[Elephantiasis of the lower limb: Treatment of seven cases using the modified Charles technique]. / L'éléphantiasis du membre pelvien : traitement de sept cas selon la technique de Charles modifiée.

INTRODUCTION: Lymphedema is an obstructive dysfunction of the lymphatic system characterised by an inability of the lymphatic system to eliminate excess lymphatic load. It can be congenital or secondary. Untreated, it progresses in three stages, the final stage being elephantiasis. We report a short series of 7 cases of elephantiasis of the lower limb treated with the Charles technique. Our aim was to describe the results of the surgical treatment. METHOD: This was a retrospective descriptive and analytical study from January 2010 to December 2020. Patients with at least one lower limb elephantiasis of any aetiology of any age and gender who underwent excisional surgery with a complete medical record containing clinical and therapeutic data were included. RESULTS: During the study period, we received 710 patients with a prevalence of elephantiasis of 1.69%. The mean age was 43.3±14.5years with a male predominance. No etiology or co-morbidity factors (diabetes, hypertension, VRS) were found. In our mini-series, the average time between the two procedures was 34.3±9.6days. The mean time to healing was 82.3±15.1days. All patients healed with two excellent results. CONCLUSION: excisional surgery with two-stage repair combined with compression therapy gave satisfactory results.

A qualitative process evaluation of a community conversation intervention to reduce stigma related to lower limb lymphoedema in Northern Ethiopia.

BACKGROUND: Lower limb lymphoedema (swelling of the lower leg) due to Neglected Tropical Diseases (NTDs) such as podoconiosis, lymphatic filariasis and leprosy is common in Ethiopia, imposing huge burdens on affected individuals and communities. Stigma significantly increases the disease burden and acts as a major barrier to accessing lymphoedema care services. A multi-component stigma reduction intervention was implemented in Northern Ethiopia. Community Conversation (CC) was one of the components implemented, and aimed to reduce stigma and enhance access to and uptake of integrated lymphoedema care services with the active engagement of community members. METHODS: A cross-sectional qualitative process evaluation was conducted to document lessons focusing on CC's relevance, outcomes and implementation challenges. Data were collected from a total of 55 purposively selected participants (26 from the CC intervention site and 29 from the control site) through key informant interviews, in-depth individual interviews and focus group discussions. RESULTS: Community Conversations increased acceptability of health messages about lymphoedema and created peer learning opportunities for unaffected community members. Improvement in the awareness of CC participants about the causes, prevention and treatment of lymphoedema contributed significantly to the reduction of stigmatizing attitudes and discriminatory behaviors, thereby improving access to and utilization of lymphoedema care services provided through primary health care facilities. However, a range of challenges affecting implementation of CC and outcome quality were identified, including perceived complexity of the facilitation guide among facilitators, expectation of incentives among CC participants, inadequate implementation of facilitation principles and procedures, inadequacy of supportive supervision, and low engagement of untrained health workers in CC. CONCLUSIONS: With these challenges addressed, the implementation of CC integrated with other lymphoedema care services shows potential to reduce stigma and promote access to lymphoedema care services.

With Bare Feet in the Soil: Podoconiosis, a Neglected Cause of Tropical Lymphoedema.

Podoconiosis is a form of lymphoedema that occurs in tropical highland areas in genetically susceptible individuals who are exposed to irritant volcanic soils. The disease is preventable through consistent use of footwear and attention to foot hygiene; however, in endemic areas there is a strong barefoot tradition, and many cannot afford shoes. Patients with podoconiosis face significant physical disability, psychological comorbidity, reduced quality of life and experience frequent episodes of systemic illness due to acute dermatolymphangioadenitis. This review provides an overview of this important and neglected tropical skin disease and summarizes the latest research findings.

A case of elephantiasis nostras verrucosa treated successfully by a new type of compressive garment.

Elephantiasis nostras verrucosa (ENV) is a clinical manifestation composed of hyperkeratotic, verrucous, and papillomatous lesions and dermal fibrosis, which complicate chronic lymphedema. There is currently no cure for ENV, however, several measures have been used to reduce lymphedema and the resultant pseudoepidermal hyperplasia. Supportive dressings and compression therapy still constitute an important part of the treatment. In this report, we present a 69-year-old male patient with ENV developed due to chronic lymphedema caused by venous insufficiency. After failure of healing with conventional two- and three-layered bandages, and elastic stockings, he was successfully treated by a new type of compression garment. We recommend this user friendly garment for prevention of frictional trauma, contact dermatitis, and secondary infection, which all may complicate compression treatments.

Generalized Verrucosis Revealing a Life-Threatening and Unlabeled T-Cell Lymphopenia Associated With Autoimmune Hemolytic Anemia: A Case Report and Review of Literature.

Primary immunodeficiencies are inherited disorders, which may be revealed in the context of autoimmune hemolytic anemia (AIHA). We report the case of a girl presenting with an enterovirus-related AIHA. Despite being in complete remission for her anemia after treatment, the initial CD4/CD8 lymphopenia dramatically worsened with time. Its sole clinical presentation was generalized verrucosis. Cellular quantitative and functional immunodeficiency was evidenced but no known molecular defect was identified despite extensive workup. This unlabeled profound naive T-lymphopenia was cured by bone marrow transplantation. No similar case was ever described in the scientific literature. Patients with AIHA and/or generalized verrucosis should be screened for primary immunodeficiency, before initiating any immunomodulatory treatment.

Peno-Scrotal Elephantiasis Nostras Verrucosa: Rare Disorder in a Young Nigerian.

Elephantiasis Nostras Verrucosa (ENV) is a rare cutaneous complication of chronic lymphatic obstruction. It represents the late stage of chronic non-filarial lymphoedema, resulting in the recurrent and progressive swelling of the affected part, and is marked by both physical and psychological impairment in health-related quality of life. Morphologically it appears as clusters of verrucous (wart-like) papules and nodules arranged in a cobblestone-like pattern, often presenting a mossy appearance. I hereby describe the case of a young man with progressively worsening peno-scrotal ENV; highlighting the delay in diagnosis occasioned by the low level awareness of this harrowing affliction among medical practitioners, and mentioning the negative impact on the patient's health-related quality of life (HRQoL). Filarial lymphoedema is predominantly seen in the tropics; however, despite the dearth of reports, this case confirms the existence of ENV in this region. Following an extensive literature search and to the best of my knowledge, I am yet to come across other reported cases of elephantiasis nostras verrucosa emanating from Africa.

Integrated morbidity management for lymphatic filariasis and podoconiosis, Ethiopia.

PROBLEM: Lymphatic filariasis and podoconiosis are the major causes of tropical lymphoedema in Ethiopia. The diseases require a similar provision of care, but until recently the Ethiopian health system did not integrate the morbidity management. APPROACH: To establish health-care services for integrated lymphoedema morbidity management, the health ministry and partners used existing governmental structures. Integrated disease mapping was done in 659 out of the 817 districts, to identify endemic districts. To inform resource allocation, trained health extension workers carried out integrated disease burden assessments in 56 districts with a high clinical burden. To ensure standard provision of care, the health ministry developed an integrated lymphatic filariasis and podoconiosis morbidity management guideline, containing a treatment algorithm and a defined package of care. Experienced professionals on lymphoedema management trained government-employed health workers on integrated morbidity management. To monitor the integration, an indicator on the number of lymphoedema-treated patients was included in the national health management information system. LOCAL SETTING: In 2014, only 24% (87) of the 363 health facilities surveyed provided lymphatic filariasis services, while 12% (44) provided podoconiosis services. RELEVANT CHANGES: To date, 542 health workers from 53 health centres in 24 districts have been trained on integrated morbidity management. Between July 2013 and June 2016, the national health management information system has recorded 46 487 treated patients from 189 districts. LESSONS LEARNT: In Ethiopia, an integrated approach for lymphatic filariasis and podoconiosis morbidity management was feasible. The processes used could be applicable in other settings where these diseases are co-endemic.

A randomized controlled trial to evaluate the effect of a new skincare regimen on skin barrier function in those with podoconiosis in Ethiopia.

BACKGROUND: Podoconiosis affects an estimated 3 million people in Ethiopia with a further 19 million at risk. Volcanic soil and pathogens enter skin breaches in the feet causing inflammation, lymphoedema and hyperkeratosis. There is no robust evidence on optimal podoconiosis skincare regimens to improve skin barrier function (SBF). OBJECTIVES: To evaluate the effectiveness of a new, low-cost, evidence-based intervention to improve SBF in the lower limbs of those with podoconiosis. METHODS: A randomized controlled trial (NCT02839772) was conducted over 3 months in two podoconiosis clinics (n = 193). The intervention comprised 2% (v/v) glycerine added to a reduced volume of soaking water. The control group received the current skincare regimen. Primary outcome measures were transepidermal water loss (TEWL) and stratum corneum hydration (SCH) at four specific sites on the lower limbs. RESULTS: Improvement in SBF was observed in both groups across all measurement sites and time points, although this was significantly greater in the experimental group. TEWL reduced in both groups at all sites. For example, on top of the foot the estimated group difference in TEWL at visit 4 was 1·751 [standard error (SE) = 0·0390] in favour of the experimental group [t = 3·15, degrees of freedom (df) = 189·58, P = 0·002, 95% confidence interval (CI) 0·066-2·85], indicating a greater reduction in TEWL in the experimental group. Similarly, at the same site the estimated group difference in SCH at visit 4 was -2·041 (SE = 0·572) in favour of the experimental group (t = -3·56, df = 186·74, P < 0·001, 95% CI -3·16 to -0·91), indicating a greater increase in SCH in the experimental group. There were also significantly greater reductions in odour, number of wounds and largest foot circumference in the experimental vs. the control group. CONCLUSIONS: The addition of 2% (v/v) glycerol to a reduced volume (83% reduction) of soaking water significantly improved SBF.

Podoconiosis patients' willingness to pay for treatment services in Northwest Ethiopia: potential for cost recovery.

BACKGROUND: Podoconiosis is non-filarial elephantiasis of the lower legs. It is more commonly found in tropical Africa, Central and South America, and northwest India. In Ethiopia, a few non-governmental organizations provide free treatment to podoconiosis patients, but sustainability of free treatment and scale-up of services to reach the huge unmet need is challenged by resource limitations. We aimed to determine podoconiosis patient's willingness to pay (WTP) for a treatment package (composed of deep cleaning of limbs with diluted antiseptic solution, soap, and water, bandaging, application of emollient on the skin, and provision of shoes), and factors associated with WTP in northwestern Ethiopia. METHODS: A cross-sectional study was conducted among randomly selected untreated podoconiosis patients (n=393) in Baso Liben woreda, northwestern Ethiopia. The contingent valuation method was used with a pre-tested interviewer-administered questionnaire. RESULTS: The majority of podoconiosis patients (72.8%) were willing to pay for treatment services. The median WTP amount was 64 Birr (US$ 3.28) per person per year. More than one-third of patients (36.7%) were willing to pay at least half of the full treatment cost and 76.2% were willing to pay at least half of the cost of shoes. A multivariate analysis showed that having a higher monthly income, being a woman, older age, being aware of the role of shoes to prevent podoconiosis, and possession of a functional radio were significantly associated with higher odds of WTP. CONCLUSIONS: The considerable WTP estimates showed that podoconiosis treatment could improve sustainability and service utilization. A subsidized cost recovery scheme could reduce treatment costs and more feasibility integrate podoconiosis treatment service with other NTDs and the government's primary health care system.

'My feet cannot stand on their own': podoconiosis patient healthcare expenditures and income impacts in Rwanda.

BACKGROUND: Podoconiosis is a progressive and debilitating form of tropical lymphoedema endemic to Rwanda. Although the physical and psychological consequences are well known, few studies have evaluated the financial burden of podoconiosis. METHODS: This cross-sectional, quantitative study aimed to characterize direct treatment costs and impacts on annual earnings among individuals living with podoconiosis. Participants from two highly endemic districts were invited to complete a survey focused on health-seeking history, insurance status, out-of-pocket costs and income changes. Direct treatment costs included medical expenditures (consultation, diagnostics, medication) and non-medical expenditures (food, transportation, accommodation). RESULTS: Overall, 226 adults (≥18 y of age) diagnosed with podoconiosis participated. Most had access to community-based health insurance (91.6%) but were unable to work (71.7%). Respondents sought care from health centres/posts (61.9%), hospitals (25.1%), traditional healers (5.8%) and/or community health workers (4.0%). On average, study participants paid US$32.50 (range US$0-779.23) annually, or 11.7% of their household salary, on podoconiosis treatments. CONCLUSIONS: This study demonstrates the significant financial burden of podoconiosis on individuals and their communities. Increased attention on integrating podoconiosis management into primary care systems and testing cost-effective solutions is needed to protect those who are most vulnerable.

Elephantiasis mimicry in recurrent lower limb skin infections in a diabetic patient: a case report.

BACKGROUND: Chronic edema as a complication of systemic diseases or infections can mimic filarial lymphedema (also known as elephantiasis) and considered so. We describe a case of chronic lymphedema that mimicked elephantiasis in a diabetic man. CASE PRESENTATION: The patient was a 70-year-old black man, bed-bound at the time of admission following a diagnosis of stroke and hypertension in the previous 5 years. He had been diabetic for 20 years with poorly controlled diabetes mellitus. He suffered recurrent bilateral lower limb skin infections for 5 years prior to admission that culminated into progressive lowerlimb edema. The infections eventually complicated into skin edema, hardening, fissuring, and hyperkeratotic plaques. The physical examination revealed Tinea pedis and bilateral non-pitting edema of lowerlimbs to the level of the knees. Investigations confirmed non-filarial lymphedema-related skin changes. The absence of the classic pebbly/cobblestone skin changes ruled out elephantiasis nostra verrucosa (ENV), with a possibility of it being in the early stages of evolution. The patient's skin fissuring and infections were successfully treated with antibiotics and antifungals while compression stockings helped to relieve the edema. CONCLUSIONS: Chronic lymphedema can complicate repeated non-filarial infections of lower limbs. Its fissures are a risk factor for cellulitis, prompting early identification and management of both infections and lymphedema to halt their vicious cycle, especially in at risk populations like diabetics.

Factors related to discontinued clinic attendance by patients with podoconiosis in southern Ethiopia: a qualitative study.

BACKGROUND: Podoconiosis is a lymphoedema of non-infectious cause which results in long-term ill health in affected individuals. Simple, effective treatment is available in certain parts of Ethiopia, but evidence indicates that not all patients continue collecting treatment supplies from clinic sites once started. We used qualitative techniques to explore factors related to discontinued attendance at outreach clinics of a non-government organization in southern Ethiopia. METHODS: A cross-sectional qualitative study was conducted in four clinic sites through unstructured in-depth interviews, key informant interviews and focus group discussions with the involvement of 88 study subjects. RESULTS: Discontinuation of clinic visits is common among podoconiosis patients. The reasons were: remoteness from the clinic sites, unrealistic expectation of 'special' aid, worry about increasing stigma, illness and misconceptions about treatment. CONCLUSIONS: Several of these factors are remediable through community and individual information and education. Appropriate routes to deliver this information must be identified. Certain factors (such as distance to clinic sites and stigma) require substantial expansion of services or liaison with village-level government health services.

[Current wound care in patients with elephantiasis--third-stage lymphedema]. / Suvremeno lijecenje rana kod bolesnika s elefantijazom --trecim stadijem limfedema.

Lymphedema resulting from fluid accumulation due to impairment in the lymphatic system drainage leads to enlargement of the body part involved. If left untreated, in its third stage it results in elephantiasis. Elephantiasis is frequently accompanied by papillomatosis and lymphocutaneous fistulas with lymphorrhoea, erosions and ulcers, frequently with the loss of function in the respective part of the body. Unlike other chronic wounds, wound healing in lymphedema is highly dependent on the use of combined therapies because local treatment with modern supportive dressings and compression therapy with adhesive and non-adhesive short-stretch systems is only part of the complete treatment. This treatment also includes sub-bandage foamy materials, kinesitherapy with tapes (kinesiotaping), intermittent local application of high-pressure oxygen, breathing exercise, and manual lymph drainage and exercises.

Stakeholder perspectives on an integrated package of care for lower limb disorders caused by podoconiosis, lymphatic filariasis or leprosy: A qualitative study.

BACKGROUND: Lower limb disorders including lymphoedema create a huge burden for affected persons in their physical and mental health, as well as socioeconomic and psychosocial consequences for them, their families and communities. As routine health services for the integrated management and prevention of lower limb disorders are still lacking, the 'Excellence in Disability Prevention Integrated across Neglected Tropical Diseases' (EnDPoINT) study was implemented to assess the development and delivery of an integrated package of holistic care-including physical health, mental health and psychosocial care-within routine health services for persons with lower limb disorders caused by podoconiosis, lymphatic filariasis and leprosy. METHODOLOGY/PRINCIPAL FINDINGS: This study was part of the first of three phases within EnDPoINT, involving the development of the integrated care package. Focus group discussions and key informant interviews were undertaken with 34 participants between January-February 2019 in Awi zone, Ethiopia, in order to assess the draft care package's feasibility, acceptability and appropriateness. Persons affected by lower limb disorders such as lymphoedema experience stigma, exclusion from families, communities and work as well as physical and financial hardship. Beliefs in disease causation inhibit affected persons from accessing care. Ignorance was a barrier for health care providers as well as affected persons. Training and education of affected persons, communities and caregivers is important in improving care access. It also requires time, space, materials and financial resources. Both top-down and grass roots input into service development are key, as well as collaboration across stakeholders including charities, community leaders and "expert patients". CONCLUSIONS/SIGNIFICANCE: This study highlighted the need for the EnDPoINT integrated care package and provided suggestions for solutions according to its three aspects of integrated care (integration into routine care; integration of mental health and psychosocial care; and integration of care across the three diseases), thereby giving support for its feasibility, acceptability and appropriateness.

The impact of podoconiosis, lymphatic filariasis, and leprosy on disability and mental well-being: A systematic review.

Leprosy, podoconiosis, and lymphatic filariasis (LF) are among the priority neglected tropical diseases (NTDs) in Ethiopia. The disability, psychosocial, and mental health status of people affected by these NTDs are still overlooked in global NTD discourse. The objective of this systematic review was to synthesize the existing evidence describing the disability, psychosocial, and mental health status of people affected by leprosy, podoconiosis, and LF prior to developing a holistic physical and psychosocial care package for these individuals. We searched papers reporting on disability, psychosocial, and mental health status linked to these 3 NTDs. The protocol was registered in PROSPERO with registration number CRD42019128400. Peer-reviewed articles were searched and extracted from Medline, PsycINFO, Global Health, and Embase. Articles published in English, irrespective of the year of publication, using a quantitative study methodology, were included. Abstracts and full texts were reviewed by 2 reviewers. Data were extracted and narratively summarized, as the studies were heterogeneous and used different outcome measures. Out of 1,318 titles/abstracts screened and 59 full text studies reviewed, 24 fulfilled the inclusion criteria. Fourteen studies provided evidence of the disability associated with leprosy, podoconiosis, or LF. Ten studies provided evidence on the association between the 3 NTDs and mental health or psychosocial outcomes. The prevalence of grade 2 disability varied from 3.9% to 86%. The most commonly reported mental health impacts were depression and mental distress. A high burden of mental illness was reported, varying from 12.6% to 71.7%; the suicidal ideation was also high (18.5%). In conclusion, disability and poor psychosocial and mental health status are associated with leprosy, podoconiosis, and LF. For optimum management of these NTDs, holistic care including both physical and psychosocial interventions is vital.

Integration of Management Strategies for Skin-Related Neglected Tropical Diseases.

The concept of skin neglected tropical diseases has been widely adopted into the policy and strategy of various organizations, governments, nongovernmental organizations, and health agencies. By pooling information and resources across different diseases, whose primary manifestations affect the skin, it is possible to deliver integrated surveillance and control programs and promote advocacy and reduction of disability and stigma. A further key part of the skin neglected tropical diseases program is the development and validation of training methods for front-line health workers. Networks that allow those involved in this work to share and compare expertise are being developed through various organizations.

Podoconiosis - non-filarial geochemical elephantiasis - a neglected tropical disease?

Podoconiosis or mossy foot is a form of non-filarial lymphedema. This geochemical elephantiasis is a disabling condition caused by the passage of microparticles of silica and aluminum silicates through the skin of people walking barefoot in areas with a high content of soil of volcanic origin. Podoconiosis is widespread in tropical Africa, Central America and North India, yet it remains a neglected and under-researched condition. The disabling effects of podoconiosis cause great hardship to patients. It adversely affects the economic (reduced productivity and absenteeism), social (marriage, education, etc.) and psychological (social stigma) well-being of those affected. Podoconiosis can be prevented; the main primary preventive measure is protective footwear. Secondary measures include a strict hygiene regimen and compression therapy, which can reverse initial lesions. Tertiary approaches include surgical management, such as shaving operations to reduce hyperplastic and verrucous elephantiasis.

Podoconiosis in Rwanda: Knowledge, attitudes and practices among health professionals and environmental officers.

BACKGROUND: Podoconiosis is a neglected tropical disease commonly found in volcanic regions, where soil is rich in silica. It usually manifests as bilateral lower limb edema. The majority of people affected by podoconiosis are farmers who do not wear shoes. The condition was recently documented in all 30 districts in Rwanda but knowledge, attitudes and practices (KAP) of Rwandan health professionals and environmental officers towards podoconiosis are unknown. METHODOLOGY/FINDINGS: The objective of this study was to assess the knowledge, attitudes and practices (KAP) of Rwandan health providers and environmental officers towards podoconiosis in order to improve patient healthcare experiences and health outcomes, and to reduce stigma against affected individuals. To achieve this goal, we administered a KAP assessment to physicians (N = 13), nurses/midwives (N = 59), community health workers (N = 226), and environmental officers (N = 38) in the third highest podoconiosis prevalence district in Rwanda (Musanze). All 336 respondents had heard of podoconiosis, but 147 (44%) respondents correctly identified soil as the only direct cause of podoconiosis. The awareness of signs and symptoms and risk groups was lower than any other category (31.5% and 47.5%, respectively). The overall attitude toward podoconiosis was positive (86.1%), with CHWs least likely to harbor negative beliefs against podoconiosis patients. One particular area where most respondents (76%) expressed negative attitude was that they saw people with podoconiosis as a threat to their own health and their family's health. Prescription of antibiotics and use of ointments/soap to manage wounds was low (5% and 32.2%, respectively), in part due to supply shortages at health facilities. CONCLUSIONS: This study identified clear gaps in health provider knowledge and practices that affect patient care for those with podoconiosis. Improved access to essential medicines at health facilities and podoconiosis-focused training sessions for practicing health providers are necessary to minimize the burden and stigma of affected individuals.

Economic assessment of a community-based care package for people with lower limb disorder caused by lymphatic filariasis, podoconiosis and leprosy in Ethiopia.

We conducted an implementation research study to integrate a holistic package of physical health, mental health and psychosocial care for podoconiosis, lymphatic filariasis and leprosy into routine healthcare in Gusha cluster, Guagusa Shikudad district, northwest Ethiopia. The healthcare package included training patients in lower limb hygiene and skin care and provision of shoes, hygiene supplies and medication. The implementation activities included training events, workshops, awareness raising, self-help groups, supportive supervision, staff secondments and advisory board meetings. The cost of implementing the care package in Gusha cluster, with a population of 30 558 people, was 802 655 Ethiopian birr (ETB) (£48 159) and the cost of delivering care to 235 participants was 204 388 ETB (£12 263), or 870 ETB (£52) per person. There was a 35% decrease in the mean disability scores (measured using the World Health Organization Disability Assessment Schedule 2.0) and a 45% improvement in the dermatology-specific quality of life (measured using the Dermatology Life Quality Index) at the 3-month follow-up compared with baseline. There were reductions in the number of days with symptoms, days off usual activities/work and days with reduced activity due to illness, all of which were statistically significant. Our pilot suggests that integration of the care package into routine healthcare in Ethiopia may be effective in improving health-related quality of life and disability and reducing time out of economic activity due to illness.

Compression therapy and liposuction of lower legs for bilateral hereditary primary lymphedema praecox.

In this report, we describe a case of bilateral non-syndromic hereditary lymphedema praecox of lower legs. The patient was diagnosed at age 16. Ten years later, he was unable to ambulate due to increased bilateral lower leg volume, continuous pain, and recurrent episodes of cellulitis. He was treated at our tertiary-care center with compression therapy and circumferential liposuction of lower legs, ankles, and dorsum of feet in order to remove hypertrophic fat deposits, facilitate conservative therapy, and decrease further risk of cellulitis. No complications were seen and compression therapy was continued. Fourteen month follow-up reveals no increase in leg volume over time, absence of pain, and no further episodes of cellulitis with complete ability to ambulate and return to normal activities. Even when it does not eliminate the underlying cause of primary lymphedema, combined therapy consisting of compression and liposuction is safe and is able to achieve control, at least on a short term, of clinically disabling conditions associated with advanced stages.