Complex regional pain syndrome (CRPS) is a rare chronic pain condition characterised by severe pain, sensory, motor, autonomic, and trophic abnormalities. Effective treatment options are limited, and international guidelines rely on low-quality evidence and consensus. Two interventions-memantine, an N-methyl-D-aspartate receptor antagonist, and graded motor imagery, a rehabilitation approach targeting sensorimotor processing-have shown promise in pilot studies but lack definitive evaluation in large-scale trials. MEMOIR aims to evaluate the benefits and harms of memantine and graded motor imagery for CRPS. MEMOIR is a fully decentralised, 2 × 2 factorial, randomised trial comparing memantine with placebo and graded motor imagery with no graded motor imagery in adults with CRPS. A total of 204 participants with CRPS of 6 months to 5 years duration will be randomised to one of four groups: (i) memantine and graded motor imagery, (ii) memantine only, (iii) placebo and graded motor imagery, or (iv) placebo only. Memantine will be administered at 40 mg/day (or maximum tolerated dose); graded motor imagery will comprise seven 1-h sessions delivered via telehealth. The treatment period is 16 weeks. The dual primary outcomes are pain intensity (11-point numeric rating scale) and PROMIS pain interference assessed at 16 weeks. Secondary outcomes include physical function, fatigue, cognitive function, depressive symptoms, self-efficacy, health-related quality of life, CRPS severity, healthcare use, and adverse events. The follow-up period is 52 weeks. The estimands of interest are the mean effect of memantine compared to placebo and the mean effect of graded motor imagery compared to no graded motor imagery on all outcomes. All analyses will follow the intention-to-treat principle. MEMOIR will be the largest investigator-initiated CRPS trial to date. The 2 × 2 factorial design and decentralised delivery aim to maximise efficiency, accessibility, and equity. If effective, memantine and graded motor imagery represent scalable, low-cost treatments that can be given in clinics or at home, with the potential to transform CRPS management. Australian New Zealand Clinical Trials Registry ( ACTRN12621000175875 ). Registered on 12 February 2021.

The long-term effects of SARS-CoV-2 infection represent a relevant global health problem. Long COVID (LC) is defined as a complex of signs and symptoms developed during or after SARS-CoV-2 infection and lasting > 12 weeks. In common variable immunodeficiency (CVID) patients, we previously reported higher risk of hospitalization and death during SARS-CoV-2 infection, as well as prolonged swab positivity and frequent reinfections. The aim of the present study was to assess the risk of LC in an Italian cohort of CVID patients. We used a translated version of the survey proposed by Centers for Disease Control and Prevention (CDC) to collect data on LC. In the enrolled cohort of 175 CVID patients, we found a high prevalence of LC (65.7%). The most frequent LC symptoms were fatigue (75.7%), arthralgia/myalgia (48.7%), and dyspnea (41.7%). The majority of patients (60%) experienced prolonged symptoms, for at least 6 months after infection. In a multivariate analysis, the presence of complicated phenotype (OR 2.44, 95% CI 1.88-5.03; p = 0.015), obesity (OR 11.17, 95% CI 1.37-90.95; p = 0.024), and female sex (OR 2.06, 95% CI 1.09-3.89; p = 0.024) significantly correlated with the development of LC. In conclusion, in this multicenter observational cohort study, we demonstrated that CVID patients present an increased prevalence of LC when compared to the general population. Improved awareness on the risk of LC in CVID patients could optimize management of this new and alarming complication of SARS-CoV-2 infection.

Dear Editor, Ticks carry many diseases, bacteria, and viruses and represent a very important healthcare issue both in Croatia and globally. Although most ticks are not infected with pathogens dangerous to humans, some ticks can transmit infectious diseases with significant morbidity and mortality. This is caused by the increasing incidence of many tick-borne diseases over a growing geographical area. Many factors influence which species of ticks are present in a given geographical area, as well as the density of their population and the risk of human exposure to infected ticks. The average morbidity from Lyme borreliosis in the Republic of Croatia is 6.51 infected per 100,000 inhabitants. There can be no Lyme borreliosis without ticks infected by Borrelia burgdorferi (1,2). In Europe, Lyme borreliosis (LB) is caused by the Borrelia burgdorferi sensu lato complex genotype. There are three skin manifestations of LB: erythema migrans (EM), borrelial lymphocytoma (BL), and acrodermatitis chronica atrophicans (ACA) (3,4). Herein we describe a female patient with a diagnosis of Lyme disease based on the non-specific clinical picture and laboratory diagnostics, in whom successful treatment led to complete regression of all skin manifestations. The patient was a 58-year-old woman with no previous history of severe illness. Notably, the patient history showed that, eight months prior to presenting for the dermatological exam, the patient had observed the appearance of edema and demarcated macular exanthema around both ankles and subsequently on the dorsum of the right hand, which spread to the left hand and with gradual spread to both lower legs and the lower extremities, with more pronounced changes on the left leg. The initial dermatological examination found pronounced skin changes on both legs, especially the left leg, with erythematous changes in the form of figurate erythema forming confluences up to the size of a smaller palm; the skin of the left leg was partially mottled with normal turgor and elasticity (Figure 1a and Figure 1b). Inguinal lymph nodes were enlarged and painless on palpation. Changes were minimal and discrete on the right leg and were absent on the torso, upper extremities, and skin. Subjectively, there was no itching, burning, or tingling sensation in the affected areas of the skin. The patient subjectively reported feeling well. Family history showed that the patient's father had died from prostate cancer and that the mother had died from melanoma. Laboratory findings were as follows: hematological, biochemical, and immunological parameters were normal. Venous and arterial ultrasound of both legs was normal, with the presence of reactively enlarged left inguinal lymph nodes. Lyme disease was suspected based on the clinical picture, with a differential diagnosis of possible livedo reticularis. A biopsy of the skin changes was also performed, with the results showing that the histological picture in the examined material could be compatible with the provisional clinical diagnosis of livedo reticularis. IgM and IgG specific for Borrelia burgdorferi was also performed: IgG was borderline, whereas IgM was positive at 218 U/mL. Over the next 3 weeks, Amoxil 500 mg thrice daily was introduced to the treatment. After completion of the treatment, there was a gradual regression of all skin changes without the appearance of new lesions (Figure 2a and Figure 2b) (Figure 3a and Figure 3b). Patient follow-up over the next year did not find any recurrence of similar skin changes. Herein we have described the case of a patient with atypical skin changes in which the presence of antibodies for Borrelia burgdorferi was demonstrated, in which regression of all skin manifestations was achieved after diagnosis and adequate antibiotic treatment. Lyme disease has a wide spectrum of clinical manifestations that can generally be observed in three stages: the early localized stage, the early disseminated stage, and the late stage of the disease. However, it is also possible for the different stages to overlap and even for the late stage to manifest without any signs and symptoms of the earlier stages. Early localized stage. Characterized by skin changes - erythema migrans (EM) - usually manifests within a month of the tick bite (usually 7-14 days after the bite) (Figure 4 and Figure 5). EM manifests in approximately 80% of patients, but only 25% of patients can recall the tick bite. The skin changes are usually localized in the axilla, the groin, the cubital area, or around the waist. The changes are generally not painful, but can itch or be warm to the touch. They gradually spread over days or weeks and can grow to a radius of up to 20 cm. Initially, the coloration can be uniform for several days, after which the redness disappears around a central zone (4-6). Multiple skin changes are a sign of spirochetemia and not the result of multiple tick bites. Due to timely antimicrobial treatment, multiple skin changes are much rarer today. In the initial days or weeks after infection, patients with early, localized, or disseminated Lyme disease often present with non-specific signs and symptoms resembling a viral infection: fatigue, headache, loss of appetite, joint pain, and regional lymphadenopathy. Fever can be present in approximately 20% of patients. Laboratory findings in this phase are non-specific. Erythrocyte sedimentation can be slightly increased, leukocyte counts are mostly normal, and anemia and thrombocytopenia are present only rarely (7,8). Early disseminated stage. This stage is marked by numerous EM lesions (that generally appear days or weeks after the infection) and/or neurological and/or cardiac manifestations (occurring weeks or months after infection). Some of these patients have no data on the presence of early localized Lyme disease. The most common triad of neurological manifestations are meningitis, neuropathy (usually of the facial nerve) and motor or sensory radiculopathy (Bannwarth syndrome). All these manifestations can appear individually. Cranial nerve neuropathies can often be bilateral. Late-stage Lyme disease. Characterized by intermittent or permanent arthritis in one joint or several large joints, most commonly the knees, and/or more rarely by neurological symptoms such as discrete encephalopathy or polyneuropathy. Late-stage Lyme disease can develop several years after primary infection, and arthritis can be the first manifestation of the disease, with the early localized and early disseminated stages not manifesting at all. In Europe, patients with late-stage Lyme disease can present with chronic skin changes (acrodermatitis chronica atrophicans), which is not observed in the USA. It is caused by B. afzelii and is typically localized to the extensor surfaces of the hands and feet. It is most common in women >40 years of age but can also present in younger populations. However, due to early antimicrobial treatment of the earlier stages of the disease, late-stage manifestations are rare (9). The discovery of the etiology of this disease showed that some well-known clinical entities were also a manifestation of Borrelia infection. The etiology of other dermatologic diseases was thus determined, such as lymphocytoma (or lymphadenosis cutis benigna), which was recognized as an entity as early as 1884, as well as acrodermatitis chronica atrophicans, described in 1888, erythema chronicum migrans (Afzelius-Lipschütz), and the neurological disease called Bannwarth syndrome, the symptoms of which were described as early as 1922 (10,11). LB and all its dermatological manifestations occur in almost all European countries, predominantly in the central part of the continent. The annual incidence is between 9.4 cases per 100,000 inhabitants in France to 120 cases per 100,000 inhabitants in northeastern Poland, 130 cases per 100,000 inhabitants in Austria, and 155 cases per 100,000 inhabitants in Slovenia (12). The total prevalence of ACA in all European patients with LB is 1-10%, depending on the region. For example, BL and ACA comprise 0.3% of LB cases in Bulgaria. In Norway, ACA comprises 5% of all clinical LB cases, and in northern Italy that number is 2.5%. Establishing a diagnosis of ACA is much more difficult than diagnosing EM or benign lymphocytoma (BL) because the clinical manifestations of ACA can vary. Acrodermatitis chronica atrophicans is probably the most common late and chronic manifestation of LB that can be observed in European patients. The skin changes in our patient were fairly non-specific, based on descriptions from the literature, but positivity for IgM antibodies was important for establishing the diagnosis, along with the very good response to antibiotics regarding regression of skin changes as well as the histological analysis that, according to the pathohistological diagnosis, indicated livedo reticularis, which is in turn also described in the literature as a possible form of ACA depending on the stage of the disease. Skin changes on the lower extremities are often incorrectly interpreted as vascular insufficiency, e.g. chronic venous insufficiency, superficial thrombophlebitis, hypostatic eczema, obliterative arterial disease, acrocyanosis, livedo reticularis, or lymphoedema, but they can also be the result of ACA, as in our case (13-15). In cases such as the one we have described, clinical manifestations of Lyme disease can very often vary and differ greatly from the typical clinical picture. This is demonstrated by our case, which also shows that LB and its idiosyncratic manifestations can lead physicians astray in a condition where failing to establish a timely diagnosis can be fatal for the patient. This case report also serves as a reminder that Lyme disease should be considered whenever atypical skin changes are encountered. Given that ACA is a disease in the late stage of Lyme disease and that the changes in our patient were noticed at the very beginning, the disease did not develop to the later stage.

Germ cell tumors and sex cord stromal tumors are rare cancers of the ovary. They mainly affect young women and are associated with a high survival rate. The standard treatment mainly involves conservative surgery combined with chemotherapy [bleomycin, etoposide and cisplatin (BEP)] depending on the stage and the prognostic factors, as for testicular cancers. As reported in testicular cancer survivors, chemotherapy may induce sequelae impacting quality of life, which has not yet been evaluated in survivors of germ cell tumors and sex cord stromal tumors. The GINECO-VIVROVAIRE-Rare tumor study is a two-step investigation aiming to assess i) chronic fatigue and quality of life and ii) long-term side-effects of chemotherapy with a focus on cardiovascular and pulmonary disorders. Using self-reported questionnaires, chronic fatigue and quality of life are compared between 134 ovarian cancer survivors (cancer-free ≥2 years after treatment) treated with surgery and chemotherapy and 2 control groups (67 ovarian cancer survivors treated with surgery alone and 67 age-matched healthy women). Medical data are collected from patient records. In the second step evaluating the long-term side-effects of chemotherapy, a subgroup of 90 patients treated with chemotherapy and 45 controls undergo the following work-up: cardiovascular evaluation (clinical examination, non-invasive cardiovascular tests to explore heart disease, blood tests), pulmonary function testing, audiogram, metabolic and hormonal blood tests. Costs of sequelae will be also assessed. Patients are selected from the registry of the INCa French Network for Rare Malignant Ovarian Tumors, and healthy women by the 'Seintinelles' connected network (collaborative research platform). This study will provide important data on the potential long-term physical side-effects of chemotherapy in survivors of Germ Cell Tumors (GCT) and Sex Cord Stromal Tumors (SCST), especially cardiovascular and pulmonary disorders, and neurotoxicity. The identification of long-term side-effects can contribute to adjusting the treatment of ovarian GCT or SCST patients and to managing follow-up with adapted recommendations regarding practices and chemotherapy regimens, in order to reduce toxicity while maintaining efficacy. Based on the results, intervention strategies could be proposed to improve the management of these patients during their treatment and in the long term. This trial was registered at clinicaltrials.gov : 03418844 , on 1 February 2018. This trial was registered on 25 October 2017 under the unique European identification number (ID-RCB): 2017-A03028-45. Recruitment Status: Recruiting. Version n° 4.2 dated from Feb 19, 2021. Centre François Baclesse, 3 avenue du Général Harris, F-14076 Caen cedex 05, France.

Little is known about persistence of or recovery from chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in adolescents. Previous studies have small sample sizes, short follow-up or have focused on fatigue rather than CFS/ME or, equivalently, chronic fatigue, which is disabling. This work aimed to describe the epidemiology and natural course of CFS/ME in adolescents aged 13-18 years. Longitudinal follow-up of adolescents enrolled in the Avon Longitudinal Study of Parents and Children. Avon, UK. We identified adolescents who had disabling fatigue of >6 months duration without a known cause at ages 13, 16 and 18 years. We use the term 'chronic disabling fatigue' (CDF) because CFS/ME was not verified by clinical diagnosis. We used multiple imputation to obtain unbiased estimates of prevalence and persistence. The estimated prevalence of CDF was 1.47% (95% CI 1.05% to 1.89%) at age 13, 2.22% (1.67% to 2.78%) at age 16 and 2.99% (2.24% to 3.75%) at age 18. Among adolescents with CDF of 6 months duration at 13 years 75.3% (64.0% to 86.6%) were not classified as such at age 16. Similar change was observed between 16 and 18 years (75.0% (62.8% to 87.2%)). Of those with CDF at age 13, 8.02% (0.61% to 15.4%) presented with CDF throughout the duration of adolescence. The prevalence of CDF lasting 6 months or longer (a proxy for clinically diagnosed CFS/ME) increases from 13 to 18 years. However, persistent CDF is rare in adolescents, with approximately 75% recovering after 2-3 years.