What are the management options for brain fog in long COVID (Coronavirus Disease 2019)?

Management of Brain Fog in Long COVID

Brain fog in long COVID should be managed with a multidisciplinary approach prioritizing cognitive pacing, symptom-specific interventions, and emerging therapies including noninvasive brain stimulation and hyperbaric oxygen therapy, while strictly avoiding exercise-based rehabilitation that can worsen symptoms. 1, 2

Initial Assessment and Recognition

Brain fog affects 9-26% of long COVID patients and represents a distinct symptom cluster characterized by:

• Memory impairment and word-finding difficulties 3
• Fatigue (measured by Chalder Fatigue Scale) 3
• Dizziness and myalgia 3
• Slowed cognitive processing and reaction times 3

The prevalence increases over time, from 16% at 2 months to 26% at 12 months post-infection, and symptoms can persist for at least 2 years. 1, 4

Women are at higher risk and report more severe symptoms. 5

Critical Management Principle: Avoid Exercise

Exercise is contraindicated in long COVID patients with brain fog and postexertional malaise—75% of patients worsen with physical activity and less than 1% improve. 1 This is a common pitfall that can significantly harm patients.

Primary Management Strategies

Cognitive and Physical Pacing

• Implement cognitive pacing protocols adapted from ME/CFS management 1
• Use postconcussion syndrome protocols for cognitive dysfunction 1
• Patients must learn to stay within their energy envelope to prevent symptom exacerbation 1

Symptom-Specific Pharmacological Interventions

For cognitive dysfunction specifically:

• Low-dose aripiprazole for fatigue, unrefreshing sleep, and brain fog 1
• Low-dose naltrexone for pain, fatigue, and neurological symptoms (substantial anecdotal support) 1

For associated autonomic dysfunction (common with brain fog):

• β-blockers, pyridostigmine, fludrocortisone, or midodrine for POTS symptoms 1
• Increase salt and fluid intake, consider IV saline or compression stockings 1

Mitochondrial and Metabolic Support

• Coenzyme Q10 and D-ribose for fatigue (evidence from ME/CFS literature) 1
• These supplements address the mitochondrial dysfunction and oxidative stress found in long COVID 1

Emerging Therapies with Promising Evidence

Noninvasive Brain Stimulation

All six studies examining noninvasive brain stimulation showed improvement in cognitive ability. 2 This addresses the cortical excitability changes and neuroinflammation underlying brain fog. 2

Hyperbaric Oxygen Therapy

Three studies demonstrated improvements in both cognitive assessment tests and brain perfusion with hyperbaric oxygen therapy. 2 This targets the brain hypometabolism and microvascular dysfunction documented in long COVID. 1, 6

Palmitoylethanolamide and Luteolin (PEA-LUT)

Two studies showed cognitive improvement with PEA-LUT administration, which addresses neuroinflammation. 2

Antiviral Therapy

• Paxlovid showed 25% reduction in long COVID incidence when used for acute COVID-19 1
• Case reports document resolution of long COVID symptoms with Paxlovid treatment 1
• Consider for patients with suspected viral persistence 1

Addressing Underlying Mechanisms

For Immune Dysfunction

• Intravenous immunoglobulin (consult immunology for implementation) 1
• Addresses the widespread immune dysregulation and autoimmunity found in long COVID 1

For Abnormal Clotting (if present)

• Triple anticoagulant therapy showed symptom resolution in all 24 patients in one study 1
• Apheresis has shown promise but is expensive with uncertain benefits 1

For Autoimmunity

• BC007 neutralizes G protein-coupled receptor autoantibodies (case report evidence) 1

Managing Comorbid Symptoms

Brain fog commonly co-exists with:

• Insomnia (22% prevalence): Address with sleep hygiene and consider autonomic dysfunction 4
• Gastrointestinal symptoms: Probiotics showed resolution of GI and other symptoms in pilot studies 1, 5
• Mood disturbances: These are significant predictors of brain fog severity and require concurrent treatment 5

The relationship between gastrointestinal symptoms and brain fog is particularly strong—GSRS scores are significant predictors of brain fog severity. 5

Monitoring and Follow-up

Assess cognitive function objectively with:

• Computer-based cognitive tasks (reaction time, processing speed) 3
• Physical performance measures (gait speed, grip strength) as functional consequences 3
• Standardized scales for fatigue, depression, and post-traumatic stress 3

Objective measures detect impairment more frequently than subjective reports, as some patients may not recognize their deficits. 1

Key Pathophysiological Targets

The management approach addresses multiple documented mechanisms:

• Neuroinflammation with widespread microglial reactivity 1
• Brain hypometabolism in cingulate cortex and other regions 6
• Endothelial dysfunction and microvascular damage 1
• Kynurenine pathway activation (quinolinic acid, 3-hydroxyanthranilic acid) 1
• Hypothalamic-pituitary-adrenal axis dysfunction with low cortisol 1