Post-mortem analysis of dolutegravir, tenofovir, lamivudine and efavirenz penetration in multiple CNS compartments.

BACKGROUND: Central nervous system (CNS) compartmentalization provides opportunity for HIV persistence and resistance development. Differences between cerebrospinal fluid (CSF) and cerebral matter regarding HIV persistence are well described. However, CSF is often used as surrogate for CNS drug exposure, and knowledge from solid brain tissue is rare. METHODS: Dolutegravir, tenofovir, lamivudine and efavirenz concentrations were measured across 13 CNS regions plus plasma in samples collected during autopsy in 49 Ugandan decedents. Median time from death to autopsy was 8 (IQR 5,15) hours. To evaluate postmortem redistribution, a time course study was performed in a mouse model. RESULTS: Regions with the highest penetration ratios were choroid plexus/arachnoid (dolutegravir and tenofovir), CSF (lamivudine), and cervical spinal cord/meninges (efavirenz); the lowest were corpus callosum (dolutegravir and tenofovir), frontal lobe (lamivudine), and parietal lobe (efavirenz). On average, brain concentrations were 84%, 87%, and 76% of CSF for dolutegravir, tenofovir, and lamivudine respectively. Postmortem redistribution was observed in the mouse model, with tenofovir and lamivudine concentration increased by 350% and efavirenz concentration decreased by 24% at 24-hours post-mortem. CONCLUSION: Analysis of postmortem tissue provides a unique opportunity to investigate CNS antiretroviral penetration. Regional differences were observed paving the way to identify mechanisms of viral compartmentalization and/or neurotoxicity.

A post-mortem analysis of tenofovir, lamivudine, efavirenz and fluconazole penetration in female genital tissues.

BACKGROUND: Optimal penetration of anti-infectives in the female genital tract (FGT) is paramount in the treatment and prevention of infectious diseases. While exposure of anti-infectives in lower FGT tissues (e.g. cervix, vagina) has been described, little data exist on upper genital tissues (e.g. ovary, uterus). METHODS: Autopsies were performed and post-mortem tissues were collected within 24 h of death for female participants with advanced HIV in Uganda (n = 27). Tenofovir, lamivudine, efavirenz and fluconazole concentrations were measured using LC-MS/MS in plasma, ovarian, uterine, cervical and vaginal tissues. Tissue penetration was calculated as tissue-to-plasma concentration ratios (TPRs). RESULTS: TPRs of tenofovir, lamivudine and fluconazole were highest in vaginal tissue (medians 1.86, 1.83 and 0.94, respectively), while the TPR of efavirenz was highest in ovarian tissue (median 0.65). With cervix as a reference compartment, vaginal TPRs were significantly higher than cervical for all four drugs; TPRs of efavirenz in uterine and ovarian compartments were also significantly higher than cervical. Most of the post-mortem FGT samples had a TPR of greater than 1 for tenofovir and lamivudine, while less than 50% had a TPR of greater than 1 for both efavirenz and fluconazole. CONCLUSIONS: Penetration of anti-infectives was not homogeneous among the FGT compartments. Approximately 70% of FGT tissues had a TPR of greater than 1 for tenofovir and lamivudine, favouring the prevention of local HIV replication and transmission in the FGT.

Deep fungal infections diagnosed by histology in Uganda: a 70-year retrospective study.

Fungal infections cause substantial morbidity and mortality. However, the burden of deep fungal infections is not well described in Uganda. We aimed to estimate the burden and etiology of histologically diagnosed deep fungal infections in Uganda. We retrospectively reviewed histology reports at the Pathology Reference Laboratory, Department of Pathology, Makerere University, Kampala, Uganda from January 1950 to September 2019 to identify any reports that had a fungal infection as the diagnosis. Over the study period, 697 cases of deep fungal infections were identified with an average incidence of 0.73/100,000 persons per decade. There was a general decline in the number of cases detected. Median age of the cases was 28 years (IQR: 11-40) and majority (59%) were male. The age group of 0-10 years were the most affected. The foot was the most affected part of the body (26%). Deep mycoses identified include eumycetoma (32%), subcutaneous phycomycosis (26%), histoplasmosis (9.2%), chromoblastomycosis (4.6%), aspergillosis (3.3%), cryptococcosis (3.3%), blastomycosis (1.6%), subcutaneous mycosis (1.4%), dermatomycosis (1.3%), coccidioidomycosis (0.6%), mucormycosis (0.6%), and sporotrichosis (0.1%). Histoplasma was the commonest causative agent (9.2%) followed by Aspergillus (3.4%) and Cryptococcus (3.3%), while 81% of the fungal pathogens were not identified to genus/species level. Only 31% of the cases were diagnosed clinically as deep fungal infections. There is a substantial burden of deep fungal infections caused by multiple fungal pathogens in Uganda. There is need to build local capacity for mycology so as to improve on the index of clinical suspicion and diagnostic capabilities.

Drivers of advanced stage at breast cancer diagnosis in the multicountry African breast cancer - disparities in outcomes (ABC-DO) study.

Breast cancer (BC) survival rates in sub-Saharan Africa (SSA) are low in part due to advanced stage at diagnosis. As one component of a study of the entire journey of SSA women with BC, we aimed to identify shared and setting-specific drivers of advanced stage BC. Women newly diagnosed in the multicountry African Breast Cancer-Disparities in Outcomes (ABC-DO) study completed a baseline interview and their stage information was extracted from medical records. Ordinal logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for advanced stage (I, II, III, IV) in relation to individual woman-level, referral and biological factors. A total of 1795 women were included from Nigeria, Uganda, Zambia, and the multiracial populations of Namibia and South Africa, 1091 of whom (61%) were stage III/IV. Stage was lower in women with greater BC knowledge (OR 0.77 (95% CI: 0.70, 0.85) per point on a 6 point scale). More advanced stage was associated with being black (4.00 (2.79, 5.74)), having attended

Breast diseases histologically diagnosed at a tertiary facility in Uganda (2005-2014).

BACKGROUND: The prevalence and distribution of histologically diagnosed breast disease are not well documented in low income countries, Uganda inclusive. Although the greater majority of breast lesions globally are benign, breast cancer is the most frequently diagnosed cancer all over the world. We aimed at documenting the prevalence of different breast diseases histologically diagnosed at the histopathology laboratory of the Department of Pathology of the Makerere University College of Health Sciences (MakCHS Lab) over a decade (2005-2014). We also describe the demographic characteristics of the patients in Uganda diagnosed with breast disease at the MakCHS Lab during the same period. METHODS: This was a 10 year retrospective study of histologically diagnosed breast disease between 2005 and 2014 inclusive at the MakCHS Lab. We extracted information from hard copies of all 2510 histopathology reports retrieved from archives of the Department of Pathology at the MakCHS Lab. 640 records that were either damaged beyond recognition of key details, were duplicated, were implausible or had no conclusive diagnosis made were excluded. Information to be analyzed was then entered into Epidata (version 3.1) on a password protected laptop. Data analysis was done using SPSS software (v16 for Windows × 64). RESULTS: From the 1870 patients' records eventually analyzed, breast disease was most diagnosed in female patients (97.1%). The overall mean age for breast disease diagnosis was 33 years (S.D ± 16.46) and median age 26 years (IQR: 20-43). Fibroadenoma (40.1%) was the most diagnosed breast disease overall. We noticed steadily increasing frequency of diagnosis of cancerous breast diseases over the last half of the study period. Invasive ductal carcinoma was the most diagnosed breast cancer (326 cases, 55.6%). A high female to male breast cancer ratio of 48:1 was observed. The highest regional breast cancer proportion was from the Western region of the Country. CONCLUSIONS: There is need for more research into the picture of breast disease in the country, covering various demographic characteristics of the country's population for all regions and informing about its incidence rates and prevalence and also the breast cancer risk estimate for benign breast disease.

Accuracy of Lipoarabinomannan and Xpert MTB/RIF Testing in Cerebrospinal Fluid To Diagnose Tuberculous Meningitis in an Autopsy Cohort of HIV-Infected Adults.

Point-of-care tests for tuberculous meningitis (TBM) are needed. We studied the diagnostic accuracy of the lipoarabinomannan (LAM) lateral flow assay (LFA), LAM enzyme-linked immunosorbent assay (ELISA), and Xpert MTB/RIF in cerebrospinal fluid (CSF) in an autopsy cohort of Ugandan HIV-infected adults. We obtained written informed consent postmortem from the next of kin. A complete autopsy was done and CSF obtained. We performed LAM LFA (on unprepared and supernatant CSF after heating and spinning), LAM ELISA, and Xpert MTB/RIF on the CSF samples. Accuracy parameters were calculated for histopathological TBM and also for the composite standard, including Xpert MTB/RIF-positive cases. We tested CSF of 91 patients. LAM LFA had a sensitivity of 75% for definite histopathological TBM, ELISA a sensitivity of 43%, and Xpert MTB/RIF a sensitivity of 100% and specificities of 87%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 50% for definite and probable histopathological TBM, ELISA a sensitivity of 38%, and Xpert MTB/RIF a sensitivity of 86% and specificities of 70%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 68% for the composite standard and ELISA a sensitivity of 48% and specificities of 78% and 98%, respectively. The rapid diagnostic tests detected TBM in 22% to 78% of patients not on anti-TB treatment. Point-of-care tests have high accuracy in diagnosis of TBM in deceased HIV-infected adults. LAM LFA in CSF is a useful additional diagnostic tool.

Task Shifting and Skin Punch for the Histologic Diagnosis of Kaposi's Sarcoma in Sub-Saharan Africa: A Public Health Solution to a Public Health Problem.

Fueled by HIV, sub-Saharan Africa has the highest incidence of Kaposi's sarcoma (KS) in the world. Despite this, KS diagnosis in the region is based mostly on clinical grounds. Where biopsy is available, it has traditionally been excisional and performed by surgeons, resulting in multiple appointments, follow-up visits for suture removal, and substantial costs. We hypothesized that a simpler approach - skin punch biopsy - would make histologic diagnosis more accessible. To address this, we provided training and equipment for skin punch biopsy of suspected KS to three HIV clinics in East Africa. The procedure consisted of local anesthesia followed by a disposable cylindrical punch blade to obtain specimens. Hemostasis is facilitated by Gelfoam®. Patients removed the dressing after 4 days. From 2007 to 2013, 2,799 biopsies were performed. Although originally targeted to be used by physicians, biopsies were performed predominantly by nurses (62%), followed by physicians (15%), clinical officers (12%) and technicians (11%). There were no reports of recurrent bleeding or infection. After minimal training and provision of inexpensive equipment (USD 3.06 per biopsy), HIV clinics in East Africa can integrate same-day skin punch biopsy for suspected KS. Task shifting from physician to non-physician greatly increases access. Skin punch biopsy should be part of any HIV clinic's essential procedures. This example of task shifting may also be applicable to the diagnosis of other cancers (e.g., breast) in resource-limited settings.

Practice of percutaneous needle autopsy; a descriptive study reporting experiences from Uganda.

BACKGROUND: Percutaneous needle autopsy can overcome a number of barriers that limit the use of complete autopsies. We performed blind-and ultrasound guided needle autopsies in HIV-infected adults in Uganda. In this study we describe in detail the methods we used, the ability of both procedures to obtain sufficient tissue for further examination and the learning curve of the operators over time. METHODS: If written informed consent was granted from the next of kin, we first performed a blind needle autopsy, puncturing brain, heart, lungs, liver, spleen and kidneys using predefined surface marking points. We then performed an ultrasound guided needle autopsy puncturing heart, liver, spleen and kidneys. The number of attempts, expected success and duration of the procedure were noted. A pathologist read the slides and indicated if the target tissue was present and of sufficient quality for pathological review. We report the predicted and true success rates, compare the yield of blind to ultrasound guided needle biopsies and evaluate the failure rate over time. RESULTS: Two operators performed 96 blind needle autopsies and 95 ultrasound guided needle autopsies. For blind needle biopsies true success rates varied from 56-99% and predicted success rates from 89-99%. For ultrasound guided needle biopsies true success rates varied from 72-100% and predicted success rates from 84-98%. Ultrasound guidance led to a significantly higher success rate in heart and left kidney. A learning curve was observed over time with decreasing failure rates with increasing experience and a shorter duration of the needle autopsy. CONCLUSION: Needle autopsy can successfully obtain tissue for further pathological review in the vast majority of cases, with a decrease in failure rate with increasing experience of the operator. The benefit of ultrasound guidance will depend on the population, the disease and organ of interest and the local circumstances. Our results justify further evaluation of needle autopsies as a method to establish a cause of death.

Self-Rated Competence of Ugandan Healthcare Workers to Obtain Informed Consent for Autopsy.

We examined the self-rated competence of Ugandan healthcare workers (HCWs) in obtaining informed consent for autopsies, considering the challenges of low autopsy acceptance rates globally. In September and October 2023, we conducted a nationwide cross-sectional study of HCWs, who provided informed consent to participate and completed an online, self-administered questionnaire. Participants' self-rated competence in obtaining informed consent for autopsy was assessed through Likert scale questions. Knowledge and practices were also assessed. All scores were converted to percentages, with scores ≥80% indicating higher competence. We enrolled 216 HCWs (including 145 [67.1%] doctors), with a mean age of 31.6 ± 7.2 years. Overall, 55.6% (n = 120) had ever assisted in obtaining consent for autopsy, 43.6% (n = 100) had ever obtained consent for autopsy themselves, and 13.4% (n = 29) had ever attended training on obtaining consent for autopsy. The mean competency score was 59.8 ± 17.0% (perfect score, 100%), with 29 (13.4%) participants demonstrating high competence. Healthcare workers with adequate knowledge had higher competence scores (odds ratio [OR]: 15.0, 95% CI: 6.17-36.58, P <0.001). Compared with nurses/midwives, doctors had 73% lower odds of having a high competence score (adjusted OR: 0.27, 95% CI: 0.08-0.94, P = 0.040). Fewer than one in five Ugandan HCWs demonstrated high self-rated competence or possessed adequate knowledge regarding informed consent for autopsies, and only a few had received specialized training on how to obtain consent for an autopsy. Therefore, there is a pressing need for enhanced training and increased awareness among Ugandan HCWs in obtaining informed consent for autopsies.

Correlation of the ultrasound thyroid imaging reporting and data system with cytology findings among patients in Uganda.

BACKGROUND: Ultrasonography is a noninvasive modality for the initial assessment of thyroid nodules. The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) has demonstrated good performance in differentiating malignant thyroid nodules. However, the combination of ACR TI-RADS categories and cytology has not been studied extensively, in Uganda. The study aims to correlate ACR TI-RADS with cytology among patients referred for US-guided fine-needle aspiration at Mulago National Referral Hospital. METHODS: This was a hospital-based cross-sectional study that recruited 132 patients with thyroid nodules. Spearman's correlation was used to establish a relationship between TI-RADS and cytology findings. The diagnostic accuracy of TI-RADS was assessed using sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. RESULTS: Of 132 study participants, 90% (n = 117) were females, and the mean age was 41 ± 13 years. One hundred sixty-one thyroid nodules were analyzed. More than half of the thyroid nodules (54.7%, n = 87) were solid or almost solid, 96.9% (n = 154) were shaped wider than tall, 57.2% (n = 91) had smooth margins, 83.7% (n = 133) were hyperechoic or isoechoic, and 88.7% (n = 141) had no echogenic foci. TI-RADS 3 was the most common at 42.9% (n = 69). The proportions of malignancy for TI-RADS 4 and TI-RADS 5 were 73.3% and 85.7%, respectively. The correlation between ACR TI-RADS and the Bethesda system of thyroid classification scores was r = 0.577. The sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios of ACR TI-RADS were 90.9%, 98.5%, 90%, 99.3%, 62.3, and 0.1, respectively. CONCLUSION: We found that ACR TI-RADS classification is an appropriate and noninvasive method for assessing thyroid nodules in routine practice. It can safely reduce the number of unnecessary fine-needle aspiration in a significant proportion of benign thyroid lesions. Thyroid nodules classified as TI-RADS 3 should be followed routinely. ACR TI-RADS should be standardized as the screening tool in resource-limited areas.

Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.

SUMMARY STATEMENT: HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels.

LAMP-enabled diagnosis of Kaposi's sarcoma for sub-Saharan Africa.

Kaposi's sarcoma (KS) is an endothelial cancer caused by the Kaposi's sarcoma-associated herpesvirus (KSHV) and is one of the most common cancers in sub-Saharan Africa. In limited-resource settings, traditional pathology infrastructure is often insufficient for timely diagnosis, leading to frequent diagnoses at advanced-stage disease where survival is poor. In this study, we investigate molecular diagnosis of KS performed in a point-of-care device to circumvent the limited infrastructure for traditional diagnosis. Using 506 mucocutaneous biopsies collected from patients at three HIV clinics in Uganda, we achieved 97% sensitivity, 92% specificity, and 96% accuracy compared to gold standard U.S.-based pathology. The results presented in this manuscript show that LAMP-based quantification of KSHV DNA extracted from KS-suspected biopsies has the potential to serve as a successful diagnostic for the disease and that diagnosis may be accurately achieved using a point-of-care device, reducing the barriers to obtaining KS diagnosis while increasing diagnostic accuracy.

Microglia are not protective against cryptococcal meningitis.

Microglia provide protection against a range of brain infections including bacteria, viruses and parasites, but how these glial cells respond to fungal brain infections is poorly understood. We investigated the role of microglia in the context of cryptococcal meningitis, the most common cause of fungal meningitis in humans. Using a series of transgenic- and chemical-based microglia depletion methods we found that, contrary to their protective role during other infections, loss of microglia did not affect control of Cryptococcus neoformans brain infection which was replicated with several fungal strains. At early time points post-infection, we found that microglia depletion lowered fungal brain burdens, which was related to intracellular residence of C. neoformans within microglia. Further examination of extracellular and intracellular fungal populations revealed that C. neoformans residing in microglia were protected from copper starvation, whereas extracellular yeast upregulated copper transporter CTR4. However, the degree of copper starvation did not equate to fungal survival or abundance of metals within different intracellular niches. Taken together, these data show how tissue-resident myeloid cells may influence fungal phenotype in the brain but do not provide protection against this infection, and instead may act as an early infection reservoir.

Feasibility and acceptability of undertaking postmortem studies for tuberculosis medical research in a low income country.

Introduction: If we are to break new ground in difficult-to-treat or difficult-to-vaccinate diseases (such as HIV, malaria, or tuberculosis), we must have a better understanding of the immune system at the site of infection in humans. For tuberculosis (TB), the initial site of infection is the lungs, but obtaining lung tissues from subjects suffering from TB has been limited to bronchoalveolar lavage (BAL) or sputum sampling, or surgical resection of diseased lung tissue. Methods: We examined the feasibility of undertaking a postmortem study for human tuberculosis research at Mulago National Referral Hospital in Kampala, Uganda. Results: Postmortem studies give us an opportunity to compare TB-involved and -uninvolved sites, for both diseased and non-diseased individuals. We report good acceptability of the next-of-kin to consent for their relative's tissue to be used for medical research; that postmortem and tissue processing can be undertaken within 8 hours following death; and that immune cells remain viable and functional up to 14 hours after death. Discussion: Postmortem procedures remain a valuable and essential tool both to establish cause of death, and to advance our medical and scientific understanding of infectious diseases.

Pathology for Thoracic Conditions in Low- and Middle-Income Countries.

Pulmonary disease in low- and middle-income countries is highly diverse and dependent on the population, background epidemiology, environmental exposures, and smoking status. Credible evaluation of lung diseases requires skilled clinicians, imaging infrastructure, microbiology, and pathologic diagnostics, including imaging-guided cytology and biopsy. When these tools are available, improvement in patient outcomes is feasible. Pathologic diagnostics of lung lesions, including histology, immunohistochemistry, and molecular testing, are critical to properly stratify patient risk and determine exact therapies for each patient. A critical focus on research and directed interventions in lung cancer treatment specifically is needed to downstage this disease and improve patient outcome.

High-resolution disease maps for cancer control in low-resource settings: A spatial analysis of cervical cancer incidence in Kampala, Uganda.

Background: The global burden of cervical cancer is concentrated in low-and middle-income countries (LMICs), with the greatest burden in Africa. Targeting limited resources to populations with the greatest need to maximize impact is essential. The objectives of this study were to geocode cervical cancer data from a population-based cancer registry in Kampala, Uganda, to create high-resolution disease maps for cervical cancer prevention and control planning, and to share lessons learned to optimize efforts in other low-resource settings. Methods: Kampala Cancer Registry records for cervical cancer diagnoses between 2008 and 2015 were updated to include geographies of residence at diagnosis. Population data by age and sex for 2014 was obtained from the Uganda Bureau of Statistics. Indirectly age-standardized incidence ratios were calculated for sub-counties and estimated continuously across the study area using parish level data. Results: Overall, among 1873 records, 89.6% included a valid sub-county and 89.2% included a valid parish name. Maps revealed specific areas of high cervical cancer incidence in the region, with significant variation within sub-counties, highlighting the importance of high-resolution spatial detail. Conclusions: Population-based cancer registry data and geospatial mapping can be used in low-resource settings to support cancer prevention and control efforts, and to create the potential for research examining geographic factors that influence cancer outcomes. It is essential to support LMIC cancer registries to maximize the benefits from the use of limited cancer control resources.

Autopsy acceptance rate and reasons for decline in Mulago Hospital, Kampala, Uganda.

OBJECTIVE: To determine the autopsy acceptance rate and reasons for decline at Mulago Hospital, Kampala, Uganda. METHODS: The next of kin of patients who died in a combined infectious diseases and gastro-enterology ward of Mulago Hospital were approached to answer a questionnaire concerning characteristics of their deceased relative. During the interview their consent was asked to perform a complete autopsy. If autopsy was declined, the next of kin were asked to provide their reason for the decline. RESULTS: Permission to perform an autopsy was requested in 158 (54%) of the 290 deaths that occurred during the study period. In 60 (38%) cases autopsy was accepted. Fifty-nine autopsies were performed. For 82% of refusals a reason was listed; mainly 'not wanting to delay the burial' (58%), 'no use to know the cause of death' (16%) and 'being satisfied with the clinical cause of death' (10%). CONCLUSION: The autopsy rate achieved under study conditions was 38% compared to rates of 5% in Mulago Hospital over the past decade. Timely request and rapid performance of autopsies appear to be important determinants of autopsy acceptance. A motivated team of pathologists and clinicians is required to increase autopsy acceptance.

Rates of refusal of clinical autopsies among HIV-positive decedents and an overview of autopsies in Uganda.

Background: Human immunodeficiency virus (HIV)-related mortality remains high in sub-Saharan Africa. Clinical autopsies can provide invaluable information to help ascertain the cause of death. We aimed to determine the rate and reasons for autopsy refusal amongst families of HIV-positive decedents in Uganda. Methods: We consented the next-of-kin for post-mortem examinations among Ugandan decedents with HIV from 2017-2020 at Kiruddu National Referral Hospital. For those who refused autopsies, reasons were recorded. Results: In this analysis, 165 decedents with HIV were included from three selected wards at Kiruddu National Referral Hospital.  Autopsy was not performed in 45% of the deceased patients; the rate of autopsy refusal was 36%. The most common reasons for autopsy refusal were time constraints (30%), family satisfaction with clinical diagnosis (15%), fear of disfigurement of the remains (15%), and lack of perceived benefit (15%). By seeking consent from multiple family members and clearly explaining to them the purpose of performing the autopsy, we found a reduction in the rate of autopsy refusal among relatives of the deceased patients at this hospital compared to previous studies at the same site (36% vs. 60%). Conclusions: We found lower rates of autopsy refusal compared to previous studies at the same site. This underscores the importance of clearly explaining the purpose of autopsies as they increase active sensitization about their relevance and dispel myths related to autopsies among the general population. Good, culturally sensitive, and timely explanations to the family of the benefits of autopsy increase the rate of obtaining permission. Building capacity for performing autopsies by training more pathologists and increasing laboratory resources to decrease the turn-around-time for autopsy reports and extending these services to peripheral health facilities could improve autopsy acceptance rates.

Neuropathological Changes in Nakalanga Syndrome-A Case Report.

Nakalanga syndrome is a clinical manifestation of onchocerciasis-associated epilepsy characterized by stunting, delayed or absent secondary sexual development and skeletal deformities, and is often accompanied by epileptic seizures. The pathophysiology of Nakalanga syndrome is unknown. Here, we describe the post-mortem findings of a 17-year-old female who died with Nakalanga syndrome in northern Uganda. Macroscopic and histopathological examination of all major organs (liver, lungs, kidney and heart), including the brain and the pituitary gland, was performed. The suspected cause of death was malaria, and all major organs and pituitary gland appeared normal, except the lungs, which were edematous consistent with the malaria. Neuropathological changes include signs of neuro-inflammation (gliosis and activated microglia), which co-localized with tau-reactive neurofibrillary tangles and threads. The pathology was most abundant in the frontal cortex, thalamic and hypothalamic regions, and mesencephalon. The choroid plexus showed psammoma bodies. These findings indicate accelerated aging, probably due to repeated seizures. The neuropathological findings were similar to other persons who died with onchocerciasis-associated epilepsy. Examination of the pituitary gland did not reveal new information concerning the underlying pathophysiological mechanism of Nakalanga syndrome. Therefore, more post-mortem studies should be performed.