Long COVID has a lot of nerve

By Warren R. Heymann, MD, FAAD
Dec. 17, 2025
Vol. 7, No. 49

The profound medical and socioeconomic trauma of the COVID-19 pandemic may seem as though it is in the rearview mirror, but it is not. As of April 15, 2025, the CDC estimated that COVID-19 infections are growing or likely growing in 2 states (Minnesota and Hawaii), declining or likely declining in 23 states, and not changing in 21 states. (1)

Last week, I evaluated a 37-year-old man complaining of “feeling thousands of small paper cuts” on his abdomen, back, and thighs for the past couple of months. There was no rash. His symptoms appeared a month after his severe pulmonary symptoms during a three-month course of COVID-19 resolved. My presumptive diagnosis was that he had a post-COVID-19 peripheral neuropathy. I requested that he see a neurologist. If agreed upon, we will consider skin biopsies for routine histology and a small fiber neuropathy (SFN). Should topical pramoxine prove unhelpful, gabapentin will be considered. What surprised me was the realization that I had never considered this diagnosis before throughout the pandemic and its aftermath. This commentary focuses on post-COVID peripheral neuropathy (adverse reactions to the COVID-19 vaccines will not be discussed).

Long COVID (aka “post-acute (sequelae of) COVID-19,” “chronic COVID-19,” or “post-COVID-19 condition”) is generally defined as symptoms persisting for 3 months or more after an acute COVID-19 infection. Long COVID can affect multiple organ systems, leading to severe and protracted impairment of function as a result of organ damage. (2)

Infectious agents, primarily bacteria (Borrelia burgdoferi, Corynebacterium diphtheria, Mycobacterium leprae) and viruses (HIV, hepatitis viruses, Herpes viruses [HSV, VZV], Flaviviruses [West Nile, Zika], Rabies) can affect the peripheral nerves, resulting in various clinical syndromes such as mononeuropathy or mononeuropathy multiplex, distal symmetric polyneuropathy, radiculopathy, inflammatory demyelinating polyradiculoneuropathy, and motor neuronopathy. (3)

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Using the national health care databases of the U.S. Department of Veterans Affairs, Xu et al. compared a cohort of 154,068 individuals with COVID-19 to 5,638,795 contemporary controls and 5,859,621 historical controls to estimate the risks and burdens of incident neurologic disorders at 12 months following acute SARS-CoV-2 infection. The authors demonstrated that in the post-acute phase of COVID-19, there was an increased risk of incident neurologic sequelae, including ischemic and hemorrhagic stroke, cognition and memory disorders, peripheral nervous system disorders, episodic disorders (migraine and seizures), extrapyramidal and movement disorders, mental health disorders, musculoskeletal disorders, sensory disorders, Guillain-Barré syndrome, and encephalitis or encephalopathy. (4) In their study of 400 patients, Saif et al. reported a prevalence of peripheral neuropathy and myopathy in post-COVID-19 patients of 56.3%. (5) Based on their assessment of 109 patients referred to their neurological post-COVID outpatient clinic, Grisanti et al. classified patients in two categories. Long-COVID type 1 includes patients with memory disturbances, psychological impairment, headache, anosmia, and ageusia, while long-COVID type 2 contains all the subjects with reported symptoms related to peripheral nervous system involvement. (6)

According to Xu et al., “The neurologic manifestations of Long Covid are hypothesized to be driven by neuro-inflammation with trafficking of immune cells (T cells and natural killer cells), cytokines and antibodies to the brain parenchyma resulting in activation of microglia and astrocytes, disturbances in synaptic signaling of upper-layer excitatory neurons, impaired neurogenesis and neuroblast formation, loss of oligodendrocytes and reduced myelinated axon density. Other mechanisms may involve endothelial cell injury, complement activation and complement-mediated coagulopathy and microangiopathy leading to microbleeds or microclots. Evidence from brain lysates of people with COVID-19 (compared with noninfected controls) demonstrates upregulation of transforming-growth-factor-beta signaling, hyperphosphorylation and posttranslational modification of receptor and channel proteins typically linked to Alzheimer’s disease. Direct invasion of the virus into the central nervous system has also been proposed as a putative hypothetical mechanism of neuronal injury.” (4)

Grieco et al. assessed 6 long COVID patients manifesting paroxysmal diffuse burning and itching sensations. The histologic investigation showed hypertrophic glomus vascular bodies with hypertrophic S100+ perineural sheath cells and adjacent hypertrophy of the nerve branches associated with increased basophil polysaccharide matrix. Electroneurography (in two patients) revealed disturbances of A-delta and C dermal neuronal fibers. These histopathologic findings are consistent with hypertrophy of nerve endings, suggesting “dermal hyperneury,” a recently reported small nerve hypertrophy condition affecting sensory C fibers. (Please see the prior DWI&I commentary for a discussion of “dermal hyperneury”). The authors conclude, “Such a neuropathic basis could explain dysesthesia experienced by the patients, as previously described in postherpetic neuralgia.” (7)

Abrams et al. documented SFN in 6 of 13 patients who developed new-onset paresthesias within 2 months following SARS-CoV-2 infection. (8) Gemignani believes that the association of SFN with long COVID may be underestimated, as the diagnosis is difficult when the presentation is atypical. He suggests that future studies assessing the actual prevalence and incidence of SFN in long COVID are warranted. (9)

I agree with Gemignani. Somehow, patients with long COVID and cutaneous paresthesias fell beneath my radar. In fairness, perhaps patients like mine, without an accompanying rash, sought help elsewhere. Regardless, dermatologists should be aware of this long COVID complication.

Point to Remember: COVID-19 is associated with multiple neurological complications. Dermatologists may encounter patients experiencing paresthesias due to a small fiber neuropathy affecting A-delta and C dermal neuronal fibers.

Our expert’s viewpoint

Hanie Babaie, MD
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Long COVID, defined as symptoms persisting beyond 4 weeks after acute SARS-CoV-2 infection, impacts a substantial number of patients, varying from 13% to more than 50% in different reports. (10) Neurological side effects like paresthesia are one of the most common and disabling symptoms. The pathophysiology related to it seems to be predominantly determined by the presence of ongoing neuroinflammation, rather than direct viral invasion. Increased levels of cytokines, such as IL-6, TNF-α, and IFN-γ, are indicative of an ongoing immune activation. (11) Interestingly, early antiviral treatment (e.g., nirmatrelvir) appears to be associated with a lower risk of long COVID, probably by modulating post-infectious inflammation. (10)

In my own clinical experience, paresthesias haven’t been the most common long-COVID complaint, but when they do show up, they can be quite distressing. These symptoms are usually diffuse with no evident neuroanatomical distribution, nor any specific dermatologic findings, and are suggestive of small fiber neuropathy or post-viral inflammatory changes. I typically prescribe anti-inflammatory agents (e.g., corticosteroids) and neuropathic pain medications like gabapentin or NSAIDs, which mostly result in positive responses. It is also important to note that transient paresthesia have been reported following COVID-19 vaccination (11); hence, differentiating between postvaccine effects, long COVID, and other mimickers such as diabetic neuropathy or Guillain–Barré syndrome is crucial for an accurate diagnosis and management. I have also noticed that many of these patients suffer from significant anxiety, which makes me wonder: are we sometimes seeing the nervous system’s psychological distress expressed physically? And could anti-anxiety meds help more than we realize? At the end, the line between body and mind is blurrier than we used to think.

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References

1. https://www.cdc.gov/cfa-modeling-and-forecasting/rt-estimates/index.html (Accessed April 25, 2025)

2. Greenhalgh T, Sivan M, Perlowski A, Nikolich JŽ. Long COVID: a clinical update. Lancet. 2024 Aug 17;404(10453):707-724. doi: 10.1016/S0140-6736(24)01136-X. Epub 2024 Jul 31. PMID: 39096925.

3. Boegle AK, Narayanaswami P. Infectious Neuropathies. Continuum (Minneap Minn). 2023 Oct 1;29(5):1418-1443. doi: 10.1212/CON.0000000000001334. PMID: 37851037.

4. Xu E, Xie Y, Al-Aly Z. Long-term neurologic outcomes of COVID-19. Nat Med. 2022 Nov;28(11):2406-2415. doi:

5. 10.1038/s41591-022-02001-z. Epub 2022 Sep 22. PMID: 36138154; PMCID: PMC9671811.

   Saif DS, Ibrahem RA, Eltabl MA. Prevalence of peripheral neuropathy and myopathy in patients post-COVID-19 infection. Int J Rheum Dis. 2022 Nov;25(11):1246-1253. doi: 10.1111/1756-185X.14409. Epub 2022 Aug 1. PMID: 35915515; PMCID: PMC9538868.

6. Grisanti SG, Garbarino S, Barisione E, Aloè T, Grosso M, Schenone C, Pardini M, Biassoni E, Zaottini F, Picasso R, Morbelli S, Campi C, Pesce G, Massa F, Girtler N, Battaglini D, Cabona C, Bassetti M, Uccelli A, Schenone A, Piana M, Benedetti L. Neurological long-COVID in the outpatient clinic: Two subtypes, two courses. J Neurol Sci. 2022 Aug 15;439:120315. doi: 10.1016/j.jns.2022.120315. Epub 2022 Jun 3. PMID: 35717880; PMCID: PMC9212262.

7. Grieco T, Gomes V, Rossi A, Cantisani C, Greco ME, Rossi G, Sernicola A, Pellacani G. The Pathological Culprit of Neuropathic Skin Pain in Long COVID-19 Patients: A Case Series. J Clin Med. 2022 Jul 31;11(15):4474. doi: 10.3390/jcm11154474. PMID: 35956094; PMCID: PMC9369885.

8. Abrams RMC, Simpson DM, Navis A, Jette N, Zhou L, Shin SC. Small fiber neuropathy associated with SARS-CoV-2 infection. Muscle Nerve. 2022 Apr;65(4):440-443. doi: 10.1002/mus.27458. Epub 2021 Nov 22. PMID: 34766365; PMCID: PMC8661991.

9. Gemignani F. Small Fiber Neuropathy and SARS-CoV-2 Infection. Another piece in the long COVID puzzle? Muscle Nerve. 2022 Apr;65(4):369-370. doi: 10.1002/mus.27495. Epub 2022 Jan 31. PMID: 35014706.

10. Leng A, Shah M, Ahmad SA, Premraj L, Wildi K, Li Bassi G, et al. Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells. 2023;12(5).

11. Stefanou MI, Panagiotopoulos E, Palaiodimou L, Bakola E, Smyrnis N, Papadopoulou M, et al. Current update on the neurological manifestations of long COVID: more questions than answers. Excli j. 2024;23:1463-86.

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