Neuropsychiatric and Cognitive Symptoms of PASC

Please Note: The information below is intended for healthcare professionals, specifically primary care providers. These are not meant to be guidelines or supplant individual provider discretion in the management of PASC, as evidence-based consensus guidelines for the diagnosis of management of this new disease do not exist currently. The following represents the expert opinions of an interprofessional group that is appraising emerging evidence and should be interpreted as recommendations and clinical guidance rather than the standard of care.

Neuropsychiatric and Cognitive Symptoms of PASC

Written May 12, 2021 by: Matthew Seghers, MS3, Esther Melamed, MD, PhD, Faith Noah, MS3, and W. Michael Brode, MD

Cognitive impairment or “brain fog” is one of the most common symptoms in PASC and can persist for months. The differential diagnosis for PASC cognitive impairment includes both neurological and systemic conditions. The initial evaluation should include a cognitive screen, such as Montreal Cognitive Assessment (MoCA) or Mini-Mental State Examination (MMSE), as well as identifying reversible causes of dementia, worsening or new onset autoimmunity, and considering brain imaging if warranted based on the neurological exam.

No evidence-based treatments exist currently. It is recommended to closely monitor patients with supportive care focused on improving sleep, increasing exercise, and managing comorbid conditions.

Referral for formal neuropsychological testing is recommended for symptoms that are not improving or causing severe functional impairment.

Neuropsychiatric and cognitive symptoms of COVID-19 are very common, with several studies noting neurologic symptoms in up to 80% of patients during acute infection1. Three months later, > 55% of patients still report lingering neurologic symptoms.2

  • Hospitalized patients have been found to have symptoms including headache (38%), confusion (32%), dizziness (30%), loss of taste (16%), and loss of smell (11%).3 While most patients (65%) experience full resolution of symptoms within weeks of their diagnosis, confusion may still be present in up to 20% of patients.1,4

Neurological symptoms in PASC are present in patients who have been hospitalized or in patients who had mild COVID-19 and did not require hospitalization. In one study, 85% of non-hospitalized COVID-19 positive patients reported neurological symptoms after 5 months. These include “brain fog” (81%), fatigue (85%), headache (68%), numbness/tingling (60%, anosmia (55%), myalgia (55%), dizziness (47%), blurred vision (30%), and tinnitus (29%). The severity of fatigue is closely associated with the severity of cognitive dysfunction.5

Post-COVID-19 encephalopathy, or “brain fog,” is a common lingering symptom in PASC. Specifically, it is characterized by difficulty focusing, difficulty with short-term memory, and decreased ability to manage complex tasks. Proposed mechanisms include persistent systemic inflammation, cardio-pulmonary inflammation, rise of autoimmunity, post-infectious neurological inflammation, systemic or neurological microvascular damage, hypoxemia, and sleep dysregulation.6,7

Although cognitive impairment is widely recognized as a symptom of PASC, there are no consensus criteria for evaluation and management at this time. Therefore, while it is highly likely that patients’ symptoms can be attributed to PASC (especially if they were previously healthy) it remains a diagnosis of exclusion, with initial workup focused on detecting reversible causes or direct CNS damage.

Initial workup should include:

  • Detailed history of present illness to evaluate for systemic and neurological causes, and should include an evaluation for autoimmune and dysautonomia syndromes (e.g., Postural Orthostatic Tachycardia Syndrome (POTS)
  • Inflammatory labs (e.g., ESR, CRP, Anti-nuclear antibody with reflex panel, anti-neutrophil antibodies, etc.)
  • Reversible dementia labs (Vitamin B12, methylmalonic acid, TSH, CBC, BMP, HIV, RPR)
  • Vitamin D level
  • Screening for cognitive impairment with a standardized tool: Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE) or MoCA blind (may be more suitable for telephone visits when visual testing may not be available)
  • Screening for sleep disorders, such as sleep apnea and referral to sleep study if positive
    • Note that the MoCA will not identify subtle deficits like slowed thinking or word finding difficulty, this is better captured by a timed test evaluating reaction time for a cognitive process. While these tests are typically performed by a speech-language pathologist or neuropsychologist, a history focused on functional ability (e.g., ability to perform work duties, ability to follow the plot of a book or TV show) can also elicit the type and severity of deficit.

The role of routine neurological imaging like brain MRI is not clear at this time, but is reasonable if patient has focal neurological deficits or if they had a severe initial COVID-19 illness or other comorbidities increasing their risk for ischemic/hemorrhagic stroke, demyelinating conditions or encephalitis.

Treatment should focus on addressing the underlying condition(s).

If the initial workup is normal, a course of supportive management and symptom monitoring in primary care is reasonable, as initial reports suggest these symptoms will improve gradually over time.

  • Referral to a memory clinic for neuropsychological testing or cognitive evaluation by a speech-language pathologist is recommended if the cognitive symptoms show no improvement over time and limit a patient’s functional capacity to perform normal daily activities.

Advanced neurological imaging like functional MRI, PET, or SPECT/CT scans are available in some centers but are recommended to be ordered and interpreted by a specialist.

Improved sleep may mitigate cognitive dysfunction and fatigue seen in PASC. Symptomatic treatments for sleep disturbances include:

  • Melatonin nightly at two hours prior to bedtime
  • Improved sleep hygiene and cognitive behavioral therapy for insomnia (CBT-i)
  • Sleep aid medications (e.g., trazodone, zolpidem) or sedating medications (e.g., OTC diphenhydramine) can exacerbate cognitive dysfunction and are not recommended as first-line management

Interventions for headache may be considered, including abortive and preventative therapies.

Symptoms of inattention or severe fatigue may be managed with:

  • Graduated exercise plan with or without supervision of physical therapy or rehab specialist
  • Trial pharmacologic intervention(s) in refractory cases with close monitoring: dextroamphetamine (Adderall) or modafinil

Comorbid anxiety or depression may be managed with counseling and SSRIs/SNRIs, although sedating medications should be avoided.

1. Chou SH-Y, Beghi E, Helbok R, et al. Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19—A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. JAMA Netw Open. 2021;4(5):e2112131. doi:10.1001/jamanetworkopen.2021.12131

2. Lu Y, Li X, Geng D, et al. Cerebral Micro-Structural Changes in COVID-19 Patients - An MRI-based 3-month Follow-up Study. EClinicalMedicine. 2020;25:100484. doi:10.1016/j.eclinm.2020.100484

3. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifestations and encephalopathy-associated morbidity in Covid-19 patients. Ann Clin Transl Neurol. 2020;7(11):2221-2230. doi:10.1002/acn3.51210

4. Tenforde MW, Kim SS, Lindsell CJ, et al. Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network - United States, March-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993-998. doi:10.15585/mmwr.mm6930e1

5. Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers.” Ann Clin Transl Neurol. 2021;8(5):1073-1085. doi:10.1002/acn3.51350

6. Vlachoyiannopoulos PG, Magira E, Alexopoulos H, et al. Autoantibodies related to systemic autoimmune rheumatic diseases in severely ill patients with COVID-19. Ann Rheum Dis. 2020;79(12):1661-1663. doi:10.1136/annrheumdis-2020-218009

7. Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783. doi:10.1016/S1474-4422(20)30221-0