3.DISCUSSION
This paper presents a case that developed a complex regional pain syndrome (CRPS) of the knee after the Pfizer-BioNTech vaccine, an mRNA-based vaccine administered against the COVID-19 virus.
Vaccines are the most effective ways to stop the spread of the coronavirus disease-2019 (COVID-19) and as the vaccination continue, more patients are likely to present with complications.
Various types of vaccines have been approved worldwide and have been shown to be safe and effective in preventing severe cases of COVID-19 especially in the elderly and patients with comorbidities [3]. Until now, 13.34 billion doses have been administered worldwide and approximately 69.8 % of the global population has received at least one dose [https://ourworldindata.org/covid-vaccinations]. The common side effects following COVID-19 vaccines include tenderness at the injection site, headache, fatigue, fever or myalgia. More serious events including life threatening allergic reactions, neurological manifestations, thrombocytopenia and myocarditis have been reported [4,5].
However, some uncommon and rare events after COVID-19 vaccination have been also reported and should not be ignored for early diagnosis and management. Recently, probable association between COVID-19 vaccine administration and CRPS has been shown by few cases [2, 6,7,8] .Clinically, Complex regional pain syndrome (CRPS), previously described as reflex sympathetic dystrophy (RSD) or algoneurodystrophy, is a disabling condition characterized by some clinical features :continuing regional pain with allodynia, hyperalgesia, autonomic changes, trophic changes, vasomotor edema, joint stifness and functional loss [1, 9] that frequently affects the limbs. The upper extremities are more likely affected than the lower extremities and clinical manifestations are often most severe in the extremity that has experienced acute injury, but any part of the body can be affected. The symptoms can manifest on the right side like our case , on the left side or bilaterally in few cases [1].
Like our patient, most patients with CRPS experience many motor dysfunction, including restricted range of motion, muscle weakness, some patients complain from tremor or dystonia.
The current knowledge of CRPS remains insufficient, but it is now believed that the aetiology of CRPS involves a variety of pathological processes with an exaggeration of physiological responses (central and peripheral sensitization, sympathetic dysfunction, overproduction of proinflammatory cytokines ) leading to enhanced bone resorption. The current taxonomy classify two types of CRPS : type I (occurring in the absence of nerve injury) and type II formerly named « causalgia » (occuring in the presence of nerve injury). This condition often develops after trauma even minor, blunt traumatic injuries excluding fractures (e.g., sprains), or surgery, stroke, myocardial infarction. Female gender (reported female-to-male ratio ranged from 2:1 to 4:1 [1]), inflammatory chronic diseases and vaccinations also increase risk of developing CRPS [10].
The contribution of psychological factors including anxiety and despression to the development of CRPS is controversial. However, many research found a correlation between psychological factors and CRPS [1].
The pathophysiological mechanisms that lead to CRPS after COVID-19 vaccines are thought to be the same and can be explicated by injection trauma leading to CRPS of the upper limb, nerve damage by invasion of the virus or may be an hypersensitivity reaction to the component of the vaccine [2]. In a case-series of CRPS after HPV, the authors described peripheral sympathetic nerve dysfunction in 40 Japanese girls [11]. It remains difficult to know whether CRPS could occur as an indirect effect of tissue injury following the intramuscular injection, or caused by auto-inflammatory response triggered by the vaccine antigens or the two mechanisms in predisposing individuals. In our case, the causative mechanism of CRPS may be immune hyperactivity to a vaccine constituent supporting an immune-mediated mechanism as the CRPS affected the lower extremity.
The diagnosis of CRPS is based on clinical manifestations and there are criteria developed by The International Association for the Study of Pain (IASP) known as The Budapest criteria with a senstitivity and a specificity of 99 % an 68 % respectively [12].
There are no specific tools with limited role of laboratory tests or image studies to fulfill these criteria. However, some general laboratory tests are recommended to help rule out infection , inflammatory/auto-immune diseases and vascular diseases, such erythrocyte sedimentation rate , C-reactive protein, a full blood count , and serum autoantibodies [1].
Some imaging methods including conventional radiographs, bone scintigraphy, computed tomography, MRI may be beneficial for ruling out differential diagnoses.
MRI can reveal periarticular bone-marrow edema, soft-tissue swelling, joint effusions, and atrophy of periarticular structures in later stages, same findings in our case.
To confirm post-vaccination CRPS diagnosis, requires the absence of other etiologies and beginning of the symptoms within few weeks after receiving the vaccine. In our case, the patient did not report any symptoms and all investigations were normal (no recent surgery or trauma , no infections, no metabolic or inflammatory disorders, no vascular disorders, no stress fracture, no nerve injury) except for a history of COVID-19 vaccination.
Reports of CRPS after a vaccine are extremely rare and only few cases of CRPS after vaccination such as the hepatitis B [13], influenza [14] , rubella [15], and human papillomavirus [16] vaccines have been published.
Horisawa S et al [2] reported the case of a 17-year-old woman diagnosed with CRPS if her left hand after the second dose of the mRNA COVID-19 vaccine. Praveena Raman, an active 33-year-old dentist, reported her experience of living with CRPS of her left hand post COVID-19 vaccine shot [7].
The management includes a different therapeutic approaches (analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), local corticosteroids , calcitonin, opioids, analgesics, sympatholytic agents and sympathetic nerve and ganglion blockade, bisphosphonate in some refractory cases) and rehabilitation.
In our report, the patient was first treated with NSAIDS, local steroid injection and pregabalin and then with bisphosphonate (alendronate) with regular physiotherapy with partial response.
The natural history of CRPS is influenced by many factors and remains a challenge for most physicians especially for refractory cases. A good prognosis with successful outcome relies on early diagnosis and treatment. however, many patients have a poor prognosis with severe impact in their quality of life as CRPS affects daily function and activities , sleep with significant effect on mental health, like in our case.
In the literatture, most of patients who developed CRSP after vaccination showed complete improvement of their symptoms within few months [2,13]. Many studies showed that pain and functional loss may last for a long time despite mediactions and physical therapy. In our case, range of motion of the right knee had improved, however, pain had not completely resolved eight months after diagnosis and different medications, which can be explained by a late diagnosis.