Localized scleroderma (also named morphea) is a rare inflammatory disorder of the skin and subcutaneous tissue, characterized by collagen deposition and fibrosis of the skin and soft tissues (1). It is classified into four main subtypes: circumscribed morphea, generalized morphea, pansclerotic morphea and linear morphea. Linear scleroderma (LS) is the most common subtype of localized scleroderma and predominantly affects children (2). To date, LS remains a rare and poorly understood condition, with an reported incidence of 2.5 per million children per year in the UK and Ireland (3). LS typically presents with linear atrophy and/or hardening of the skin and subcutaneous tissue, occasionally extending to involve underlying muscles and bones (4). When LS involves the head region (such as the forehead, scalp, or chin), it is often termed “en coup de sabre” (ECDS), due to the resemblance of the skin lesions to the stroke of a sabre (5). Whether progressive hemifacial atrophy (PHA), or Parry-Romberg syndrome represents a more severe form of localized craniofacial scleroderma remains a subject of debate (6). Extra-cutaneous involvements, including neurological abnormalities, ocular complications, and cosmetic morbidity, are rising and more frequently encountered in children than in adult-onset localized scleroderma (7). Neurological involvement has been observed in 19% of children with localized craniofacial scleroderma (8), and it occurs almost exclusively in LS en coup de sabre (ECDS) (9, 10). Common neurological manifestations include seizures and headaches, although other symptoms such as focal neurological deficits may also occur (11, 12).

Treatment of LS depends on its subtypes, the depth of tissue involvement, and disease activity. The European Dermatology Forum (EDF) experts recommend topical agents and ultraviolet phototherapy for LS limited to the skin, and methotrexate (either as monotherapy or in combination with systemic corticosteroids) for LS ECDS (1, 12). However, most reported LS therapies have focused primarily on skin manifestations. In a systematic review investigating the treatment of LS ECDS, which included 34 articles (4 retrospective cohort studies, 2 prospective cohort studies, 4 case series, and 24 case reports), only 3 out of 69 patients received treatment for extracutaneous (neurological and ophthalmic) involvement (5). The clinical course and long-term outcomes of LS with CNS involvement remain poorly understood, as only 15 cases with detailed treatment response data have been identified in the literature (Supplementary Table S1). Herein, we present the clinical and neuroimaging characteristics, as well as the long-term outcomes of immunotherapy, with a focus on the treatment of CNS involvement in seven pediatric patients with LS.

We reviewed the medical records of pediatric patients (<18 years) diagnosed with “Linear scleroderma en coup de sabre” who visited the Pediatric Neurology Department of our hospital between June 1, 2004, and June 30, 2022. Seven patients meeting all the following criteria were included: (1) presence of en coup de sabre (2) presence of newly developed neurological symptoms; and (3) completion of serial cranial MRI scans (at least two examinations). Detailed clinical data was collected included demographics, age at onset and diagnosis, clinical manifestations of cutaneous and neurological systems, results of serological and cerebrospinal fluid tests, pathological features of skin or brain biopsy (if performed), immunotherapy regimens (drugs, doses, and duration), and treatment response. All cranial MRI scans were reviewed by a neuroradiologist masked to the clinical outcomes. Follow-up imaging was performed to assess for resolution or progression of imaging abnormalities at 6–12 months intervals and when there were acute neurological manifestations. Treatment response was categorized as improved, stable, or deteriorated in three domains: skin lesions, CNS symptoms, and cranial MRI findings. Improvement was defined as absence or reduction in the extent of skin lesion, substantial resolution of neurological symptoms, and disappearance or reduction of active lesions on follow-up MRI. Stability was defined as no significant changes in the extent of skin lesions, CNS symptoms, or MRI abnormalities. Deterioration was defined as enlargement of pre-existing skin lesions or development of new skin lesions, recurrence or worsening of CNS symptoms, or enlargement of pre-existing MRI lesions or emergence of new lesions. All patients were followed up at the outpatient clinic for 6 months to 15 years (4.11 ± 4.88 years).

Central nervous system involvement in linear scleroderma is extremely rare. Only case reports and small case series have been reported (13). Neurological involvement typically develops after cutaneous manifestations (12); occasionally it may occur prior to or synchronously with cutaneous findings (9, 14, 15). In young children who first present with neurological symptoms, LS could be easily missed in the early stages (16). In the present study, two of the seven cases (Cases 2 and 5) presented with seizures as the initial symptom; the diagnosis was not confirmed until skin rashes were recognized 1 and 9 months later, respectively. For patients with typical dermatological changes, early and serial brain MRI is crucial to identify CNS involvement, especially in asymptomatic individuals. In Chiu’s report, 19% of children with ECDS or PRS showed intracranial abnormalities on MRI, half of whom were asymptomatic (17). All patients in this cohort exhibited both neurological symptoms and abnormal MRI findings. Notably, the interval between the onset of skin rash and neurological symptoms can be as long as 2.5 years, which emphasizes the importance of serial MRI examinations.

In patients with ECDS, MRI abnormalities are usually located ipsilateral to extracranial lesions, most of which are restricted to the supratentorial regions (11, 18). Both left-side (19, 20) and right-side (15) involvement have been reported in the literature, with a predominance on the left side (10, 18, 21). White matter abnormalities in the frontal lobe are the most common MRI findings, followed by those in the parietal, temporal, and occipital lobes (21). Consistent with previous reports, all seven patients in this cohort had left-sided white matter abnormalities, which were ipsilateral to their skin lesions. In contrast to previous reports, cyst-like lesions were more common in our cohort (4/7). Brain biopsy in Case 1 revealed white matter demyelination and perivascular inflammation, suggesting that vasculitis may contribute to the formation of these cyst-like lesions. This is consistent with a previous case report (22)and other histopathological studies of brain involvement in LS ECDS (23–25).

Management of LS varies in the literature, and optimal therapy remains unknown. It has been reported that juvenile-onset LS ECDS can exhibited persistent disease activity in adulthood (26). Systemic treatment is commonly employed for active LS with CNS involvement in most case series (10) and case reports (27). MTX combined with corticosteroids is the first-line treatment according to the consensus of the European Society of Pediatric Rheumatology (28), which is also our practice principle. All our patients received corticosteroids, with five of them combined with MTX. With respect to other immunosuppressants, mycophenolate mofetil is considered as a second-line treatment in current United Kingdom clinical practice (29), additionally, tocilizumab (25) and cyclophosphamide (19) have been occasionally utilized in case reports, and these agents were also administered in our patients due to recurrence of neurological symptoms and/or progression of MRI abnormalities. Due to the small sample size, It was difficult to determine which agent was more effective. However, it is interesting to note that two cases (Cases 6 and 7) failed conventional immunosuppressive therapies but ultimately achieved significant improvement with tocilizumab. Together with previous reports of successful treatment with tocilizumab (25, 30) We suggest that tocilizumab may be a viable option for refractory LS cases.

Treatment responses vary across the literature. Improvements in MRI findings following immunosuppressive treatment have been reported (31),while MRI lesions progressed despite intensive immunosuppressive therapy have also been reported (32). There is no standard method to evaluate the response. The inconsistency between neurological symptoms and neuroimaging findings increases the complexity of evaluation. It has been reported that some patients with neurological symptoms had normal imaging findings (21), whereas some patients with brain imaging abnormalities were asymptomatic (17). A similar phenomenon was observed in this study. Brain lesions progressed with fluctuations without recurrence of neurological symptoms were observed in two cases (Cases 1 and 6). It is important to note that in Case 1, MRI abnormalities fluctuated and stabilized spontaneously in the absence of further immunosuppressive therapy, whereas intensive immunotherapy was applied due to progressive MRI abnormalities in Case 6. For children with ECDS, contrast-enhanced brain MRI was recommended at baseline and upon the development of any new neurological symptoms (28).However, the clinical significance of asymptomatic MRI changes is unclear, and it is unknown whether treatment should be modified based solely on MRI abnormalities. Given the side effects of immunosuppressant in children, we suggest that both neurological symptoms and MRI findings in asymptomatic patients with ECDS should be monitored closely and carefully evaluated, and the use of immunosuppressants should be considered with caution.

LS en coup de sabre, a rare subtype of localized scleroderma, most frequently affects girls and may be accompanied by CNS involvement ipsilateral to the craniofacial skin lesions. In LS ECDS, supratentorial white matter lesions represent the most common neuroimaging abnormality, with cyst-like lesions also being frequently observed. Notably inconsistencies exist between skin lesions and CNS involvement, as well as between neurological symptoms and MRI abnormalities. Corticosteroids combined with MTX are regarded as the first-line therapy, while tocilizumab may be beneficial for refractory cases. To optimize treatment and improve prognosis, close long-term follow-up and repeated evaluation are essential for all patients with LS ECDS.