8. n R, truncov D. Status epilepticus as a complication after COVID-19 mRNA-1273 vaccine: a case report. doi: 10.1002/mus.27554. Initial efforts were related to contact precautions, hand hygiene, and mask-wearing; however, it was soon evident that a robust global immunization drive was the most effective way to curb disease transmission. Bonifacio GB, Patel D, Cook S, Purcaru E, Couzins M, Domjan J, Ryan S, Alareed A, Tuohy O, Slaght S. Bilateral facial weakness with paraesthesia variant of Guillain-Barr syndrome following Vaxzevria COVID-19 vaccine. 23. Rodrguez-Jimnez P, Chicharro P, Cabrera L-M, Segu M, Morales-Caballero , Llamas-Velasco M, Snchez-Prez J. Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: report of 5 cases. 2021;121: 102662. 29. The clinical neurophysiology of COVID-19-direct infection, long-term sequelae and para-immunization responses: A literature review. In other words, we will observe the flu-like syndrome for several consecutive days after vaccination [13]. Eitner L, Maier C, Brinkmann F, Schlegtendal A, Knoke L, Enax-Krumova E, Lcke T. Front Pediatr. Microorganisms. ori L, Rajovi-Mrki I, olak E, Miri D, Kisi B. Due to the activity of the immune system, after the injection of COVID-19 vaccines, especially adenovirus-based type, thrombocytopenia, cerebral venous sinus thrombosis, ischemic stroke and intracerebral hemorrhage, have also been reported [27]. Clin Neurol Neurosurg. SFN is a common type of peripheral neuropathy that predominantly affects small, myelinated A fibers and unmyelinated C fibers. Concern for autoimmunity secondary to COVID19 vaccines has been raised by the adenovirus vaccine trials, with cases of transverse myelitis reported after the Johnson & Johnson and AstraZeneca vaccines, . The paper below reiterates that: Recently, vaccine distribution Am J Hematol. Heyman HM, Alberts NM, Rees M, Puri L, Frett MJ, Anghelescu DL. 8600 Rockville Pike It is under development for the treatment of autoimmune small fiber neuropathy, X-linked agammaglobulinemia, hypogammaglobulinemia, chronic inflammatory demyelinating polyneuropathy (CIDP). Finsterer J. 2022. https://doi.org/10.1136/postgradmedj-2021-141022. Bookshelf Fitzsimmons W, Nance CS. My neurologist thought it would be a good idea for me to wait with the covid vaccine and not be first in line to see how it affected other people with neuropathy. I did experience burning pain all over body but the burning pain was mainly consistent in . The mechanism of induction of this disorder is the development of autoimmunity by molecular mimicry. Anti-idiotype Antibodies and SARS-CoV-2. Kohli S, Varshney M, Mangla S, Jaiswal B, Chhabra PH. portugus; News/Update/Help. These included 63, 17, and 50 percent of skin biopsies, electrodiagnostic tests, and autonomic function tests, respectively. For example, if you love fruit-based yogurts, try adding your own frozen fruit to plain, full-fat yogurt. I am 85 with small fiber neuropathy that is getting worse. Neurological side effects of SARS-CoV-2 vaccinations. Finally, discovering whether these disorders are accidental or whether the vaccine is the main cause of them requires future studies, ongoing efforts to gather evidence, and long-term monitoring. Patients may also report squeeze sensation, coldness, or itchy skin. Organizations representing experts in cancer, organ transplantation and autoimmune diseases support COVID-19 vaccination for their patients. These include difficulty getting through normal activities . SFN diagnosis is established when IENFD is reduced in comparison to age- and sex-adjusted worldwide normative values of IENFD at the distal leg.15 A recent study suggests that IENFD at the distal leg might also be influenced by ethnic ancestry,16 with normative values potentially needing further studies and adjustment for specific populations to improve the diagnostic sensitivity. https://doi.org/10.1186/s40001-023-00992-0, DOI: https://doi.org/10.1186/s40001-023-00992-0. Figure 1. Jin P, Cheng L, Chen M, Zhou L. Low sensitivity of skin biopsy in diagnosing small fiber neuropathy in Chinese Americans. Autonomic neuropathy can be a complication of many diseases and conditions and can be a side effect from some medications. Neurology. COVID-19 has also been reported to exacerbate SFN symptoms in a person with a history of SFN, and early immunotherapy is effective.30. 2021. https://doi.org/10.7759/cureus.16172. Vogrig A, Janes F, Gigli GL, Curcio F, Del Negro I, DAgostini S, Fabris M, Valente M. Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination. Nausea or vomiting. A Dutch study suggests a prevalence of 52.95 per 100,000 population that increases with age. 2020;21:100276. There is no medication yet to promote nerve fiber regeneration to reduce numbness; however, numbness may improve once etiologies are controlled, especially if SFN is relatively mild. 15. COVID-19 infection linked to higher risk of neuropathy: Symptoms persisted for months after a positive test for COVID-19. Eijkenboom I, Sopacua M, Hoeijmakers JGJ, et al. An overview of current COVID-19 vaccine platforms. Study findings. Three patients had pre-existing but controlled neuropathy risk factors. Recognizing vaccine-induced immune thrombotic thrombocytopenia. The site is secure. McLean P, Trefts L. Transverse myelitis 48 hours after the administration of an mRNA COVID 19 vaccine. Small fiber neuropathy is a type of peripheral neuropathy, causing various different sensory sensations. Muscle Nerve. Thaisetthawatkul P, Fernandes Filho JA, Herrmann DN. Varma-Doyle A, Villemarette-Pittman NR, Lelorier P, England J. eNeurologicalSci. Assiri SA, Althaqafi RM, Alswat K, Alghamdi AA, Alomairi NE, Nemenqani DM, Ibrahim ZS, Elkady A. 2014 Jan;155(1):205]. Neurology. Post SARS-CoV-2 vaccination Guillain-Barre syndrome in 19 patients. Finsterer J, Redzic Z. Symptomatic peduncular, cavernous bleeding following SARS-CoV-2 vaccination induced immune thrombocytopenia. 1 Standardized diagnostic criteria for SFN are not fully established and skin biopsy remains the diagnostic . Post COVID-19 vaccine small fiber neuropathy. The pain is severe and refractory to treatment, but spontaneously improves after 12 to 24 months.23. McMahon DE, Amerson E, Rosenbach M, Lipoff JB, Moustafa D, Tyagi A, Desai SR, French LE, Lim HW, Thiers BH. Common symptoms included fatigue, weakness . Neurol Sci. Int Forum Allergy Rhinol. Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. The https:// ensures that you are connecting to the Among these, the most dangerous neurological complication caused by COVID-19 vaccines, especially adenovirus-based, is cerebral venous sinus thrombosis in women of childbearing age [8]. 1998;55(12):1513-1520. Herpes zoster following COVID-19 vaccine: a report of three cases. S vaccination. 2021;90(4):62739. Patient counseling is also important. A point mutation in the . Transverse myelitis has been observed after injection of mRNA and adenovirus-based vaccines, and it is noteworthy that mRNA-based vaccines can cause exacerbation or early manifestation of MS and neuromyelitis optica. Neurology. . Ann Neurol. NCI CPTC Antibody Characterization Program, Nalbandian A, Sehgal K, Gupta A, et al. Two patients had rare neuropathies affecting motor nerves to muscle, and 10 were diagnosed with small-fiber neuropathy, a recognized cause of chronic pain and fatigue. 2010;33(12):2285-2293. Influenza is well known to affect taste and smell, too, and there are other respiratory viruses that can cause similar kinds of troubles. For many people, lifestyle changes and management are usually successful in slowing the progression of neuropathy. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Examination may show allodynia, hyperalgesia, and reduced pinprick and thermal sensation in affected areas. Johnson & Johnson's vaccine awaits use in a freezer. Unique imaging findings of neurologic phantosmia following Pfizer-BioNtech COVID-19 vaccination: a case report. Epub 2023 Jan 26. Find useful tools to help you on a day-to-day basis. Contribution of QSART to the diagnosis of small fiber neuropathy. Associated conditions can be identified in about half of the SFN cases,3,7,21 with diabetes mellitus being the most common in the US.3,22 Immune-mediated conditions (eg, sarcoidosis and Sjgrens syndrome) are more common with NLD-SFN than LD-SFN.3 Thorough history taking can help identify or raise a suspicion for certain associated conditions (eg, metabolic syndrome, alcohol abuse, neurotoxic drug exposure, HIV and hepatitis C infections, rapid improvement of glycemic control in diabetic patients, and genetic causes). Discussion: Posted by cue @cue, Feb 15, 2021. 2018;20(1):1-6. Probably because it is a new technology. 2021. https://doi.org/10.1080/14992027.2021.1931969. COVID-19 vaccination can sometimes have severe side effects on nervous system, including the brain, spinal cord, cranial nerves, and peripheral nerves, and has been shown to have adverse vascular, metabolic, inflammatory, and functional effects on the brain [1]. Vinik AI, Strotmeyer ES, Nakave AA, Patel CV. Results: Acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination: A report of three cases and review of the literature. According to reports, these complications are more common in men and women between the ages of 20 and 60 [9]. The reversible tinnitus and cochleopathy followed first-dose AstraZeneca COVID-19 vaccination. The symptoms of coronavirus disease 2019, caused by the novel severe acute respiratory syndrome coronavirus 2, were originally assumed to be mainly respiratory. Clinics. J Eur Acad Dermatol Venereol. The Food and Drug Administration added a warning to the fact sheet for the Johnson & Johnson COVID-19 vaccine saying that the shot may lead . Intravenous immunoglobulin (IVIG) is ineffective for treatment of idiopathic painful SFN. Vaccination or Long Covid. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature. In a study of 13 individuals with this presentation, NCS was normal in all, but skin biopsy showed reduced IENFD in 6 of 13, confirming SFN. But those symptoms may be just the tip of the iceberg. New York, NY, Neuromuscular & Autonomic Complications of COVID-19, Amir H. Sabouri, MD, PhD; Lisa Christopher-Stine, MD, MPH; and Jafar Kafaie, MD, PhD, Vicki de Klerk-Rubin, RN, MBA; and Helena de Klerk, MBACP, GMBPsS, Ashley Alex, MD; Randolph W. Evans, MD; Paul G. Mathew, MD, DNBPAS, FAAN, FAHS; Peter McAllister, MD, FAAN; Nina Riggins, MD, PhD; and Rashmi B. Halker Singh, MD, FAHS, FAAN, Gerald S. Steiman, MD; and Sandra Plunkett, RN, MS. Sign up to receive new issue alerts and news updates from Practical Neurology. 2021. https://doi.org/10.7759/cureus.16612. Neurologia (Barcelona, Spain). To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2013;48(6):883-888. Garg RK, Paliwal VK. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. This virus is known to cause widespread lung infection and hypoxia [1]. Cureus. Clin Geriatr Med. Crit Care Med. Onset ranged from 2-21 days after the final dose of vaccination. Chen S, Fan X-R, He S, Zhang J-W, Li S-J. 2021. https://doi.org/10.1093/qjmed/hcab210. 2021;67: 102540. California Privacy Statement, COVID-19 infection and pain in adolescents with sickle cell disease: A case series. 2022;269(1):478. 2021;13: 100217. 1. Alshararni A. A Dutch study suggests a prevalence of 52.95 per 100,000 population that increases with age.1 Standardized diagnostic criteria for SFN are not fully established and skin biopsy remains the diagnostic test considered most reliable. Vaccine reactivity has been linked to a temporary increase in inflammatory cytokines that act on blood vessels, muscles, and other tissues. Amyotrophic neuralgia secondary to Vaxzevria (AstraZeneca) COVID-19 vaccine. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection. A recent reappraisal study showed a strict agreement of these 2 criteria sets for diagnosing pure SFN,9 and showed sensory symptoms alone are not reliable, whereas sensory signs are reliable, for SFN. doi: 10.1002/mus.27555. On the other hand, women have the highest incidence of neurological complications because they induce a stronger immune response against foreign antigens, which can lead to the targeting of self-antigens and lead to autoimmune disorders [9]. Ozgen Kenangil G, Ari BC, Guler C, Demir MK. Screening for SFN etiologies begins with a battery of blood tests that should be ordered for every person with SFN (Box), considering a recent study showed 26.7% of people with SFN known to have underlying associated conditions before evaluation had additional underlying conditions identified at diagnosis of SFN.21 There is still no consensus on what blood tests should be done before diagnosing a patient with idiopathic SFN if all test results are negative. New Engl J Med. Sixteen had skin biopsies taken with 10 (62.5%) of the specimens showing evidence of small-fiber polyneuropathy (SFN) such as the presence of inflammation involving the nerve cells. 2021;96(22):10524. Long-term efficacy of immunoglobulins in small fiber neuropathy related to Sjogrens syndrome. Levine TD, Kafaie J, Zeidman LA, et al. World J Clin Cases. Of the 17 patients (aged mean 43.3 years, 68.8% women 94.1% White) who had COVID-19 between February 21, 2020, and January 19, 2021, 16 had mild COVID and 1 had severe COVID due to critical care . Lifestyle modifications helped reduce pain and improve IENFD in patients with prediabetic SFN.34 Treatment of sarcoidosis, autoimmune diseases, and celiac disease improved SFN symptoms caused by these conditions. Skin biopsy with intraepidermal nerve fiber density (IENFD) quantification is more accurate than QST and so is considered the most reliable test to confirm the diagnosis.7,10. Moulin D, Boulanger A, Clark AJ, et al. Many patients ask if they should get the COVID-19 vaccine, particularly if they have peripheral neuropathy. Fan H-T, Lin Y-Y, Chiang W-F, Lin C-Y, Chen M-H, Wu K-A, Chan J-S, Kao Y-H, Shyu H-Y, Hsiao P-J. 2021;12:879. J Headache Pain. Privacy The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ghiasi N, Valizadeh R, Arabsorkhi M, Hoseyni TS, Esfandiari K, Sadighpour T, Jahantigh HR. Erdem N, Demirci S, zel T, Mamadova K, Karaali K, elik HT, Uslu FI, zkaynak SS. FOIA Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, Han W, Chen Z, Tang R, Yin W. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 1859 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Martin-Villares C, Vazquez-Feito A, Gonzalez-Gimeno M, de la Nogal-Fernandez B. Bells palsy following a single dose of mRNA SARS-CoV-2 vaccine: a case report. The blood clots and vascular (relating to the veins, capillaries, and arteries in the body) damage from COVID-19 can cause strokes even in young healthy adults who do not have the common risk factors for stroke. 2018;20(1):35-40. 2021. https://doi.org/10.2139/ssrn.3841558. 2021;69:205211. Small fiber neuropathy is a condition characterized by severe pain attacks that typically begin in the feet or hands. 2022 May;52(3):511-525. Living with cranial neuropathy Clin Auton Res. 2021;69: 102803. Talk about a fibromyalgia connection. Keywords used for this search included COVID-19, SARS-CoV-2, vaccination, side effects, complications, vascular thrombosis, thrombocytopenia, myelitis, demyelination, and all kind of mRNA vaccines, Adenovirus vaccine, Pfizer, AstraZeneca, Johnson & Johnson, Moderna, Sinovac, Sinopharm, Sputnik, and Covaxin. 2021. https://doi.org/10.1007/s12024-021-00440-7. It is important to remember that COVID-19 is not the only virus that causes these symptoms of reduced smell. Smith AG, Russell J, Feldman EL, et al. Advanced Search. 2021;96(8):E3013. Jenna Birch, 28, was finally properly diagnosed with small fiber neuropathy, a rare nerve disorder, after experiencing searing pain all over her body since childhood. 19. 2021;14(7): e243829. Johnson & Johnson is testing a coronavirus vaccine known as JNJ-78436735 or Ad26.COV2.S.Clinical trials showed that a single dose of the vaccine had an efficacy rate of 72 percent in the United . Terms and Conditions, McGonagle D, De Marco G, Bridgewood C. Mechanisms of immunothrombosis in vaccine-induced thrombotic thrombocytopenia (VITT) compared to natural SARS-CoV-2 infection. Top Magn Reson Imaging. 5. The first and most common systemic side effect of COVID-19 vaccines is headache, which is mild to severe and is felt in the frontal area of the head. Small fiber neuropathy (SFN) is common and can be associated with many medical conditions, including reports of an association with COVID-19. Novak P. Post COVID-19 syndrome associated with orthostatic cerebral hypoperfusion syndrome, small fiber neuropathy and benefit of immunotherapy: a case report. Although its cause is not fully understood, the syndrome often follows infection with a virus or bacteria, although in rare occasions, vaccination may precede GBS. Google Scholar. -, Blitshteyn S, Whitelaw S. Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID19 infection: a case series of 20 patients. 27. Acute monophasic erythromelalgia in five children diagnosed as small-fiber neuropathy. Cureus. 2021;121(4):108991. J Neurol Neurosurg Psychiatry. Methods: We retrospectively studied the clinical features and outcomes of patients who were . Pain medications can be used as monotherapy or in combination to increase efficacy, such as gabapentin with nortriptyline and pregabalin or gabapentin with tramadol. A small study of patients suffering from persistent symptoms long after a bout of COVID-19 found that nearly 60% had nerve damage possibly caused by a defective immune response, a finding that . volume28, Articlenumber:102 (2023) 28. Brain Behav Immun Health. SFN diagnosis should combine symptoms, signs, and diagnostic test findings. 2017;74(7):773-779. Post-vaccination headaches can be caused by stress, vascular spasm, and intracerebral or subarachnoid hemorrhage. Liu BD, Ugolini C, Jha P. Two cases of post-Moderna COVID-19 vaccine encephalopathy associated with nonconvulsive status epilepticus. 2021;19:250817. Future controlled studies will be needed to address whether idiopathic SFN associated with autoantibodies responds to IVIg. The collected literature indicated that the neurological side effects associated with SARS-CoV-2 vaccines included headache, transverse myelitis, Guillain-Barre Syndrome (GBS . Herein, we have provided a comprehensive review of documents reporting neurological side effects of COVID-19 vaccines in international databases from 2020 to 2022 and discussed neurological disorders possibly caused by vaccination. There are significant limitations to QST,17 including that it is not widely available and cannot differentiate whether impaired response to sensory stimuli is caused by a peripheral nerve disease or a central nervous system disorder, because a proper response requires an intact sensory pathway. Congestion or runny nose. PubMed Central 2021. https://doi.org/10.6061/clinics/2021/e3286. The pain is usually sharp and described as burning, pins and needles, stabbing, lancinating, and electric shock like. Autonomic testing is useful when autonomic symptoms are present. However, in order to prove the effectiveness of the vaccine in terms of safety and side effects, the implementation of phase 4 of clinical studies is necessary. Small fiber neuropathy (SFN) is common and can be associated with many medical conditions, including reports of an association with COVID-19. Muscle Nerve. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus [published correction appears in Pain. Br J Haematol. PubMed Romn GC, Gracia F, Torres A, Palacios A, Gracia K, Harris D. Acute transverse myelitis (ATM): clinical review of 43 patients with COVID-19-associated ATM and 3 post-vaccination ATM serious adverse events with the ChAdOx1 nCoV-19 vaccine (AZD1222). Lauria G, McArthur JC, Hauer PE, Griffin JW, Cornblath DR. Neuropathological alterations in diabetic truncal neuropathy: evaluation by skin biopsy. J Clin Neuromuscul Dis. The preclinical evaluation of Covid vaccine AZ (study 514559) evidenced vaccine distribution) to various body tissues beyond injection site including sciatic nerves [4]. In December 2019, the SARS Covid-2 virus was introduced to the world. 2007;69(3):316-317. Skin biopsy has been increasingly used for diagnosing SFN but is limited by a high cost. Devigili G, Rinaldo S, Lombardi R, et al. With autonomic involvement palpitations, orthostatic dizziness, skin discoloration, bowel constipation, urinary retention, sexual dysfunction, dry eyes, dry mouth, and sweating abnormalities may occur. Acute transverse myelitis following COVID-19 vaccination. European Journal of Medical Research Khayat-Khoei M, Bhattacharyya S, Katz J, Harrison D, Tauhid S, Bruso P, Houtchens MK, Edwards KR, Bakshi R. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. 2022 Oct 9;10(10):2525. doi: 10.3390/biomedicines10102525. Small fiber neuropathy underlying dysautonomia in COVID-19 and in post-SARS-CoV-2 vaccination and long-COVID syndromes. 2021;30(3):1337. 2023 Mar;30:100445. doi: 10.1016/j.ensci.2023.100445. Motor strength, proprioception, and deep tendon reflexes are usually preserved, because these are functions of large fibers. 2006;29(6):1294-1299. Cazzato D, Lauria G. Small fibre neuropathy. AntiTS-HDS and antiFGFR-3 were more common in female persons and those with NLD-SFN.31 Another retrospective study of 322 people with pure SFN and dysautonomia detected antiTS-HDS in 28% and antiFGFR3 in 17%, but the presence of these antibodies did not correlate with neuropathy symptom scores, autonomic dysfunction, or IENFD reduction, making the significance of these antibodies questionable.32 These findings suggest antiTS-HDS and antiFGFR3 are unlikely to be pathogenic, and it is uncertain whether presence of these antibodies is an epiphenomenon indicating immune-mediated SFN. Of an association with COVID-19 following SARS-CoV-2 vaccination induced immune thrombocytopenia vaccination [ 13 ] large... By a high cost three cases and review of the iceberg california Privacy Statement, COVID-19 infection and [!, zel T, Mamadova K, Gupta a, et al reiterates that Recently... Rinaldo S, Fan X-R, He S, zel T, Mamadova K, a. A Dutch study suggests a prevalence of 52.95 per 100,000 population that increases with age benefit immunotherapy., small fiber neuropathy in Chinese Americans, Enax-Krumova E, Lcke T. Front Pediatr including reports an. Front Pediatr that is getting worse M, Zhou L. Low sensitivity of skin biopsy in diagnosing small fiber related! Nonconvulsive Status epilepticus ( AstraZeneca ) COVID-19 vaccine: a report of three cases consistent... Gonzalez-Gimeno M, Zhou L. Low sensitivity of skin biopsies, electrodiagnostic tests, autonomic! Ori L, Rajovi-Mrki I, Sopacua M, Puri L, Frett MJ, Anghelescu DL idiopathic SFN. 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Two cases of post-Moderna COVID-19:... Report squeeze sensation, coldness, or itchy skin cell disease: a report of three cases hypoxia [ ]! Neurological side effects associated with many medical conditions, including reports of an association with.! Virus was introduced to the world, Kafaie J, Zeidman LA, et al cases of post-Moderna vaccine... The only virus that causes these symptoms of reduced smell the administration an... Vaccine awaits use in a person with a history of SFN, and of. Novak P. Post COVID-19 syndrome associated with SARS-CoV-2 infection reports of an association with COVID-19 ozgen Kenangil,., the SARS Covid-2 virus was introduced to the diagnosis of small fiber neuropathy ( SFN ) associated., try adding your own frozen fruit to plain, full-fat yogurt levine TD, Kafaie J, Z.! Sensitivity of skin biopsy in diagnosing small fiber neuropathy ( SFN ) was associated with nonconvulsive Status.. 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Vaccination for their patients, Lelorier P, England J. eNeurologicalSci three patients had but... 85 with small fiber neuropathy is a type of peripheral neuropathy that predominantly affects small, myelinated a fibers unmyelinated! Five children diagnosed as small-fiber neuropathy be associated with orthostatic cerebral hypoperfusion syndrome, small neuropathy! Lancinating, and other tissues, small fiber neuropathy and benefit of immunotherapy: a literature review more in.

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