Suicidal thoughts, “paranoia-like fears,” delusions and “foggy brain” have been identified in three adolescents who had mild or asymptomatic COVID-19. Now, a new study into their immune responses identifies a potential mechanism by which these symptoms emerged.
The study, led by researchers at the UCSF Weill Institute for Neurosciences and the UCSF Department of Pediatrics, is the first to look at anti-neural antibodies – “turncoat” antibodies that may attack brain tissue – in pediatric patients who had been infected with SARS-CoV-2.
Over a duration of five months in 2020, a total of 18 children and teens were hospitalized with confirmed COVID at UCSF Benioff Children’s Hospital San Francisco, according to the study publishing in JAMA Neurology on Oct. 25, 2021. They included the three patients in the study who underwent neurological evaluations.
The researchers examined the patients’ cerebrospinal fluid, obtained via lumbar puncture, and found that two of the patients, both of whom had histories of unspec
ified depression and/or anxiety, had antibodies indicating that SARS-CoV-2 may have invaded the central nervous system. The same patients, who had mild/asymptomatic COVID, also had anti-neural antibodies in their cerebrospinal fluid, which were identified by immunostaining brain tissue. This suggests an immune system running amok, mistakenly targeting the brain instead of infectious microbes.
Autoantibody Parallel in Adults with Neurological Symptoms
The research follows a UC San Francisco study with Yale, published on May 18, 2021, in Cell Reports Medicine, that also found a high level of autoantibodies in the cerebrospinal fluid of adult patients with acute COVID, who had neurological symptoms, including intractable headaches, seizures and loss of smell.
Samuel Pleasure, MD, Ph.D. Photo by UC Regents
“It is way too soon to know whether COVID is a common trigger for neuropsychiatric illnesses, but it does seem to be a potent trigger for the development of autoantibodies,” said co-corresponding author Samuel Pleasure, MD, Ph.D., of the UCSF Department of Neurology and of the UCSF Weill Institute.
“It is currently totally unknown whether patients predisposed to neuropsychiatric illnesses are more likely to develop worsened symptoms after COVID, or whether COVID infection can act as an independent trigger.”
Efforts to identify an autoantibody shared by patients with similar neuropsychiatric symptoms have so far failed, said co-first author Christopher Bartley, MD, Ph.D., of the UCSF Department of Psychiatry and of the UCSF Weill Institute. “These autoantibodies may be most clinically meaningful as markers of immune dysregulation, but we haven’t found evidence that they are actually causing the patients’ symptoms. There’s certainly more work to be done in this area.”
Unlike most psychiatric presentations, the three patients in the UCSF study had symptoms with sudden onset and rapid progression, representing a marked change from their baselines, said co-first author Claire Johns, MD, of the UCSF Department of Pediatrics. “The patients had significant neuropsychiatric manifestations despite mild respiratory symptoms, suggesting potential short and long-term effects of COVID.”
After weekslong hospitalizations and ongoing psychiatric medications, the two UCSF patients, whose cerebrospinal fluid tested positive for SARS-CoV-2 antibodies and anti-neural antibodies, were treated with intravenous immunoglobulin, an immunomodulatory therapy that curbs inflammation in autoimmune disorders. Five days later, the first patient had “more organized thoughts, decreased paranoia and improved insight.”
This patient was also found to have autoantibodies targeting the protein TCF4, which is genetically implicated in some cases of schizophrenia. However, “we don’t know that the antibodies are actually interfering with the protein’s function,” said co-corresponding author, Michael R. Wilson, MD, of the UCSF Department of Neurology and of the UCSF Weill Institute, noting that the diagnosis of schizophrenia is based on a constellation of symptoms, rather than a specific biomarker.
The second patient appeared to have a modest response to immunotherapy with improved cognition and working memory, but continued to have “impaired mood and cognitive symptoms” six months later. The third patient, who had no psychiatric history and had neither SARS-CoV-2 antibodies nor anti-neural antibodies in their cerebrospinal fluid, made a complete recovery with psychiatric medications. His symptoms were ultimately attributed to recreational drug use.
Immunotherapy Prompts Swift Response in Adult with Psychosis
A more dramatic response was reported in a case-study by Yale and UCSF, published in Biological Psychiatry, on April 9, 2021, that documented a 30-year-old patient with mildly symptomatic COVID who presented at a hospital emergency department with delusions, violent outbursts, hyper-anxiety and paranoia.
After failing to achieve a lasting remission with antipsychotic medications, he was diagnosed with possible “autoimmune-mediated psychosis” and was treated with intravenous immunoglobulin. His symptoms improved after the first day of treatment and he was eventually discharged without antipsychotic medications.
“We can’t say, based on such a limited number of patients, whether immunotherapy played any role in the patients’ clinical course,” cautioned Wilson. “In the cases of the two UCSF patients, we cannot rule out that they improved independent of immunotherapy, due either to concurrent treatment with psychiatric medications or the passage of time.”
Nonetheless, the researchers agree it’s unlikely that there were pre-existing autoantibodies, and they point to other disorders with psychiatric symptoms, like anti-NMDAR encephalitis syndrome, that are caused by anti-neural antibodies and respond to treatment directed at these rogue antibodies.
The researchers agree that more study is warranted, although Pleasure noted that one obstacle in expanding this research is the paucity of cerebrospinal fluid samples from pediatric patients. “We don’t get to study the cerebrospinal fluid in kids very often,” he said.
Meanwhile, mounting research suggests that COVID increases one’s risk for psychiatric and neurological effects. A study from the United Kingdom published earlier this year found that of approximately 250,000 patients with COVID over the age of 10, the estimated incidence of a neurological or psychiatric diagnosis in the following six months was 34 percent; with 13 percent receiving their first such diagnosis.
The presence and prevalence of neuropsychiatric manifestations in COVID-19 patients
Neurological and psychiatric complications of COVID-19 are increasingly reported, but most are individual cases or case series. Headache, anosmia, and myalgia are most commonly reported in patients infected with SARS-CoV-2. SARS-CoV-2 infection can attack the CNS and induce spine demyelinating lesions , which could further lead to neuropsychiatric symptoms affecting cognitive, affective, behavioral, and perceptual domains.
These neuropsychiatric symptoms, including cerebrovascular, psychiatric, and neuromuscular disorders, frequently occur in elderly patients and individuals with multiple comorbidities or severe infection. Both SARS and MERS are associated with delirium, depression, anxiety, memory impairment, and insomnia during the acute phase. Depression, insomnia, anxiety, memory impairment, and sleep disorders are frequently reported during the post-illness phase .
A significant proportion of patients with COVID-19 develop delirium, agitation, altered consciousness, and other neuropsychiatric symptoms, including encephalopathy, encephalitis, depression, anxiety, and post-traumatic stress disorder .
A UK-wide surveillance study of acute neurological and psychiatric complications in 153 COVID-19 patients demonstrated that cerebrovascular events (62%) and altered mental status (31%, including encephalopathy, encephalitis, and psychiatric disorders, were reported, often occurring in younger patients .
An observational series of 58 COVID-19 patients in Strasbourg, France reported encephalopathy, prominent agitation and confusion, corticospinal tract signs, and acute ischemic strokes . A tertiary-care hospital at Karachi, Pakistan reported on 350 patients with COVID-19 describing headache (6%), vertigo (3.4%), numbness/paresthesia (3.1%), impaired consciousness (2%), hyposmia/anosmia (1.4%), and encephalitis (0.9%) .
A retrospective, observational case series of 214 patients in Wuhan, China found that 78 patients (36.4%) had neurologic manifestations, including acute cerebrovascular diseases, impaired consciousness, and skeletal muscle injury . Analysis of data from 86 critically ill COVID-19 patients at the intensive care unit (ICU) of Tongji Hospital, Wuhan, China showed that 26 patients (30.2%) presented with neurological symptoms including delirium, stroke, cerebrovascular, and neuromuscular diseases .
A retrospective multicenter cohort study of 917 patients in three regions in China demonstrated that new-onset critical neurologic events, mainly impaired consciousness and stroke, occurred in 3.5% of the total population and in 9.4% of severe or critical patients . A prospective multicenter observational study in New York City showed that 13.5% (606/4491) hospitalized COVID-19 patients developed a new neurological disorder including encephalopathy (309/606, 51%), strokes (84/606, 14%), seizures (74/606, 12%), and hypoxic/ischemic brain injury (65/606, 11%), and these disorders led to higher rates of in-hospital mortality and lower rates of discharge home .
A survey of physician-reported neurological symptoms in COVID-19 patients from Italy showed that 87.3% of practitioners reported neurological symptoms, mainly mild and nonspecific manifestations such as headache, myalgia, and loss of smell .
GBS and myelitis are also reported in COVID-19 patients, indicating a post-infective autoimmune reaction in peripheral nerves . COVID-19 patients frequently presented with stroke and subsequent mortality when complicated by older age, comorbidities, and severe respiratory symptoms . A meta-analysis of 58,104 COVID-19 patients revealed a 0.46% hemorrhagic stroke rate and a 1.11% ischemic stroke rate, with mortality rates of 44.7% for hemorrhagic and 36.2% for ischemic stroke .
Evidence from tissue histology, neuroimaging, and clinic symptoms revealed that 1.4% of COVID-19 patients (23/1683) developed cerebral ischemia, intracerebral hemorrhage, or encephalopathy . A possible pathophysiology for this cerebrovascular damage may be BBB dysfunction and subsequent cytokine release induced by SARS-CoV-2 infection of the brain itself .
During the COVID-19 pandemic, psychiatric disorders such as depression, anxiety, post-traumatic stress disorder, and insomnia have also been frequently reported in COVID-19 patients, vulnerable populations, healthcare workers, and even the general population [23, 42,43,44,45,46,47,48]. Poor sleep is associated with worsened clinical outcomes in hospitalized patients with COVID-19, and long-term sustainable improvements in sleep quality are needed for this subpopulation [49, 50].
The prevalence and severity of these psychiatric symptoms, attention deficits, and hyperactivity symptoms increased the risk for problematic internet use during the COVID-19 pandemic . Moreover, a case series reported that critically ill COVID-19 patients with multiple acute bilateral ischemic lesions exhibited alterations of mental status but no neurological deficits .
A group of experts convened by the UK Academy of Medical Sciences and the mental health research charity also advocate monitoring and evaluating brain function, and mental health issues such as anxiety, depression, insomnia, self-harm, and suicide in COVID-19 patients and related vulnerable populations .
A Nationwide Cohort Study also revealed that hospitalization with infection increased the risk of death by suicides in prospective and dose–response relationships . Another cohort study demonstrated that a history of schizophrenia spectrum disorder was significantly associated with an increased risk for mortality among COVID-19 patients .
However, it is difficult to distinguish whether this high prevalence is due to direct SARS-CoV-2 infection or the adverse psychological effects of other social and environmental factors such as social distancing and quarantine, self-isolation, changes in sleep and lifestyle behaviors, fear of death, and economic burden .
Overall, neurologic and neuropsychiatric manifestations, such as alterations of mental status and stroke, are common among hospitalized COVID-19 patients and could be predictors of disease severity and mortality [57, 58]. A retrospective cohort study of 236,379 COVID-19 survivors revealed that the incidence of neurological or psychiatric morbidity (e.g., intracranial hemorrhage, ischemic stroke, dementia, and anxiety disorder) was 33.6% in the 6 months follow-up, indicating the neuropsychiatric sequela was long-lasting .
An international cohort study found that neurological symptoms did not recover in COVID-19 patients at 7-month follow-up . Clinicians should seriously consider these neurological and neuropsychiatric symptoms to avoid delayed diagnosis or misdiagnosis and to reduce the risk of death.
The potential mechanisms underlying the invasion of SARS-CoV-2 into the nervous system
Growing and convincing evidence supports the neurotropism of SARS-CoV-2 (Table 2), similar to other coronaviruses. Quantitative data for tropism, replication kinetics, and cell damage revealed that SARS-CoV-2 modestly replicated in neuronal cells, highlighting the potential that this virus can cause neuropsychiatric manifestations in COVID-19 patients . This virus could affect the CNS and cause brain damage and neuropsychiatric alterations through several pathways (Fig. 1).
reference link :https://www.nature.com/articles/s41398-021-01629-8
More information: Christopher M. Bartley et al, Anti–SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms, JAMA Neurol. (2021). DOI: 10.1001/jamaneurol.2021.3821
Eric Song et al, Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms, Cell Reports Medicine (2021). DOI: 10.1016/j.xcrm.2021.100288