As a proof-of-concept study, our findings should be interpreted with caution. The observed increase in case referrals may reflect improved clinician awareness rather than pathway efficacy per se, given the lack of control groups.
CPs have the potential to improve patient outcomes and reduce health care costs18; therefore, we developed a neurological CP for leprosy for use in areas with low leprosy endemicity in China, assessed the effectiveness of the neurological CP and provided evidence that CP implementation coincided with increased case detection, but its impact on long-term outcomes and cost-effectiveness requires further evaluation.
Since implementation of the optimized neurological CP for the diagnosis of suspected leprosy in patients whose main complaints are neurological symptoms, the number of leprosy cases referred from neurology departments has increased significantly. Although the diagnostic intervals increased slightly after implementation of the neurological CP, the minimum diagnostic interval was reduced to as short as 1.5 months for PNL patients. Moreover, patients who had leprosy for as long as 25 years were also detected. Suspected leprosy patients with skin lesions (Ridley-Jopling classification) and without skin lesions (PNL) from high, middle, and low endemic regions of leprosy in China were successfully screened, referred, and diagnosed. In addition, 2 patients experienced early diagnosis after implementation of the neurological CP and received early therapy from the MDT to avoid permanent disability. The preliminary data revealed an increase in case referrals after CP implementation (13 vs. 4), although diagnostic intervals remained highly variable (1.5 months to 25 years).
However, some challenges still exist. After implementation of the neurological CP, among patients with newly diagnosed leprosy, the rates of G2D and delayed diagnosis were extremely high. This may be due to the following. In borderline leprosy patients, especially those with PNL, neurological symptoms and signs are the first or only symptoms and are characterized by insidious onset and a slow course of illness; thus, diagnosis is difficult. The inherent and notable link between peripheral nervous system symptoms and signs and leprosy has not attracted widespread attention in communities, general hospitals or professional leprosy control and prevention institutions. Clinical dermatological findings in outpatients have received much attention, whereas neurological manifestations associated with leprosy have received little attention.
Considering the results of our previous study, we propose that neurological symptoms may be the primary symptoms of leprosy, that patients with peripheral nerve damage are potential candidates for leprosy screening, that neurology clinics can potentially aid in the identification of suspected leprosy cases, and that neurologists should be the target population for training in leprosy prevention and control. Learning more about neurological features combined with early diagnosis technology and strengthening the training of neurologists will be helpful in identifying leprosy patients early, reducing the risks of disability and deformity, and mitigating the harm caused by leprosy6,7,8,9,10,11,12,13,14,15,16,17.
After the neurological CP was implemented, the benefits were confirmed. Notably, before a confirmed diagnosis of leprosy in Beijing, the capital of China, neurological patients with leprosy often seek healthcare in local hospitals, which are often regional medical centers located in large cities. Expanding the scope of application for this neurological CP is expected in the future.
Leprosy is an infectious neglected tropical disease that can cause irreversible disability if not diagnosed in time. The high rates of leprosy-related disability are mainly due to a delay in diagnosis. The determinants of diagnostic delays in leprosy patients, a cross-national analysis of contributing factors and intervention strategies, is shown in Supplementary Table S2.
In Brazil, the main reasons for the delayed diagnosis of leprosy involved participants who suspected that they had leprosy but feared community isolation, who thought that their symptoms were not serious, and who initially received a diagnosis other than leprosy. Educating patients regarding leprosy symptoms, reducing stigma to encourage patients to seek treatment, and increasing clinician suspicion of leprosy are the main strategies to prevent delayed diagnosis19. In India, the major contributors to the delayed diagnosis of leprosy are patient-related factors. Patient delay is a crucial factor responsible for disability among new leprosy patients, which reflects that the community is not aware of the signs and symptoms of leprosy. Reducing patient delay is very important for reducing disabilities in newly diagnosed patients20. In Colombia, the main reasons for the delayed diagnosis of leprosy at the health system level include accessibility issues, such as a lack of expertise by health staff, and barriers related to the organization of the care pathway. Individual- and community-level factors included a lack of leprosy awareness among the general population and leprosy-related stigma. Structural changes within the health system, such as organizing integral leprosy care centers and highlighting leprosy in the medical curriculum, as well as awareness-related interventions among the general population, might help reduce diagnostic delays21. In Shaanxi Province, China, newly detected leprosy patients have a long time to diagnosis and a high rate of deformity22. In Wuhan, Hubei Province, China, the top 5 misdiagnosed cases were rash (23/71, 32.39%), rheumatism (10/71, 14.08%), skin ulceration (9/71, 12.68%), dermatitis (9/71, 12.68%), and neuritis (9/71, 12.68%)23. In this study, the neurological patients with leprosy were subjected to multiple consultations in different departments of different hospitals, and misdiagnosis and delayed diagnosis occurred before confirmed diagnosis. These findings are consistent with those of previous studies. It is highly important to gain professional knowledge about leprosy, establish and perform MDT consultation, and make timely referrals.
Leprosy classically presents with cutaneous and neural involvement. In addition to being detected by a dermatologist, leprosy can be detected by a neurologist24,25,26,27,28 or a rheumatologist29.
Kar et al.30 noted that leprosy involves peripheral nerves sooner or later in the course of the disease, leading to gross deformities and disabilities. Sadly, by the time it becomes clinically apparent, nerve damage is already quite advanced. However, if preclinical damage is detected early during disease, it can be prevented to a large extent30. Learning more about neurological manifestations can decrease the degree of disability and deformity associated with leprosy.
In addition to neurological manifestations, rheumatological manifestations are also common in leprosy patients but are often underrecognized31. A study involving North Indian leprosy patients reported that musculoskeletal manifestations included arthritis (22/44, 50.00%), swollen hands and feet syndrome (SHFS) (11/44, 25.00%), tenosynovitis (9/44, 20.45%), painful swollen feet (9/44, 20.45%), arthralgias (7/44, 15.90%) and vasculitis (1/44, 2.27%). The distribution of joints mimicked rheumatoid arthritis (14/44, 31.81%) and spondyloarthropathy (7/44, 15.90%)32. A study involving Brazilian leprosy patients also revealed that leprosy involves the musculoskeletal system and that systemic manifestations with nonspecific symptoms such as fever, fatigue and myalgia occur. Therefore, leprosy can often mimic autoimmune diseases such as arthritis, vasculitis, or collagenosis and can be misdiagnosed33. Autoantibodies such as rheumatoid factor and anticardiolipin are markers of rheumatic autoimmune diseases but are also present in leprosy patients34.
Despite having a low prevalence, rare diseases affect more than 300 million people worldwide. Almost half of these diseases are neurological. Research progress is gaining momentum; for example, the integration of whole-genome sequencing into routine clinical practice could substantially increase the number of diagnoses of rare diseases. Collaboration is essential to avoid geographic or disease-based silos35. In China, the overall low prevalence and highly imbalanced endemic status of leprosy (endemic region in the southwest) make it a rare disease, especially in eastern developed cities. The following strategies would be helpful for the early diagnosis of leprosy: making more efforts for basic scientific research; further developing early diagnostic technology; establishing collaborative relationships in high-, medium-, and low-prevalence regions; and applying a multidisciplinary consultation model for leprosy disease.
Limitations
This study has three principal limitations. First, its single-center design and small sample size limit its generalizability. Second, the absence of randomization prevents causal inferences about the neurological CP’s efficacy. Third, the lack of cost‒benefit analysis precludes health economic assessments. Future studies should prioritize prospective, cluster-randomized designs across endemic gradients.
