Severe fatigue that impairs usual function has long been described throughout recorded human history. The neurologists Beard and Charcot were among the first to characterize the health condition ‘neurasthenia’ in the latter half of the 19th century. Based on this common historical root in neurasthenia, two divergent scholarly and clinical paths have taken shape over time. The first path involves a pathogenic disease model rooted in the scientific process, resulting in a rich literature describing pathobiology and various attempts at creating specific case definition criteria. This path has resulted in the label of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The second path is a psychosomatic/sociogenic illness construction that has incorporated ideas from contemporary neuroscience into an unbroken conceptual chain linking back to neurasthenia. This path has resulted in the label of functional neurologic disorders (FND).
Long COVID has caused a renewed scholarly and clinical focus on complex chronic conditions associated with infections. According to the National Academy of Science, Engineering, and Medicine definition, long COVID is “an infection-associated chronic condition that occurs after SARS-CoV-2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.” Long COVID consists of single or multiple symptoms attributable to single or multiple diagnosable conditions. It can follow asymptomatic, mild, or severe SARS-CoV-2 infection.
Among individuals with a positive COVID-19 test, approximately 43% of non-hospitalized cases and over half of hospitalized cases report symptoms and signs of long COVID, according to data from the first two years of the pandemic. More recently, testing for SARS-CoV-2 infection has become far less frequent within society, and surveillance testing has been discontinued. In addition, many individuals with COVID-19 now convalesce outside the medical system, so these cases are undetected. These observations suggest the prolonged decreases in function and delayed recovery associated with COVID-19 may be undercounted and accelerating over time.
The intensity and disablement of fatigue associated with long COVID are similar to other post-viral conditions, including post-treatment Lyme disease, chronic Epstein–Barr infection, and post-mononucleosis syndrome. The condition may range from mild impairment of function to severely disabling exhaustion. Patient complaints include severe waxing and waning fatigue, worsening fatigue the day after exertion, and dramatic exacerbation by efforts to exercise. Associated symptoms, including cognitive impairment (often referred to by patients as brain fog), diffuse chronic pain, sleep disruption, and autonomic dysfunction, including POTS, migraine, gastrointestinal dysmotility, and temperature intolerance, are common concomitants. The onset of symptoms may be continuous from the time of infection or delayed in onset by weeks or months following an apparent full recovery from the acute phase of infection.
Long COVID disablement can range from mild to severe, and it can resolve in a period of months, or it can persist and worsen over time. Disablement related to long COVID may result in profound functional impairments in self-care, as well as family, social, school, and occupational roles. Post-exertional malaise/post-exertional neuroimmune exhaustion (PEM/PENE) is common among people with long COVID, which accounts for the persistent, severe, and often progressive pattern of disablement in long COVID. PEM/PENE is a clinical hallmark of ME/CFS, suggesting an ME-like subtype of long COVID is prevalent. Therefore, it is perhaps unsurprising that many of the same themes historically characterizing the narrative about ME/CFS are still influencing the discourse surrounding long COVID.
An accumulating body of research indicates the underlying pathophysiology of long COVID involves a complex interaction between processes and systems. Long COVID has been acknowledged to exacerbate pre-existing health conditions, or it may present as new diagnosable health conditions. However, psychosomatic/sociogenic illness constructs continue to influence the contemporary discourse related to long COVID. This clinical perspective will anchor the current discourse regarding long COVID into the historical context involving a parallel development of ME/CFS (predominately pathobiological) and FND (predominately psychosomatic/sociogenic) diagnostic constructs. This perspective will now review the clinical findings and neurobiological pathology of long COVID, developing a clinical and scientific rationale for why it is inappropriate to consider long COVID as FND.
| Concept | Explanation |
|---|---|
| Long COVID | A condition where people continue to have symptoms for at least three months after a COVID-19 infection. These symptoms can affect many parts of the body and can continue or come and go over time. |
| Neurasthenia | An old term used to describe extreme tiredness and weakness, believed to be caused by the exhaustion of the nervous system. |
| Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | A disease that causes long-term fatigue and other symptoms that don’t improve with rest. It was first recognized as a distinct condition in the mid-1980s. |
| Functional Neurologic Disorder (FND) | A condition where people have physical symptoms like weakness or movement problems that cannot be explained by medical tests. It is considered to be related to psychological or emotional stress. |
| Post-exertional Malaise (PEM/PENE) | A key symptom of ME/CFS and long COVID where people feel extremely tired and unwell after physical or mental exertion. This fatigue can last for days or even weeks. |
| Pathophysiology | The study of changes in the body that occur due to disease. In long COVID, this includes problems with the immune system, blood flow, and nerve function. |
| Psychosomatic/Sociogenic Illness | Illnesses that are believed to be caused by psychological factors such as stress or social influences, rather than physical causes. |
| Autonomic Dysfunction | Problems with the part of the nervous system that controls involuntary actions like heart rate, blood pressure, and digestion. This is common in long COVID. |
| Gray Matter and White Matter Changes | Changes in the brain that can be seen with imaging techniques. Gray matter consists of brain cells, while white matter consists of connections between those cells. Long COVID has been shown to cause changes in both types of brain matter. |
| Neuroinflammation | Inflammation in the brain, which has been observed in people with long COVID. This can cause symptoms like brain fog and cognitive impairment. |
| Blood-Brain Barrier (BBB) Permeability | The blood-brain barrier is a protective shield that keeps harmful substances out of the brain. In people with long COVID, this barrier can become “leaky,” allowing harmful substances to enter the brain and cause problems. |
| Cognitive Impairment (Brain Fog) | Problems with thinking, memory, and concentration. This is a common symptom in people with long COVID. |
| Dysautonomia | A disorder of the autonomic nervous system, which can cause symptoms like dizziness, lightheadedness, and fainting. This is often seen in long COVID. |
| Hoover’s Sign and Hip Abductor Sign | Clinical tests used to differentiate true muscle weakness from functional weakness. In long COVID, true weakness is usually not seen in these tests. |
| Give-way Weakness | A type of muscle weakness where the muscle suddenly gives out, usually due to pain or fatigue rather than actual muscle damage. Seen in long COVID but not indicative of FND. |
| Tremor Entrainment | A test where a person with a tremor is asked to perform a rhythmic task with another part of the body. If the tremor changes to match the rhythm of the task, it suggests the tremor is functional (psychological) rather than neurological. |
| Anoxic Seizures | Seizures caused by a lack of oxygen to the brain, often seen in people with syncope (fainting). In long COVID, these are sometimes mistaken for functional seizures. |
| Syncope and Presyncope | Syncope is fainting, and presyncope is the feeling of about to faint. These can be caused by autonomic dysfunction in long COVID. |
| Tilt Table Test | A test used to diagnose the cause of fainting or dizziness. The patient is tilted at different angles to see how the body reacts. Useful for differentiating syncope from functional (psychological) causes. |
| Dynamic Contrast-Enhanced MRI (DCE-MRI) | An imaging technique that shows how contrast agents move through the brain, used to identify issues like increased BBB permeability in long COVID patients. |
| Diffusion Tensor Imaging (DTI) | An MRI-based technique that looks at the movement of water in the brain to identify changes in brain structure. Used to study white matter changes in long COVID. |
| Positron Emission Tomography (PET) | An imaging technique that shows how tissues in the body are working. It has been used to identify areas of inflammation in the brains of people with long COVID. |
| International Classification of Diseases (ICD) | A global health standard for diagnosing diseases. Long COVID has been given its own code (U09.9) in this classification system, recognizing it as a distinct condition. |
| Secondary Gain | The benefits a person might receive from their symptoms, such as attention or avoidance of responsibilities. This concept is part of the theory behind functional disorders. |
| DSM-V-TR (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision) | A manual used by clinicians to diagnose mental disorders. It includes criteria for diagnosing FND. |
Pathobiological Disease Characterization: From Neurasthenia to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Some neurologists considered neurasthenia as a form of nervous exhaustion that caused severe mental and physical fatigue, even following the mild exertions associated with normal daily functions like self-care, family and community activities, and remunerative work. Weakness characterized by abnormally rapid fatiguability and slow recovery following exertion were classically associated with neurasthenia. Yet, people with neurasthenia generally had unremarkable findings on physical examination despite having often severe functional limitations from a whole constellation of associated signs and symptoms. Nervous system exhaustion, nerve over-excitability, and impaired cerebral blood flow all were implicated as potential patho-etiological factors, perhaps secondary to overwork, toxicity, or infection. The absence of remarkable physical findings consistent with neurasthenia, perhaps combined with a high prevalence of neurasthenia in women, led to early psychological theories suggesting that emotional disturbances corresponding to the severe physical and mental symptoms, signs, and disablement must be causal factors.
The personal and societal challenges of persistent fatigue never abated, even as the diagnosis of neurasthenia began to fall out of favor. It was during this time that the association between persistent fatigue and infection began to be more deeply explored. In 1934, Gilliam documented an outbreak of infectious disease that caused lingering signs and symptoms at Los Angeles County General Hospital in the United States. Poliomyelitis was the best-known epidemic at the time, so Gilliam called this new condition atypical poliomyelitis. Outbreaks of atypical poliomyelitis were also documented in Iceland in 1946–1947 and 1948–1949. In 1955, the term benign myalgic encephalomyelitis (ME) was introduced to describe the post-acute signs and symptoms following infectious disease at the Royal Free Hospital (London, UK). The term epidemic ME was then coined at a 1978 symposium of the Royal Society of Medicine. This development was the medical community’s first acknowledgment of ME as a distinct disease process, instead of a behavioral disorder. ME began to reach the popular consciousness in the mid-1980s US following an outbreak of post-infectious illness in Incline Village, Nevada. Work surrounding this outbreak led to assigning the name chronic fatigue syndrome (CFS) to signs and symptoms following an infection. Although clinicians and researchers thought this term best described the phenomenon, people with ME believe it poorly represents their lived experience. Unsurprisingly, the term CFS remains deeply unpopular among people living with ME/CFS even as it continues to find common usage.
The nature of lingering symptoms, signs, and disability was the subject of exploration as the various outbreaks were documented. Ramsay first coined the term epidemic malaise to describe the phenomenon of muscle weakness that was worsened upon repeat testing. This observation of a physical performance decline in response to a previous exertion was formative to developing contemporary case definition criteria for ME/CFS. PEM/PENE is now recognized as a whole host of unusual signs and symptoms following exertion, such as profound fatigue, cognitive dysfunction (such as impairment in attention, short-term memory, and performing mental calculations), sleep disturbance, clinical presentations consistent with viral reactivation (such as fevers, swollen glands, and pharyngitis), body and joint pains, headaches, and muscle weakness. PEM/PENE appears responsible for the episodic disability observed in people living with ME/CFS. Episodic disability suggests a person’s physical and cognitive abilities may vary substantially within a short term of hours to days (i.e., microcycling) and a long term of weeks, months, and years (i.e., macrocycling). In addition, PEM/PENE has increasingly become a component of case definition criteria over time to differentiate the phenomenon of debilitating fatigue, among other signs and symptoms, after exposure to a pathogen or toxin from other causes of fatigue.
Various case definitions to describe ME have been created throughout the late 20th century and early 21st century. These case definitions include the Holmes et al. criteria (1988), Oxford criteria (1991), Fukuda et al. criteria (1994) and its elaboration by Reeves et al. (2005), Canadian Consensus Criteria (CCC; 2003), International Consensus Criteria for ME (ICC-ME; 2011), criteria for Systemic Exertional Intolerance Disease (SEID; 2015), and the UK National Institute for Health and Care Excellence guideline (UK NICE; 2021). There has been a progressively increasing prominence for the role of PEM/PENE as an important differentiating factor between ME/CFS and other health conditions associated with fatigue. PEM/PENE is now perhaps the most important specific (rule-in) consideration to identify ME/CFS and distinguish it from other health conditions that involve disabling fatigue.
ME was first discussed as being different from other neurological disease processes in a 1956 paper that first used the term “benign myalgic encephalitis” to distinguish it from other infectious encephalitic infections and, perhaps most importantly, hysteria. It was first assigned an International Classification of Diseases (ICD) code in the ICD-8 1969 (code 332). ME and CFS are included in ICD-11 as post-viral syndromes (8E49). Inclusion of ME is evidence of improving legitimacy within the biomedical community, as the clinical characteristics and courses of these conditions have become better understood over time.
Notably, ME and CFS are not included in the ICD as mental or behavioral disorders. Key points in the development of a pathobiological disease construction resulting in the collective understanding of ME/CFS highlight the transition from early theories of neurasthenia to the current recognition of ME/CFS as a distinct biomedical entity.
Here is a detailed scheme table with all the symptoms of long COVID and their descriptions:
| Symptom | Description |
|---|---|
| Fatigue | Extreme tiredness that doesn’t improve with rest and can severely limit daily activities. |
| Post-Exertional Malaise (PEM) | Worsening of symptoms after physical or mental exertion, which can last for days or weeks. |
| Brain Fog | Cognitive impairment that includes difficulty thinking, concentrating, and remembering. |
| Shortness of Breath | Difficulty breathing or feeling breathless, often exacerbated by physical activity. |
| Cough | Persistent cough that can be dry or produce mucus. |
| Chest Pain | Discomfort or pain in the chest, which may be sharp or dull and can occur with or without exertion. |
| Heart Palpitations | Sensation of a racing or irregular heartbeat. |
| Dizziness | Feeling lightheaded, faint, or unsteady, which can be due to orthostatic intolerance or other issues. |
| Joint Pain | Aching or pain in the joints, which can be persistent or intermittent. |
| Muscle Pain | Soreness or aching in the muscles, often accompanied by weakness. |
| Headaches | Frequent or severe headaches that can vary in intensity and duration. |
| Sleep Disturbances | Problems with falling asleep, staying asleep, or experiencing non-restorative sleep. |
| Loss of Smell (Anosmia) | Inability to smell, which can be partial or complete. |
| Loss of Taste (Ageusia) | Inability to taste, which can be partial or complete. |
| Sore Throat | Pain or irritation in the throat, often accompanied by hoarseness or difficulty swallowing. |
| Fever | Elevated body temperature, often occurring in episodes. |
| Night Sweats | Excessive sweating during sleep, which can soak clothing and bedding. |
| Gastrointestinal Issues | Symptoms such as nausea, diarrhea, abdominal pain, and bloating. |
| Skin Rashes | Various types of skin rashes, including redness, bumps, or hives. |
| Hair Loss | Increased hair shedding or thinning. |
| Mood Changes | Symptoms such as depression, anxiety, and irritability. |
| Eye Problems | Issues such as dry eyes, blurred vision, and sensitivity to light. |
| Tinnitus | Ringing, buzzing, or other noises in the ears that are not caused by an external source. |
| Ear Pain | Discomfort or pain in the ear, which can be persistent or intermittent. |
| Temperature Intolerance | Sensitivity to hot or cold temperatures, which can cause discomfort or worsening of symptoms. |
| Swollen Lymph Nodes | Enlargement of lymph nodes, which can cause lumps under the skin, particularly in the neck, armpits, or groin. |
| Autonomic Dysfunction | Issues with the autonomic nervous system, leading to symptoms like heart palpitations, blood pressure changes, and digestive problems. |
| Small Fiber Neuropathy | Damage to the small nerves, causing symptoms like pain, burning, tingling, and numbness, particularly in the hands and feet. |
| Malaise | General feeling of being unwell or discomfort. |
| Throat Clearing | Frequent need to clear the throat, often due to mucus or irritation. |
| Hoarse Voice | Raspy or strained voice, often due to inflammation or irritation of the vocal cords. |
| Weight Loss or Gain | Unexplained changes in weight, either loss or gain. |
| Exercise Intolerance | Inability to exercise or engage in physical activity without significant worsening of symptoms. |
| Paresthesia | Abnormal sensations such as tingling, prickling, or numbness, often in the hands and feet. |
| Peripheral Neuropathy | Damage to the peripheral nerves causing weakness, numbness, and pain, usually in the hands and feet. |
| Heart Problems | Issues like myocarditis (inflammation of the heart muscle) or pericarditis (inflammation of the lining around the heart), leading to chest pain and other symptoms. |
| Kidney Issues | Problems with kidney function, which can lead to symptoms like swelling, fatigue, and changes in urination. |
| Liver Issues | Problems with liver function, which can cause symptoms like jaundice (yellowing of the skin and eyes), dark urine, and abdominal pain. |
| Vascular Problems | Issues with blood vessels, such as clotting disorders or poor circulation, which can cause pain, swelling, and other symptoms. |
| Immune System Dysfunction | Abnormalities in immune function, which can lead to increased susceptibility to infections or autoimmune reactions. |
| Endocrine Issues | Problems with hormone-producing glands, leading to symptoms like fatigue, weight changes, and mood disturbances. |
| Blood Pressure Changes | Unexplained fluctuations in blood pressure, which can cause dizziness, fainting, or headaches. |
| Dry Mouth | Reduced saliva production, leading to dryness and discomfort in the mouth. |
| Chronic Pain | Persistent pain that can affect any part of the body, often without a clear cause. |
| Cognitive Difficulties | Problems with thinking skills, such as difficulty concentrating, planning, and organizing tasks. |
| Peripheral Edema | Swelling in the extremities, particularly the legs and ankles, often due to fluid retention. |
| Gastroesophageal Reflux Disease (GERD) | A condition where stomach acid frequently flows back into the esophagus, causing heartburn and other symptoms. |
| Fibromyalgia-like Symptoms | Widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood issues. |
| Thrombosis | Formation of blood clots within blood vessels, which can lead to serious complications if they block blood flow. |
Psychosomatic/Sociogenic Illness Construction: From Neurasthenia to Functional Neurologic Disorder
While decades of scientific work have led down the path of iterative case definition criteria and the determining of the underlying pathophysiology of ME/CFS, a parallel path largely has repeated old thinking with new labels. The first edition of the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association listed hysteria as conversion reaction, transitioning to hysterical neurosis in the DSM’s second edition. These titles were based on the early concepts of hysteria as a uterine disorder in women. A major underlying hypothesis advanced by Freud is that hysterical disorders involved the conversion between a somatic symptom and a repressed feeling or idea, such as a somatic symptom arising from anxiety, hence the term conversion disorder. With the transition away from a system classifying disorders based on putative etiology and toward a contemporary system of psychodiagnostics by clinical phenomenology, the third edition of the DSM replaced hysterical neurosis with dissociative disorders and conversion disorders under the broader classification of somatoform disorders. Early hypotheses regarding the etiology of hysteria were carried forward into thinking about somatoform disorders. Psychoanalytic theories suggested the repressed expression of conflicted unconscious drives, learning theories held that people with conversion disorders benefitted from secondary gain of their somatic symptoms, and sociocultural hypotheses were that somatic symptoms occur in substitution of the expression of intense forbidden ideas and emotions.
In 2013, the term ‘functional neurological symptom disorder’ was introduced in the DSM Version 5 Text Revision (DSM-V-TR), and conversion disorder remained the main nomenclature. The 2022 revision of DSM-V-TR then changed the primary name to functional neurological symptom disorder and maintained conversion disorder as a synonym. FND is now classified by the International Classification of Diseases (ICD-11) as a dissociative neurological symptom disorder, defined as a mental health condition involving a loss of connection between thoughts, memories, feelings, surroundings, behavior, and identity. More recent data from neuroscientific studies have been used to support claims of emotional processing that might be familiar to earlier advocates of hysteria and somatoform conditions. Despite poor-quality supporting research, mainstay interventions for FND continue to include psychodynamic and cognitive-behavior therapies to address emotional processing. Thus, despite the original intent and subsequent rationalizations of the principal proponents of FND, this brief historical analysis indicates a continuous underlying conceptual thread that remains unbroken between neurasthenia, through hysterical neurosis and somatoform disorders, leading to the contemporary psychosomatic/sociogenic illness construction of FND.
Proponents suggest that just the label of FND may be helpful for some patients who live with troublesome but medically unexplained symptoms and signs. Even still, the DSM-V-TR diagnostic criteria for FND indicate this label should not be provided when an alternative diagnosis is more compelling. For example, ME/CFS should not be considered as a functional disorder because more specific case definition criteria best explain its constellation of symptoms, signs, and pathophysiology. However, some prominent medical organizations have conflated PEM/PENE with FND because some symptoms of PEM/PENE are represented among the DSM-V-TR case definition criteria for FND. For example, the UK NICE attempted to classify ME/CFS as a functional disorder in 2017. This action was met with significant opposition from the ME community. The dispute lasted over two years with the subsequent guideline removing the reference to ME/CFS as FND. Both individual clinicians (generally from the fields of neurology and psychiatry) and prominent national medical organizations in European countries persist in classifying ME/CFS as FND despite compelling evidence to the contrary.
Evidence Refutes That Long COVID Should Be Considered a Functional Neurologic Disorder
FND refers to medical and neurologic symptoms that fail to match any existing medical or neurological conditions. It is a rare syndrome, affecting around 4–12 per 100,000 people despite a suggestion that it is commonly diagnosed in neurology clinics. FND is usually diagnosed when patients are observed to experience seizure-like spells in the setting of normal electroencephalography (EEG) or when they demonstrate abnormal movements or paralysis that are incongruent with their neurologic exam and neuroimaging. In some patients, FND may occur alongside other diagnosable entities, such as long COVID. In this scenario, the clinician should evaluate and treat those diagnosable entities and refrain from considering the entire patient presentation as “functional” simply because functional aspects may be present. While the rate of misdiagnosis with FND in patients with long COVID is unknown, clinical experience suggests that many patients with complex chronic disorders in general have been misdiagnosed with anxiety, depression, or FND at some point in the course of their illness.
Refutative Evidence from Pathophysiology
The scope and severity of Long COVID-related disablement in individuals and in society have incentivized investigations into the pathophysiology of this novel infection-associated chronic disease. Long COVID is now understood as an umbrella term encompassing a complex pathophysiology affecting multiple organ systems. Various potential aspects of long COVID pathobiology include autonomic manifestations; vascular and endothelial dysfunction in the context of hypercoagulability; viral persistence; abnormalities in T cell populations and responses; impaired cardiopulmonary function; autoimmunity; bioenergetic impairments; small fiber neuropathy; and alterations in the gut microbiome. In 2021, post-COVID-19 condition (or, long COVID) was assigned an ICD code (U09.9). The collective understanding of long COVID is far from settled. However, an accumulating science now provides a more compelling pathophysiological basis for testing and interventions than considering long COVID as a functional disorder. Long COVID should not be broadly considered as FND because of its “organic” nature, requiring FND to be ruled out according to DSM-V-TR criteria.
Refutative Evidence from Clinical Presentation
Typically, people with functional disorders often exhibit numerous multi-systemic and multi-organ concerns, including various neurologic and psychiatric manifestations such as sensory disturbance, motor weakness, balance difficulty, chronic dizziness, chronic vertigo, chronic pain, chronic fatigue, sleep impairment, urinary and gastrointestinal symptoms, and cognitive dysfunction. The symptom experience and distress associated with symptoms in people with FND are frequently not supported or incongruent with objective findings on neurologic examination and diagnostic testing. People with functional disorders also may have comorbid psychiatric conditions, such as depression and anxiety. It remains unclear whether the prevalence and severity of psychiatric comorbidities among those with functional disorders is greater than people living with other types of chronic illnesses, and whether psychiatric conditions contributed to other signs and symptoms or are a secondary reaction to their presence. In addition, inventories used to measure anxiety and depression often may capture the autonomic signs and symptoms of underlying pathobiological process. FND, if diagnosed correctly through positive signs on neurologic examination, does not appear to be as common although true prevalence is unknown and needs to be studied. Moreover, no carefully designed research studies have been conducted to systematically test the hypothesis that long COVID is a functional disorder and the extant literature is poor in methodological quality.
The diagnosis of FND requires the presence of discrete neurologic deficits, which are usually elicited as part of the neurologic examination. Presenting features may include weakness in the lower or upper extremities of sudden onset and can be unilateral or bilateral. A neurologic examination is used to demonstrate evidence of internal inconsistency between voluntary movements and automatic movements through findings of a positive Hoover’s sign and hip abductor sign. While weakness in the extremities is a common concern in many people living with long COVID, clinical experience indicates that the neurologic examination typically reveals an unremarkable motor examination without Hoover’s or hip abductor signs. Give-way weakness may be present in patients with long COVID, but it is usually diffuse and non-lateralizing and occurs secondary to pain, fatigue, PEM/PENE, or orthostatic intolerance. In the context of these companion findings, give-way weakness should not be interpreted as evidence of a functional etiology.
A common presenting feature of FND is sensory disturbance that fails to fit into defined patterns of neuropathy, radiculopathy, or the central lesion of the brain. Sensory testing as part of neurologic examination in a patient with FND may reveal complete anesthesia in non-anatomic distributions, such as involving an entire extremity, located exactly at the midline, or below the waist. While sensory disturbance is common in patients with long COVID due, in part, to post-COVID-19 small fiber neuropathy, sensory exam findings usually correspond to a neuropathic pattern with decreased pinprick and temperature sensations in the feet or hands, distally more than proximally. However, a patchy sensory loss distribution is not uncommon in those who present with non-length-dependent patchy small fiber neuropathy, a form that is especially prevalent in people with autoimmune disorders.
Tremor may be another presenting feature of FND with examination findings revealing tremor entrainment and other inconsistent tremor characteristics. Tremor and other abnormal movements may be among common complaints of patients with long COVID, but often involve diffuse, whole-body body tremors or shaking, which may be associated with dysautonomia and hyperadrenergic state, including abnormal blood pressure, heart rate, and blood volume. Autonomic dysfunction affects nearly 70% of patients with long COVID, so improvement or resolution of abnormal movements associated with dysautonomia may be noted with hydration, increased salt intake, or medications. Additionally, the sensation of “internal vibrations” is often described by people living with long COVID; although the etiology of this concern is not fully understood, clinical experience suggests it often occurs in patients with hypovolemia, dysautonomia, and small fiber neuropathy. These features should not be attributed to functional causes or FND.
Spells of unknown etiology are often attributed to FND, especially when accompanied by normal EEG in the setting of convulsive activity. While a small subset of people living with long COVID could have non-epileptic functional seizures, many patients with long COVID have post-COVID-19 dysautonomia in the form of neurocardiogenic syncope, postural orthostatic tachycardia syndrome, orthostatic hypotension, and orthostatic intolerance. These patients often experience spells of presyncope or syncope, some with convulsive activity during syncope, which is termed anoxic seizures. Patients with presyncope and syncope may be misdiagnosed with FND by neurologists with limited knowledge of the phenomenology of syncope. In cases where the etiology of spells is unclear, a tilt table test can provide differentiation between syncope and pseudo-syncope with adequate sensitivity and specificity. A video recording of the spells obtained by the family also may be reviewed by a neurologist to assist with differentiating between syncope and dissociative/functional seizures.
Gait examination of people living with long COVID is typically unremarkable, although some people may have unsteadiness due to orthostasis or poor proprioception related to large fiber neuropathy, chronic vestibulopathy, or hypermobility spectrum disorders. Clinical features of abnormal gait and movements consistent with FND, such as dystonia, ticks, twitches, and jerks, are typically uncommon in people with long COVID. Concerns about gait and findings in the gait examination explainable by other causes should not be taken as signs of FND.
Urinary retention is sometimes listed as a feature of FND, but clinical experience suggests that urinary retention rarely occurs in people with long COVID. Urinary retention is a common feature of autonomic neuropathy and, if present in patients with long COVID, should prompt an investigation for post-COVID-19 autonomic neuropathy or ganglionopathy which have been described as rare post-COVID-19 conditions.
Cognitive concerns, such as difficulty with attention, concentration, and memory, have been endorsed by some proponents of FND as being functional in nature. One review suggested that almost one quarter of patients attending memory clinics may have functional cognitive disorders. However, it is unclear how these complaints are differentiated from the cognitive impairment—commonly referred to as brain fog—in patients with long COVID. Numerous studies suggested neuroinflammation and microglial activation as mechanisms of post-COVID-19 neurologic sequelae. Importantly, several studies identified neuropsychological deficits via cognitive testing in patients with long COVID.
Moreover, traditional screening tests for evaluation of cognitive impairment designed to screen patients for Alzheimer’s disease are not useful in patients with cognitive impairment secondary to long COVID. Thus, currently available screening tests that were designed for neurodegenerative conditions and not neuroinflammatory or neuroimmune conditions are inadequate to rule in or out impairments secondary to neuroinflammatory and neuroimmune processes, and, therefore, cannot be utilized to diagnose as functional by default if results are “normal” in patients with long COVID and other disorders that are associated with cognitive complaints. Cognitive tests to assess patients with non-neurodegenerative cognitive complaints need to be designed to provide clinicians with validated tools to better evaluate and quantify the extent of cognitive impairment in patients with post-COVID-19 neurocognitive syndrome.
In summary, FND and long COVID can be effectively differentiated through a comprehensive clinical examination. One caveat is the difficulty that arises when a patient presents with some evidence of functional neurologic disorder on physical examination (e.g., with tremor entrainment or positive Hoover’s sign) in conjunction with postural tachycardia, acrocyanosis, and other features of long COVID and post-COVID-19 dysautonomia or small fiber neuropathy. In cases like these, management of non-FND disorders and symptoms should be the top priority. Clinical experience suggests that a significant number of patients with long COVID are being misdiagnosed with FND without diagnosing and addressing the primary long COVID pathophysiology or symptoms, such as dizziness, palpitations, tachycardia, and pain. In these cases, FND-tailored diagnostic and therapeutic approaches delay improvement and recovery by failing to implement the pharmacologic and non-pharmacologic therapies targeting underlying autonomic, neuropathic, and cardiovascular pathophysiologies. Referral to FND-tailored rehabilitation programs should be considered only for patients, in whom post-COVID-19 FND is determined to be the main component of long COVID and in strict adherence with relevant case definition criteria.
Refutative Evidence from Neuroimaging
Despite its relatively recent recognition, the literature describing significant structural brain abnormalities in long COVID is already extensive. This literature suggests FND cannot commonly explain long COVID, because it indicates neurologic signs, symptoms, and disability may be caused by structural changes in the brain. Such abnormalities have been demonstrated using various imaging modalities and range from changes in gray matter thickness and volume, to macro- and microstructural white matter changes and evidence of metabolic and neuroinflammatory derangement. It is also important to note that despite clearly distinctive systemic immunological abnormalities and abnormal neuroimmune profiles in long COVID, routine clinical structural magnetic resonance imaging (MRI) sequences often return normal findings.
Douaud et al. examined structural brain changes in a biobank cohort based in the United Kingdom, before and after SARS-CoV-2 infection. Compared to uninfected controls, the authors found significant gray matter thickness reduction following infection, with a reduction in global brain size. Hosp et al. used an MRI diffusion microstructure imaging technique to evaluate subtle changes in both gray and white matter integrity. Compared to recovered infected patients, those with ongoing symptoms demonstrated widespread changes in microstructure, which correlated with evaluations of cognitive dysfunction. Wu et al. used another diffusion tensor imaging (DTI) technique to evaluate the perivascular space and glymphatic system. These authors calculated flow in the perivascular spaces alongside medullary veins, which lie orthogonal to the projection and association nerve fibers in the periventricular deep white matter. They reported reduction in the indices for glymphatic function in people living with long COVID even following a mild acute infection. Another small cohort study compared recovered, brain fog positive, and brain fog negative patients with long COVID. Dynamic contrast-enhanced MRI (DCE-MRI) showed significant whole brain leakage, indicating increased blood–brain barrier (BBB) permeability, in only the ‘brain fog’ sub-group. Chaganti et al. combined techniques in a longitudinal study of 14 patients with long COVID-related cognitive impairment. DCE-MRI and DTI revealed impairments in the integrity of BBB and white matter microstructure. Simultaneously, MR spectroscopy demonstrated reduced glutamate/glutamine in these areas, leading the authors to suggest that white matter injury may result from glutamatergic excitotoxicity, secondary to reduced BBB integrity associated with neuroinflammation. VanElzakker et al. used positron emission tomography (PET) with a tracer for activated microglia ([11C]PBR28) to report evidence of significantly increased neuroinflammation in many brain regions in long COVID. Peluso et al. used a novel PET tracer ([18F]F-AraG) to tag activated T cells. Following SARS-CoV-2 infection, activated T cells were found in multiple organs including the bowel and bone marrow, but notably had trafficked into central nervous system (CNS) sites such as the brainstem and spinal cord, where they should be absent. This finding was more exaggerated in patients with long COVID signs and symptoms. Biopsy-accessible tissues such as colon tissue demonstrated residual viral components, and the authors speculated they also might be present in the CNS.
A 2021 review article canvased the literature of neuroimaging in FND. The highlighted modalities were functional MRI (fMRI), using both resting-state and task-based paradigms; high-resolution structural MRI evaluation of gray matter; DTI of white matter microstructure; MR spectroscopy; CT/MR positron emission tomography; and near-infrared spectroscopy. The authors note that neuroimaging in FND is early in its development, with few replicated studies, and with confounding factors in terms of clinical heterogeneity and co-morbidities. They conclude by encouraging a multimodal neuroimaging approach to advance the field. Most fMRI studies using blood oxygen level-dependent (BOLD) techniques have shown abnormalities in specific brain regions, yet data have been inconsistent. Very recently, Schneider et al. have attempted to further define the variability of BOLD signal in FND, with particular emphasis on the somatomotor, limbic, and salience networks. However, when structural abnormalities have been found in gray or white matter, it remains unclear whether they are a cause, consequence, or comorbidity.
While neuroimaging in FND is an evolving field, there are already replicated findings in long COVID that point toward a coherent structural pathophysiology. Aspects highlighted in the literature to date involve neuroinflammation with microglial activation, a dysfunctional blood–brain barrier, white matter microstructural changes, as well as reduction in gray matter volume. Systemic dysfunction, such as orthostatic intolerance with reduced cerebral blood flow, is also shown to be a key contributor to symptoms. The detail of how these findings are driven from specific and potentially correctable upstream causes is enthusiastically anticipated by patients, clinicians, and researchers alike.
reference : https://www.mdpi.com/2075-4426/14/8/799
