Acute small fiber neuropathy after Oxford‐AstraZeneca ChAdOx1‐S vaccination: A report of three cases and review of the literature

Abstract Small fiber neuropathy usually presents with gradual and progressive chronic length‐dependent pain. Acute small fiber neuropathy is rarely reported. Three patients with acute onset neuropathic pain after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and one patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra‐epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. Neuropathic symptoms (burning pain, dysaesthesias) developed in the hands and feet within 2 weeks of vaccination. On clinical examination, there was pinprick and thermal hyposensitivity in the area of neuropathic pain. Laboratory investigation, nerve conduction tests, sympathetic skin responses, and MRI showed no relevant abnormalities. Thermal thresholds were abnormal and intra‐epidermal nerve fiber density in the lower leg was reduced. In two cases symptoms persist after several months. Three cases of definite acute small fiber neuropathy after Oxford‐AstraZeneca ChAdOx1‐S vaccination are described. At follow up, neuropathic pain was present in two of the patients.


| BACKGROUND AND AIMS
Small fiber neuropathy is defined as a structural abnormality of distal termination of the small fibers (which are the thinly myelinated and unmyelinated fibers of sensory afferent and autonomic neurons).
Chronic pain, in a length-dependent pattern, is almost always the presenting complaint with gradual onset and slow progression. 1 In contrast, acute onset sensory small fiber neuropathy is rare. To date, only several case reports of acute onset small fiber neuropathy are described. [2][3][4][5][6][7] In these instances, patients present with acute onset numbness and burning pain, either in the extremities or more generalized, that reaches a peak within 6 weeks. Some patients report symptoms after vaccination 3,4,6,7 or an antecedent illness, such as diarrhea or COVID-19 infection. Some observers speculate that acute small fiber neuropathy may represent a sensory variant of Guillain-Barré syndrome, if symptoms peak within 6 weeks. In our case series, we report three patients with acute onset small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination. Symptoms within two of our three patients still persist after several months.
Two patients were identified at the Oxford University NHS Foundation Trust, Oxford, UK and a single patient in Red de Salud UC Christus, Santiago, Chile. All patients underwent a clinical assessment that included a detailed neurological examination, laboratory investigations, nerve conduction studies, thermal threshold testing, and skin biopsy for intra-epidermal nerve fiber density. Patients seen in Oxford underwent MRI of the brain and spinal cord. Cerebrospinal analysis was not performed. A comprehensive structured upper and lower limb neurological examination was performed to detect clinical signs of a peripheral neuropathy. The examination included assessment of temperature, light touch and pinprick sensation, joint position proprioception, vibration perception, deep-tendon reflexes, muscle bulk, and motor power. Orthostatic hypotension, as a marker of autonomic neuropathy, was assessed by measuring lying and standing blood pressure in accordance with established protocols. Orthostatic hypotension was defined as either a 20 mm Hg reduction in systolic or a 10 mm Hg reduction in diastolic blood pressure assessed 2 minutes after standing. Laboratory investigations included: general hematology (full blood count); hematinic (vitamin B12, folate); general biochemistry (urea, creatinine, electrolytes, liver function tests, C-reactive protein, HbA1c, angiotensin-converting enzyme, triglycerides, copper); endocrinology (thyroid stimulating hormone, T4); specialist protein (serum protein electrophoresis, immunoglobulins, serum free light chains); autoimmune serology (ANA, ANCA, tissue transglutaminase); and microbiology (HIV, syphilis, hepatitis B and C). Nerve conduction studies were performed in line with those recommended by the American

Academy of Neurology and American Association of Electrodiagnostic
Medicine. Sensory nerve responses were recorded from the radial, median, ulnar, and sural nerve. Motor nerve responses and F waves were recorded from the median, ulnar, peroneal, and tibial nerves. The minimum case definition criterion for electrodiagnostic confirmation of distal symmetrical polyneuropathy was an abnormality of any attribute of nerve conduction in two separate nerves, one of which was the sural nerve. Sympathetic skin response was tested from the hand and foot. Cold and warm detection thresholds, using methods of limits, were measured from the dorsum of the right foot and com-    COVID-19 infection. 11 In these cases, the onset is more often between 2 and 6 weeks post-exposure. Furthermore, small fiber neuropathy was detected in 62.5% (10/16) patients diagnosed with postacute sequelae of SARS CoV-2 infection. 12 Other neurological complications are linked to COVID-19 vaccination. 13 The most commonly reported is facial nerve palsy. There is a small increased risk of hospital admission from Guillain-Barré syndrome, myasthenic disorder, and Bell's palsy after Oxford-AstraZeneca ChAdOx1-S vaccination; however, this risk is still lower than after primary SARS-CoV-2 infection. 13 We can only speculate as to possible pathophysiological mechanisms of acute small fiber neuropathy. Reports implicate immune or inflammatory mechanisms. Several cases of small fiber neuropathy after preceding illness showed albumin-cytological dissociation on cerebrospinal fluid analysis. 5 This suggests proximal demyelination normally observed in inflammatory demyelinating polyradiculoneuropathies. Although in a separate case series there was a dramatic improvement after corticosteroid therapy. 2 We propose that acute small fiber neuropathy may be caused by the combination of an underlying, unrecognized risk factor with another trigger, such as an immune response to an infection or vaccination.
In conclusion, we report three cases of acute small fiber neuropathy after Oxford-AstraZeneca ChAdOx1-S vaccination, with two patients developing chronic pain. Hence, we hypothesize that acute small fiber neuropathy may develop in the context of an unknown underlying risk factor combined with an immune or inflammatory trigger. Our case series highlights that acute small fiber neuropathy can follow COVID-19 vaccination and lead to chronic complications.

AUTHOR CONTRIBUTIONS
Conception and design of the study: Andreas C. Themistocleous and Molly G. Abbott. Acquisition and analysis of data: all authors. Drafting a significant portion of the manuscript or figures: all authors.