Long-Term Neurologic Complications of COVID-19: A Practical Overview

Long COVID, also referred to as postacute sequelae of COVID-19, is a constellation of symptoms that occurs in up to 10% to 15% of individuals after recovery from the acute phase of COVID-19. Individuals with long COVID are a heterogenous group; however, many of their symptoms are neurologic, including dysautonomia (particularly orthostatic intolerance), brain fog or cognitive disturbance, fatigue, headaches, sleep disturbances, and sensory disturbances or paresthesias. Many of the symptoms observed in long COVID share striking parallels with sickness behavior (ie, the autonomic nervous system [ANS] response to proinflammatory cytokines).¹

In this review, we present a practical overview of the presentation and management of these common neurologic symptoms associated with long COVID. Because there are no Food and Drug Administration–approved medications for long COVID, all the treatments discussed are off-label. Acute COVID-19–related neurologic complications, post–intensive care unit syndromes, rare autoimmune neurologic syndromes that may be triggered by SARS-CoV-2 infection (ie, demyelination or Guillain-Barré syndrome), or functional neurologic disorders that present after COVID-19 are outside the scope of this article and are not discussed.

Cognitive Dysfunction and Brain Fog

Neurocognitive concerns after recovery from the acute phase of COVID-19 are among the most common and distressing symptoms reported by individuals with long COVID. Although many people experience considerable improvement in cognitive symptoms within 4 to 12 weeks after having COVID-19, recent studies have suggested that up to 25% of people continue to have cognitive symptoms >3 months after acute illness. The range of cognitive symptoms is broad, with people commonly experiencing fatigue (28% to 87%), impaired short-term memory (18% to 21%), and poor concentration (16%).^2-4 Taken together, any combination of these symptoms can lead to a subjective feeling often reported as brain fog.

A large proportion of individuals with long COVID have been shown to have objective impairments in cognition when formally assessed with cognitive batteries in research settings, although the precise estimates vary widely by the type of assessment and study population. According to a recent meta-analysis, 36% of people have objective cognitive deficits after COVID-19.⁵ Deficits in attention, executive function, and delayed recall are most common, whereas language and visuospatial deficits are rare.⁶ Many people presenting to the clinic with post–COVID-19 cognitive concerns, however, may not have detectable cognitive abnormalities on bedside testing or even with a full neuropsychologic test battery.

All individuals with cognitive concerns after the acute illness phase should be evaluated with a full neurologic examination and focused cognitive screening (including testing such as complex commands, serial 7s, delayed word recall, and the Trail Making Test, or a full Montreal Cognitive Assessment). Individuals with abnormalities on bedside testing or persistent symptoms may be referred for formal neurocognitive testing, as both a diagnostic aid and a tool for targeted cognitive therapy. Progressive cognitive symptoms are not typical for post–COVID-19 cognitive dysfunction and should prompt evaluation for alternative diagnoses.

Small research studies have documented neuroimaging irregularities in individuals with long COVID, including cerebral hypoperfusion observed through arterial spin-labeling MRI, as well as anomalies in [11C]PBR28 positron emission tomography signal indicative of neuroinflammation across multiple brain regions, including the thalamus, basal ganglia, corpus callosum, anterior cingulate cortex, and periventricular areas.^7,8 In a clinical setting, however, there is limited evidence to support the utility of neuroimaging such as MRI in the diagnosis of post–COVID-19 cognitive dysfunction, and advanced imaging is typically reserved for people with a presentation concerning for alternative contributing factors to their cognitive dysfunction.

The therapeutic approach to cognitive complaints is focused on management of concomitant fatigue, sleep, autonomic dysfunction, and mood disorders and may also include physical or cognitive therapy in select cases. Although no individual therapy has demonstrated benefit in post–COVID-19 cognitive concerns in prospective randomized trials, therapeutic options can be extrapolated from studies in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and neuroinflammatory conditions such as multiple sclerosis (Table). A recent case series reported reduced cognitive deficits in 8 of 12 individuals with post–COVID-19 cognitive difficulties after use of the alpha2-adrenoceptor agonist guanfacine together with N-acetylcysteine.⁹ Ongoing clinical trials are exploring the efficacy of interventions such as amantadine, transcranial direct current stimulation, tianeptine (an atypical tricyclic antidepressant, not approved for use in the United States), methylprednisolone, and various cognitive rehabilitation strategies for COVID-19–related cognitive dysfunction.

Fatigue and ME/CFS

Fatigue is one of the most commonly reported symptoms after COVID-19, with ~33% of individuals reporting fatigue ≥12 weeks after the acute illness phase.⁵ Although fatigue gradually improves for most individuals, others will experience persistent long-term fatigue.

Some individuals with long COVID experiencing fatigue meet diagnostic criteria for ME/CFS, estimated to affect between 13% and 50% of all individuals with long COVID. The risk of ME/CFS is independent of initial COVID-19 severity.¹⁰ However, the diagnosis of ME/CFS is often challenging because of lack of diagnostic biomarkers, variability in clinical presentation and severity, and variable diagnostic criteria. The Institute of Medicine’s 2015 diagnostic criteria for ME/CFS require (1) substantial reduction in activity levels lasting >6 months accompanied by profound fatigue not alleviated by rest; (2) postexertional malaise (PEM) causing symptom exacerbation after exertion; (3) unrefreshing sleep; and (4) either orthostatic intolerance or cognitive impairment. Additional features of joint pains, myalgias and sensory dysesthesias, autonomic symptoms, and irritable bowel symptoms may also be present. Severity ranges from mild (able to work or go to school but limiting other activities) to moderate (reduced capacity for activities of daily living), severe (housebound), or very severe (bedbound).¹¹ Exercise intolerance or PEM—where symptoms worsen with physical or mental activity within a 12- to 48-hour period—is a pathognomonic symptom of ME/CFS (whether related to long COVID or other triggers), and can be quantified using invasive cardiopulmonary exercise testing (iCPET).¹¹ iCPET has demonstrated impaired systemic oxygen extraction in individuals with long COVID and exercise intolerance. However, iCPET is invasive, is not widely available, and can worsen symptoms in some people.¹²

There are no neurologic signs specific to ME/CFS, although neurologic examination may demonstrate subtle cognitive deficits in attention or memory and subjective sensory deficits. Systemically, tender points (as seen in those with fibromyalgia), hypermobile joints, enlarged lymph nodes, tachycardia, and abdominal tenderness can be present. Autonomic testing can demonstrate postural orthostatic tachycardia syndrome (POTS) (either by tilt-table testing or active standing). Decreased cerebral blood flow has also been noted in people with long COVID ME/CFS, although abnormalities are not typically seen on structural MRI.¹³ Frequent comorbidities include neurologic disorders, such as migraines, sleep apnea, and autonomic dysregulation, as well as Ehlers-Danlos syndrome and other hypermobility disorders, histamine or allergic disorders, and mood or anxiety disorders. Evaluation for anemia, infections, and vitamin deficiencies; inflammatory marker testing (eg, erythrocyte sedimentation rate, C-reactive protein); comprehensive metabolic panel; thyroid and baseline endocrine function testing (eg, cortisol); and rheumatologic screening (eg, antinuclear antibodies, rheumatoid factor) are suggested baseline evaluations.¹¹

Symptomatic management in the form of both nonpharmacologic and off-label pharmacologic treatments are suggested for symptoms of ME/CFS in individuals with long COVID (Table). Evaluation and appropriate treatment of comorbid sleep disturbances or mood disorders are key first steps. Pacing, or energy management aimed at regulating activity to avoid PEM, is often useful,¹⁴ whereas graded exercise therapy is controversial. Pharmacologic options for fatigue, whether as part of an ME/CFS diagnosis or not, may include coenzyme Q10, pyridostigmine, serotonergic modulators, other activating psychotropic drugs such as bupropion or low-dose aripiprazole, and stimulants such as modafinil, methylphenidate, and amantadine (Table).¹⁵

Sensory Symptoms and Paresthesias

Paresthesias and sensory symptoms have been reported in up to 33.3% of individuals after COVID-19.¹⁶ Many individuals with long COVID experience transient sensory disturbances or pain and do not have an identified etiology for their symptoms or evidence of neuropathy on physical examination. This may be partially explained by evidence that COVID-19 causes a reduction in the threshold of sensory sensitivity and a relative increase in reported unpleasant sensation, which was evaluated using administration of the same standard electric current to people who had recently had COVID-19 and controls.¹⁷ People with neuropathy may have a large-fiber neuropathy as a postviral syndrome or a critical illness neuropathy,¹⁸ which has been reported in 10% of intubated individuals with COVID-19. Others may present with symptoms of small fiber neuropathy (SFN), including sensory loss, neuropathic pain, allodynia, and hyperesthesia.¹⁹ SFN may present with a length-dependent distribution or in a non–length-dependent pattern with patchy loss of sensation and paresthesias in different areas of the trunk, face, arms, or torso early in the disease course.¹⁹ Nerve conduction studies and EMG are useful tools for the diagnosis of large fiber neuropathies, but results for these tests will be normal in cases of SFN.¹⁹ A suspicion of SFN may be confirmed with skin biopsy at an experienced center.¹⁹

The prevalence of SFN after COVID-19 is unknown, but several case series have reported new-onset skin biopsy–confirmed SFN within several months of COVID-19.^18,20,21 Treatment options for post–COVID-19 SFN include treatments often used for large fiber neuropathy, such as gabapentin, pregabalin, duloxetine, and nortriptyline or amitriptyline, as well as additional options derived from the fibromyalgia and ME/CFS literature, such as low-dose naltrexone. There is anecdotal support for intravenous immunoglobulin in select cases,²¹ and clinical trials for this potential therapy are ongoing.

Autonomic Symptoms

Many individuals with long COVID report disabling symptoms that reflect a disorder of the ANS, such as postural lightheadedness, presyncope, syncope, hyperhidrosis, exertional intolerance, or unexplained dyspnea, tachycardia, chest pains, or palpitations.²² However, these symptoms are not specific to ANS disorders and may instead suggest a hyperadrenergic state. It can be difficult to determine whether autonomic symptoms reflect an appropriate compensation to an unrecognized underlying stressor or a dysautonomia (ie, a problem with the ANS).

Rare cases of post–COVID-19 autonomic failure have been reported,²³ but these likely suggest temporal association due to conditions such as Guillain-Barré syndrome or premorbid unrecognized synucleinopathy. Classifiable autonomic disorders, such as POTS, are seen in a substantial minority of individuals with long COVID evaluated at tertiary autonomic centers,^24,25 but many individuals with long COVID–associated autonomic symptoms do not have abnormalities detectable on a standard autonomic reflex battery.²⁵ In aggregate, studies have shown increased abnormalities of heart rate variability,²⁶ reduced respiratory sinus arrythmia, and increased heart rate with standing in cohorts of individuals with long COVID compared with healthy controls.²⁷

Regardless of autonomic testing results, hyperadrenergic symptoms associated with long COVID can be treated effectively (Table). Many individuals have had their symptoms trivialized or dismissed, so providing accurate diagnosis and evidence-based education about excessive sympathetic activity and its treatment is critical. Nonpharmacologic management of hyperadrenergic symptoms includes removing stressors, ensuring adequate intravascular volumes with hydration and salt intake, removing exacerbating sympathomimetic or vasodilatory agents, wearing compression garments, performing breathing training for dysfunctional breathing or hyperventilation, and engaging in personalized graded exercise therapy to restore orthostatic tolerance for people who do not experience exacerbation of symptoms with exercise. Pharmacologic management (all off-label) may include sympatholytic drugs, such as low-dose propranolol (eg, 10 or 20 mg TID), clonidine, or guanfacine; selective serotonin reuptake inhibitors; low-dose tricyclic antidepressants; ivabradine; or treatments aimed at increasing cerebral perfusion (eg, fludrocortisone, midodrine, pyridostigmine). These recommendations are based on expert opinion and borrowed from other applications (eg, POTS).²⁸ Stellate ganglion block also has anecdotal support for relief of autonomic symptoms, and randomized trials are ongoing. Stellate ganglion block is hypothesized to mediate its effect through attenuation of sympathetic hyperactivity, although its precise mechanism of action in long COVID is unknown.^29,30 Operating under the assumption that post–COVID-19 POTS may be related to autoimmunity, immunoglobulins and related immunotherapies such as efgartigimod are being tested in randomized trials as is ivabradine.

Headaches

Headache is one of the most frequent manifestations of long COVID, with one large study showing that 16% of individuals who had headache during acute COVID-19 had persistent headache at 9 months,³¹ half of whom had no history of headache before COVID-19.³² There is also clear evidence that individuals with a history of migraine or other preexisting headache disorders can have an exacerbation of their headache condition in the setting of COVID-19.^31,32 These post–COVID-19 headaches most commonly present with a tension-type or migrainous phenotype, although headache characteristics are heterogeneous. Many people without a previous headache history may develop a new persistent daily headache after COVID-19, which can be particularly severe and refractory to analgesics.³¹ MRI is typically not indicated, unless there are headache red flags concerning for a secondary headache related to conditions such as venous sinus thrombosis or idiopathic intracranial hypertension.

There are no clinical trials to guide treatment for post–COVID-19 headache. As in other similar headache conditions, treatment is based on the headache semiology and classification (ie, migraine, tension-type, new persistent daily headache), comorbidities, and the individual’s current medications and response to previous medications. For example, if the headaches have migrainous characteristics, then symptomatic and preventative strategies for the type and frequency of migraine should be initiated (Table). When planning treatment, other associated post–COVID-19 symptoms, such as fatigue, mood disturbances, and cognitive and sleep disorders, should be considered, as many medications used to treat headache may affect these symptoms. Treatment can also include a combination of nonpharmacologic therapies, such as physical therapy, lifestyle modifications, and regular exercise.

Conclusion

Although understanding of the underlying mechanisms of and treatments for long COVID is limited, the profound effects of symptoms on quality of life must be acknowledged. Dismissing, downplaying, or psychologizing these symptoms disregards extensive evidence of their biologic basis and hinders effective care. Neurologists, historically accustomed to supporting people with complex conditions and limited therapeutic options, are well-positioned to address the diverse manifestations of long COVID. Drawing on experience treating fatigue, brain fog, sensory symptoms, autonomic symptoms, and headaches associated with other neurologic conditions, neurologists can extrapolate treatment options and offer guidance and off-label treatment options. Given the frequency of COVID-19, it is also crucial to conduct careful evaluation for coincident primary neurologic conditions to prevent misdiagnosis. Ensuring individuals with long COVID receive appropriate recognition, validation, and specialized support is imperative, with neurologists serving as key members of the multidisciplinary care team.