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Sunday, March 08, 2020

Schizophrenia as a complication of virus infection

How respiratory viruses can trigger the immune system and cause psychosis

W hen a pregnant female gets rubella (German measles) there's a good chance the baby will have serious neurological disorders, including microcephaly, mental retardation, and autism. This is called congenital rubella syndrome and it's one reason doctors are so insistent that everyone should get an MMR vaccine.

Many infections passed down from the mother cause serious brain problems in the fetus. They're called TORCH agents, which is an acronym for Toxoplasmosis, rubella, cytomegalovirus, and herpes simplex viruses. As with Epstein-Barr virus, they're all neurotropic, which means they can affect the brain.

Most neurologists assumed these pathogens were somehow unique. But in 2011, researchers at Johns Hopkins[1] studied 106 patients with recent psychotic symptoms and 196 nonpsychiatric controls. They found that serum antibodies against three non-SARS coronaviruses (HKU1, NL63, and OC43) were higher in the patients. This suggested that the psychotic patients had previous exposure to the virus and then recovered, only to be afflicted with schizophrenia-spectrum disorders.

This suggests that not only rubella, but also respiratory viruses like coronaviruses and influenza can cause brain disorders. But it sounds crazy. How could a respiratory virus affect the brain?

The answer is that the immune system faces a constant struggle to discriminate between pathogens and the body's own cells. When it fails, we get an autoimmune disorder. These diseases start with a trigger, maybe a dysbiotic microbiome, which is to say bad gut bacteria[6], or a bacterium or virus that triggers an immune response. If the trigger is too similar to some protein in the patient, or if the patient's immune system is weak, those antibodies—and what is even worse, those T cells, which are designed to kill other cells—can turn against the patient.

This may be exactly what happens in schizophrenia. Researchers tested a vast number of genetic variations in a test called a GWAS to see if any genetic variations correlated with the disease. These studies pointed unequivocally to the MHC/HLA (major histocompatibility complex and human leukocyte antigen) proteins, whose purpose is to help the immune system discriminate between virus proteins and the molecules in one's own body. This is prima facie evidence of an autoimmune response.

Another piece of evidence is from diseases called PANDAS, or pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, also known as PANS. These diseases are not as cute or cuddly as the name sounds. They're a type of acute onset obsessive-compulsive disorder caused by an autoimmune response to group A streptococcal infection. They can also be caused by varicella-zoster virus (VZV), which causes chicken pox, or by Mycoplasma pneumoniae, which causes a respiratory bacterial infection sometimes called “walking pneumonia.”

Children with PANDAS experience severe compulsions like licking shoes, barking, or wringing their hands along with extreme anxiety or aggression and eating problems. Sometimes they also get psychotic symptoms including visual or auditory hallucinations just like patients with schizophrenia.[7]

In one case[2], a 14-year-old girl developed acute-onset psychosis, including hearing voices, after being treated for H1N1 influenza virus. Over time the illness changed to a depressive-type psychosis and she was forced to drop out of school. The only effective treatment was to give her aripiprazole—an ‘atypical’ antipsychotic drug commonly used for treating schizophrenia.

Psychiatric symptoms such as auditory and visual hallucinations can occur in patients infected with SARS coronavirus.[3] Coronavirus RNA was also found in the brains of patients with multiple sclerosis.[4]

Epidemics of psychosis also occurred after the 1918 influenza pandemic. There are reports that the epidemic caused an increase in schizophrenia and Parkinson's disease; the famous psychiatrist Karl Menninger talked about “the almost unequalled neurotoxicity of influenza.”[8]

So many victims of the Spanish flu had neurological complications that doctors invented a new term for it: encephalitis lethargica, a type of influenza-induced encephalopathy that affected up to a million people worldwide, most often children, starting in 1916[10]. The symptoms were intractable somnolescence followed months later by parkinsonian-like features such as bradykinesia, rigidity, and resting tremor, caused by lesions in the substantia nigra and striatum, along with dystonia, motor tics, facial grimacing, depression, agitation, and panic attacks.[11] Up to 50% of patients died. Children between six months and 5 years got seizures, a non-aspirin Reye-like syndrome, and severe encephalopathy leading to coma and death.[9]

All strong evidence that, as strange as it sounds, respiratory diseases can indeed cause serious neurological and neuropsychiatric problems.

There's no evidence that this is due to the infection reaching the brain. Most researchers think what's happening is an autoimmune response to a trigger such as a viral challenge.

But paradoxically, mental illness can sometimes protect against diseases, and vice versa. During the 1887 typhus epidemic, doctors observed that 39% of the guards in a mental asylum became infected by Salmonella typhi, while only 17% of the patients were infected.[5] The psychiatrist Julius Wagner von Jauregg also found that 52% of the mentally ill patients who recovered from typhus either showed improvement or complete recovery from their mental illness. Schizophrenia also protects against rheumatoid arthritis, which is an autoimmune disease.

Microglia, the brain's immune cells, are the Joe Bidens of the brain, reaching out to touch the entire brain volume every few hours. It's now known that antipsychotics such as aripiprazole and clozapine act on the microglia. So schizophrenia is not an imbalance of dopamine as once believed, but a problem with the brain's innate immune system.

Nowadays it's well established that the immune system is important in brain development. From the evidence summarized above, we now suspect that the immune system plays a role in neuro­psychi­atric diseases as well. If we should ever experience a pandemic of some viral disease, it would be prudent to prepare for the outbreak of acute mental disorder that will surely follow it.

But mostly it's good news: the idea that schizophrenia is an autoimmune disorder is a scientific and conceptual breakthrough that will give new hope for suffering people.

1. Severance EG, Dickerson FB, Viscidi RP, Bossis I, Stallings CR, Origoni AE, Sullens A, Yolken RH (2011). Coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms. Schizophr Bull. 37, 101–107. doi: 10.1093/schbul/sbp052 Link

2. Chang CH, Chang YC, Tzang RF (2015). Childhood psychosis after H1N1 influenza. J Neuropsychiatry Clin Neurosci. 27, e87–89. PMID: 25716513 DOI: 10.1176/appi.neuropsych.14010012 Link

3. Cheng SKW, Tsang JSK, Ku KH, Wong CW, Ng KY (2004).Psychiatric complications in patients with severe acute respiratory syndrome (SARS) during the acute treatment phase: a series of 10 cases. Br J Psychiatry 184, 359–360

4. Arbour N, Day R, Newcombe J, Talbot PJ (2000). Neuroinvasion by human respiratory coronaviruses. J Virol. 74, 8913–8921

5. Wagner-Jauregg J (1926). Fieberbehandlung bei psychosen. Wein Med Wochenschr 76, 79–82. Cited in Müller N (2020). A brief history of immunological research into psychosis and pathways for immune influence of the brain. Curr Topics Behav Neurosci 44, 1–8

6. Severance EG, Dickerson FB, Yolken RH (2018). Autoimmune phenotypes in schizophrenia reveal novel treatment targets. Pharmacol Ther. 189, 184–198. doi: 10.1016/j.pharmthera.2018.05.005. PMID: 29742478 PMCID: PMC6097895

7. Chang C, Frankovich J, Cooperstock M, Cunningham MW, Latimer E, Murphy TK, Pasternack M, Thienemann M, Williams K, Walter J, Swedo SE (2015). Clinical Evaluation of Youth with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS): Recommendations from the 2013 PANS Consensus Conference J Child Adolesc Psychopharmacol. 25, 3–13. doi: 10.1089/cap.2014.0084 PMCID: PMC4340805 PMID: 25325534 Link

8. Barry JM (2005) The Great Influenza: The Story of the Deadliest Pandemic in History. Penguin Books, New York

9. Wijdicks EFM, Neurologic complications of critical illness, Oxford University Press, p.128

10. Foley PB (2009). Encephalitis lethargica and influenza. I. The role of the influenza virus in the influenza pandemic of 1918/1919. J Neural Transm (Vienna). 116, 143–150. doi: 10.1007/s00702-008-0161-1. PMID: 19082525 Link

11. Hoffman LA, Vilensky VA (2017). Encephalitis lethargica: 100 years after the epidemic. Brain 140, 2246–2251. https://doi.org/10.1093/brain/awx177

mar 08 2020, 7:14 am. edited to make less technical 7:08 pm. last edited mar 11 2020, 7:04 am

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