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Journal of Medical Cases

Case Report

Volume 15, Number 8, August 2024, pages 195-200

Methylphenidate for the Treatment of Post-COVID Cognitive Dysfunction (Brain Fog)

Although most individuals recover from acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a significant minority develop persistent symptoms known as long-coronavirus disease (COVID) or post-acute sequelae of SARS-CoV-2 (PASC). Up to 35% of these individuals develop unexplained cognitive symptoms that are frequently referred post-COVID cognitive dysfunction (PCCD) [1]. Although there is no standardized definition of PCCD, it is generally described as a condition in which patients with a history of SARS-CoV-2 infection, usually 3 months from the onset, exhibit subsequent cognitive impairment in various cognitive domains, and cannot be explained by an alternative diagnosis [1]. By contrast, “brain fog” is a colloquial term that may encompass anxiety, mood alterations, forgetfulness, trouble focusing, and a general sense of mental sluggishness [2]. PCCD incorporates symptoms in multiple cognitive domains such as concentration issues, word-finding difficulties, memory impairment, disorientation and executive functions [3]. PCCD is correlated with psychological distress and decreased psychomotor performance and continued disability [4]. An analysis of retrospective cohort studies including nearly 1.3 million patients showed that up to 2 years after COVID-19 infection, risk of PCCD continued to be elevated [5].

Despite the urgent and overwhelming clinical need, there are currently no proven interventions to treat PCCD. Neurobiological data can help in hypothesizing treatments for PCCD. Methylphenidate is a piperidine-derived central nervous system stimulant and is approved for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It works as a central norepinephrine and dopamine reuptake inhibitor.

A recent systematic review reports that methylphenidate can improve attention and memory in ADHD [6]. Additionally, our group previously used methylphenidate to successfully treat apathy in dementia, which has several phenomenological similarities with PCCD [7], such as diminished motivation not attributable to diminished level of consciousness, cognitive impairment, or emotional distress [8]. Therefore, we hypothesized that methylphenidate could be an effective intervention for PCCD. This approach is based on the understanding that motivated behaviors rely not only on the dopaminergic mesolimbic brain reward system but also on newly evolved prefrontal cortical circuits [9] which may be dysregulated in long-COVID and methylphenidate may enhance both noradrenergic and dopaminergic signals to strengthen cognitive function. Methylphenidate has been found to be safe and well-tolerated in multiple previous studies [10, 11]. We present a case series of six patients presenting for treatment of cognitive deficits associated with COVID-19 treated with methylphenidate in the context of routine clinical care.

We followed six patients treated at Johns Hopkins Post-Acute COVID-19 Team (PACT). All of these patients reported functionally limiting post-COVID cognitive impairment, with subjective complaints of impaired memory, concentration, fatigue, confusion and listed “brain fog” as one of the main reasons for not being able to return to work post-COVID-19 illness. Mean duration of the post-COVID symptoms was 2.1 years. They were treated with methylphenidate 5 - 20 mg and followed for 4 to 8 weeks. This treatment was in the context of routine clinical care and thus did not require any ethics board approval. We used cognitive assessment procedures based on previously developed measures of cognitive dysfunction in the long-COVID patients [12], to monitor clinical progress, which included the following components.

The HVLT-R is a test of new auditory-verbal learning, memory, and recognition discrimination. A list of 12 words is read aloud over three consecutive exposure trials, each of which is followed immediately by the testing of free recall. Following a 20-min delay, a delayed free recall trial is administered followed by a test of yes/no recognition memory for target words versus foils. Scores reflect the correct numbers of words recalled over immediate recall trials (range = 0 - 36), delayed recall (range = 0 - 12), and in response to recognition testing (range = -12 to 12). Administration time is approximately 10 min [13].

The oral TMT is a brief, motor-free test of mental processing speed (part A) and executive functioning requiring sequential set shifting (part B). Part A involves asking the participant to count from 1 to 25 aloud as quickly as possible. Part B requires participants to count aloud while switching between numbers (1-13) and letters (A-L) as quickly as possible. Performances are based on the time in seconds required to complete each part. Administration time is 5 min [14].

Letter-cued verbal fluency assesses speeded word retrieval in response to phonetic cues. The participant is asked to name as many words as possible beginning with a certain letter of the alphabet. The score reflects the total number of unique responses beginning with the given letter across two 1-min trials. Cues are letters S, and P. Perseverations (repeated words) and intrusions (words that break the task rules, such as starting with a different letter) are also recorded. Administration time is 4 min [15].

Category-cued verbal fluency assesses rapid access to semantic information. The participant is asked to name as many items of a given semantic category as possible. The score reflects the total number of unique category-congruent responses given across two 1-min trials. Cues for English are animals and supermarket items. Cues for Spanish trials are animals. Perseverations (repeated words) and intrusions (words that break the task rules, such as stating a proper noun) are also recorded. Administration time is 3 min [15].

Narrative results are presented in Table 1. Methylphenidate was well-tolerated, and four of six patients did not report any adverse effects. The remaining two patients complained of gastric upset and increased fatigue, with one discontinuing methylphenidate due to the adverse effects. Another patient was advised to stop all psychiatric medications by her pharmacist after being started on clopidogrel for concerns of drug-drug interactions. One patient decided to go back to his old regimen of modafinil after trying methylphenidate for 4 weeks without any cognitive improvement. Three out of the six patients reported subjective improvement with methylphenidate, one patient described it as “notable” and another as “marked” improvement in memory and concentration.

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Table 1. Qualitative Visit Notes on Pre-/Post-Psychostimulant Drug

Patient demographics and cognitive scores at baseline and follow-up are summarized in Table 2. We found significant subjective complaints of cognitive dysfunction during this case series: qualitatively defined as complaints of having “word finding difficulties, slow processing speed, difficulty paying attention and concentrating, and difficulty reading and retaining read information and general increased feelings of physical and mental fatigue”. The main complaint was the patient’s report of reduced energy levels. Four out of the six patients reported feeling that their cognition worsens in the evening, some referring to this as feeling “spent”, experiencing mental “crashes” or having a “heaviness on (their) brain that slows (them) down”. We prescribed immediate-release generic formulation of methylphenidate and patients were instructed to take it in the morning. Despite these subjective complaints, formal cognitive assessment scores were not severely impaired. We found a statistically significant difference in pre and post scores for HVLT immediate recall (mean difference: 3.3, 95% confidence interval (CI): 1.02 - 5.64, P = 0.006), HVLT delayed recall (mean difference: 1.0, 95% CI: 0.75 - 1.93, P = 0.019) and category-cued verbal fluency (mean difference: 3.3, 95% CI: 0.89 - 7.56, P = 0.05). The scores from cognitive assessment and results of the statistical analyses are summarized in Table 3.

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Table 2. Demographic Characteristics, Baseline, Follow-Up Scores and Adverse Effects Reported by the Patients

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Table 3. Cognitive Assessment Scores at Baseline and Follow-Up Analysis Results

PCCD continues to be one of the most prevalent and challenging manifestations of long-COVID syndrome. A recent analysis has shown that a year after SARS-CoV-2 infection, PCCD persists in a third of patients with long-COVID [1]. PCCD is associated with other long-COVID symptoms and is independently associated with persistent debility [16]. The underlying physiological mechanisms contributing to PCCD are unknown. Physiological responses specific to SARS-CoV-2 may contribute to long-term brain pathology, particularly immune-mediated neuroinflammation and neuronal loss in hippocampus [17]. Neuroinflammation, even without viral invasion of the central nervous system, may also trigger decreased hippocampal neurogenesis affect cognition [18]. A recent study exploring cognitive dysfunction in PCCD through eye movement abnormalities suggests impairments in frontal subcortical circuits PCCD patients who report subjective cognitive complaints [19].

This case series suggests that methylphenidate may be helpful in improving free or spontaneous recall. A previous study found that spontaneous recall is the most severely impacted cognitive domain in PCCD [20]. In our case series, methylphenidate was well-tolerated; however, two patients reported increased complaints of fatigue, although on clinical assessment they seemed to be functioning better. The association between depressed mood and cognitive complaints following COVID-19 also continues to be explored. In a study of 137 patients a year after COVID-19 recovery, depression was found to be the strongest predictor of PCCD [21]. In this study, patients with long-COVID did not have severe cognitive deficits on formal testing despite subjective complaints of brain fog. However, it should be noted that this study used self-rated depression scale (SDS) to screen depression, which includes somatic symptoms that can be caused by other long-COVID comorbid conditions. We noticed a similar trend in our case series, where patients mentioned feeling “dispirited” or “mentally empty”. It has been hypothesized that viral infection and type I interferon-driven inflammation reduces peripheral serotonin, in turn impeding the activity of the vagus nerve and thereby impairing hippocampal responses and memory [22]. However, to date, there is no conclusive evidence that serotonergic enhancers such as selective serotonin reuptake inhibitors improve PCCD.

Currently, there are no proven treatments for PCCD. There are several ongoing clinical trials to test the safety and efficacy of potential drugs for the treatment of PCCD, including donepezil (IRCT2021081605 2203N1), famotidine (IRCT20090117001556N138), vortioxetine (NCT05047952), temelimab (NCT05497089) and atorvastatin (NCT04904536). In addition, nirmatrelvir/ritonavir, is also currently undergoing clinical trials, with cognitive function as a primary (NCT05595369) and secondary (NCT05668091, NCT05576662) outcome measure. There is also preliminary evidence that luteolin, a natural flavonoid, may alleviate cognitive impairment by inhibiting mast cell and microglial activation [23]. A case series reported that a combination of guanfacine and N-acetylcysteine improved cognitive symptoms in eight of the 12 long-COVID patients; however, four patients discontinued the regimen due to the adverse effects of hypotension and/or dizziness related to guanfacine [24]. A previous case report also reported improvement in post-COVID inattention and fatigue symptoms with methylphenidate, along with lisdexamfetamine and bupropion in a 61-year-old patient [25]. These observations suggest some of the symptoms of PCCD may present as an ADHD-like syndrome, despite the evidently different etiology of symptoms.

There are several case reports of non-pharmacological interventions as well. A case series of 23 PCCD reported that repetitive transcranial magnetic stimulation (rTMS) may have beneficial effects on neuropsychiatric symptoms, including depressive symptoms, chronic fatigue, and cognitive impairment [26]. Another case report of two patients reported that neuromodulation with non-invasive brain stimulation using microcurrent (NIBS) was effective in improving visual and cognitive deficits in two confirmed SARS-CoV-2 patients [27].

This case series has several limitations. The dose of methylphenidate was low (5 to 20 mg per day). This limitation is important in the light of recent guidelines recommending dose optimization for methylphenidate for treatment of inattentive symptoms in adult ADHD [28]. Therefore, use of higher doses may have resulted in additional benefits such as reduction in fatigue. Furthermore, we used the immediate-release dose of methylphenidate, which may have been insufficient for symptom control throughout the day. In addition, due to the very small sample size, the statistical inferences derived in our analysis may not be valid.

The current report suggests potential beneficial neurocognitive effects of methylphenidate for long-COVID cognitive impairment. Future placebo-controlled trials are warranted to rigorously evaluate the role of methylphenidate in PCCD but given methylphenidate’s relatively favorable safety profile, it can be considered as a potential therapy for this often-disabling condition at a time when there are no approved interventions.

Acknowledgments

We acknowledge Karthik Suresh, Megan Hosey, Ashraf Fawzy, and Ed Chen for assisting in conducting this work.

Financial Disclosure

This work was supported by the National Institute on Aging (NIA)/National Institutes of Health (NIH) (R01AG057725).

Conflict of Interest

None to declare.

Informed Consent

All patients provided informed consent.

Author Contributions

Phoebe Clark, Paul Rosenberg, and Mansoor Malik: analysis of data and writing the manuscript. Esther S. Oh, Ann Parker, Tracy Vannorsdall, Alba Azola, Elizabeth Nickles, and Panagis Galiatsatos: review of manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

1. Quan M, Wang X, Gong M, Wang Q, Li Y, Jia J. Post-COVID cognitive dysfunction: current status and research recommendations for high risk population. Lancet Reg Health West Pac. 2023;38:100836.
   doi pubmed pmc
2. Lauria A, Carfi A, Benvenuto F, Bramato G, Ciciarello F, Rocchi S, Rota E, et al. Neuropsychological measures of post-COVID-19 cognitive status. Front Psychol. 2023;14:1136667.
   doi pubmed pmc
3. Delgado-Alonso C, Valles-Salgado M, Delgado-Alvarez A, Yus M, Gomez-Ruiz N, Jorquera M, Polidura C, et al. Cognitive dysfunction associated with COVID-19: a comprehensive neuropsychological study. J Psychiatr Res. 2022;150:40-46.
   doi pubmed pmc
4. Jennings G, Monaghan A, Xue F, Duggan E, Romero-Ortuno R. Comprehensive clinical characterisation of brain fog in adults reporting long COVID symptoms. J Clin Med. 2022;11(12):3440.
   doi pubmed pmc
5. Taquet M, Sillett R, Zhu L, Mendel J, Camplisson I, Dercon Q, Harrison PJ. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry. 2022;9(10):815-827.
   doi pubmed pmc
6. Vertessen K, Luman M, Swanson JM, Bottelier M, Stoffelsen R, Bet P, Wisse A, et al. Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial. Eur Child Adolesc Psychiatry. 2024;33(2):495-504.
   doi pubmed pmc
7. Drye LT, Scherer RW, Lanctot KL, Rosenberg PB, Herrmann N, Bachman D, Mintzer JE, et al. Designing a trial to evaluate potential treatments for apathy in dementia: the apathy in dementia methylphenidate trial (ADMET). Am J Geriatr Psychiatry. 2013;21(6):549-559.
   doi pubmed pmc
8. Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry. 1990;147(1):22-30.
   doi pubmed
9. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76(3):470-485.
   doi pubmed pmc
10. Godfrey J. Safety of therapeutic methylphenidate in adults: a systematic review of the evidence. J Psychopharmacol. 2009;23(2):194-205.
    doi pubmed
11. Jaeschke RR, Sujkowska E, Sowa-Kucma M. Methylphenidate for attention-deficit/hyperactivity disorder in adults: a narrative review. Psychopharmacology (Berl). 2021;238(10):2667-2691.
    doi pubmed pmc
12. Vannorsdall TD, Brigham E, Fawzy A, Raju S, Gorgone A, Pletnikova A, Lyketsos CG, et al. Cognitive dysfunction, psychiatric distress, and functional decline after COVID-19. J Acad Consult Liaison Psychiatry. 2022;63(2):133-143.
    doi pubmed pmc
13. Brandt J. The Hopkins verbal learning test: development of a new memory test with six equivalent forms. Clin Neuropsychol. 1991;5:125-142.
14. Axelrod BN, Lamberty GJ. The oral trail making test. In: Poreh AM, editor. Neuropsychological assessment: a quantified process approach. Lisse, the Netherlands: Swets & Zeitlinger; 2006. p. 45-52.
15. Schretlen DJ, Vannorsdall TD. Calibrated ideational fluency assessment (CIFA) professional manual. Odessa, FL: Psychological Assessment Resources; 2010.
16. Reiss AB, Greene C, Dayaramani C, Rauchman SH, Stecker MM, De Leon J, Pinkhasov A. Long COVID, the brain, nerves, and cognitive function. Neurol Int. 2023;15(3):821-841.
    doi pubmed pmc
17. Bayat AH, Azimi H, Hassani Moghaddam M, Ebrahimi V, Fathi M, Vakili K, Mahmoudiasl GR, et al. COVID-19 causes neuronal degeneration and reduces neurogenesis in human hippocampus. Apoptosis. 2022;27(11-12):852-868.
    doi pubmed pmc
18. Saikarthik J, Saraswathi I, Alarifi A, Al-Atram AA, Mickeymaray S, Paramasivam A, Shaikh S, et al. Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in post-acute COVID-19 syndrome - a narrative review. PeerJ. 2022;10:e14227.
    doi pubmed pmc
19. Benito-Leon J, Lapena J, Garcia-Vasco L, Cuevas C, Viloria-Porto J, Calvo-Cordoba A, Arrieta-Ortubay E, et al. Exploring cognitive dysfunction in long COVID patients: eye movement abnormalities and frontal-subcortical circuits implications via eye-tracking and machine learning. Am J Med. 2024:.
    doi pubmed
20. Taskiran Sag A. COVID-19 associated brain fog and neurocognitive assessment. Cyprus J Med Sci. 2023;8:115-120.
21. Cristillo V, Pilotto A, Piccinelli SC, Gipponi S, Leonardi M, Bezzi M, Padovani A. Predictors of "brain fog" 1 year after COVID-19 disease. Neurol Sci. 2022;43(10):5795-5797.
    doi pubmed pmc
22. Wong AC, Devason AS, Umana IC, Cox TO, Dohnalova L, Litichevskiy L, Perla J, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186(22):4851-4867.e4820.
    doi pubmed pmc
23. Theoharides TC, Cholevas C, Polyzoidis K, Politis A. Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue. Biofactors. 2021;47(2):232-241.
    doi pubmed pmc
24. Fesharaki-Zadeh A, Lowe N, Arnsten AF. Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in “long-COVID19”. Neuroimmunol Reports. 2023;3:100154.
25. Victor MM, Muller Haas L, Grevet EH, Rohde LA. Successful treatment of post-COVID-19 ADHD-like syndrome: a case report. J Atten Disord. 2023;27(10):1092-1098.
    doi pubmed pmc
26. Noda Y, Sato A, Shichi M, Sato A, Fujii K, Iwasa M, Nagano Y, et al. Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan. Asian J Psychiatr. 2023;81:103438.
    doi pubmed pmc
27. Sabel BA, Zhou W, Huber F, Schmidt F, Sabel K, Gonschorek A, Bilc M. Non-invasive brain microcurrent stimulation therapy of long-COVID-19 reduces vascular dysregulation and improves visual and cognitive impairment. Restor Neurol Neurosci. 2021;39(6):393-408.
    doi pubmed pmc
28. Eom TH, Kim YH. Clinical practice guidelines for attention-deficit/hyperactivity disorder: recent updates. Clin Exp Pediatr. 2024;67(1):26-34.
    doi pubmed pmc

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Journal of Medical Cases is published by Elmer Press Inc.