotizing myelitis. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e803. Published 2020 Jun 10. doi:10.1212/NXI.0000000000000803
Geographic discrepancies in prevalence of olfactory and gustatory dysfunction in COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
6/8/2020
Early studies on COVID-19 from China first revealed that SARS-CoV-2 infection can lead to anosmia (lack of smell) and ageusia (lack of taste). These early studies reported that these symptoms were uncommon, listing the prevalence at 5% of COVID-19 cases (Mao et al., 2020). However, more recent studies from Europe report a much higher prevalence of anosmia and ageusia, with one study from France reporting that 49 COVID-19 patients out of the 72 enrolled (68%) reported both symptoms, a significantly higher prevalence than in China (Luers et al., 2020).
In an opinion piece responding to these findings, John Gourtsoyannis summarized some different possibilities for this discrepancy. It may be that there are cultural differences in how these symptoms are experienced and reported among patients and medical professionals, but this explanation is less likely due to the massive discrepancy in reported symptoms. Another explanation is that there may be differences in the ACE2 receptor expression in the nasopharynx between East Asian and European populations. The last possible explanation he lists is that mutations in the spike protein of the virus may be mediating this difference. The majority of COVID-19 cases in Europe have been caused by SARS-CoV-2 with the D416G mutation. It may be the case that this variant of the virus is the cause for differences in symptomatology, and if this is the case, would represent a clinically distinct strain.
Writing in response to this opinion piece, Luers et al. gave their opinions on the geographical discrepancy. So far, ACE2 receptor expression in the nasopharynx has not been definitively shown to be different between East Asian and European populations, but the authors note that SARS-CoV-2 has been shown to infiltrate non-neuronal mucosal membranes in the olfactory system in Asian populations, so there needs to be more work to identify if ACE2 receptor expression is different between these populations. The authors agreed with the possibility that the viral mutation brought up by Gourtsoyannis is at play. They also brought up the interesting idea that if the spike protein mutation in the European virus does enable stronger infiltration into neurons of the olfactory system, this may lead to an overall strong neurotropism compared to the Wuhan strain. If this hypothesis is true, it could mean that the European virus would lead to a higher prevalence of neurological symptoms, as others have hypothesized that the peripheral olfactory system may be the portal through which the virus accesses the CNS. More work needs to be done to confirm or refute this concerning scenario.
References
Gourtsoyannis, J. (2020). COVID-19: Possible reasons for the increased prevalence of Olfactory and Gustatory dysfunction observed in European studies. Clinical Infectious Diseases.
Luers, J. C., Rokohl, A. C., Loreck, N., Wawer Matos, P. A., Augustin, M., Dewald, F., … & Heindl, L. M. (2020). Reply to Gourtsoyannis. Clinical Infectious Diseases.
Luers, J. C., Rokohl, A. C., Loreck, N., Wawer Matos, P. A., Augustin, M., Dewald, F., … & Heindl, L. M. (2020). Olfactory and gustatory dysfunction in Coronavirus disease 19 (COVID-19). Clinical Infectious Diseases.
Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., … & Li, Y. (2020). Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: a retrospective case series study.
The Gut-Brain Axis May Mediate Gastrointestinal and Neurological Symptoms of COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
6/2/2020
The gut microbiome and the gut-brain connection are currently hot topics in neuroimmunology, so I am constantly on the lookout for studies describing dysbiosis in COVID-19 patients. There are currently no large-scale studies on changes to the microbiome after SARS-CoV-2 infection, but there have been some interesting theories posed as to how the gut microflora and gut-brain axis may be mediating neurological and gastrointestinal (GI) symptoms.
Writing in Inflammatory Bowel Disease, Mehmet Bostancıklıoğlu hypothesizes that after the initial respiratory symptom onset, the neurological and GI symptoms that develop at nearly the same time during the course of the infection may be interlinked via the gut-brain axis. The author starts by describing the incidence of GI symptoms in cases of COVID-19. Despite initial studies demonstrating low incidence of GI symptoms, more recent estimates place the incidence at 11.4%-24.2% (Bostancıklıoğlu, 2020). He then cites a study in China that revealed GI symptoms from COVID-19 do not necessarily correlate with RNA shedding into the feces (Lin et al., 2020). Out of the 95 patients studied, 11 had GI symptoms upon admission and 47 developed symptoms upon hospitalization, with the most common symptoms being diarrhea (24.2%), anorexia (17.9%), and nausea (17.9%). They then analyzed the fecal samples of patients with and without GI symptoms for the presence of SARS-CoV-2 RNA and found there was not a significant difference. Based on this result, Mehmet Bostancıklıoğlu claims that this discrepancy can be explained by gut-brain crosstalk.
The most direct proposed mechanism for SARS-CoV-2-related GI symptoms is the direct invasion of the virus via ACE2, which is expressed in the gut. This explanation does not provide the full picture because of the discrepancy mentioned above, as we would expect that all GI distress associated with viral inflammation would lead to viral shedding. Instead, the author describes the possibility that the virus can invade the lateral hypothalamic nuclei, which would lead to GI symptoms such as anorexia and nausea without viral infection of the gut. This would explain why GI symptoms occur without viral RNA shedding. Alternatively, the virus may invade the GI tract and cause inflammation and gut microbiome dysbiosis. This would then lead to viral RNA shedding into the feces, as other studies have demonstrated intestinal inflammation during COVID-19 is correlated with the presence of viral RNA in fecal samples (Effenberger et al., 2020). Additionally, the author goes on to say that proinflammatory mediators from the gut can then reach the brain via the lymph or blood, or perhaps through activation of the vagal nerve, which would go on to cause neurological symptoms.
This opinion piece brings up a lot of interesting questions that have yet to be answered. So far, there are no studies on how GI symptoms develop during COVID-19, so I wonder how the virus is entering the GI tract. From what I’ve read, it seems like no one has been able to isolate and culture viable, intact virus from patient blood, so perhaps the virus is entering via the oral route – maybe from eating infected food or swallowing a significant amount of infected aerosol droplets. It will be interesting to see if anyone is able to isolate and culture viable virus from the digestive tract of COVID-19 patients. Additionally, it will be interesting to see if COVID-19 patients (with varying severities of GI and neurological symptoms) have dysbiotic gut microbiomes and then look at which bacterial species are over- and under-represented across the spectrum of symptom severity. Perhaps this may offer some insight into how different gut microbiome compositions may affect clinical outcomes for COVID-19. Finally, more studies need to be done on the neuroinvasive potential of SARS-CoV-2, and how this hypothesized invasion of the CNS may mediate symptoms in other organ systems.
References
Bostancıklıoğlu, M. (2020). Temporal Correlation Between Neurological and Gastrointestinal Symptoms of SARS-CoV-2. Inflammatory Bowel Diseases.
Lin, L., Jiang, X., Zhang, Z., Huang, S., Zhang, Z., Fang, Z., … & Liu, Y. (2020). Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut, 69(6), 997-1001.
Effenberger, M., Grabherr, F., Mayr, L., Schwaerzler, J., Nairz, M., Seifert, M., … & Bellmann-Weiler, R. (2020). Faecal calprotectin indicates intestinal inflammation in COVID-19. Gut.
Health Outcomes of Multiple Sclerosis Patients with COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
5/25/2020
This week, I would like to focus on a topic that our lab has been interested in understanding for a long time, which is the health outcomes of multiple sclerosis (MS) patients with COVID-19. There have been primarily two published papers that discuss this topic and I will summarize the findings from one paper that came out earlier this week on MedRxive.
Parrotta and colleagues, from NYU Langone Multiple Sclerosis Comprehensive Care Centers (MSCCC), applied descriptive statistics to summarize demographic and clinical characteristics of MS patients or patients with similar autoimmune disorders that have been diagnosed with COVID-19 in order to better understand how COVID-19 affects health outcomes in patients with autoimmune disorders. Patients were recruited into this study after admission to the hospital with COVID-19 symptoms, or after describing symptoms of COVID-19 during teleneurology appointments.
76 total patients met the inclusion criteria, with 72 having MS and the other 4 having related disorders such as neuromyelitis optica spectrum disorder (NMOSD), chronic-relapsing-inflammatory-optic-neuropathy (CRION), neurosarcoidosis, and myelin-oligodendrocyte-glyocoprotein-IgG-associated disorder (MOGAD). The average age of enrolled patients was 44.9 years old, with 61.8% being female, which is typical for autoimmune disorders. 55 of the patients (76.4%) had relapsing-remitting MS (RRMS) while 17 (23.6%) had primary- or secondary-progressive MS (PPMS/SPMS). The most common symptoms seen in these patients were fever, cough, fatigue, shortness of breath, myalgia/arthralgia, anosmia, ageusia, and headache, which are all typical symptoms of COVID-19. More pertinent to autoimmune disorders, 21.1% reported neurologic symptom re-crudescence, which is suggestive of a pseudo-relapse. In some of these pseudo-relapses, the neurologic symptoms preceded the viral symptoms by a few days, which suggests that the virus may be mediating neurologic symptoms in patients with existing neurological autoimmune conditions during the incubation period ahead of actual viral syndrome.
84% of patients were on disease-modifying therapies (DMT). 44.7% of these patients were on anti-CD20 therapies such as rituximab and ocrelizumab, 13.5% were on sphingosine-1-phosphate modulations such fingolimod and siponimod, 7.9% were on glatiramer acetate (Copaxone), 5.3% were on natalizumab, 5.3% were on dimethyl fumarate, and 3.9% were on beta-interferons. The authors found that there were no significant differences between DMT use among patients who were either hospitalized or not hospitalized. Additionally, they did not find a statistical difference between hospitalization rates in patients taking or not taking anti-CD20 therapies, which is important because this has been a concern for some time since B-cell depletion may be a worrisome side effect of these drugs in patients who are battling an infectious respiratory virus.
18 of 76 patients were hospitalized (23.7%). Hospitalized patients were more likely to be older, have PPMS/SPMS, be less ambulatory, have comorbid obesity, have coronary artery disease, and have a history of venous thromboembolism. Eight patients had critical illness as defined by ICU admission or death. Like the hospitalized group, critically ill patients were more likely to be older, have PPMS/SPMS, be less ambulatory, have comorbid obesity, have coronary artery disease, and have a history of venous thromboembolism. There were also 9 patients with pediatric-onset MS, who were much younger and tended to fare better compared to older patients with COVID-19.
Overall, the rate of hospitalization (24%) and mortality (7.9%) in this subset of patients was similar to the data from another published MS patient database (Sormani, 2020). The subset of patients in both studies also did not have significantly higher or lower hospitalization and mortality rates than the general population of patients with COVID-19. The MS-specific symptoms strongly associated with more severe COVID-19 outcomes included non-ambulatory status and a progressive disease course rather than relapsing-remitting disease. One limitation of this study is the small sample size, which makes it difficult to determine whether these patients with non-ambulatory status and progressive disease subtype fared worse because of their advanced age and other comorbidities or whether the MS-specific disability itself contributed to additional risk for COVID-19-related complications. Another limitation is that because of the way patients were recruited, the data set was skewed to represent patients with more severe outcomes, so asymptomatic cases were not adequately assessed. The authors recognize these limitations. Nonetheless, it is interesting to see in this early data that there has not been any additional risk attributed to taking B cell-depleting or other immunosuppressive/immunomodulatory therapies. It will be important to see if this conclusion still holds in future larger population studies.
References
Sormani, M. P. (2020). An Italian programme for COVID-19 infection in multiple sclerosis. The Lancet Neurology.
Parrotta, E., Kister, I., Charvet, L., Sammarco, C., Saha, V., Charlson, R. E., … Zhovtis Ryerson, L. (2020). COVID-19 Outcomes in MS: Early experience from NYU multiple sclerosis comprehensive care center. MedRxiv, 2020.05.12.20094508. https://doi.org/10.1101/2020.05.12.20094508
Encephalitis in COVID-19 Patients
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
5/18/2020
Encephalitis (inflammation of the brain) has now been associated with COVID-19 in several published case studies from around the world. This week’s blog post will focus on several of these encephalitis case studies.
Case Presentation: A male patient from Wuhan (age not provided in the article) presented with typical COVID-19 symptoms, including fever and shortness of breath. His disease progressed and he began to show signs of confusion and altered consciousness. At the time of presentation, he was found to have low white blood cell count with lymphopenia. CT of the head was normal, but chest CT revealed ground glass opacities typical of COVID-19 infection. The patient showed signs of meningeal irritation, including neck rigidity, Kernig and Brudzinski signs. His physicians performed a lumbar puncture to collect cerebrospinal fluid (CSF) and CSF pressure was elevated at 220 mmHg. CSF was tested for SARS-CoV-2 and was negative. His final diagnosis was encephalitis due to systemic SARS-CoV-2 infection (Ye, et al., 2020). The patient went on to recover fully by the time of his hospital discharge.
Case #2: Another case involves a 24-year-old male patient from Japan who first presented with headache, generalized fatigue, and fever. He was prescribed the influenza prophylactic drug, Laninamivir, and fever-reducing medications under the diagnosis of influenza. His symptoms worsened and another clinic conducted chest X-rays and blood tests, which were both negative. On day 9 post-onset of symptoms, he was found unconscious on the floor and was immediately taken to the hospital. During transport, he had a generalized seizur. He had a Glasgow coma scale of 6 and had neck stiffness on presentation to the ER. Blood work revealed an increased white cell count, decreased lymphocytes, and increased C-reactive protein. CT scans revealed no signs of brain edema, but chest CT showed ground glass opacity in the chest. Lumbar puncture revealed that CSF pressure was above 320 mmH2O. The patient was tested for SARS-CoV-2 via pharyngeal swab, which resulted as negative, but interestingly in this patient, the CSF was positive for SARS-CoV-2. MRI of the brain at 20 hours post admission demonstrated hyperintense signal within the right mesial temporal lobe and hippocampus as well as mid hippocampal atrophy and pan-paranasal sinusitis (Moriguchi, et al., 2020). The patient remained encephalopathic in the intensive care unit by day 15 of hospitalization and was treated for bacterial pneumonia. This case raises the question of whether temporal lobe/hippocampal injury was due to direct viral infection or post infectious autoimmune phenomenon.
These two clinical cases share some similarities – in both cases, the patients presented with symptoms of encephalitis: neck stiffness and altered consciousness in context of an upper respiratory infection and ground glass opacities on the CT chest, which are telltale signs of COVID-19. There were also important differences in their presentation and outcomes. Only one of the patients with encephalitis had SARS-CoV-2 in the CSF, and the positive test was associated with a worse clinical outcome compared to the patient with negative SARS-CoV-2 CSF test. Given these emerging clinical cases of SARS-CoV-2 associated encephalitis, it is important to monitor COVID-19 patients for neurological signs of encephalitis as well as to consider COVID-19 in patients who initially present with neurological symptoms that suggest meningitis/encephalitis. Prompt attention to the diagnosis of SARS-CoV-2 related encephalitis will hopefully facilitate prompt treatment and improved patient outcomes.
References
Moriguchi, T., Harii, N., Goto, J., Harada, D., Sugawara, H., Takamino, J., … & Nakao, A. (2020). A first Case of Meningitis/Encephalitis associated with SARS-Coronavirus-2. International Journal of Infectious Diseases.
Ye, M., Ren, Y., & Lv, T. (2020). Encephalitis as a clinical manifestation of COVID-19. Brain, behavior, and immunity.
COVID-19 and Guillain-Barré Syndrome
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
5/11/2020
This week I would like to focus on Guillain-Barré Syndrome (GBS) and the published reports on the association between GBS and COVID-19. GBS is a rare neurological autoimmune disorder that affects the peripheral immune system, characterized by sensory deficits, and in some cases leading to acute paralysis and neuromuscular respiratory failure. A case study from Italy was recently published in Neurology: Neuroimmunology & Neuroinflammation, describing an older patient who was diagnosed with GBS following COVID-19 infection (Alberti, et al., 2020). The patient was a 71-year-old man who initially presented with paresthesias (burning or prickling sensation in extremities). The paresthesias quickly evolved into a severe flaccid quadriparesis. On neurological exam, the patient retained normal consciousness and language skills and had no cranial nerve deficits. He was noted to have a stocking-and-glove hypesthesia and severe hypoxia on arterial blood gas evaluation. Brain CT scan was normal, but a chest CT scan revealed ground glass opacities typically seen in COVID-19. This workup prompted SARS-CoV-2 testing, which came back positive. The symptoms were interpreted as an acute form of polyradiculoneuritis with demyelinating features and the diagnosis of GBS associated with COVID-19 was made. Shortly afterwards, the patient developed severe respiratory failure and did not survive.
This case highlights the varied neurological presentations of COVID-19 as well as the need for more research to understand the association between viral infections and autoimmunity, particularly with GBS. Two-thirds of patients with GBS typically describe preceding symptoms of respiratory or gastrointestinal infection within four weeks of onset of the syndrome (Willison, Jacobs, von Doorn, 2016). Additionally, GBS is associated with gastrointestinal infections, such as Campylobacter jejuni, and other viruses, such as cytomegalovirus and Zika (Cao-Lormeau, et al., 2016, Visser, et al., 1996). Despite being generally rare, GBS’s strong association with preceding infections may shed light on how autoimmunity develops. Additionally, because GBS symptoms tend to resolve with time, it would be interesting to compare this condition to other autoimmune disorders where autoimmunity remains permanent. Perhaps particular viruses cause acute autoimmunity in some cases and chronic autoimmunity in others.
References
Alberti, P., Beretta, S., Piatti, M., Karantzoulis, A., Piatti, M. L., Santoro, P., … & Appollonio, I. (2020). Guillain-Barré syndrome related to COVID-19 infection. Neurology-Neuroimmunology Neuroinflammation, 7(4).
Cao-Lormeau, V. M., Blake, A., Mons, S., Lastère, S., Roche, C., Vanhomwegen, J., … & Vial, A. L. (2016). Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. The Lancet, 387(10027), 1531-1539.
Visser, L. H., Van der Meché, F. G. A., Meulstee, J., Rothbarth, P., Jacobs, B. C., Schmitz, P. I. M., & Van Doorn, P. A. (1996). Cytomegalovirus infection and Guillain-Barré syndrome: the clinical, electrophysiologic, and prognostic features. Neurology, 47(3), 668-673.
Willison, H. J., Jacobs, B. C., & Van Doorn, P. A. (2016). Guillain-barre syndrome. The Lancet, 388(10045), 717-727.
Debate on the Significance of Neurological Symptoms of COVID
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
5/4/2020
During the past week, while I was surveying the literature for any new neurological reports in COVID-19, I found a paper that casted doubt on the connections between neurological disease and COVID-19, which led me down a rabbit hole of dissenting papers. A few weeks ago, I wrote a blog post that briefly outlined the possibility that SARS-CoV-2 may perhaps invade the CNS and infect neurons in the brainstem that affect respiration and that this may play in part in respiratory failure. (Li, Bai, and Hashikawa, 2020) This week, in the Journal of Medical Virology, Lance Turtle dissents with this conclusion, suggesting that respiratory failure alone is not sufficient to suggest the involvement of the CNS because the type of respiratory failure that occurs typically from neurological failure (ventilatory failure, Type 2) is distinct from the type of respiratory failure seen in COVID-19 patients (hypoxic, Type 1). The author also claims that while some connection between human coronaviruses (HCoVs) and CNS cells has been explored in vitro, HCoVs have never been definitively linked with directly causing CNS disease. (Turtle, 2020) To the author’s point, many of the neurological symptoms seen in patients with COVID-19 so far have been relatively “nonspecific” (except for stroke) and may be secondary results of the inflammatory cytokine storm. While multiple mechanisms have been proposed such as ACE-2-mediated entry into neurons and glia, there is currently no evidence to support these hypotheses. However, SARS-CoV-2 has proven to be a different beast than the previous SARS outbreak and there also has not been evidence that contradicts the idea that SARS-CoV-2 can directly invade the CNS. Additionally, there have been reported cases of acute neurological symptoms such as stroke and acute necrotizing encephalopathy.(Poyiadji, et al., 2020)
In a response to Turtle, Li, et al. describe how at least four human coronaviruses have been shown to invade the nervous system, which opens up many questions regarding neurological symptoms not only during the normal course of the respiratory illness, but also well after the acute disease has subsided. (Li, Bai, and Hashikawa, 2020) These viruses are HCoV-229E, HCoV-OC43, SARS-CoV, and MERS-CoV. (Arbour, et al., 2000, Gu, et al., 2005, Xu, et al., 2005, Li, et al., 2016) Of these studies, one found that in post-mortem human brain tissue, patients with multiple sclerosis had significantly higher levels of HCoV-OC43 RNA than in healthy controls. (Arbour, et al., 2000) This finding raises interesting questions about potential long-term effects of coronavirus infection on neurological disease beyond just the normal course of respiratory illness. It may be the case that the neurological symptoms seen with COVID-19 may be secondary to the inflammation due to the cytokine storm, but there does seem to be some link between viral infections and chronic autoimmune disease. The same phenomenon has been observed with Guillaine-Barré Syndrome (GBS), where two-thirds of patients with this autoimmune disorder reported symptoms of respiratory or gastrointestinal infection within 4 weeks preceding the onset of the syndrome. (Willison, et al., 2016) As the number of cases of COVID-19 begin to fall, it will be important to track the long-term health outcomes of those who have been infected. More work needs to be done to identify the role of infection in autoimmunity, and the mechanism by which viruses enter the CNS.
References
Arbour, N., Day, R., Newcombe, J., & Talbot, P. J. (2000). Neuroinvasion by human respiratory coronaviruses. Journal of virology, 74(19), 8913-8921.
Gu, J., Gong, E., Zhang, B., Zheng, J., Gao, Z., Zhong, Y., … & Zhuang, H. (2005). Multiple organ infection and the pathogenesis of SARS. The Journal of experimental medicine, 202(3), 415-424.
Li, Y. C., Bai, W. Z., & Hashikawa, T. (2020). The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal of Medical Virology.
Li, Y., Bai, W. Z., & Hashikawa, T. (2020). Response to Commentary on:“The neuroinvasive potential of SARS‐CoV‐2 may play a role in the respiratory failure of COVID‐19 patients”. Journal of Medical Virology.
Li, K., Wohlford-Lenane, C., Perlman, S., Zhao, J., Jewell, A. K., Reznikov, L. R., … & McCray Jr, P. B. (2016). Middle East respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. The Journal of infectious diseases, 213(5), 712-722.
Poyiadji, N., Shahin, G., Noujaim, D., Stone, M., Patel, S., & Griffith, B. (2020). COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology, 201187.
Turtle, L. (2020). Respiratory failure alone does not suggest central nervous system invasion by SARS‐CoV‐2. Journal of Medical Virology.
Willison, H. J., Jacobs, B. C., & Van Doorn, P. A. (2016). Guillain-barre syndrome. The Lancet, 388(10045), 717-727.
Xu, J., Zhong, S., Liu, J., Li, L., Li, Y., Wu, X., … & Ding, Y. (2005). Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis. Clinical infectious diseases, 41(8), 1089-1096.
Mental Health During the Pandemic
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
4/27/2020
As people grow restless during self-isolation as a result of stay-at-home orders (especially as shown by the growing amount of protests across the USA), I think it is important to look at psychological responses to this crisis around the world. It may seem obvious that people respond negatively to a global infectious disease and being isolated indoors, but issues of mental health and psychiatric disorders during this crisis are not reported on nearly as much as the biological and economic impact of this disease.
One study from China showed that during the early phase of the pandemic, 16.5% of responders reported moderate to severe depressive symptoms, 28.8% reported moderate to severe anxiety symptoms, and 8.1% reported moderate to severe stress symptoms (Wang, et al., 2020). Factors that were associated with greater psychological impact of the pandemic were female gender, student status, physical symptoms, and poor self-rated health status. These factors were also associated with higher levels of stress, anxiety, and depression.
Another paper published in the Lancet focused on the lack of mental health services for older adults in China. China has 241 million people over the age 60, comprising the largest aging population globally as of 2017. Unfortunately, Chinese adults over the age of 55 have a higher prevalence of depressive symptoms (23.6%), which could be exacerbated by the high mortality rate of COVID-19 in this age group (Yang, et al., 2020). Despite the advantages of telemedicine, older adults in China are less likely to have access to the internet and smartphones. Additionally, older psychiatric patients in most parts of China obtain their medications in person from outpatient clinics, which has created a large barrier for many people. This has created a situation where many older people cannot access appropriate mental health services, which is made particularly more devastating due to mass restrictions on public movement.
infectious diseases in the past have created fear, isolation, and suffering at both the individual and community level. During the H1N1 influenza pandemic in the US, individuals were more likely to take part in risky behaviors such as smoking, drinking, drug misuse, recklessness, and unsafe work practices (Pfefferbaum, et al., 2012). Perhaps the many protests occurring across the US aimed at lifting stay-at-home orders are driven more by these well-documented psychological responses to pandemic (in addition to financial vulnerability) rather than an earnest belief in the effectiveness of lifting restrictions (Mogaji, 2020). This pandemic has not only created a need to produce medications and vaccines, but also the need to rethink how leadership can better meet the needs of people suffering from mental health disorders, as well as stymie the spread of misinformation and mistrust that naturally arises during crises like this.
References
Mogaji, E. (2020). Financial Vulnerability During a Pandemic: Insights for Coronavirus Disease (COVID-19). Mogaji, E, 57-63.
Pfefferbaum, B., Schonfeld, D., Flynn, B. W., Norwood, A. E., Dodgen, D., Kaul, R. E., … & Jacobs, G. A. (2012). The H1N1 crisis: a case study of the integration of mental and behavioral health in public health crises. Disaster medicine and public health preparedness, 6(1), 67-71.
Wang, C., Pan, R., Wan, X., Tan, Y., Xu, L., Ho, C. S., & Ho, R. C. (2020). Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China. International journal of environmental research and public health, 17(5), 1729.
Yang, Y., Li, W., Zhang, Q., Zhang, L., Cheung, T., & Xiang, Y. T. (2020). Mental health services for older adults in China during the COVID-19 outbreak. The Lancet Psychiatry, 7(4), e19.
Possible Mechanisms of Neurological Symptoms in COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
4/20/2020
In this week’s neurology blog, I would like to highlight a review published in Neurology Clinical Practice, in which Dr. Carlos A. Pérez from the University of Texas Health Science Center at Houston, outlines some of the newly appreciated neurologic complications of COVID-19.
Currently, it is thought that neurological complications of COVID-19 result in part from indirect actions of SARS-CoV-2 on peripheral organs. For example, injury to the lungs, kidneys, liver, and heart could result in dysregulation of homeostasis and indirectly lead to neurological signs (eg uremia could lead to altered mental status.) In particular, the “cytokine storm,” hypercoagulability and direct myocardial invasion by SARS-CoV-2 could increase the risk of cardiac failure and arrhythmias, which could in turn increase the risk of stroke (Pérez, 2020).
What is also very interesting, but less understood, is the potential mechanism of direct neurologic damage by SARS-CoV-2. Like the previous SARS virus (SARS-CoV), SARS-CoV-2 can enter human host cells by binding to angiotensin-converting enzyme 2 (ACE2) receptor. While the exact mechanism of CNS injury is not established, SARS-CoV is known to enter the CNS and many neurons express ACE2 receptor, suggesting a potential target for injury. An alternative route into the CNS is via the olfactory bulb, as shown in experimental animal models (Netland, et al., 2020). Via this route, SARS-CoV-2 could lead to direct neuronal injury within different brain regions, including the brainstem cardiorespiratory centers, which could account for the cardiovascular/respiratory complications observed in COVID-19 patients. ACE2 receptors have also been shown to be expressed in microvillar cells and Bowman’s gland cells within the nasal passages, though it is unknown whether SARS-CoV-2 actually enters these cells (Gupta, et al., 2020). Nevertheless, it is possible that the observed dysfunction within the gustatory and olfactory systems, ie lack of smell (anosmia) and lack of taste (ageusia), may be due to direct viral invasion and damage to the olfactory system. Alternatively, these neurological symptoms may be due to a secondary inflammatory process within the nasal mucosa.
Lastly, Dr. Perez’ review covered post-infectious neurologic complications. Dr. Pérez suggested that the “presence and persistence of human coronaviruses within the CNS may lead to misdirected host immune responses, which may lead to autoimmune inflammatory and demyelinating syndromes in some people.” (Pérez, 2020).
References
Gupta, K., Mohanty, S. K., Kalra, S., Mittal, A., Mishra, T., Ahuja, J., … & Ahuja, G. (2020). The molecular basis of loss of smell in 2019-nCoV infected individuals.
Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., & Perlman, S. (2008). Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. Journal of virology, 82(15), 7264–7275. https://doi.org/10.1128/JVI.00737-08
Pérez, C. A. (2020). Looking ahead: The risk of neurologic complications due to COVID-19. Neurology: Clinical Practice.
Talbot, P. J., Paquette, J. S., Ciurli, C., Antel, J. P., & Ouellet, F. (1996). Myelin basic protein and human coronavirus 229E cross‐reactive T cells in multiple sclerosis. Annals of neurology, 39(2), 233-240.
MS and COVID-19
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
4/13/2020
In a review published by Neurology this week, recommendations were made on how to adjust disease-modifying therapies (DMTs) for people with MS who are infected with SARS-CoV-2 (Brownlee, et al., 2020). In summary, MS patients with minor COVID-19 symptoms should not alter their therapy, as the risk of MS symptoms worsening is generally not worth the potential benefit of altering therapy. If symptoms of COVID-19 are severe, the authors recommend that physicians should consider altering DMTs “with greater immunosuppressant effects. “
It is currently unknown if MS patients are at a higher risk of COVID-19 infection, or if they are at risk of developing more severe symptoms if they get infected. In general, people with MS are at higher risk of infection with pneumonia and influenza (especially if they have bulbar weakness), but generally not upper respiratory tract infections (Wijnands JM et al., 2017, Marrie RA et al., 2014). In addition, patients are at a higher risk of ICU admission for infections and have a higher 1-year mortality rate after admission. Therefore, those with autoimmune conditions such as MS or NMOSD should be particularly careful about adhering to the infection prevention guidelines set out by the CDC and WHO.
Another important consideration is how particular DMTs affect infection risk. A 2018 paper in the Journal of Neurology, Neurosurgery, and Psychiatry found that first generation DMTs were not associated with higher infection risk, but second generation DMTs were (see Table 1 below). This effect with second generation DMTs was largely driven by natalizumab (Tysabri). Natalizumab was associated with a 59% higher chance of infection risk (Wijnands, et al., 2018). Alemtuzumab and cladribine lead to a period of lymphopenia (low level of lymphocytes in the blood), which could increase the chance of infection and should be considered during the time of COVID-19.
During COVID19, extended interval dosing of DMTs has been suggested for consideration in patients on anti-CD20 B-cell depleting therapies, including ocrelizumab and rituximab, especially for patients who continue to be B-cell depleted beyond 6 months since last medication dose (Brownlee, et al., 2020.) Extended interval dosing strategy is already used for natalizumab in context of decreasing the risk of developing progressive multifocal leukoencephalopathy. Another consideration is whether or not to use steroids during COVID-19. While chronic use of steroids may predispose to higher risk of infection, short term use of steroids may be beneficial in MS patients with worsening of MS symptoms due to COVID-19 (Brownlee, et al., 2020).
Another interesting point to consider is the importance of fever management for MS patients with COVID-19. Fevers can temporarily worsen existing symptoms for people with MS (due to Uhthoff phenomenon) and even bring back old symptoms that had resolved (Brownlee, et al., 2020). Thus, MS patients should be counseled about fever management if they develop COVID-19.
References
Battaglia, M., Kobelt, G., Ponzio, M., Berg, J., Capsa, D., Dalén, J., & European Multiple Sclerosis Platform. (2017). New insights into the burden and costs of multiple sclerosis in Europe: Results for Italy. Multiple Sclerosis Journal, 23(2_suppl), 104-116.
Brownlee, W., Bourdette, D., Broadley, S., Killestein, J., & Ciccarelli, O. (2020). Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic. Neurology.
Wijnands, J. M. A., Zhu, F., Kingwell, E., Fisk, J. D., Evans, C., Marrie, R. A., … & Tremlett, H. (2018). Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study. Journal of Neurology, Neurosurgery & Psychiatry, 89 (10), 1050-1056.
Neurological COVID-19 Case Studies
Written by: Sam Bazzi
Edited by: Jina Zhou and Esther Melamed
4/5/2020
Summary:
Currently, there is evidence to suggest that some patients suffering from COVID-19 experience a variety of neurological symptoms, including stroke, delirium, anosmia, epileptic seizures, vomiting, dizziness, and headache. It is unclear how or why these symptoms arise, but some clues exist based on previous coronavirus outbreaks (see Potential Mechanisms).
In Wuhan, China, a retrospective study done on 214 confirmed COVID-19 cases assessed neurological symptoms in patients. The cases were classified as severe (88, 41.1%) and non-severe (126, 58.9%). Severe patients were not only older and more likely to have underlying health problems but were also more likely to have neurological symptoms. 78 total patients had neurological symptoms, with 40 of them being severe cases (45.5%) and 38 of them being non-severe cases (30.2%) (Mao, et al., 2020).
According to Dr. Alessandro Pezzini, some COVID-19-positive patients in Italy are experiencing neurological symptoms including stroke, delirium, epileptic seizures, and others. A separate neuro-COVID-19 unit has been established to manage these patients (Talan, 2020).
Potential Mechanisms for Neurological Symptom onset:
- Previous SARS virus (SARS-CoV1) was reported to infect the brainstem in some patients as well as in experimental animals. Some coronaviruses are able to spread trans-synaptically through neurons from the mechanoreceptors and chemoreceptors in the lung to the medullary cardiorespiratory center. SARS-CoV-2 may operate in a similar manner(Li, et al., 2020).
- It is possible that the simple lack of oxygen and elevated level of CO2in the blood due to diminished respiratory function is primarily responsible for neurological symptoms.
- SARS-CoV-2’s main site of entry is angiotensin-converting enzyme 2 (ACE2). While predominantly present in the respiratory and gastrointestinal systems, ACE2 is also present in the CNS, specifically in neurons and glia (Gowrisankar, et al., 2020, Xia, Lazartigues, 2020). The brain regions where ACE2 is expressed are the brainstem and other regions that regulate cardiovascular function such as the subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla. Some believe that SARS-CoV-2 may be able to enter the CNS via clathrin-mediated endocytosis into astrocytes, much in the same way that HEV 67N (another coronavirus) does, though there is no evidence yet for this claim (Steardo, et al., 2020). Contradicting this claim is a single case study so far that found no presence of the virus in the CSF of a COVID-19 patient (Filatov, et al., 2020).
- Some evidence exists that a cytokine storm is present in severe COVID-19 cases (Mehta, McAuley, and Brown, 2020). Intracranial cytokine storms can lead to blood-brain barrier breakdown (Poyiadji, et al., 2020), which could contribute to further virus infiltration and the development of neurological symptoms. How the cytokine storm initiates intracranially is unclear at this time.
Case Studies in the USA:
COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features. (Poyiadji, et al., 2020)
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- Airline worker, female, in her 50s
- 3-day history of cough, fever, and altered mental status
- Tested negative for influenza, positive for COVID-19
- Tests for herpes simplex virus 1 and 2, varicella zoster virus, and West Nile virus were negative
- First presumptive case of COVID-19-associated acute necrotizing hemorrhagic encephalopathy, a rare encephalopathy that has been associated with other viral infections but has yet to be demonstrated as a result of COVID-19 infection
Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. (Filatov, et al., 2020)
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- 74-year old man from the Netherlands arrives in USA, presents symptoms within 1 week of arrival
- Past medical history of atrial fibrillation, cardioembolic stroke, Parkinson’s disease, chronic obstructive pulmonary disease (COPD), and recent cellulitis presented to the emergency department with a chief complaint of fever and cough. Tested positive for SARS-CoV-2.
- Due to the severe alteration in mental status, neurology service was consulted. Upon examination, the patient was found to be encephalopathic, nonverbal, and unable to follow any commands; however, he was able to moveall his extremities and was reacting to noxious stimuli.
- No virus found in CSF, so authors believe SARS-Cov 2 can not cross the blood-brain barrier or cause meningitis or encephalitis.
Additional Interesting Info
One study found that 29% of T-cells isolated from multiple sclerosis patients cross-reacted with both myelin basic protein and coronavirus antigens from a different human coronavirus (strain 229E), compared to only 1.3% of T-cells from control patients. This study established that some molecular mimicry exists between myelin proteins and pathogenic coronavirus proteins (Talbot, et al., 1996). This study lends some evidence to the idea that infectious insults could prime the immune system for subsequent autoimmunity.
References
Filatov, A., Sharma, P., Hindi, F., & Espinosa, P. S. (2020) Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. Cureus.
Gowrisankar, Y. V., & Clark, M. A. (2016). Angiotensin II regulation of angiotensin‐converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. Journal of neurochemistry, 138(1), 74-85.
Li, Y. C., Bai, W. Z., & Hashikawa, T. (2020). The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Journal of Medical Virology.
Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., … & Li, Y. (2020). Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. The Lancet.
Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., & Manson, J. J. (2020). COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet.
Poyiadji, N., Shahin, G., Noujaim, D., Stone, M., Patel, S., & Griffith, B. (2020). COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: CT and MRI Features. Radiology, 201187.
Steardo, L., Steardo, L., Zorec, R., & Verkhratsky, A. (2020). Neuroinfection may potentially contribute to pathophysiology and clinical manifestations of COVID‐19. Acta Physiologica.
Talan, J. (2020, March 27). COVID-19: Neurologists in Italy to Colleagues in US: Look for Poorly-Defined Neurologic Conditions in Patients with the Coronavirus. Neurology Today.
Talbot, P. J., Paquette, J. S., Ciurli, C., Antel, J. P., & Ouellet, F. (1996). Myelin basic protein and human coronavirus 229E cross‐reactive T cells in multiple sclerosis. Annals of neurology, 39(2), 233-240.
Xia, H., & Lazartigues, E. (2010). Angiotensin-converting enzyme 2: central regulator for cardiovascular function. Current hypertension reports, 12(3), 170-175.