Article

Key clinical point: Atopic dermatitis (AD) is prevalent among young adults, with men being at increased odds of having AD in early life and decreased odds of having AD at adolescence and young adulthood.

Major finding: At 24 years, the 12-month prevalence of AD was 17.8%, with the prevalence being higher in women vs. men (20.5% vs. 14.8%; P < .0001). Men vs. women were more likely to have AD in the first year of life (odds ratio [OR] 1.31; 95% CI 1.10-1.56) but less likely to have AD at 24 years (OR 0.66; 95% CI 0.55-0.80).

Study details: This study included 3,055 individuals from the population-based BAMSE cohort, who were followed for 24 years after birth, and responded to a questionnaire regarding AD at the 24-year follow-up.

Disclosures: This study was funded by the European Research Council, Swedish Research Council, Åke Wiberg foundation, and other sources. Some of the authors declared serving as meeting experts or receiving consultancy fees and lecture fees from various sources.

Source: Johansson EK et al. J Eur Acad Dermatol Venereol. 2022 (Jan 15). Doi: 10.1111/jdv.17929

Key clinical point: Atopic dermatitis (AD) is prevalent among young adults, with men being at increased odds of having AD in early life and decreased odds of having AD at adolescence and young adulthood.

Major finding: At 24 years, the 12-month prevalence of AD was 17.8%, with the prevalence being higher in women vs. men (20.5% vs. 14.8%; P < .0001). Men vs. women were more likely to have AD in the first year of life (odds ratio [OR] 1.31; 95% CI 1.10-1.56) but less likely to have AD at 24 years (OR 0.66; 95% CI 0.55-0.80).

Study details: This study included 3,055 individuals from the population-based BAMSE cohort, who were followed for 24 years after birth, and responded to a questionnaire regarding AD at the 24-year follow-up.

Disclosures: This study was funded by the European Research Council, Swedish Research Council, Åke Wiberg foundation, and other sources. Some of the authors declared serving as meeting experts or receiving consultancy fees and lecture fees from various sources.

Source: Johansson EK et al. J Eur Acad Dermatol Venereol. 2022 (Jan 15). Doi: 10.1111/jdv.17929

Key clinical point: Atopic dermatitis (AD) is prevalent among young adults, with men being at increased odds of having AD in early life and decreased odds of having AD at adolescence and young adulthood.

Major finding: At 24 years, the 12-month prevalence of AD was 17.8%, with the prevalence being higher in women vs. men (20.5% vs. 14.8%; P < .0001). Men vs. women were more likely to have AD in the first year of life (odds ratio [OR] 1.31; 95% CI 1.10-1.56) but less likely to have AD at 24 years (OR 0.66; 95% CI 0.55-0.80).

Study details: This study included 3,055 individuals from the population-based BAMSE cohort, who were followed for 24 years after birth, and responded to a questionnaire regarding AD at the 24-year follow-up.

Disclosures: This study was funded by the European Research Council, Swedish Research Council, Åke Wiberg foundation, and other sources. Some of the authors declared serving as meeting experts or receiving consultancy fees and lecture fees from various sources.

Source: Johansson EK et al. J Eur Acad Dermatol Venereol. 2022 (Jan 15). Doi: 10.1111/jdv.17929

Key clinical point: Children with inadequately controlled moderate-to-severe atopic dermatitis (AD) presented with a high disease burden characterized by itch, impaired quality of life (QoL), and disturbed sleep, which may be attributed to lower use of systemic therapies.

Major finding: Most of the children were receiving nonsystemic medications (77.2%) and reported a mean Eczema Area and Severity Index of 14.4 and Patient-Oriented Eczema Measure score of 15.6. Patients aged 6 to <12 years reported an itch score of 4.9; infants (0-3 years) and children (4 to <12 years) reported QoL scores of 10.3 and 10.8, respectively, and 31% of patients reported disturbed sleep because of AD.

Study details: Findings are based on interim baseline data from an ongoing, longitudinal study including 732 children aged <12 years with moderate-to-severe AD.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals. The authors declared serving as investigators, consultants, speakers, and advisory board members or receiving research grants and honoraria from various sources. Some authors declared being employees or stockholders of Sanofi Genzyme or Regeneron Pharmaceuticals.

Source: Paller AS et al. J Am Acad Dermatol. 2022 (Jan 23). Doi: 10.1016/j.jaad.2022.01.018

Key clinical point: Children with inadequately controlled moderate-to-severe atopic dermatitis (AD) presented with a high disease burden characterized by itch, impaired quality of life (QoL), and disturbed sleep, which may be attributed to lower use of systemic therapies.

Major finding: Most of the children were receiving nonsystemic medications (77.2%) and reported a mean Eczema Area and Severity Index of 14.4 and Patient-Oriented Eczema Measure score of 15.6. Patients aged 6 to <12 years reported an itch score of 4.9; infants (0-3 years) and children (4 to <12 years) reported QoL scores of 10.3 and 10.8, respectively, and 31% of patients reported disturbed sleep because of AD.

Study details: Findings are based on interim baseline data from an ongoing, longitudinal study including 732 children aged <12 years with moderate-to-severe AD.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals. The authors declared serving as investigators, consultants, speakers, and advisory board members or receiving research grants and honoraria from various sources. Some authors declared being employees or stockholders of Sanofi Genzyme or Regeneron Pharmaceuticals.

Source: Paller AS et al. J Am Acad Dermatol. 2022 (Jan 23). Doi: 10.1016/j.jaad.2022.01.018

Key clinical point: Children with inadequately controlled moderate-to-severe atopic dermatitis (AD) presented with a high disease burden characterized by itch, impaired quality of life (QoL), and disturbed sleep, which may be attributed to lower use of systemic therapies.

Major finding: Most of the children were receiving nonsystemic medications (77.2%) and reported a mean Eczema Area and Severity Index of 14.4 and Patient-Oriented Eczema Measure score of 15.6. Patients aged 6 to <12 years reported an itch score of 4.9; infants (0-3 years) and children (4 to <12 years) reported QoL scores of 10.3 and 10.8, respectively, and 31% of patients reported disturbed sleep because of AD.

Study details: Findings are based on interim baseline data from an ongoing, longitudinal study including 732 children aged <12 years with moderate-to-severe AD.

Disclosures: This study was funded by Sanofi and Regeneron Pharmaceuticals. The authors declared serving as investigators, consultants, speakers, and advisory board members or receiving research grants and honoraria from various sources. Some authors declared being employees or stockholders of Sanofi Genzyme or Regeneron Pharmaceuticals.

Source: Paller AS et al. J Am Acad Dermatol. 2022 (Jan 23). Doi: 10.1016/j.jaad.2022.01.018

Key clinical point: Adults with atopic dermatitis (AD) who received COVID-19 vaccination did not show a higher risk for any assessed adverse events (AE) than those without AD; however, a minimal risk persisted among patients with a 1-year history of immunosuppressive or immunomodulatory therapy.

Major finding: The risk for 1-day immediate AEs, AEs at 30/60/90-day follow-up, and breakthrough infections was similar between vaccinated adults with vs. without AD; however, those who had a 1-year history of immunosuppressant or immunomodulatory therapy were at a higher risk for all-cause hospitalization at 30 days (adjusted hazard ratio [aHR] 2.14; 95% CI 1.27-3.59), 60 days (aHR 1.77; 95% CI 1.22-2.56), and 90 days (aHR 1.68; 95% CI 1.25-2.27) after vaccination.

Study details: Findings are from a retrospective cohort study including 1,262,306 vaccinated adults, of which 1.2% of adults had a history of AD.

Disclosures: This study did not report any source of funding. Some of the authors declared serving as consultants, honoraria speakers, and receiving research funding from several sources.

Source: Pakhchanian H et al. Br J Dermatol. 2022 (Jan 27). Doi: 10.1111/bjd.21038

Key clinical point: Adults with atopic dermatitis (AD) who received COVID-19 vaccination did not show a higher risk for any assessed adverse events (AE) than those without AD; however, a minimal risk persisted among patients with a 1-year history of immunosuppressive or immunomodulatory therapy.

Major finding: The risk for 1-day immediate AEs, AEs at 30/60/90-day follow-up, and breakthrough infections was similar between vaccinated adults with vs. without AD; however, those who had a 1-year history of immunosuppressant or immunomodulatory therapy were at a higher risk for all-cause hospitalization at 30 days (adjusted hazard ratio [aHR] 2.14; 95% CI 1.27-3.59), 60 days (aHR 1.77; 95% CI 1.22-2.56), and 90 days (aHR 1.68; 95% CI 1.25-2.27) after vaccination.

Study details: Findings are from a retrospective cohort study including 1,262,306 vaccinated adults, of which 1.2% of adults had a history of AD.

Disclosures: This study did not report any source of funding. Some of the authors declared serving as consultants, honoraria speakers, and receiving research funding from several sources.

Source: Pakhchanian H et al. Br J Dermatol. 2022 (Jan 27). Doi: 10.1111/bjd.21038

Key clinical point: Adults with atopic dermatitis (AD) who received COVID-19 vaccination did not show a higher risk for any assessed adverse events (AE) than those without AD; however, a minimal risk persisted among patients with a 1-year history of immunosuppressive or immunomodulatory therapy.

Major finding: The risk for 1-day immediate AEs, AEs at 30/60/90-day follow-up, and breakthrough infections was similar between vaccinated adults with vs. without AD; however, those who had a 1-year history of immunosuppressant or immunomodulatory therapy were at a higher risk for all-cause hospitalization at 30 days (adjusted hazard ratio [aHR] 2.14; 95% CI 1.27-3.59), 60 days (aHR 1.77; 95% CI 1.22-2.56), and 90 days (aHR 1.68; 95% CI 1.25-2.27) after vaccination.

Study details: Findings are from a retrospective cohort study including 1,262,306 vaccinated adults, of which 1.2% of adults had a history of AD.

Disclosures: This study did not report any source of funding. Some of the authors declared serving as consultants, honoraria speakers, and receiving research funding from several sources.

Source: Pakhchanian H et al. Br J Dermatol. 2022 (Jan 27). Doi: 10.1111/bjd.21038

            Kishan et al conducted a meta-analysis to evaluate the relative effects of the addition of androgen deprivation therapy (ADT) to radiation therapy (RT) on metastasis-free survival (MFS) in patients with localized prostate cancer in the following three settings: 1) RT alone versus RT plus adjuvant ADT, 2) extension of ADT duration in the neoadjuvant setting before RT, and 3) extension of adjuvant ADT duration. MFS was increased in the adjuvant ADT setting, and prolongation of ADT duration was associated with a higher MFS than shorter duration. However, extension of neoadjuvant ADT was not associated with a higher MFS compared to a shorter duration. The meta-analysis further supports a longer versus shorter ADT duration, but it does not support a longer neoadjuvant ADT duration.

            To determine the effects of salvage RT on outcomes in the setting of biochemical relapse, Tilki et al conducted a retrospective cohort analysis of a multi-institutional database of patients with biochemical recurrence after radical prostatectomy (RP). MFS at 15 years post-RP was 84.3% in the RT group and 76.9% in the non-RT group, while overall survival (OS), also at 15 years post-RP, was 85.3% in the RT group versus 74.4% in the non-RT group (both analyses were statistically significant). While supportive of salvage RT, there was no data on prostate-specific antigen (PSA) doubling times, nor was it possible to control for imaging modality. It is possible that newer prostate-specific membrane antigen (PSMA)-based positron emission tomography imaging may affect MFS in studies such as these.

            Prostatectomy (with or without lymph node dissection), external beam RT (EBRT) with  ADT, or EBRT with brachytherapy (BT) with or without ADT are options in unfavorable intermediate-risk prostate cancer. The optimal use of BT in localized prostate cancer is somewhat uncertain, especially across the risk spectrum. Andruska et al conducted an analysis of the National Cancer Database (NCDB) to evaluate whether EBRT plus BT with or without ADT results in an improvement in overall survival (OS) compared with BT with or without ADT. OS was higher for the EBRT plus BT groups; however, when the ADT + EBRT + BT group was compared with EBRT + BT without ADT group, the improvement in OS was not statistically significant. Overall, the analysis favored EBRT + BT over BT alone, further supporting current guidelines.

            Kishan et al conducted a meta-analysis to evaluate the relative effects of the addition of androgen deprivation therapy (ADT) to radiation therapy (RT) on metastasis-free survival (MFS) in patients with localized prostate cancer in the following three settings: 1) RT alone versus RT plus adjuvant ADT, 2) extension of ADT duration in the neoadjuvant setting before RT, and 3) extension of adjuvant ADT duration. MFS was increased in the adjuvant ADT setting, and prolongation of ADT duration was associated with a higher MFS than shorter duration. However, extension of neoadjuvant ADT was not associated with a higher MFS compared to a shorter duration. The meta-analysis further supports a longer versus shorter ADT duration, but it does not support a longer neoadjuvant ADT duration.

            To determine the effects of salvage RT on outcomes in the setting of biochemical relapse, Tilki et al conducted a retrospective cohort analysis of a multi-institutional database of patients with biochemical recurrence after radical prostatectomy (RP). MFS at 15 years post-RP was 84.3% in the RT group and 76.9% in the non-RT group, while overall survival (OS), also at 15 years post-RP, was 85.3% in the RT group versus 74.4% in the non-RT group (both analyses were statistically significant). While supportive of salvage RT, there was no data on prostate-specific antigen (PSA) doubling times, nor was it possible to control for imaging modality. It is possible that newer prostate-specific membrane antigen (PSMA)-based positron emission tomography imaging may affect MFS in studies such as these.

            Prostatectomy (with or without lymph node dissection), external beam RT (EBRT) with  ADT, or EBRT with brachytherapy (BT) with or without ADT are options in unfavorable intermediate-risk prostate cancer. The optimal use of BT in localized prostate cancer is somewhat uncertain, especially across the risk spectrum. Andruska et al conducted an analysis of the National Cancer Database (NCDB) to evaluate whether EBRT plus BT with or without ADT results in an improvement in overall survival (OS) compared with BT with or without ADT. OS was higher for the EBRT plus BT groups; however, when the ADT + EBRT + BT group was compared with EBRT + BT without ADT group, the improvement in OS was not statistically significant. Overall, the analysis favored EBRT + BT over BT alone, further supporting current guidelines.

            Kishan et al conducted a meta-analysis to evaluate the relative effects of the addition of androgen deprivation therapy (ADT) to radiation therapy (RT) on metastasis-free survival (MFS) in patients with localized prostate cancer in the following three settings: 1) RT alone versus RT plus adjuvant ADT, 2) extension of ADT duration in the neoadjuvant setting before RT, and 3) extension of adjuvant ADT duration. MFS was increased in the adjuvant ADT setting, and prolongation of ADT duration was associated with a higher MFS than shorter duration. However, extension of neoadjuvant ADT was not associated with a higher MFS compared to a shorter duration. The meta-analysis further supports a longer versus shorter ADT duration, but it does not support a longer neoadjuvant ADT duration.

            To determine the effects of salvage RT on outcomes in the setting of biochemical relapse, Tilki et al conducted a retrospective cohort analysis of a multi-institutional database of patients with biochemical recurrence after radical prostatectomy (RP). MFS at 15 years post-RP was 84.3% in the RT group and 76.9% in the non-RT group, while overall survival (OS), also at 15 years post-RP, was 85.3% in the RT group versus 74.4% in the non-RT group (both analyses were statistically significant). While supportive of salvage RT, there was no data on prostate-specific antigen (PSA) doubling times, nor was it possible to control for imaging modality. It is possible that newer prostate-specific membrane antigen (PSMA)-based positron emission tomography imaging may affect MFS in studies such as these.

            Prostatectomy (with or without lymph node dissection), external beam RT (EBRT) with  ADT, or EBRT with brachytherapy (BT) with or without ADT are options in unfavorable intermediate-risk prostate cancer. The optimal use of BT in localized prostate cancer is somewhat uncertain, especially across the risk spectrum. Andruska et al conducted an analysis of the National Cancer Database (NCDB) to evaluate whether EBRT plus BT with or without ADT results in an improvement in overall survival (OS) compared with BT with or without ADT. OS was higher for the EBRT plus BT groups; however, when the ADT + EBRT + BT group was compared with EBRT + BT without ADT group, the improvement in OS was not statistically significant. Overall, the analysis favored EBRT + BT over BT alone, further supporting current guidelines.

Many neurocognitive disorders only present a phenotype after birth. Sukenik-Halevy et al sought to examine the ability to detect prenatal phenotypes in patients with a postnatally diagnosed neurocognitive syndrome and confirmed genetic diagnosis on ES. The team was not able to identify any specific prenatal phenotype associated with their cases of postnatally diagnosed neurocognitive syndromes. The interesting finding of this study is that, of the 122 patients studied, 35.3% (43) had no abnormal sonographic findings that could have been detected prenatally to suggest the need for ES testing. ES is typically used in a prenatal setting for fetuses with anomalies that have a normal KT and CMA. The results of this study raise the question of offering ES to all patients considering diagnostic genetic testing regardless of the indication, as it may be the only way to diagnose some cases of neurocognitive disorders prenatally.

Cell-free fetal DNA (cff DNA) testing for trisomy 21, 18, and 13 has classically be used for high-risk pregnant patients seeking aneuploidy screening. Dar et al sought to examine this type of testing in a low-risk population. They studied, prospectively, the performance of cff DNA testing for trisomy 21, 18, and 13 in both low and high-risk pregnant women with confirmation of results on diagnostic genetic testing. Negative predictive values (NPV) for both the low and high-risk groups were greater than 99.9%. Positive predictive value (PPV) was lower for the low-risk group in comparison to the high-risk group, with it important to note that PPV drops from 96.4% in the high-risk group to 81.8% in the low-risk group for trisomy 21. This means that low-risk patients with a positive result on cff DNA testing are at a higher risk for a false positive than patients at high-risk for an aneuploid fetus. This study shows the mounting evidence that cff DNA can be used in a low-risk population given the high NPV. Providers do still need to note the lower PPV with low-risk population patients and always offer diagnostic genetic testing with any abnormal cff DNA test result.

Many neurocognitive disorders only present a phenotype after birth. Sukenik-Halevy et al sought to examine the ability to detect prenatal phenotypes in patients with a postnatally diagnosed neurocognitive syndrome and confirmed genetic diagnosis on ES. The team was not able to identify any specific prenatal phenotype associated with their cases of postnatally diagnosed neurocognitive syndromes. The interesting finding of this study is that, of the 122 patients studied, 35.3% (43) had no abnormal sonographic findings that could have been detected prenatally to suggest the need for ES testing. ES is typically used in a prenatal setting for fetuses with anomalies that have a normal KT and CMA. The results of this study raise the question of offering ES to all patients considering diagnostic genetic testing regardless of the indication, as it may be the only way to diagnose some cases of neurocognitive disorders prenatally.

Cell-free fetal DNA (cff DNA) testing for trisomy 21, 18, and 13 has classically be used for high-risk pregnant patients seeking aneuploidy screening. Dar et al sought to examine this type of testing in a low-risk population. They studied, prospectively, the performance of cff DNA testing for trisomy 21, 18, and 13 in both low and high-risk pregnant women with confirmation of results on diagnostic genetic testing. Negative predictive values (NPV) for both the low and high-risk groups were greater than 99.9%. Positive predictive value (PPV) was lower for the low-risk group in comparison to the high-risk group, with it important to note that PPV drops from 96.4% in the high-risk group to 81.8% in the low-risk group for trisomy 21. This means that low-risk patients with a positive result on cff DNA testing are at a higher risk for a false positive than patients at high-risk for an aneuploid fetus. This study shows the mounting evidence that cff DNA can be used in a low-risk population given the high NPV. Providers do still need to note the lower PPV with low-risk population patients and always offer diagnostic genetic testing with any abnormal cff DNA test result.

Many neurocognitive disorders only present a phenotype after birth. Sukenik-Halevy et al sought to examine the ability to detect prenatal phenotypes in patients with a postnatally diagnosed neurocognitive syndrome and confirmed genetic diagnosis on ES. The team was not able to identify any specific prenatal phenotype associated with their cases of postnatally diagnosed neurocognitive syndromes. The interesting finding of this study is that, of the 122 patients studied, 35.3% (43) had no abnormal sonographic findings that could have been detected prenatally to suggest the need for ES testing. ES is typically used in a prenatal setting for fetuses with anomalies that have a normal KT and CMA. The results of this study raise the question of offering ES to all patients considering diagnostic genetic testing regardless of the indication, as it may be the only way to diagnose some cases of neurocognitive disorders prenatally.

Cell-free fetal DNA (cff DNA) testing for trisomy 21, 18, and 13 has classically be used for high-risk pregnant patients seeking aneuploidy screening. Dar et al sought to examine this type of testing in a low-risk population. They studied, prospectively, the performance of cff DNA testing for trisomy 21, 18, and 13 in both low and high-risk pregnant women with confirmation of results on diagnostic genetic testing. Negative predictive values (NPV) for both the low and high-risk groups were greater than 99.9%. Positive predictive value (PPV) was lower for the low-risk group in comparison to the high-risk group, with it important to note that PPV drops from 96.4% in the high-risk group to 81.8% in the low-risk group for trisomy 21. This means that low-risk patients with a positive result on cff DNA testing are at a higher risk for a false positive than patients at high-risk for an aneuploid fetus. This study shows the mounting evidence that cff DNA can be used in a low-risk population given the high NPV. Providers do still need to note the lower PPV with low-risk population patients and always offer diagnostic genetic testing with any abnormal cff DNA test result.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

To the Editor:

Pretibial myxedema (PTM) is bilateral, nonpitting, scaly thickening and induration of the skin that most commonly occurs on the anterior aspects of the legs and feet. Pretibial myxedema occurs in approximately 0.5% to 4.3% of patients with hyperthyroidism.¹ Thyroid dermopathy often is thought of as the classic nonpitting PTM with skin induration and color change. However, rarer forms of PTM, including plaque, nodular, and elephantiasic, also are important to note.²

Elephantiasic PTM is extremely rare, occurring in less than 1% of patients with PTM.² Elephantiasic PTM is characterized by the persistent swelling of 1 or both legs; thickening of the skin overlying the dorsum of the feet, ankles, and toes; and verrucous irregular plaques that often are fleshy and flattened. The clinical differential diagnosis of elephantiasic PTM includes elephantiasis nostra verrucosa, a late-stage complication of chronic lymphedema that can be related to a variety of infectious or noninfectious obstructive processes. Few effective therapeutic modalities exist in the treatment of elephantiasic PTM. We present a case of elephantiasic PTM.

A 59-year-old man presented to dermatology with leonine facies with pronounced glabellar creases and indentations of the earlobes. He had diffuse woody induration, hyperpigmentation, and nonpitting edema of the lower extremities as well as several flesh-colored exophytic nodules scattered throughout the anterior shins and dorsal feet (Figure 1). On the left posterior calf, there was a large, 3-cm, exophytic, firm, flesh-colored nodule. Examination of the hands revealed mild hyperpigmentation of the distal digits, clubbing of the distal phalanges, and cheiroarthropathy.

The patient was diagnosed with Graves disease after experiencing the classic symptoms of hyperthyroidism, including heat intolerance, tremor, palpitations, and anxiety. He received thyroid ablation and subsequently was supplemented with levothyroxine 75 mg daily. Twelve years later, he was diagnosed with Graves ophthalmopathy with ocular proptosis requiring multiple courses of retro-orbital irradiation and surgical procedures for decompression. Approximately 1 year later, he noted increased swelling, firmness, and darkening of the pretibial surfaces. Initially, he was referred to vascular surgery and underwent bilateral saphenous vein ablation. He also was referred to a lymphedema specialist, and workup revealed an unremarkable lymphatic system. Minimal improvement was noted following the saphenous vein ablation, and he subsequently was referred to dermatology for further workup.

At the current presentation, laboratory analysis revealed a low thyrotropin level (0.03 mIU/L [reference range, 0.4–4.2 mIU/L]), and free thyroxine was within reference range. Radiography of the chest was unremarkable; however, radiography of the hand demonstrated arthrosis of the left fifth proximal interphalangeal joint. Nuclear medicine lymphoscintigraphy and lower extremity ultrasonography were unremarkable. Punch biopsies were performed of the left lateral leg and posterior calf. Hematoxylin and eosin staining demonstrated marked mucin deposition extending to the deep dermis along with deep fibroplasia and was read as consistent with PTM. Colloidal iron highlighted prominent mucin within the dermis (Figure 2).

The patient’s medical history, physical examination, laboratory analysis, imaging, and biopsies were considered, and a diagnosis of elephantiasic PTM was made. Minimal improvement was noted with initial therapeutic interventions including compression therapy and application of super high–potency topical corticosteroids. After further evaluation in our multidisciplinary rheumatology-dermatology clinic, the decision was made to initiate rituximab infusions.

Two months after 1 course of rituximab consisting of two 1000-mg infusions separated by 2 weeks, the patient showed substantial clinical improvement. There was striking improvement of the pretibial surfaces with resolution of the exophytic nodules and improvement of the induration (Figure 3). In addition, there was decreased induration of the glabella and earlobes and decreased fullness of the digital pulp on the hands. The patient also reported subjective improvements in mobility.

Our patient demonstrated all 3 aspects of the Diamond triad: PTM, exophthalmos, and acropachy. Patients present with all 3 features in less than 1% of reported cases of Graves disease.³ Although all 3 features are seen together infrequently, thyroid dermopathy and acropachy often are markers of severe Graves ophthalmopathy. In a study of 114 patients with Graves ophthalmopathy, patients who also had dermopathy and acropachy were more likely to have optic neuropathy or require orbital decompression.⁴

After overcoming the diagnostic dilemma that the elephantiasic presentation of PTM can present, therapeutic management remains a challenge. Heyes et al⁵ documented the successful treatment of highly recalcitrant elephantiasic PTM with rituximab and plasmapheresis therapy. In this case, a 44-year-old woman with an 11-year history of Graves disease and elephantiasic PTM received 29 rituximab infusions and 241 plasmapheresis treatments over the course of 3.5 years. Her elephantiasic PTM clinically resolved, and she was able to resume daily activities and wear normal shoes after being nonambulatory for years.⁵

Rituximab is a monoclonal antibody against CD20, a protein found primarily on the surface of B-cell lymphocytes. Although rituximab initially was approved by the US Food and Drug administration for the treatment of malignant lymphoma, it has had an increasing role in the treatment of autoimmune disorders such as rheumatoid arthritis. Rituximab is postulated to target B lymphocytes and halt their progression to plasma cells. By limiting the population of long-lasting, antibody-producing plasma cells and decreasing the autoantibodies that cause many of the symptoms in Graves disease, rituximab may be an effective therapy to consider in the treatment of elephantiasic PTM.⁶

Although the exact mechanism is poorly understood, PTM likely is a sequela of hyperthyroidism because of the expression of thyroid-stimulating hormone receptor proteins found on normal dermal fibroblasts. Thyroid-stimulating hormone receptor autoantibodies are thought to stimulate these fibroblasts to produce glycosaminoglycans. Histopathologically, accumulation of glycosaminoglycans deposited in the reticular dermis with high concentrations of hyaluronic acid is observed in PTM.⁷

Treatment of elephantiasic PTM remains a therapeutic challenge. Given the rarity of the disease process and limited information on effective therapeutic modalities, rituximab should be viewed as a viable treatment option in the management of recalcitrant elephantiasic PTM.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Edoardo Caronna, MD and Patricia Pozo-Rosich, MD, PhD,  Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; and Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. Dr. Pozo-Rosich also serves on the boards of the International Headache Society and Council of the European Headache Federation and is an editor for various peer-reviewed journals, including Cephalalgia and Headache.

Headache is a symptom of the coronavirus disease 2019 (Covid-19), caused by the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the pandemic began, researchers have tried to describe, understand, and help clinicians manage headache in the setting of Covid-19.

The reason is simple: Headache is common, often debilitating, and difficult to treat.¹

Moreover, headache could manifest both in the acute phase of the infection and, once the infection has resolved, in the post-acute phase.¹ Therefore, it is critical for clinicians to know more about headache, as headache can be a common reason that patients seek help, both in the specialized and non-specialized medical care setting.

Definitions and manifestations

While the first step in such a communication would be to define headache attributed to Covid-19, no specific definition exists, as this is a new disease. Therefore, headache attributed to Covid-19 should be defined under the diagnostic criteria, as contained in the International Classification of Headache Disorders-3, as headache attributed to a systemic viral infection.² As this is a secondary headache appearing with an infection, the treating physician needs to rule out possible underlying meningitis and/or encephalitis in the diagnosis. Moreover, other secondary headaches (eg, cerebral venous thrombosis) may appear, so clinicians need to carefully evaluate patients with headache during Covid-19 to detect signs or symptoms that point to other etiologies.

It is also advisable to know the clinical manifestations of headache attributed to Covid-19. Studies published so far have observed two main phenotypes of headache in the acute phase of the infection: one resembles migraine, the other, a tension-type headache.^1,3 Although patients with history of migraine who contract Covid-19 report headache that is more similar to primary headache disorder,⁴ two relevant aspects should be considered. Namely, migraine-like features can be observed in patients without personal migraine history; and Covid-19 patients with such history may perceive that headache they experience in the infection’s acute phase differs from their usual experience, especially regarding increased severity or duration.^5,6 Of note, headache can be a prodromal symptom of the SARS-CoV-2 infection.¹

Evolution of a headache

 Because headache appearing after the acute phase of the infection can persist, often manifesting migraine-like features, it is inordinately helpful for clinicians to know its evolution.¹ This persistent headache, sometimes referred to as post-covid headache, is not aptly named because the post-covid headache is not just one type of headache, but instead can manifest as different headache types.

 A recently published case series in Headache discussed three Covid patients who all experienced persistent headache during the infection’s post-acute phase.⁷ These patients experienced a migraine-like phenotype as have others with mild Covid-19, but their personal history of migraine, as well as their experience with Covid-19 related headache, were substantially different. Some patients had personal migraine history while others did not; some patients experienced no headache in the acute phase but did so in the post-acute phase; and the concomitant symptoms of the post-acute phase, such as insomnia, memory loss, dizziness, fatigue, and brain fog, were differentially expressed by patients.⁷ 

 This case series introduces the concept that patients with no prior history of migraine or any other primary headache disorder can develop a de novo headache because of their SARS-CoV-2 infection. Moreover, it could manifest as a new daily persistent headache. And patients with personal history of migraine may experience sudden chronification in their headache’s characteristics, rather than develop a new type of headache.⁷

 In another study, soon to be published in Cephalalgia, researchers observed that the median duration of headache in the acute phase is 2 weeks. This multicenter Spanish study, in which data on headache duration were available for 874 patients, found that 16% of these particular patients had persistent headache after 9 months. According to this study, headache that does not resolve within the first 3 months is less likely to do so later on.

Treatment

For clinicians, the significance of these findings is straightforward: Patients with headache experienced in the infection’s acute phase that does not seem to resolve post-infection requires continued medical attention. Patients should be monitored, carefully managed, and treated to avoid the onset of a persisting headache. This applies to patients with or without personal migraine history.

But which treatments should be prescribed? As there are no specific therapies for headache attributed to Covid-19, either in the acute or post-acute phase of the infection, clinicians must turn to existing therapies.

As with patients with migraine, patients with persistent headache post-Covid infection need a headache prevention strategy.

The strategy should be based on the following principles:

• treat headache
• treat comorbidities including mood disorders,  insomnia, and so on
• avoid complications such as medication overuse, which may be very common in these patients.

Acute medications

Despite the lack of specific literature on this matter, migraine-like phenotypes may respond to triptans and probably, where available, lasmiditan and gepants. These medications probably represent a therapeutic option for Covid patients with headache, but before prescribing them clinicians should carefully evaluate their use.

Before deciding on the prescription, clinicians should consider not only the medications’ most common contraindications, but also those that are related to Covid-19: the phase of the infection (acute/post-acute); the infection’s severity; and the presence of other Covid-related health problems. The concerns over the use of nonsteroidal anti-inflammatory medications (NSAIDs) and corticosteroids, raised when the pandemic first struck, have greatly dissipated.^8,9 Some patients with prolonged headache may benefit from a brief cycle of corticosteroids, similar to the treatment given to those patients with status migrainosus. Nerve blocks could also be considered.

Preventive medications

Drugs can be prescribed according to the headache phenotype too, but there are no published studies that specifically evaluate headache prevention treatments in patients with persistent headache post-infection. The case series mentioned earlier in this article recorded that patients whose headaches were treated with amitriptyline and onabotulinumtoxinA had reported variable treatment responses to this regimen, according to the patients’ characteristics.⁷

However, one important question regarding the safety of Covid patients with migraine – specifically patients on preventive treatments during the infection’s acute phase – has been somewhat resolved.

Medications such as renin-angiotensin system (RAS) blockers, suspected of possible involvement in the SARs-CoV-2 pathogenicity, seem to be safe.^8,10 And, in another multicenter Spanish study, researchers found that the use of anti-CGRP monoclonal antibodies did not seem to be associated with worse Covid-19 outcomes despite the possible implication of CGRP in modulating inflammatory responses during a viral infection.¹¹

The study of anti-CGRP monoclonal antibodies could be important in the future for another reason: To see whether these medications could be effective as a preventive treatment in patients with persistent headache after Covid-19, regardless of whether these patients have personal migraine history.

An interesting and important message to close this article. Although headache experienced in the infection’s acute phase could be extremely disabling for patients, the evidence points to the presence of headache as a marker of a better Covid-19 prognosis, in terms of a shorter infection period and a lower risk of mortality among hospitalized patients.^1,3,12  

This brief communication contains current information to help clinicians treat and inform their patients with Covid-sourced headache. Yet, we must keep in mind that the majority of the data reported here and published in the literature refer to studies conducted during the first wave of the pandemic. The emergence of new SARS-CoV-2 variants and vaccines have enormously changed the disease’s clinical presentation and course, so future studies are warranted to re-assess the validity of these findings under new conditions.

Key clinical point: Advanced age and liver stiffness measurement (LSM) on transient elastography, both pretreatment and at 24-week sustained virological response (SVR24), may aid in predicting the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) who achieved SVR to interferon (IFN)-free direct-acting antivirals (DAA).

Main finding: Multivariate analysis revealed age ≥71 years (adjusted hazard ratio [aHR] 3.402; P = .005) and LSM ≥9.2 kPa (aHR 6.328; P < .001) to be the significant predictive factors at pretreatment and age ≥71 years (aHR 2.689; P = .014) and LSM ≥8.4 kPa (aHR 6.642; P < .001) at SVR24.

Study details: This was a multicenter retrospective study including 567 patients with no history of HCC but with HCV infection treated with DAAs and who achieved SVR24.

Disclosures: The study was sponsored by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Society for the Promotion of Science; Japan Agency for Medical Research and Development; and Ministry of Health, Labor, and Welfare of Japan. Some authors declared receiving speaker fees/research grants from various pharmaceutical companies.

Source: Nakai M et al. Sci Rep. 2022;12:1449 (Jan 27). Doi: 10.1038/s41598-022-05492-5.

Key clinical point: Advanced age and liver stiffness measurement (LSM) on transient elastography, both pretreatment and at 24-week sustained virological response (SVR24), may aid in predicting the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) who achieved SVR to interferon (IFN)-free direct-acting antivirals (DAA).

Main finding: Multivariate analysis revealed age ≥71 years (adjusted hazard ratio [aHR] 3.402; P = .005) and LSM ≥9.2 kPa (aHR 6.328; P < .001) to be the significant predictive factors at pretreatment and age ≥71 years (aHR 2.689; P = .014) and LSM ≥8.4 kPa (aHR 6.642; P < .001) at SVR24.

Study details: This was a multicenter retrospective study including 567 patients with no history of HCC but with HCV infection treated with DAAs and who achieved SVR24.

Disclosures: The study was sponsored by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Society for the Promotion of Science; Japan Agency for Medical Research and Development; and Ministry of Health, Labor, and Welfare of Japan. Some authors declared receiving speaker fees/research grants from various pharmaceutical companies.

Source: Nakai M et al. Sci Rep. 2022;12:1449 (Jan 27). Doi: 10.1038/s41598-022-05492-5.

Key clinical point: Advanced age and liver stiffness measurement (LSM) on transient elastography, both pretreatment and at 24-week sustained virological response (SVR24), may aid in predicting the risk of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) who achieved SVR to interferon (IFN)-free direct-acting antivirals (DAA).

Main finding: Multivariate analysis revealed age ≥71 years (adjusted hazard ratio [aHR] 3.402; P = .005) and LSM ≥9.2 kPa (aHR 6.328; P < .001) to be the significant predictive factors at pretreatment and age ≥71 years (aHR 2.689; P = .014) and LSM ≥8.4 kPa (aHR 6.642; P < .001) at SVR24.

Study details: This was a multicenter retrospective study including 567 patients with no history of HCC but with HCV infection treated with DAAs and who achieved SVR24.

Disclosures: The study was sponsored by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Japan Society for the Promotion of Science; Japan Agency for Medical Research and Development; and Ministry of Health, Labor, and Welfare of Japan. Some authors declared receiving speaker fees/research grants from various pharmaceutical companies.

Source: Nakai M et al. Sci Rep. 2022;12:1449 (Jan 27). Doi: 10.1038/s41598-022-05492-5.

Key clinical point: Robot-assisted liver resection (RALR) and laparoscopic liver resection (LLR) show similar long-term oncological outcomes to open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC) along with allowing faster patient recovery.

Main finding: OLR, LLR, and RALR achieved 5-year overall survival rates of 78.6%, 76.8%, and 74.4% (P = .90) and 5-year disease-free survival rates of 57.9%, 51.3%, and 51.8% (P = .64), respectively. Patients undergoing LLR (6 days) or RALR (8 days) vs. OLR (12 days) recovered faster (both P < .001).

Study details: The data come from a single-center prospective study that compared 3 propensity score-matched cohorts of 56 patients each who were aged 14-75 years and received no previous treatment before undergoing either ALR, LLR, or OLR due to BCLC stage 0-A HCC.

Disclosures: The study was supported by the Key Project of Science and Technology in Hubei Province, General Project of Natural Science Foundation of Hubei Province, and General Project of Health Commission of Hubei Province. No conflicts of interest were disclosed.

Source: Zhu P et al. Ann Surg. 2022 (Jan 25). Doi: 10.1097/SLA.0000000000005380.

Key clinical point: Robot-assisted liver resection (RALR) and laparoscopic liver resection (LLR) show similar long-term oncological outcomes to open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC) along with allowing faster patient recovery.

Main finding: OLR, LLR, and RALR achieved 5-year overall survival rates of 78.6%, 76.8%, and 74.4% (P = .90) and 5-year disease-free survival rates of 57.9%, 51.3%, and 51.8% (P = .64), respectively. Patients undergoing LLR (6 days) or RALR (8 days) vs. OLR (12 days) recovered faster (both P < .001).

Study details: The data come from a single-center prospective study that compared 3 propensity score-matched cohorts of 56 patients each who were aged 14-75 years and received no previous treatment before undergoing either ALR, LLR, or OLR due to BCLC stage 0-A HCC.

Disclosures: The study was supported by the Key Project of Science and Technology in Hubei Province, General Project of Natural Science Foundation of Hubei Province, and General Project of Health Commission of Hubei Province. No conflicts of interest were disclosed.

Source: Zhu P et al. Ann Surg. 2022 (Jan 25). Doi: 10.1097/SLA.0000000000005380.

Key clinical point: Robot-assisted liver resection (RALR) and laparoscopic liver resection (LLR) show similar long-term oncological outcomes to open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC) along with allowing faster patient recovery.

Main finding: OLR, LLR, and RALR achieved 5-year overall survival rates of 78.6%, 76.8%, and 74.4% (P = .90) and 5-year disease-free survival rates of 57.9%, 51.3%, and 51.8% (P = .64), respectively. Patients undergoing LLR (6 days) or RALR (8 days) vs. OLR (12 days) recovered faster (both P < .001).

Study details: The data come from a single-center prospective study that compared 3 propensity score-matched cohorts of 56 patients each who were aged 14-75 years and received no previous treatment before undergoing either ALR, LLR, or OLR due to BCLC stage 0-A HCC.

Disclosures: The study was supported by the Key Project of Science and Technology in Hubei Province, General Project of Natural Science Foundation of Hubei Province, and General Project of Health Commission of Hubei Province. No conflicts of interest were disclosed.

Source: Zhu P et al. Ann Surg. 2022 (Jan 25). Doi: 10.1097/SLA.0000000000005380.