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Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.