Case Report: Borderline Lepromatous Leprosy Therapy Complicated by Type 1 Leprosy Reaction and Adverse Reactions with Dapsone and Clofazimine.

Leprosy is a global health issue, causing long-term functional morbidity and stigma. Rapid diagnosis and appropriate treatment are important; however, early diagnosis is often challenging, especially in nonendemic areas. Here, we report a case of borderline lepromatous leprosy accompanied by dapsone-induced (neutropenia, anemia, and methemoglobinemia) and clofazimine-induced (skin discoloration and ichthyosis) side effects and type 1 leprosy reactions during administration of the multidrug therapy. The patient completely recovered without developing any deformities or visual impairment. To ensure early diagnosis and a favorable outcome, clinicians should be aware of the diminished sensation of skin lesions as a key physical finding and manage the drug toxicities and leprosy reactions appropriately in patients on multidrug therapy.

Exploration of Neurofilament Light Chain and Nerve Ultrasound in Leprotic Neuropathy.

OBJECTIVES: To explore neurofilament light chain (NfL) levels in leprotic neuropathy compared to controls, and to determine if the changes correlate with ultrasonographic nerve findings. METHODS: Individuals with leprosy with signs or symptoms suggestive of peripheral nerve involvement were recruited. They were evaluated by clinical examination, functional scores, laboratory assessments (including NfL), nerve conduction studies (NCS), and ultrasound. Ultrasound was conducted in bilateral median, ulnar, tibial, fibular, sural, and vagus nerves as well as cervical roots 5 and 6. Results were compared to age, sex, and body mass index matched healthy controls. RESULTS: A total of 320 nerves from 20 patients and 480 nerves from 30 controls were evaluated. NfL was significantly elevated in those with leprosy with a mean and standard deviation of 7.50 + 2.83 compared with 3.42 + 1.18 in controls (P < .001). Ultrasound showed focal enlargement of the nerves, particularly at entrapment sites. Additionally, there were noticeable changes in neural Doppler signal, echogenicity, and epineural thickness among the measured nerve sites. NfL levels in those with leprosy correlated closely with nerve cross-sectional area at all sites (P < .05). Functional and clinical assessment scores correlated with NfL and sonographic cross-sectional area as well (P ≤ .05). CONCLUSIONS: NfL is elevated in leprotic neuropathy. Ultrasound showed specific morphological changes in individuals with leprosy, and nerve enlargement correlated with NfL levels. Thus, both modalities may be useful for the diagnosis, prognosis, and disease monitoring in those with leprotic neuropathy, and further investigations are warranted.

Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.

BACKGROUND: M. leprae preferentially infects Schwann cells (SCs) in the peripheral nerves leading to nerve damage and irreversible disability. Knowledge of how M. leprae infects and interacts with host SCs is essential for understanding mechanisms of nerve damage and revealing potential new therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: We performed a time-course single-cell sequencing analysis of SCs infected with M. leprae at different time points, further analyzed the heterogeneity of SCs, subpopulations associated with M. leprae infection, developmental trajectory of SCs and validated by Western blot or flow cytometry. Different subpopulations of SCs exhibiting distinct genetic features and functional enrichments were present. We observed two subpopulations associated with M. leprae infection, a stem cell-like cell subpopulation increased significantly at 24 h but declined by 72 h after M. leprae infection, and an adipocyte-like cell subpopulation, emerged at 72 h post-infection. The results were validated and confirmed that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. CONCLUSIONS/SIGNIFICANCE: Our results present a systematic time-course analysis of SC heterogeneity after infection by M. leprae at single-cell resolution, provide valuable information to understand the critical biological processes underlying reprogramming and lipid metabolism during M. leprae infection of SCs, and increase understanding of the disease-causing mechanisms at play in leprosy patients as well as revealing potential new therapeutic strategies.

Evidencing leprosy neuronal inflammation by 18-Fluoro-deoxy-glucose.

BACKGROUND: Leprosy is caused by multiple interactions between Mycobacterium leprae (M. leprae) and the host's peripheral nerve cells. M. leprae primarily invades Schwann cells, causing nerve damage and consequent development of disabilities. Despite its long history, the pathophysiological mechanisms of nerve damage in the lepromatous pole of leprosy remain poorly understood. This study used the findings of 18F-FDG PET/CT on the peripheral nerves of eight lepromatous patients to evaluate the degree of glucose uptake by peripheral nerves and compared them with clinical, electrophysiological, and histopathological evaluations. METHODS: Eight patients with lepromatous leprosy were included in this study. Six patients were evaluated up to three months after leprosy diagnosis using neurological examination, nerve conduction study, 18F-FDG PET/CT, and nerve biopsy. Two others were evaluated during an episode of acute neuritis, with clinical, neurophysiological, and PET-CT examinations to compare the images with the first six. RESULTS: Initially, six patients already had signs of peripheral nerve injury, regardless of symptoms; however, they did not present with signs of neuritis, and there was little or no uptake of 18F-FDG in the clinically and electrophysiologically affected nerves. Two patients with signs of acute neuritis had 18F-FDG uptake in the affected nerves. CONCLUSIONS: 18F-FDG uptake correlates with clinical neuritis in lepromatous leprosy patients but not in silent neuritis patients. 18F-FDG PET-CT could be a useful tool to confirm neuritis, especially in cases that are difficult to diagnose, such as for the differential diagnosis between a new episode of neuritis and chronic neuropathy.

Case Report: Upper Thoracic Esophageal Paralysis Accompanying a Type 1 Leprosy Reaction.

Type 1 leprosy reactions (T1LRs) occur mainly in patients with borderline leprosy and an unstable immune status. The main symptoms of T1LRs include aggravated skin lesions and nerve damage. Nerve damage involving the glossopharyngeal and vagus nerves causes dysfunction of the nose, pharynx, larynx, and even the esophagus, which are innervated by these nerves. Here, we report a case of upper thoracic esophageal paralysis caused by vagus nerve involvement in a patient with T1LRs. Although infrequent, this serious emergency merits attention.

Aetiology, pathogenesis and management of neuropathic itch: A narrative review with recent updates.

Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. It is a debilitating condition often associated with pain, which impairs the patient's quality of life. Although much literature exists about renal and hepatic pruritus, there is a dearth of information and awareness about neuropathic itch. The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. There are several causes of neuropathic itch, many of which do not produce any skin lesions and are thus, often missed. A detailed history and clinical examination are necessary for the diagnosis, while laboratory and radiologic investigations may be needed in select cases. Several therapeutic strategies currently exist involving both non-pharmacological and pharmacological measures, the latter including topical, systemic, and invasive options. Further research is ongoing to clarify its pathogenesis and to design newer targeted therapies with minimal adverse effects. This narrative review highlights the current understanding of this condition, focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs.

Progressive neuropathy in patients with lepromatous leprosy after multidrug therapy.

BACKGROUND: The lepromatous pole is a stigmatising prototype for patients with leprosy. Generally, these patients have little or no symptoms of peripheral nerve involvement at the time of their diagnosis. However, signs of advanced peripheral neuropathy would be visible during the initial neurological evaluation and could worsen during and after multidrug therapy (MDT). Disabilities caused by peripheral nerve injuries greatly affect these patients' lives, and the pathophysiological mechanisms underlying nerve damage remain unclear. OBJECTIVES: To evaluate the outcome of peripheral neuropathy in patients with lepromatous leprosy (LL) and persistent neuropathic symptoms years after completing MDT. METHODS: We evaluated the medical records of 14 patients with LL who underwent nerve biopsies due to worsening neuropathy at least four years after MDT. FINDINGS: Neuropathic pain developed in 64.3% of the patients, and a neurological examination showed that most patients had alterations in the medium- and large-caliber fibers at the beginning of treatment. Neurological symptoms and signs deteriorated despite complete MDT and prednisone or thalidomide use for years. Nerve conduction studies showed that sensory nerves were the most affected. MAIN CONCLUSIONS: Patients with LL can develop progressive peripheral neuropathy, which continues to develop even when they are on long-term anti-inflammatory and immunosuppressive therapy.

Effect of adipose derived stromal vascular fraction on leprosy neuropathy: A Preliminary report.

BACKGROUND: Adipose derived stromal vascular fraction (SVF) contains a heterogeneous population of mononuclear cells, progenitor cells and about 1-10% are mesenchymal stromal cells. These cells are an ideal candidate for regenerative medicine for peripheral neuropathy. Leprosy is a disabling disorder with neuropathy, usually with consequences of permanent disability of the extremities. We conducted a preliminary study to evaluate the cell yield, its characteristics and clinical outcomes after SVF injections in four leprosy patients. METHODS: Four post leprosy patients were recruited and evaluated for sensory testing (warm detection, cold detection, vibration, pain and sensation) on the ulnar area of the hand. Liposuction was done and adipose tissue was processed into SVF with a closed system and injected to the ulnar area of the hand at the dorsal and palmar side. Evaluation of sensory testing was done after 3 days, 1 week, 1 month and 3 months following SVF injection. SVF was also characterized using flow cytometry, cell counting, sterility and presence of mycobacteria. RESULTS: The results showed that leprosy patients had a low count of mesenchymal cells and a high amount of CD34/CD45 positive cells. One patient was positive for mycobacteria from his adipose tissue and SVF. Sensory examination after SVF injection showed an improvement in temperature and pain sensation in the palmar and superficial branch. Meanwhile, touch sensation improved on the dorsal branch, and there was no improvement for vibration in all patients. CONCLUSIONS: The results showed that SVF had a potential to improve sensory loss in leprosy patients.

Systematic Review of Survival Analysis in Leprosy Studies-Including the Following Outcomes: Relapse, Impairment of Nerve Function, Reactions and Physical Disability.

Leprosy is a public health problem in South American, African and Oceanian countries. National programs need to be evaluated, and the survival analysis model can aid in the construction of new indicators. The aim of this study was to assess the period of time until the outcomes of interest for patients with or exposed to leprosy by means of survival analysis surveys. This review researched articles using the databases of PubMed, Science Direct, Scopus, Scielo and BVS published in English and Portuguese. Twenty-eight articles from Brazil, India, Bangladesh, the Philippines and Indonesia were included. The Kaplan-Meier method, which derives the log-rank test, and Cox's proportional hazards regression, which obtains the hazard ratio, were applied. The mean follow-up until the following outcomes were: (I) leprosy (2.3 years) in the population who were exposed to it, (II) relapse (5.9 years), (III) clinical manifestations before, during and after treatment-nerve function impairment (5.2 years), leprosy reactions (4.9 years) and physical disability (8.3 years) in the population of patients with leprosy. Therefore, the use of survival analysis will enable the evaluation of national leprosy programs and assist in the decision-making process to face public health problems.

Evaluation of altered patterns of tactile sensation in the diagnosis and monitoring of leprosy using the Semmes-Weinstein monofilaments.

BACKGROUND: Leprosy neuropathy is the most common peripheral neuropathy of infectious etiology worldwide; it is characterized as asymmetric and focal multiple mononeuropathy. Semmes-Weinstein monofilament (SWM) test is a simple method to assess sensory nerve function. METHODS AND FINDINGS: In this prospective cohort study, a dermatologist carried out hands and feet tactile sensation test with SWM in 107 multibacillary leprosy patients at diagnosis and in 76 patients at the end of treatment from 2016 to 2019. At diagnosis, 81/107 (75.7%) patients had some degree of functional disability, and 46 (43%) of them had altered SWM-test in the hands and 94 (87.9%) of them in the feet. After one year of multibacillary multidrug therapy, the disability decreasing to 44/76 patients (57.9%) and decreasing of the percentual of patients with altered SWM-test to 18% for the hands, and to 28.7% for the feet. At the end of treatment, the number of SMW-test points presented improvement in the hands of 22 (28.9%) patients, and in the feet of 47 (61.8%). In the hands, by SWM-test, only the radial nerve point demonstrated a significant asymmetry, while in the feet, the difference between the sum of altered SWM-test points showed significant asymmetry between both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy. In Spearman's correlation analysis, a positive correlation with statistical significance was observed between the number of hands and feet SWM altered points at diagnosis and the degree of disability at diagnosis (0.69) and at the end of the treatment (0.80). CONCLUSION: The patterns of hands and feet tactile sensation at diagnosis and their consequent modifications with the anti-leprosy drugs define the bacterial etiology of neuropathy, an important tool for the clinical diagnosis and follow up of the disease, highlighting the tibial nerve findings, the most affected nerve among leprosy patients by SWM-test, with significant asymmetry and focality impairments.

Case Report: Chemoradiation with Paclitaxel and Carboplatin Unveiling Leprosy Type 1 Downgrading Reaction.

Type 1 lepra reaction (T1R) is a major complication seen in nonpolar forms of leprosy and leads to significant morbidity. The classification of T1R as up and downgrading, based on previously defined histopathological criteria (by Ridley), has therapeutic and prognostic implications. The trigger factors for these reactions are poorly described, especially in case of downgrading T1R and we describe a case of leprosy reaction that was possibly triggered by chemoradiation and elucidate the possible mechanism.

Kynurenines in the Pathogenesis of Peripheral Neuropathy During Leprosy and COVID-19.

Inflammatory disorders are associated with the activation of tryptophan (TRYP) catabolism via the kynurenine pathway (KP). Several reports have demonstrated the role of KP in the immunopathophysiology of both leprosy and coronavirus disease 19 (COVID-19). The nervous system can be affected in infections caused by both Mycobacterium leprae and SARS-CoV-2, but the mechanisms involved in the peripheral neural damage induced by these infectious agents are not fully understood. In recent years KP has received greater attention due the importance of kynurenine metabolites in infectious diseases, immune dysfunction and nervous system disorders. In this review, we discuss how modulation of the KP may aid in controlling the damage to peripheral nerves and the effects of KP activation on neural damage during leprosy or COVID-19 individually and we speculate its role during co-infection.

Primary neural leprosy: clinical, neurophysiological and pathological presentation and progression.

Disability in leprosy is a direct consequence of damage to the peripheral nervous system which is usually worse in patients with no skin manifestations, an underdiagnosed subtype of leprosy known as primary neural leprosy. We evaluated clinical, neurophysiological and laboratory findings of 164 patients with definite and probable primary neural leprosy diagnoses. To better understand the disease progression and to improve primary neural leprosy clinical recognition we compared the characteristics of patients with short (≤12 months) and long (>12 months) disease duration. Positive and negative symptoms mediated by small-fibres were frequent at presentation (∼95%), and symptoms tend to manifest first in the upper limbs (∼68%). There is a consistent phenotypic variability between the aforementioned groups. Deep sensory modalities were spared in patients evaluated within the first 12 months of the disease, and were only affected in patients with longer disease duration (∼12%). Deep tendon reflexes abnormalities were most frequent in patients with longer disease duration (P < 0.001), as well as motor deficits (P = 0.002). Damage to large fibres (sensory and motor) is a latter event in primary neural leprosy. Grade-2 disability and nerve thickening was also more frequent in cases with long disease duration (P < 0.001). Primary neural leprosy progresses over time and there is a marked difference in clinical phenotype between patients with short and long disease duration. Patients assessed within the first 12 months of symptom onset had a non-length-dependent predominant small-fibre sensory neuropathy, whilst patients with chronic disease presented an asymmetrical all diameter sensory-motor neuropathy and patchily decreased/absent deep tendon reflexes.

Role of diffusion tensor imaging in the evaluation of ulnar nerve involvement in leprosy.

OBJECTIVE: Early detection of peripheral neuropathy is extremely important as leprosy is one of the treatable causes of peripheral neuropathy. The study was undertaken to assess the role of diffusion tensor imaging (DTI) in ulnar neuropathy in leprosy patients. METHODS: This was a case-control study including 38 patients (72 nerves) and 5 controls (10 nerves) done between January 2017 and June 2019. Skin biopsy proven cases of leprosy, having symptoms of ulnar neuropathy (proven on nerve conduction study) were included. MRI was performed on a 3 T MR system. Mean cross-sectional area, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of ulnar nerve at cubital tunnel were calculated. Additional ancillary findings and appearance of base sequences were evaluated. RESULTS: Ulnar nerve showed thickening with altered T2W signal in all the affected nerves, having an average cross-sectional area of 0.26 cm2. Low FA with mean of 0.397 ± 0.19 and high ADC with mean of 1.28 ± 0.427 x 10 -3 mm2/s of ulnar nerve in retrocondylar groove was obtained. In the control group, mean cross-sectional area was 0.71cm2 with mean FA and ADC of 0.53 ± 0.088 and 1.03 ± 0.24 x 10 -3 mm2/s respectively. Statistically no significant difference was seen in diseased and control group. Cut-off to detect neuropathy for FA and ADC is 0.4835 and 1.1020 × 10 -3 mm2/s respectively. CONCLUSION: DTI though is challenging in peripheral nerves, however, is proving to be a powerful complementary tool for assessment of peripheral neuropathy. Our study validates its utility in infective neuropathies. ADVANCES IN KNOWLEDGE: 1. DTI is a potential complementary tool for detection of peripheral neuropathies and can be incorporated in standard MR neurography protocol.2. In leprosy-related ulnar neuropathy, altered signal intensity with thickening or abscess of the nerve is appreciated along with locoregional nodes and secondary denervation changes along with reduction of FA and rise in ADC value.3. Best cut-offs obtained in our study for FA and ADC are 0.4835 and 1.1020 × 10 -3 mm2/s respectively.

Role of shear wave elastography in treatment follow-up of leprosy neuropathy.

PURPOSE: Grayscale ultrasonography when complemented with shear wave elastography helps in better evaluation of treatment response of leprosy neuropathy and in guiding appropriate management of the patient. There is limited literature regarding the use of shear wave elastography in ulnar nerve neuropathy. Our purpose was to evaluate the role of shear wave elastography in assessing stiffness changes within the ulnar nerve during treatment of leprosy. METHODS: This was a prospective study which included 30 patients diagnosed with leprosy neuropathy. Recruited patients were followed up, during the course of treatment, i.e. for 1 year. Serial ultrasonography of these patients was done at 0, 3, 6 and 12 months interval. RESULTS: Significant (P < 0.05) decrease in elastography parameters was seen in transverse imaging plane between first and third, as well as first and fourth visits (mean stiffness and velocity pretreatment ~ 25.78 ± 18 kPa and 2.74 ± 0.98 m/s, mean stiffness and velocity post-treatment 15.67 ± 5.89 kPa and 2.24 ± 0.428 m/s). Although elastography parameters decreased during these visits in the long-axis imaging plane, they were not found to be statistically significant. However, gross morphology and cross-sectional area of the nerve did not change significantly across visits. Interestingly, elastography values were higher in patients with neuritis, though not statistically significant. CONCLUSION: Shear wave elastography is a novel, upcoming modality in musculoskeletal imaging especially in the evaluation of peripheral neuropathy. It can act as an adjunct to grey-scale imaging, which can help in early diagnosis and in guiding treatment of leprosy neuropathy.

A-waves associated are with neuropathic pain in leprosy

Introduction/Aims:The A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein we have attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort. Methods: Between 2015 and 2018, 63 patients with leprosy (47 men and 16 women) had A-waves in nerve conduction studies and were included in this study. We included patients regardless of whether they were experiencing leprosy reactions ornot. We then compared clinical features in nerves with and without A-waves. Results:The mean age of study participants was 46.5 ± 12.3 years and most had borderline leprosy. From this cohort, we assessed separately 83 motor nerves that demonstrated A-waves (group A+) and 29 motor nerves that did not demonstrate A-waves (group A-). Neuropathic pain (NP) was found in 66 of 83 nerves in group A+,but only 5 of 29 in group A-(79.5 vs 17.2%,P< .001). In contrast, no significant between-group difference emerged regarding presence of reactions, sensory function (based on Semmes-Weinstein evaluations), or muscle strength. A-waves were found in nerves with neuropathic pain experiencing (39 of 66=59%) or not experiencing (27 of 66=41%) leprosy reactions. Discussion: These results show that A-waves are associated with neuropathic pain in leprosy patients, regardless of the nerves affected and the immune status (in reaction or not).

Treatment and Evaluation Advances in Leprosy Neuropathy.

Neuropathy and related disabilities are the major medical consequences of leprosy, which remains a global medical concern. Despite major advances in understanding the mechanisms of M. leprae entry into peripheral nerves, most aspects of the pathogenesis of leprosy neuropathy remain poorly understood. Sensory loss is characteristic of leprosy, but neuropathic pain is sometimes observed. Effective anti-microbial therapy is available, but neuropathy remains a problem especially if diagnosis and treatment are delayed. Currently there is intense interest in post-exposure prophylaxis with single-dose rifampin in endemic areas, as well as with enhanced prophylactic regimens in some situations. Some degree of nerve involvement is seen in all cases and neuritis may occur in the absence of leprosy reactions, but acute neuritis commonly accompanies both Type 1 and Type 2 leprosy reactions and may be difficult to manage. A variety of established as well as new methods for the early diagnosis and assessment of leprosy neuropathy are reviewed. Corticosteroids offer the primary treatment for neuritis and for subclinical neuropathy in leprosy, but success is limited if nerve function impairment is present at the time of diagnosis. A candidate vaccine has shown apparent benefit in preventing nerve injury in the armadillo model. The development of new therapeutics for leprosy neuropathy is greatly needed.

Infections of the Peripheral Nervous System.

PURPOSE OF REVIEW: This article describes infections that affect the peripheral nervous system, including their clinical features, differential diagnoses, and treatments. RECENT FINDINGS: Rates of pyomyositis have increased recently in the United States, possibly because of an increase in risk factors such as IV drug use, obesity, and diabetes. Other peripheral nervous system infections, such as diphtheria, have become more common in older patients secondary to a lack of revaccination or waning immunity. Although recommended treatment regimens for most infections remain unchanged over recent years, debate over the ideal dosing and route of administration continues for some infections such as tetanus and leprosy (Hansen disease). SUMMARY: Infections of the peripheral nervous system are varied in terms of the type of infection, localization, and potential treatment. Nerve conduction studies and EMG can help determine localization, which is key to determining an initial differential diagnosis. It is important to recognize infections quickly to minimize diagnostic delays that could lead to patient morbidity and mortality.