Schizophrenia: Reviewing an Overview.
A friend sent me a message recently asking me to comment on an article published in the JAMA Psychiatry that reviewed the current medical knowledge concerning schizophrenia. The article, Schizophrenia—An Overview was published on October 30, 2019. Schizophrenia affects about one percent of our population, and eventually those who counsel much will encounter those affected by it.[1] For many reasons, the subject deserves our attention. My goal with this blog is to summarize the article and then comment along the way with some conclusions about it and some other articles at the end.
For those in the Biblical counseling movement, schizophrenia has always been a conundrum. It is hard at times to think that the behavior of an individual may be connected to a disease process in the body, particularly if that behavior is troublesome. There is a wide range of opinions about the cause and care of schizophrenia. The disagreement starts at a very basic level. Is schizophrenia a brain-based disease, or is it a spiritual problem? Or, is it someplace in between?
Pathology: Change at the Cell Level that Changes Function.
Most in Biblical counseling have asked for pathology as the standard for calling anything a disease including schizophrenia. That is, for a collection of symptoms, emotions, thinking, or behaviors to be considered part of a disease, there ought to be a change in the physical body that results in the change in function. And, we should be able to document it.
It is important to remember that while all disease will have pathologic change causing it, we may not be able to demonstrate it. Problems like migraine headaches would be recognized as a disease problem by most physicians although we do not yet completely understand the underlying change in the brain that causes them. Schizophrenia is in the same spot in medicine today. Most physicians and researchers would say it is brain disease. In the past decade we have seen an increasing number of physical differences discovered in the brains of individuals affected by schizophrenia. The review article documents some of the changes that have been found.
Defining Schizophrenia is important.
First, the authors do a service by setting out the criteria for making the diagnosis of schizophrenia. A recent research study showed that up to 50% of those labeled as schizophrenic do not meet the criteria for the diagnosis.[2] To qualify for the diagnosis an individual must have had two of the following; delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms such as diminished emotional expression or decreased ability to think.[3] These symptoms must be present for a month or longer and one of the first three must be present as well.
Genetics play a part.
The authors divided the paper into three parts that deal with the causes, the change in brain function and treatment. The first section dealt with the family history and genetics. Advances in genome-wide association studies have identified 100 genetic areas or loci in our DNA that are associated with an increased risk of developing the symptoms associated with schizophrenia. A defect in one gene increases the risk to 30 or 40%. For those with this specific genetic change, it places them in a similar situation as those who carry the gene for Alzheimer’s with increased risk to have the problem.[4]
The authors point out that while genetic inheritance appears to play a significant role in having schizophrenia, it does not appear to be the sole cause as it would be in Huntington’s disease, a devastating degenerative brain disorder. Identical twins have a 50% chance of developing the disorder, but not 100%.[5] The authors note that problems during pregnancy and in the time around birth appears to increase the risk for developing schizophrenia by five times that which would be expected in the general population.[6]
When our immune systems attack us.
The most interesting portion of the research had to do with the potential role of the immune system in schizophrenia. A change in a gene that affects the human immune system in the complement system (complement C4) appears to result in an increased destruction or pruning of the connecting structures in the brain called synapses. The increased destruction of brain connections (by microglia) appears to be connected to symptoms.[7] This gene defect that affects C4 was identified in a large study in 2016.[8] This research described in the paper offered evidence that there was a physical process doing damage to the brain that was associated with the symptoms of schizophrenia.[9]
There are objective findings of this destructive process. It was noted that problems with the ability to think appeared in affected adolescent patients earlier than hallucinations and delusions. In adolescent patients, Brain scans done over time showed changes in the brain tissue. They noted that the cognitive/thinking problems appeared to be connected to significant loss in gray matter areas of the brain.[10]
Pathology at a cell level.
Studies performed on the brains of affected individuals after death have shown significant differences which may contribute to abnormal brain function. There are fewer dendritic spines in important areas of the brain that affect thinking. These findings are not seen in normal brains. The changes in the brain tissue would be considered pathological and support the designation of schizophrenia as a brain disease.[11]
Brain Scans: Looking through a glass darkly.
It is easy to be critical of how brain scanning is used to support psychological diagnoses today and I have been at times.[12] However, as time marches on, the scans improve and so does the information. Molecular imaging now allows researchers to look at the concentration of substances inside the living human brain. Studies have been conducted that look at the concentration of dopamine in the brains of schizophrenics and control subjects.[13]
With the molecular imaging, it has been shown that dopamine is elevated in the brains of those with psychotic symptoms as compared to normal control subjects. This was true for those taking amphetamines who developed psychosis[14]. It was also true for those with schizophrenia. The elevation of dopamine correlated with the level of psychotic symptoms of those with schizophrenia.[15] These studies do not tell us why the levels of dopamine are elevated or but they do provide an objective way to identify the difference in the brain of those with schizophrenia that is associated with the symptoms.
One last bit of observable information comes in the form of brain wave patterns as observed with electrophysiological studies. The authors described research that measured gamma brainwave activity in normal individuals and those with schizophrenia and they were different.[16] The differences were thought to accompany or be caused by the damage resulting in the decline in the thinking ability of the patient. (cognitive function)
The last section of the review article dealt with treatment. Current treatment centers around reducing the psychotic symptoms. Most all of the medications used block the D2 receptor for dopamine in the brain and by doing that, decrease the effect of dopamine and the psychosis. The effect of these medications can be seen today with positron emission tomography brain scans that can measure the amount of blockade that occurs at the receptor site. It is known that a 60% level of blockade needs to occur to lower the psychotic symptoms and that at 80% side effects occur.[17]
The fact that we can see the area that is blockaded by the medication and the level of the blockade that is required in order to stop the psychosis, is useful. It becomes a measurable piece of information that supports the designation of schizophrenia as a brain disease.
Medicine and Counseling: What Helps?
While current medicines seem to help the psychotic symptoms, they do not help the problems with declining cognitive abilities. Approximately one third of those with schizophrenia do not respond to dopamine receptor blocking medications. These individuals may be helped by other medication.[18]
The authors noted that counseling seemed to benefit those who had the psychosis symptoms of schizophrenia. They did not say what kind of counseling was used. They indicated that counseling helped the affected individual to understand and deal with the psychotic episodes better.[19]
Comments.
This review article has documented several important points which would lead most of us to the conclusion that schizophrenia is a brain disease or at the least has a significant medical/physical component. The connection between genetic defects and our immune system appears to offer a promising explanation for the damage that occurs in the brain. It may lead to the ability to validate the diagnosis with blood testing and to treatment.
The brain scans that can now measure the activity of dopamine offer an explanation for the psychotic symptoms. The autopsy reports on brains of schizophrenics confirm the presence of an ongoing destructive disease process. All of this information would point to schizophrenia being a brain disease process and among physicians, there would be few who would disagree.
It is still true that the absolute definition of the cause of symptoms in schizophrenia has not been defined. A great deal of research exists that demonstrates pathological change in the brain among those who are affected. Those of us in Biblical Counseling should approach the counseling of individuals who present with the diagnosis with a 1Thessalonians 5:14 attitude. “Admonish the unruly, encourage the fainthearted, help the weak, be patient with everyone.”
Other Research.
In the past year there have been several interesting research papers and case reports published about this subject. The one that interested me the most connects some of the dots between the genetic and pathological studies. It is a case report published in the Psychiatric Times that documented the history of two individuals who needed a bone marrow transplant for leukemia.[20] In one case the individual received a transplant from a sibling who had symptomatic schizophrenia. While he was cured of his leukemia, he developed the symptoms of schizophrenia. In the second case an individual who had schizophrenia received a bone marrow transplant from an individual who did not have schizophrenia. He was cured of his leukemia and his schizophrenia.
What does the case study imply? Bone marrow transplants require that the individuals current bone marrow be replaced. It is the source of the cancer, and to cure, the old bone marrow must go . In essence the individual receives an immune system transplant. It may well be the case that schizophrenia is an autoimmune disorder much like other autoimmune diseases that affect the brain.
There are other auto-immune disorders that affect the brain and can be treated.[21] If schizophrenia turns out to be caused by an immune disorder that attacks the tissue of the brain, then there is great potential that we will be able to test for it and eventually treat it. Currently it exists in much the same realm as Alzheimer’s disease, where we have a growing understanding of the pathology, but are struggling to create drugs that cure it.
Conclusions.
We started with the question, is schizophrenia an outcome of spiritual problems or is it a medical problem, a disease of the brain that results in the symptoms.
We are not the first to grapple with this question. Freud considered it and decided that schizophrenia was a result of unresolved conflicts in the individual’s life usually with a parent. Kraepelin believed that schizophrenia was a biological brain disorder for which there was no cure or treatment. In either case neither of them had much success in the care of those affected.
What can we say then about the cause and care of schizophrenia from the articles we have examined? First, there is a growing body of medical evidence that supports the idea that schizophrenia is a brain-based disease. Few physicians would say anything different. As we noted above, it is important to remember that schizophrenia is often over diagnosed. And, psychosis from drug use and other disease can certainly be mistaken for it.
Second, is schizophrenia primarily a spiritually caused problem? The more we know about it from a medical viewpoint, the less likely this seems. Is it a medical problem with spiritual implications? This seems to be more likely.
In either case, at this time the answer is not absolutely certain. As one writer said, the truth is probably somewhere in the middle. As a physician and Biblical counselor, I believe schizophrenia will prove to be a medical problem that will eventually have a cure. However, that is just my opinion. I do believe that opinion rests on a growing body of research findings. Current medical treatment for the psychotic symptoms can be helpful to many, but not all. I also think that individuals who struggle with the symptoms of schizophrenia will need the kind of care that comes from scripture as might anyone with a chronic medical problem.
[1] McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An Overview. JAMA Psychiatry. Published online October 30, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.3360
[2] Coulter, Chelsey, Baker, Krista K., Margolis, Russell L. Specialized Consultation for Suspected Recent-onset Schizophrenia Diagnostic Clarity and the Distorting Impact of Anxiety and Reported Auditory Hallucinations. Journal of Psychiatric Practice, 2019 DOI: 10.1097/PRA.0000000000000363
[3] Schizophrenia, McCutcheon, E2.
[4] Ibid, E2.
[5] Ibid, E2
[6] Ibid, E2
[7] Ibid, E2
[8] Aswin Sekar, Allison R. Bialas, Heather de Rivera, Avery Davis, Timothy R. Hammond, Nolan Kamitaki, Katherine Tooley, Jessy Presumey, Matthew Baum, Vanessa Van Doren, Giulio Genovese, Samuel A. Rose, Robert E. Handsaker, Mark J. Daly, Michael C. Carroll, Beth Stevens, Steven A. McCarroll. Schizophrenia risk from complex variation of complement component 4. Nature, 2016; DOI: 10.1038/nature16549
[9] Broad Institute of MIT and Harvard. "Genetic study provides first-ever insight into biological origin of schizophrenia: Finding explains clinical observations, opens new therapeutic avenues." ScienceDaily. ScienceDaily, 27 January 2016. <www.sciencedaily.com/releases/2016/01/160 This is the summary in ScienceDaily of the article noted in 7.
[10] Schizophrenia, McCutcheon, E3.
[11] Ibid, E4.
[12] For an interesting read on the pitfalls of brain scanning see “Brainwashed: The Seductive Appeal of Mindless Neuroscience,” by Sally Satel. Basic Books, New York. 2013.
[13] Ibid, E5.
[14] Lauren V. Moran, Dost Ongur, John Hsu, Victor M. Castro, Roy H. Perlis, Sebastian Schneeweiss. Psychosis with Methylphenidate or Amphetamine in Patients with ADHD. New England Journal of Medicine, 2019; 380 (12): 1128 DOI: 10.1056/NEJMoa1813751
[15] Schizophrenia, McCutcheon, E5.
[16] Schizophrenia, McCutcheon, E4.
[17] Ibid, E6.
[18] Ibid, E6.
[19] Ibid, E6.
[20] Immunotherapy as Personalized Medicine for Schizophrenia, Brian Miller, MD, Psychiatric Times, February 28, 2019, Vol 36, Issue 2. https://www.psychiatrictimes.com/special-reports/immunotherapy-personalized-medicine-schizophrenia
[21] An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models,
Josep Dalmau, PhD, Thais Armangué, PhD. Et. Al. Lancet, Published:July 17, 2019DOI:https://doi.org/10.1016/S1474-4422(19)30244-3
A friend sent me a message recently asking me to comment on an article published in the JAMA Psychiatry that reviewed the current medical knowledge concerning schizophrenia. The article, Schizophrenia—An Overview was published on October 30, 2019. Schizophrenia affects about one percent of our population, and eventually those who counsel much will encounter those affected by it.[1] For many reasons, the subject deserves our attention. My goal with this blog is to summarize the article and then comment along the way with some conclusions about it and some other articles at the end.
For those in the Biblical counseling movement, schizophrenia has always been a conundrum. It is hard at times to think that the behavior of an individual may be connected to a disease process in the body, particularly if that behavior is troublesome. There is a wide range of opinions about the cause and care of schizophrenia. The disagreement starts at a very basic level. Is schizophrenia a brain-based disease, or is it a spiritual problem? Or, is it someplace in between?
Pathology: Change at the Cell Level that Changes Function.
Most in Biblical counseling have asked for pathology as the standard for calling anything a disease including schizophrenia. That is, for a collection of symptoms, emotions, thinking, or behaviors to be considered part of a disease, there ought to be a change in the physical body that results in the change in function. And, we should be able to document it.
It is important to remember that while all disease will have pathologic change causing it, we may not be able to demonstrate it. Problems like migraine headaches would be recognized as a disease problem by most physicians although we do not yet completely understand the underlying change in the brain that causes them. Schizophrenia is in the same spot in medicine today. Most physicians and researchers would say it is brain disease. In the past decade we have seen an increasing number of physical differences discovered in the brains of individuals affected by schizophrenia. The review article documents some of the changes that have been found.
Defining Schizophrenia is important.
First, the authors do a service by setting out the criteria for making the diagnosis of schizophrenia. A recent research study showed that up to 50% of those labeled as schizophrenic do not meet the criteria for the diagnosis.[2] To qualify for the diagnosis an individual must have had two of the following; delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms such as diminished emotional expression or decreased ability to think.[3] These symptoms must be present for a month or longer and one of the first three must be present as well.
Genetics play a part.
The authors divided the paper into three parts that deal with the causes, the change in brain function and treatment. The first section dealt with the family history and genetics. Advances in genome-wide association studies have identified 100 genetic areas or loci in our DNA that are associated with an increased risk of developing the symptoms associated with schizophrenia. A defect in one gene increases the risk to 30 or 40%. For those with this specific genetic change, it places them in a similar situation as those who carry the gene for Alzheimer’s with increased risk to have the problem.[4]
The authors point out that while genetic inheritance appears to play a significant role in having schizophrenia, it does not appear to be the sole cause as it would be in Huntington’s disease, a devastating degenerative brain disorder. Identical twins have a 50% chance of developing the disorder, but not 100%.[5] The authors note that problems during pregnancy and in the time around birth appears to increase the risk for developing schizophrenia by five times that which would be expected in the general population.[6]
When our immune systems attack us.
The most interesting portion of the research had to do with the potential role of the immune system in schizophrenia. A change in a gene that affects the human immune system in the complement system (complement C4) appears to result in an increased destruction or pruning of the connecting structures in the brain called synapses. The increased destruction of brain connections (by microglia) appears to be connected to symptoms.[7] This gene defect that affects C4 was identified in a large study in 2016.[8] This research described in the paper offered evidence that there was a physical process doing damage to the brain that was associated with the symptoms of schizophrenia.[9]
There are objective findings of this destructive process. It was noted that problems with the ability to think appeared in affected adolescent patients earlier than hallucinations and delusions. In adolescent patients, Brain scans done over time showed changes in the brain tissue. They noted that the cognitive/thinking problems appeared to be connected to significant loss in gray matter areas of the brain.[10]
Pathology at a cell level.
Studies performed on the brains of affected individuals after death have shown significant differences which may contribute to abnormal brain function. There are fewer dendritic spines in important areas of the brain that affect thinking. These findings are not seen in normal brains. The changes in the brain tissue would be considered pathological and support the designation of schizophrenia as a brain disease.[11]
Brain Scans: Looking through a glass darkly.
It is easy to be critical of how brain scanning is used to support psychological diagnoses today and I have been at times.[12] However, as time marches on, the scans improve and so does the information. Molecular imaging now allows researchers to look at the concentration of substances inside the living human brain. Studies have been conducted that look at the concentration of dopamine in the brains of schizophrenics and control subjects.[13]
With the molecular imaging, it has been shown that dopamine is elevated in the brains of those with psychotic symptoms as compared to normal control subjects. This was true for those taking amphetamines who developed psychosis[14]. It was also true for those with schizophrenia. The elevation of dopamine correlated with the level of psychotic symptoms of those with schizophrenia.[15] These studies do not tell us why the levels of dopamine are elevated or but they do provide an objective way to identify the difference in the brain of those with schizophrenia that is associated with the symptoms.
One last bit of observable information comes in the form of brain wave patterns as observed with electrophysiological studies. The authors described research that measured gamma brainwave activity in normal individuals and those with schizophrenia and they were different.[16] The differences were thought to accompany or be caused by the damage resulting in the decline in the thinking ability of the patient. (cognitive function)
The last section of the review article dealt with treatment. Current treatment centers around reducing the psychotic symptoms. Most all of the medications used block the D2 receptor for dopamine in the brain and by doing that, decrease the effect of dopamine and the psychosis. The effect of these medications can be seen today with positron emission tomography brain scans that can measure the amount of blockade that occurs at the receptor site. It is known that a 60% level of blockade needs to occur to lower the psychotic symptoms and that at 80% side effects occur.[17]
The fact that we can see the area that is blockaded by the medication and the level of the blockade that is required in order to stop the psychosis, is useful. It becomes a measurable piece of information that supports the designation of schizophrenia as a brain disease.
Medicine and Counseling: What Helps?
While current medicines seem to help the psychotic symptoms, they do not help the problems with declining cognitive abilities. Approximately one third of those with schizophrenia do not respond to dopamine receptor blocking medications. These individuals may be helped by other medication.[18]
The authors noted that counseling seemed to benefit those who had the psychosis symptoms of schizophrenia. They did not say what kind of counseling was used. They indicated that counseling helped the affected individual to understand and deal with the psychotic episodes better.[19]
Comments.
This review article has documented several important points which would lead most of us to the conclusion that schizophrenia is a brain disease or at the least has a significant medical/physical component. The connection between genetic defects and our immune system appears to offer a promising explanation for the damage that occurs in the brain. It may lead to the ability to validate the diagnosis with blood testing and to treatment.
The brain scans that can now measure the activity of dopamine offer an explanation for the psychotic symptoms. The autopsy reports on brains of schizophrenics confirm the presence of an ongoing destructive disease process. All of this information would point to schizophrenia being a brain disease process and among physicians, there would be few who would disagree.
It is still true that the absolute definition of the cause of symptoms in schizophrenia has not been defined. A great deal of research exists that demonstrates pathological change in the brain among those who are affected. Those of us in Biblical Counseling should approach the counseling of individuals who present with the diagnosis with a 1Thessalonians 5:14 attitude. “Admonish the unruly, encourage the fainthearted, help the weak, be patient with everyone.”
Other Research.
In the past year there have been several interesting research papers and case reports published about this subject. The one that interested me the most connects some of the dots between the genetic and pathological studies. It is a case report published in the Psychiatric Times that documented the history of two individuals who needed a bone marrow transplant for leukemia.[20] In one case the individual received a transplant from a sibling who had symptomatic schizophrenia. While he was cured of his leukemia, he developed the symptoms of schizophrenia. In the second case an individual who had schizophrenia received a bone marrow transplant from an individual who did not have schizophrenia. He was cured of his leukemia and his schizophrenia.
What does the case study imply? Bone marrow transplants require that the individuals current bone marrow be replaced. It is the source of the cancer, and to cure, the old bone marrow must go . In essence the individual receives an immune system transplant. It may well be the case that schizophrenia is an autoimmune disorder much like other autoimmune diseases that affect the brain.
There are other auto-immune disorders that affect the brain and can be treated.[21] If schizophrenia turns out to be caused by an immune disorder that attacks the tissue of the brain, then there is great potential that we will be able to test for it and eventually treat it. Currently it exists in much the same realm as Alzheimer’s disease, where we have a growing understanding of the pathology, but are struggling to create drugs that cure it.
Conclusions.
We started with the question, is schizophrenia an outcome of spiritual problems or is it a medical problem, a disease of the brain that results in the symptoms.
We are not the first to grapple with this question. Freud considered it and decided that schizophrenia was a result of unresolved conflicts in the individual’s life usually with a parent. Kraepelin believed that schizophrenia was a biological brain disorder for which there was no cure or treatment. In either case neither of them had much success in the care of those affected.
What can we say then about the cause and care of schizophrenia from the articles we have examined? First, there is a growing body of medical evidence that supports the idea that schizophrenia is a brain-based disease. Few physicians would say anything different. As we noted above, it is important to remember that schizophrenia is often over diagnosed. And, psychosis from drug use and other disease can certainly be mistaken for it.
Second, is schizophrenia primarily a spiritually caused problem? The more we know about it from a medical viewpoint, the less likely this seems. Is it a medical problem with spiritual implications? This seems to be more likely.
In either case, at this time the answer is not absolutely certain. As one writer said, the truth is probably somewhere in the middle. As a physician and Biblical counselor, I believe schizophrenia will prove to be a medical problem that will eventually have a cure. However, that is just my opinion. I do believe that opinion rests on a growing body of research findings. Current medical treatment for the psychotic symptoms can be helpful to many, but not all. I also think that individuals who struggle with the symptoms of schizophrenia will need the kind of care that comes from scripture as might anyone with a chronic medical problem.
[1] McCutcheon RA, Reis Marques T, Howes OD. Schizophrenia—An Overview. JAMA Psychiatry. Published online October 30, 2019. doi:https://doi.org/10.1001/jamapsychiatry.2019.3360
[2] Coulter, Chelsey, Baker, Krista K., Margolis, Russell L. Specialized Consultation for Suspected Recent-onset Schizophrenia Diagnostic Clarity and the Distorting Impact of Anxiety and Reported Auditory Hallucinations. Journal of Psychiatric Practice, 2019 DOI: 10.1097/PRA.0000000000000363
[3] Schizophrenia, McCutcheon, E2.
[4] Ibid, E2.
[5] Ibid, E2
[6] Ibid, E2
[7] Ibid, E2
[8] Aswin Sekar, Allison R. Bialas, Heather de Rivera, Avery Davis, Timothy R. Hammond, Nolan Kamitaki, Katherine Tooley, Jessy Presumey, Matthew Baum, Vanessa Van Doren, Giulio Genovese, Samuel A. Rose, Robert E. Handsaker, Mark J. Daly, Michael C. Carroll, Beth Stevens, Steven A. McCarroll. Schizophrenia risk from complex variation of complement component 4. Nature, 2016; DOI: 10.1038/nature16549
[9] Broad Institute of MIT and Harvard. "Genetic study provides first-ever insight into biological origin of schizophrenia: Finding explains clinical observations, opens new therapeutic avenues." ScienceDaily. ScienceDaily, 27 January 2016. <www.sciencedaily.com/releases/2016/01/160 This is the summary in ScienceDaily of the article noted in 7.
[10] Schizophrenia, McCutcheon, E3.
[11] Ibid, E4.
[12] For an interesting read on the pitfalls of brain scanning see “Brainwashed: The Seductive Appeal of Mindless Neuroscience,” by Sally Satel. Basic Books, New York. 2013.
[13] Ibid, E5.
[14] Lauren V. Moran, Dost Ongur, John Hsu, Victor M. Castro, Roy H. Perlis, Sebastian Schneeweiss. Psychosis with Methylphenidate or Amphetamine in Patients with ADHD. New England Journal of Medicine, 2019; 380 (12): 1128 DOI: 10.1056/NEJMoa1813751
[15] Schizophrenia, McCutcheon, E5.
[16] Schizophrenia, McCutcheon, E4.
[17] Ibid, E6.
[18] Ibid, E6.
[19] Ibid, E6.
[20] Immunotherapy as Personalized Medicine for Schizophrenia, Brian Miller, MD, Psychiatric Times, February 28, 2019, Vol 36, Issue 2. https://www.psychiatrictimes.com/special-reports/immunotherapy-personalized-medicine-schizophrenia
[21] An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models,
Josep Dalmau, PhD, Thais Armangué, PhD. Et. Al. Lancet, Published:July 17, 2019DOI:https://doi.org/10.1016/S1474-4422(19)30244-3
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