Paradoxical reactions in tuberculous meningitis complicated with Signs of  Cushing’s Syndrome. A case report and literature review

Paradoxical reactions in tuberculous meningitis complicated with Signs of Cushing’s Syndrome. 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A case report and literature review Mesele Damte Argaw, Alebel Yaregal Desale, Agumasie Semahegn, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5955477/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: In 2022, African nations accounted for a quarter of all reported tuberculosis (TB) cases worldwide. This case report examines the diagnosis, treatment, drug toxicity, and patient management of tuberculous meningitis (TBM) in low-income country settings. Case presentation: A 34-year-old married Ethiopian woman, Gravida I and Para 0, presented to Private Hospital in Addis Ababa on May 5, 2022, with a two-day history of left-sided limb weakness, incontinence, fever, headache, vomiting, photophobia, and confusion. She had no history of contact with known pulmonary TB patients. On physical examination, she appeared acutely ill and was disoriented to time, place, and person. Laboratory findings revealed persistently elevated lymphocytes, platelets, and erythrocyte sedimentation rate (ESR). Cerebrospinal fluid (CSF) analysis showed low glucose (0.3 g/L) and elevated protein, but no acid-fast bacilli (AFB) were detected. The chest X-ray was unremarkable, but brain MRI revealed ring-enhancing lesions in the basal and suprasellar cisterns, suggestive of tuberculous (TB) granuloma. The patient was treated with first-line anti-tuberculosis treatment (ATT) regimen with adjuvant steroids for eight weeks and pyridoxine throughout the full course of treatment. During follow-up visits, the patient initially showed improvements in neurological symptoms but experienced a recurrence and worsening of the initial signs and symptoms on the ninth month of follow-up. Her physical examination was suggestive of signs of Cushing’s Syndrome. And, the control MRI was suggestive of hydrocephalus due to paradoxical reactions requiring placement of a ventriculoperitoneal shunt (VPS). The patient died on April 26, 2024. Conclusions: This case presents the challenges of diagnosis and treatment of paradoxical reactions complicated by signs of Cushing’s Syndrome secondary to TBM. In resource-limited countries, investigating brain imaging was an ideal diagnostic tool to identify underlying brain lesions. However, isolation of MTB is the only confirmatory diagnosis, and all the cytokines and other markers can only be supportive of prognostic biomarkers and cannot be confirmatory even if used in various combinations. The case managers denied the patient to receive high dose corticosteroid therapy during the continuation phase of her ATT. Tuberculosis Meningitis MRI Cushing’s Syndrome Ethiopia 1. Introduction TB is an infectious, preventable, and curable disease caused by Mycobacterium tuberculosis ( 1 ). Globally, one in four people carries the bacterium, but only one in ten develops active TB with clinical symptoms ( 1 ) ( 2 ). In 2022, the World Health Organization (WHO) reported 10.6 million active TB cases globally. In the same year, TB was the second leading cause of death next to COVID-19. One-fourth of the disease burden was reported from Africa ( 3 ). Ethiopia is among the 30 high TB, human immunodeficiency virus (HIV) and Multidrug Resistance- TB (MDR- TB) burden countries with an incidence rate of 126 per 100 000 population. TB associated mortality rate was 17 per 100 000 population ( 3 )–( 6 ). The clinical presentation of TB is primarily related to infection of a person’s lungs. However, other organs are susceptible to TB infection ( 1 ). TBM is an infection of the brain and spinal cord ( 7 ). It is the most severe and disabling form of extrapulmonary TB causing 100,000 new cases worldwide each year ( 8 ). More than half of TBM patients are immune-deficient due to co-infections, under-nutrition, diabetes, and chronic lung diseases ( 9 ). Health systems in developing countries face challenges in TBM diagnosis, treatment, management of drug reactions, drug resistance, and rehabilitation related services (8. This case report documented the diagnosis, and management of paradoxical reactions complicated with iatrogenic Cushing’s syndrome. 2. Case Presentation A 34-year-old Ethiopian married woman, Gravida I and Para 0, presented to a Private Hospital on May 5, 2022, with a two-day history of left-sided limb weakness, incontinence, fever, headache, vomiting, photophobia, and confusion. She had no history of TB or contact with known pulmonary TB patients. On physical examination, the patient appeared acutely ill and disoriented to time, place and person with a score of 13/15 (E4V4M5) on Glasgow Comma Scale. Neurological examination revealed neck stiffness with positive Kernig's and Brudzinski's signs. Comprehensive laboratory investigations on blood and CSF were made. The blood investigation consisted of complete blood count, peripheral blood smear, ESR, blood urea nitrogen, blood sugar, serological test syphilis screening using a Rapid Plasma Reagin (RPR) test, Provider-Initiated HIV Testing and Counseling (PITC), serum creatinine, serum electrolyte, and liver function tests. The results of her laboratory investigations showed normocytic and normochromic red cells, persistently high lymphocytes, platelets and ESR, suggesting the existence of infection or inflammation. In addition, the CSF investigations were negative for bacteria, fungi, and parasites. However, glucose level was 0.3 gm /L and protein concentration was 1.2 gm/dl. The patient had a normal chest X-ray with clear lungs, a healthy heart, and no visible nodules, tumors, or masses. The brain MRI revealed that there are multiple ring-enhancing lesions in both cisterns that were suggestive of TB granuloma. 3. Differential diagnosis An extensive differential diagnosis was considered encompassing bacterial, fungal, and autoimmune etiologies. Through comprehensive blood smears, serum testing, and cerebrospinal fluid (CSF) analysis, we excluded neurosyphilis, cryptococcal infection, toxoplasmosis, HIV, and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). The patient's medical history revealed no evidence of medication-induced abnormalities. Diagnostic workup showed no indications of neoplastic processes, and autoimmune markers were negative. The definitive diagnosis was established through synthesis of the patient's medical history, neurological examination findings, hematological and CSF analyses, and radiological imaging results. 4. Treatment and outcome As per the Ethiopian TB case management guidelines, the patient was treated for extra-pulmonary TB under the direct supervision of health workers and her husband using first-line regimen consisting of rifampicin, isoniazid, pyrazinamide, and ethambutol (RHZE) for two months (i.e., intensive phase) and a prolonged rifampicin and isoniazid (RH) treatment for nine months (i.e., continuation phase). In addition, she was supplemented with an adjuvant high-dose corticosteroid therapy with dexamethasone at 0.4 mg/kg body weight per day for fifteen days and discharged on June 25, 2022 with neurological improvement. In addition, she was supplemented with an adjuvant corticosteroid therapy with dexamethasone at 0.4 mg/kg body weight per day and then tapered off at 0.3 mg, 0.2 mg and 0.1 mg per body weight per day on the 6th, 7th and 8th weeks, respectively. She was given pyridoxine orally at 30 mg per day throughout here nine-month treatment. She also received symptomatic treatment for hypothyroidism and psychosis. She was regularly followed up on her 3rd, 6th and 9th months of ATT. During her first and second visits, she showed a significant improvement in her clinical signs and symptoms. But at the end of her 9th month follow-up visit, she developed severe headaches, confusion, left side limb weakness, and weight gain of 10 kilograms in 10 months. On physical examination, she had a moon-face appearance with truncal obesity. A brain MRI study using ST- T2W TSE Axial, Coronal and Sagittal; T1W TSE Axial. Axial FAT SAT, FLAIR, DW1 ADC and Axial SW1 techniques were done. In addition, post-contrast T1W axial, coronal, and sagittal MRI were investigated. The results revealed severely dilated bilateral ventricles with trans ependymal CSF transudation. There were multiple nodular T2 hypointense lesions in the basal and suprasellar cisterns extending along the bilateral Sylvain fissure, left thalamus, brain stem, and quadrigeminal cistern with mild edematous compression of the aqueduct causing dilatation of upstream ventricular system. In addition, on post-contrast image, the lesion showed conglomerated nodular and rim enhancement, which was bulky at the basal and suprasellar cistern, scattered discrete appearance seen in the Sylvian fissure, ambient cistern with smooth brain stem surface enhancement. The results were suggestive of hydrocephalus secondary to TBM with paradoxical reactions. Her signs and symptoms of the hydrocephalus were surgically managed using a VPS at the second Private Hospital in Addis Ababa Ethiopia. A CSF analysis revealed normal appearance with no AFB. The CSF protein was 0.20 gm/dl and glucose 0.3 gm/L (RBS 5.5 mmol/L). An infectious disease specialist reassessed the patient and ruled out the possibility of MDR TB noting her survival for 12 months with clinical and neuroimaging abnormalities and history of improvement using first-line ATT. However, the signs and symptoms of meningeal irritation were linked to paradoxical reactions complicated with hypothyroidism and iatrogenic Cushing’s syndrome. Hence, her ATT ceased at the end of the 10th month. After a three-month follow-up visit, the VPS was functional with improvements in her neurological findings. The patient’s family members were engaged in caring for her and facilitating diagnostic investigations, collecting drugs and supplies. However, they were getting limited information about her treatment plan. Due to a lack of clear information on her diagnosis, treatment and benefit of modern medical care, her family members decided to shift to traditional healing services. Within 12 months, the patient developed weakness, confusion, convulsion, loss of consciousness, and died on April 26, 2024. Discussion TB is continuing to be a public health challenge worldwide ( 10 ). Ethiopia has reported 144,457 all forms of TB cases in 2023, of which slightly less than one-third (30%) were extrapulmonary TB cases ( 11 ). The global tuberculosis report indicated that Ethiopia is in the list of high TB and TB/ HIV burden countries. In high TB or TB/HIV countries ( 10 ), TBM is the most common brain and spinal cord infection of M ycobacterium Tuberculosis ( 7 ) (. Paradoxical reactions are characterized by clinical, neuroimaging, and cerebrospinal fluid abnormalities ( 12 ) ( 13 ). This case presented the worsening of pre-existing brain lesions and development of hydrocephalus after showing improvement with ATT for nine months ( 5 ) ( 6 ). This finding was in line with previously reported paradoxical reactions. The symptoms of TBM are non-specific during the onset of illness and it took several days to narrow the list of differential diagnoses using medical history, physical examination, laboratory, and radiological imaging findings ( 8 ). Most TBM cases have a history of Pulmonary TB or contact with known tuberculosis patients ( 14 ). However, in the reported case, the patient’s family denied the history of TB infection or any known contact with the TB patient. This case was investigated with blood, CSF, and radiological imaging. The results helped to rule out bacterial, fungal, and other immunological abnormalities ( 8 ). The case clearly demonstrated the challenges of health systems in diagnosing, investigating, engaging patients and family members, and treating TBM in resource-limited settings. In resource-limited settings conducting a confirmatory test in shorter time including point of care test like Next-generation sequencing (NGS) for Mycobacterium tuberculosis (MTB) as a powerful tool for rapidly identifying drug resistance and understanding the genetic diversity of TB, enabling more accurate and targeted treatment adjustments. Though confirmatory tests Jensen culture, GeneXpert MTB, Adenosine Deaminase, and Polymerase Chain Reaction tests are not accessible for most of TBM suspected cases ( 15 ). Though there are opportunities to confirm MDR or XDR TB in Addis Ababa through sample transportation to public health facilities found in the capital city, the case managers failed to investigate this case using the recommended and highly sensitive nucleic acid amplification tests such as GeneXpert MTB/ RIF (Xpert) and MDR TB ( 16 ). This was a missed opportunity to confirm MDR TB after collecting adequate blood and CSF samples on several occasions. The final diagnosis of this case was made based on evidence of clinical, laboratory, and imaging findings. In the absence of advanced laboratory tests, use of clinical symptoms, blood, and CSF analysis supplemented by MRI was instrumental in diagnosing the brain lesion which was suggestive of tuberculoma. This finding aligned with the recommended use of the algorithm. developed using clinical, laboratory and radiological imaging findings for resource limited settings ( 17 ). The reported TBM case was treated with first line ATT ( 5 )( 6 ). This case management was in line with global and national treatment guidelines for central nervous system infection ( 18 ). In addition, the patient received vitamins, anti-inflammatory drugs, and symptomatic treatment for hypothyroidism and psychosis. However, this paradoxical reaction was complicated by signs and symptoms of iatrogenic Cushing’s syndrome secondary to sequelae of MTB. Furthermore, this clinical assessment should be confirmed using laboratory investigation of cortisol levels. And this patient at the end of nine months of ATT was diagnosed with a paradoxical reaction but not treated with the recommended high-dose corticosteroid therapy and surgical or radiological intervention to control the effect of Cushing’s syndrome. Unfortunately, alternative treatments like anti-tissue necrosis factor-α (anti–TNF-α) therapy to manage such cases ( 19 ) are not available in resource limited countries. The patient and her family members did not receive adequate information about her treatment plan which resulted in moving her to traditional healing processes from modern medical care. This decision and missing from modern medical care was one of the challenges to confirm possible spread of active TB to the abdomen through VPS using Ultrasound imaging or ascites fluid analysis. Hence, the patient suffered from signs and symptoms of hydrocephalus and a series of convulsions and died within 12 months from discharge. Conclusions This case highlights the diagnostic and therapeutic challenges of paradoxical reactions in tuberculous meningitis (TBM). In resource-limited settings, neuroimaging serves as a critical diagnostic modality for detecting characteristic of CNS lesions when advanced microbiological testing is unavailable. However, isolation of MTB is the only confirmatory diagnosis, and all the cytokines and other markers can only be supportive of prognostic biomarkers and cannot be confirmatory even if used in various combinations. This case was complicated by the development of signs of iatrogenic Cushing's syndrome. While ventriculoperitoneal shunt (VPS) placement provided temporary relief from hydrocephalus symptoms, critical gaps in patient and family education regarding the treatment plan ultimately led to abandonment of biomedical care in favor of traditional healing practices. Abbreviations AFB: Acid-Fast Bacilli; ATT: Anti Tuberculosis Treatment; COVID-19: Coronavirus Disease 19; CSF: Cerbro Spinal Fuild; ESR: erythrocytic sedimentation rates; HIV: human immunodeficiency virus; MDR – TB : Multi-Drug Resistance- TB; MRI: Magnetic Resonance Imaging; PITC: Provider-Initiated HIV Testing and Counseling; TB: Tuberculosis; TBM: Tuberclculosis Meningitis; VPS: Ventriculoperitoneal shunt; TB-IRIS: TB-associated immune reconstitution inflammatory syndrome; RBS: Random Blood Sugar; RH: Rifampicin and Isoniazid; RHZE : rifampicin, isoniazid, pyrazinamide, and ethambutol; WHO: World Health Organization. Declarations Ethical Approval and Consent to participate Not applicable. Consent for publication The patient was died. And a written informed consent was obtained from the patient’s relative for publication of this case report. Availability of data and materials The datasets used and/or analyzed during the current study are include in the case report. And the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding All authois have declared that no financial support was received form any organization for the submitted work. Authors’ contributions M.D.A., A.Y.D., develop the concept note. M.D.A., collect the data and draft the case report. M.D.A., A.Y.D., A.S., A.D.M., W.B., M.T.Y., R.M.F., N.E.T., W.S.A., Z.B., and M.T.R., participated in the analyses the data. All authors reviewed, and approved this manuscript for submission. Acknowledgements The authors are very grateful for family members who consented us to document the case report. Authors’ information MDA: Ph.D.; Technical Director for Improve Primary Health Care Service Delivery Project, at Amref Health Africa, Addis Ababa, Ethiopia AYD: MPH; Monitoring, Evaluation and Learning Manager at Clinton Health Access Initiative, Addis Ababa, Ethiopia AS: PhD; Senior Research Advisor at Amref Health Africa, Addis Ababa, Ethiopia ADM: MPH: Senor Program Manager at Project HOPE, Addis Ababa, Ethiopia WB: MD; Resident of Internal Medicine at Saint Paul Millennium Medical College, Addis Ababa, Ethiopia MTY: MD, MPH; Senor Quality Advisor at Amref Health Africa, Addis Ababa, Ethiopia. RMF: MD, Emergency Medical Care Specialist at Saint Paul Millennium Medical College, Addis Ababa, Ethiopia WSA: MPH; Health Information System Manager ICAP, Addis Ababa, Ethiopia ZB: BSc, Intensive Care Unit head at Dessie Comprehensive Referral Hospital, Dessie, Ethiopia MTR: PhD; Head of Department, Department of Nursing Education Specialization of Psychiatric-Mental Health Nursing at University of the Witwatersrand, Johannesburg, South Africa References Jilani TN, Avula A, Zafar Gondal A, Siddiqui AH. Active Tuberculosis. PMID: In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2023. p. 30020618. Gupta M, Tobin EH, Munakomi S. CNS Tuberculosis. [Updated 2024 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585138/ World Health Organization. Tuberculosis in the WHO African Region: 2023 progress update. InTuberculosis in the WHO African Region: 2023 progress update 2023. Arja A, Tadesse S, Agachew M et al. October. The Burden of Tuberculosis across Regions in Ethiopia: A Systematic Subnational Analysis for the Global Burden of Disease Study 2019. Ethiopian Journal of Health Development. 20 2023. eISSN: 1021–6790. FMoH. National Guidelines for Tuberculosis, Leprosy and TB/HIV Co-infection Prevention and Control. Addis Ababa: Federal Ministry of Health; 2017. FMOH. Guidelines for Clinical and Programmatic Management of TB, TB/HIV, DR-TB and Leprosy in Ethiopia. 7th ed. Addis Ababa: Federal Ministry of Health. 2021. pp. 79–93. Gupta S, Sinha U, Raj A. Severe Paradoxical Manifestations in an Immunocompetent Young Female With Tuberculous Meningitis. Cureus. 2022;14(10). Méchaï F, Bouchaud O. Tuberculous meningitis: challenges in diagnosis and management. Rev Neurol. 2019;175(7–8):451–7. Wondmieneh A, Gedefaw G, Getie A, Demis A. Prevalence of undernutrition among adult tuberculosis patients in Ethiopia: a systematic review and meta-analysis. J Clin Tuberculosis Other Mycobact Dis. 2021;22:100211. World Health Organization. Global tuberculosis report 2024. World Health Organization; 2024. Oct 29. FMoH. Health and Health Related Indicators of 202324. Addis Ababa: Federal Ministry of Health; 2024. Singh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, Verma R, Sharma PK. Paradoxical reaction in tuberculous meningitis: presentation, predictors and impact on prognosis. BMC Infect Dis. 2016;16:1–1. Garg RK, Malhotra HS, Kumar N. Paradoxical reaction in HIV negative tuberculous meningitis. J Neurol Sci. 2014;340(1–2):26–36. Slane VH, Chandrashekhar GU. Tuberculous meningitis. 2021. StatPearls. Treasure Island: StatPearls Publishing. 2021. Pormohammad A, Nasiri MJ, McHugh TD, Riahi SM, Bahr NC. A systematic review and meta-analysis of the diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis. J Clin Microbiol. 2019;57(6):10–128. Seddon JA, Tugume L, Solomons R, Prasad K, Bahr NC, Tuberculous Meningitis International Research Consortium. The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes. Wellcome open Res. 2019;4. Palacios CF, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. J Clin tuberculosis other Mycobact Dis. 2020;20:100164. World Health Organization. Guidelines for Treatment of Tuberculosis. 4th edition. 2010. WHO/HTM/TB/2009 .420 . www.who.int/tb/publications/2010/9789241547833/en/ Kim KW, Kim HJ, Kim HW, Kim SH, Lee SA, Koo YS. Intractable Tuberculous Meningitis With Paradoxical Reactions Treated by Anti–Tissue Necrosis Factor-α Therapy. Neurology: Clinical Practice. 2021;11(4):e555-7. Additional Declarations No competing interests reported. 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A case report and literature review","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eTB is an infectious, preventable, and curable disease caused by \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Globally, one in four people carries the bacterium, but only one in ten develops active TB with clinical symptoms (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). In 2022, the World Health Organization (WHO) reported 10.6\u0026nbsp;million active TB cases globally. In the same year, TB was the second leading cause of death next to COVID-19. One-fourth of the disease burden was reported from Africa (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Ethiopia is among the 30 high TB, human immunodeficiency virus (HIV) and Multidrug Resistance- TB (MDR- TB) burden countries with an incidence rate of 126 per 100 000 population. TB associated mortality rate was 17 per 100 000 population (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u0026ndash;(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe clinical presentation of TB is primarily related to infection of a person\u0026rsquo;s lungs. However, other organs are susceptible to TB infection (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). TBM is an infection of the brain and spinal cord (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). It is the most severe and disabling form of extrapulmonary TB causing 100,000 new cases worldwide each year (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). More than half of TBM patients are immune-deficient due to co-infections, under-nutrition, diabetes, and chronic lung diseases (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Health systems in developing countries face challenges in TBM diagnosis, treatment, management of drug reactions, drug resistance, and rehabilitation related services (8. This case report documented the diagnosis, and management of paradoxical reactions complicated with iatrogenic Cushing\u0026rsquo;s syndrome.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cp\u003eA 34-year-old Ethiopian married woman, Gravida I and Para 0, presented to a Private Hospital on May 5, 2022, with a two-day history of left-sided limb weakness, incontinence, fever, headache, vomiting, photophobia, and confusion. She had no history of TB or contact with known pulmonary TB patients. On physical examination, the patient appeared acutely ill and disoriented to time, place and person with a score of 13/15 (E4V4M5) on Glasgow Comma Scale. Neurological examination revealed neck stiffness with positive Kernig's and Brudzinski's signs.\u003c/p\u003e\u003cp\u003eComprehensive laboratory investigations on blood and CSF were made. The blood investigation consisted of complete blood count, peripheral blood smear, ESR, blood urea nitrogen, blood sugar, serological test syphilis screening using a Rapid Plasma Reagin (RPR) test, Provider-Initiated HIV Testing and Counseling (PITC), serum creatinine, serum electrolyte, and liver function tests. The results of her laboratory investigations showed normocytic and normochromic red cells, persistently high lymphocytes, platelets and ESR, suggesting the existence of infection or inflammation. In addition, the CSF investigations were negative for bacteria, fungi, and parasites. However, glucose level was 0.3 gm /L and protein concentration was 1.2 gm/dl. The patient had a normal chest X-ray with clear lungs, a healthy heart, and no visible nodules, tumors, or masses. The brain MRI revealed that there are multiple ring-enhancing lesions in both cisterns that were suggestive of TB granuloma.\u003c/p\u003e"},{"header":"3. Differential diagnosis","content":"\u003cp\u003eAn extensive differential diagnosis was considered encompassing bacterial, fungal, and autoimmune etiologies. Through comprehensive blood smears, serum testing, and cerebrospinal fluid (CSF) analysis, we excluded neurosyphilis, cryptococcal infection, toxoplasmosis, HIV, and tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS). The patient's medical history revealed no evidence of medication-induced abnormalities. Diagnostic workup showed no indications of neoplastic processes, and autoimmune markers were negative. The definitive diagnosis was established through synthesis of the patient's medical history, neurological examination findings, hematological and CSF analyses, and radiological imaging results.\u003c/p\u003e"},{"header":"4. Treatment and outcome","content":"\u003cp\u003eAs per the Ethiopian TB case management guidelines, the patient was treated for extra-pulmonary TB under the direct supervision of health workers and her husband using first-line regimen consisting of rifampicin, isoniazid, pyrazinamide, and ethambutol (RHZE) for two months (i.e., intensive phase) and a prolonged rifampicin and isoniazid (RH) treatment for nine months (i.e., continuation phase). In addition, she was supplemented with an adjuvant high-dose corticosteroid therapy with dexamethasone at 0.4 mg/kg body weight per day for fifteen days and discharged on June 25, 2022 with neurological improvement. In addition, she was supplemented with an adjuvant corticosteroid therapy with dexamethasone at 0.4 mg/kg body weight per day and then tapered off at 0.3 mg, 0.2 mg and 0.1 mg per body weight per day on the 6th, 7th and 8th weeks, respectively. She was given pyridoxine orally at 30 mg per day throughout here nine-month treatment. She also received symptomatic treatment for hypothyroidism and psychosis.\u003c/p\u003e\u003cp\u003eShe was regularly followed up on her 3rd, 6th and 9th months of ATT. During her first and second visits, she showed a significant improvement in her clinical signs and symptoms. But at the end of her 9th month follow-up visit, she developed severe headaches, confusion, left side limb weakness, and weight gain of 10 kilograms in 10 months. On physical examination, she had a moon-face appearance with truncal obesity. A brain MRI study using ST- T2W TSE Axial, Coronal and Sagittal; T1W TSE Axial. Axial FAT SAT, FLAIR, DW1 ADC and Axial SW1 techniques were done. In addition, post-contrast T1W axial, coronal, and sagittal MRI were investigated. The results revealed severely dilated bilateral ventricles with trans ependymal CSF transudation. There were multiple nodular T2 hypointense lesions in the basal and suprasellar cisterns extending along the bilateral Sylvain fissure, left thalamus, brain stem, and quadrigeminal cistern with mild edematous compression of the aqueduct causing dilatation of upstream ventricular system. In addition, on post-contrast image, the lesion showed conglomerated nodular and rim enhancement, which was bulky at the basal and suprasellar cistern, scattered discrete appearance seen in the Sylvian fissure, ambient cistern with smooth brain stem surface enhancement. The results were suggestive of hydrocephalus secondary to TBM with paradoxical reactions.\u003c/p\u003e\u003cp\u003eHer signs and symptoms of the hydrocephalus were surgically managed using a VPS at the second Private Hospital in Addis Ababa Ethiopia. A CSF analysis revealed normal appearance with no AFB. The CSF protein was 0.20 gm/dl and glucose 0.3 gm/L (RBS 5.5 mmol/L). An infectious disease specialist reassessed the patient and ruled out the possibility of MDR TB noting her survival for 12 months with clinical and neuroimaging abnormalities and history of improvement using first-line ATT. However, the signs and symptoms of meningeal irritation were linked to paradoxical reactions complicated with hypothyroidism and iatrogenic Cushing\u0026rsquo;s syndrome. Hence, her ATT ceased at the end of the 10th month. After a three-month follow-up visit, the VPS was functional with improvements in her neurological findings.\u003c/p\u003e\u003cp\u003eThe patient\u0026rsquo;s family members were engaged in caring for her and facilitating diagnostic investigations, collecting drugs and supplies. However, they were getting limited information about her treatment plan. Due to a lack of clear information on her diagnosis, treatment and benefit of modern medical care, her family members decided to shift to traditional healing services. Within 12 months, the patient developed weakness, confusion, convulsion, loss of consciousness, and died on April 26, 2024.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTB is continuing to be a public health challenge worldwide (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Ethiopia has reported 144,457 all forms of TB cases in 2023, of which slightly less than one-third (30%) were extrapulmonary TB cases (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). The global tuberculosis report indicated that Ethiopia is in the list of high TB and TB/ HIV burden countries. In high TB or TB/HIV countries (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), TBM is the most common brain and spinal cord infection of M\u003cem\u003eycobacterium Tuberculosis\u003c/em\u003e (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) \u003cem\u003e(.\u003c/em\u003e Paradoxical reactions are characterized by clinical, neuroimaging, and cerebrospinal fluid abnormalities (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). This case presented the worsening of pre-existing brain lesions and development of hydrocephalus after showing improvement with ATT for nine months (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This finding was in line with previously reported paradoxical reactions.\u003c/p\u003e\u003cp\u003eThe symptoms of TBM are non-specific during the onset of illness and it took several days to narrow the list of differential diagnoses using medical history, physical examination, laboratory, and radiological imaging findings (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Most TBM cases have a history of Pulmonary TB or contact with known tuberculosis patients (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, in the reported case, the patient\u0026rsquo;s family denied the history of TB infection or any known contact with the TB patient.\u003c/p\u003e\u003cp\u003eThis case was investigated with blood, CSF, and radiological imaging. The results helped to rule out bacterial, fungal, and other immunological abnormalities (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The case clearly demonstrated the challenges of health systems in diagnosing, investigating, engaging patients and family members, and treating TBM in resource-limited settings.\u003c/p\u003e\u003cp\u003eIn resource-limited settings conducting a confirmatory test in shorter time including point of care test like Next-generation sequencing (NGS) for Mycobacterium tuberculosis (MTB) as a powerful tool for rapidly identifying drug resistance and understanding the genetic diversity of TB, enabling more accurate and targeted treatment adjustments. Though confirmatory tests Jensen culture, GeneXpert MTB, Adenosine Deaminase, and Polymerase Chain Reaction tests are not accessible for most of TBM suspected cases (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Though there are opportunities to confirm MDR or XDR TB in Addis Ababa through sample transportation to public health facilities found in the capital city, the case managers failed to investigate this case using the recommended and highly sensitive nucleic acid amplification tests such as GeneXpert MTB/ RIF (Xpert) and MDR TB (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). This was a missed opportunity to confirm MDR TB after collecting adequate blood and CSF samples on several occasions.\u003c/p\u003e\u003cp\u003eThe final diagnosis of this case was made based on evidence of clinical, laboratory, and imaging findings. In the absence of advanced laboratory tests, use of clinical symptoms, blood, and CSF analysis supplemented by MRI was instrumental in diagnosing the brain lesion which was suggestive of tuberculoma. This finding aligned with the recommended use of the algorithm. developed using clinical, laboratory and radiological imaging findings for resource limited settings (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe reported TBM case was treated with first line ATT (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This case management was in line with global and national treatment guidelines for central nervous system infection (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In addition, the patient received vitamins, anti-inflammatory drugs, and symptomatic treatment for hypothyroidism and psychosis. However, this paradoxical reaction was complicated by signs and symptoms of iatrogenic Cushing\u0026rsquo;s syndrome secondary to sequelae of MTB. Furthermore, this clinical assessment should be confirmed using laboratory investigation of cortisol levels. And this patient at the end of nine months of ATT was diagnosed with a paradoxical reaction but not treated with the recommended high-dose corticosteroid therapy and surgical or radiological intervention to control the effect of Cushing\u0026rsquo;s syndrome. Unfortunately, alternative treatments like anti-tissue necrosis factor-α (anti\u0026ndash;TNF-α) therapy to manage such cases (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) are not available in resource limited countries. The patient and her family members did not receive adequate information about her treatment plan which resulted in moving her to traditional healing processes from modern medical care. This decision and missing from modern medical care was one of the challenges to confirm possible spread of active TB to the abdomen through VPS using Ultrasound imaging or ascites fluid analysis. Hence, the patient suffered from signs and symptoms of hydrocephalus and a series of convulsions and died within 12 months from discharge.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis case highlights the diagnostic and therapeutic challenges of paradoxical reactions in tuberculous meningitis (TBM). In resource-limited settings, neuroimaging serves as a critical diagnostic modality for detecting characteristic of CNS lesions when advanced microbiological testing is unavailable. However, isolation of MTB is the only confirmatory diagnosis, and all the cytokines and other markers can only be supportive of prognostic biomarkers and cannot be confirmatory even if used in various combinations. This case was complicated by the development of signs of iatrogenic Cushing's syndrome. While ventriculoperitoneal shunt (VPS) placement provided temporary relief from hydrocephalus symptoms, critical gaps in patient and family education regarding the treatment plan ultimately led to abandonment of biomedical care in favor of traditional healing practices.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFB: Acid-Fast Bacilli; ATT: Anti Tuberculosis Treatment; COVID-19: Coronavirus Disease 19; CSF: Cerbro Spinal Fuild; \u0026nbsp;ESR: erythrocytic sedimentation rates; HIV: human immunodeficiency virus; MDR \u0026ndash; TB : Multi-Drug Resistance- TB; MRI: Magnetic Resonance Imaging; PITC: Provider-Initiated HIV Testing and Counseling; TB: Tuberculosis; TBM: Tuberclculosis Meningitis; VPS: Ventriculoperitoneal shunt; TB-IRIS: TB-associated immune reconstitution inflammatory syndrome; RBS: Random Blood Sugar; RH: Rifampicin and Isoniazid; RHZE : rifampicin, isoniazid, pyrazinamide, and ethambutol; WHO: World Health Organization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical Approval and Consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eThe patient was died. And a written informed consent was obtained from the patient\u0026rsquo;s relative for publication of this case report. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are include in the case report. And the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eAll authois have declared that no financial support was received form any organization for the submitted work.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions\u003c/p\u003e\n\u003cp\u003eM.D.A., A.Y.D., develop the concept note. M.D.A., collect the data and draft the case report. M.D.A., A.Y.D., A.S., A.D.M., W.B., M.T.Y., R.M.F., N.E.T., W.S.A., Z.B., and \u0026nbsp; M.T.R., \u0026nbsp;participated in the analyses the data. All authors reviewed, and approved this manuscript for submission.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors are very grateful for family members who consented us to document the case report.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; information\u003c/p\u003e\n\u003cp\u003eMDA: Ph.D.; Technical Director for Improve Primary Health Care Service Delivery Project, at Amref Health Africa, Addis Ababa, Ethiopia\u003c/p\u003e\n\u003cp\u003eAYD: MPH; Monitoring, Evaluation and Learning Manager at Clinton Health Access Initiative, Addis Ababa, Ethiopia\u003c/p\u003e\n\u003cp\u003eAS: PhD; Senior Research Advisor at Amref Health Africa, Addis Ababa, Ethiopia\u003c/p\u003e\n\u003cp\u003eADM: MPH: Senor Program Manager at Project HOPE, Addis Ababa, Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWB: MD; Resident of Internal Medicine at Saint Paul Millennium Medical College, Addis Ababa, Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMTY: MD, MPH; Senor Quality Advisor at Amref Health Africa, Addis Ababa, Ethiopia.\u003c/p\u003e\n\u003cp\u003eRMF: MD, \u0026nbsp;Emergency Medical Care Specialist at Saint Paul Millennium Medical College, Addis Ababa, Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWSA: MPH; Health Information System Manager ICAP, Addis Ababa, Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eZB: BSc, Intensive Care Unit head at Dessie Comprehensive Referral Hospital, Dessie, Ethiopia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMTR: PhD; Head of Department, Department of Nursing Education Specialization of Psychiatric-Mental Health Nursing at University of the Witwatersrand, Johannesburg, South Africa\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJilani TN, Avula A, Zafar Gondal A, Siddiqui AH. Active Tuberculosis. PMID: In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2023. p. 30020618.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta M, Tobin EH, Munakomi S. CNS Tuberculosis. [Updated 2024 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK585138/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK585138/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Tuberculosis in the WHO African Region: 2023 progress update. InTuberculosis in the WHO African Region: 2023 progress update 2023.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eArja A, Tadesse S, Agachew M et al. October. The Burden of Tuberculosis across Regions in Ethiopia: A Systematic Subnational Analysis for the Global Burden of Disease Study 2019. Ethiopian Journal of Health Development. 20 2023. eISSN: 1021\u0026ndash;6790.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFMoH. National Guidelines for Tuberculosis, Leprosy and TB/HIV Co-infection Prevention and Control. Addis Ababa: Federal Ministry of Health; 2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFMOH. Guidelines for Clinical and Programmatic Management of TB, TB/HIV, DR-TB and Leprosy in Ethiopia. 7th ed. Addis Ababa: Federal Ministry of Health. 2021. pp. 79\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGupta S, Sinha U, Raj A. Severe Paradoxical Manifestations in an Immunocompetent Young Female With Tuberculous Meningitis. Cureus. 2022;14(10).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eM\u0026eacute;cha\u0026iuml; F, Bouchaud O. Tuberculous meningitis: challenges in diagnosis and management. Rev Neurol. 2019;175(7\u0026ndash;8):451\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWondmieneh A, Gedefaw G, Getie A, Demis A. Prevalence of undernutrition among adult tuberculosis patients in Ethiopia: a systematic review and meta-analysis. J Clin Tuberculosis Other Mycobact Dis. 2021;22:100211.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Global tuberculosis report 2024. World Health Organization; 2024. Oct 29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFMoH. Health and Health Related Indicators of 202324. Addis Ababa: Federal Ministry of Health; 2024.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSingh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, Verma R, Sharma PK. Paradoxical reaction in tuberculous meningitis: presentation, predictors and impact on prognosis. BMC Infect Dis. 2016;16:1\u0026ndash;1.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarg RK, Malhotra HS, Kumar N. Paradoxical reaction in HIV negative tuberculous meningitis. J Neurol Sci. 2014;340(1\u0026ndash;2):26\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSlane VH, Chandrashekhar GU. Tuberculous meningitis. 2021. StatPearls. Treasure Island: StatPearls Publishing. 2021.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePormohammad A, Nasiri MJ, McHugh TD, Riahi SM, Bahr NC. A systematic review and meta-analysis of the diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis. J Clin Microbiol. 2019;57(6):10\u0026ndash;128.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeddon JA, Tugume L, Solomons R, Prasad K, Bahr NC, Tuberculous Meningitis International Research Consortium. The current global situation for tuberculous meningitis: epidemiology, diagnostics, treatment and outcomes. Wellcome open Res. 2019;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePalacios CF, Saleeb PG. Challenges in the diagnosis of tuberculous meningitis. J Clin tuberculosis other Mycobact Dis. 2020;20:100164.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Guidelines for Treatment of Tuberculosis. 4th edition. 2010. WHO/HTM/TB/2009\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.420\u003c/span\u003e\u003cspan address=\"http://.420\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. www.who.int/tb/publications/2010/9789241547833/en/\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim KW, Kim HJ, Kim HW, Kim SH, Lee SA, Koo YS. Intractable Tuberculous Meningitis With Paradoxical Reactions Treated by Anti\u0026ndash;Tissue Necrosis Factor-α Therapy. Neurology: Clinical Practice. 2021;11(4):e555-7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tuberculosis, Meningitis, MRI, Cushing’s Syndrome, Ethiopia","lastPublishedDoi":"10.21203/rs.3.rs-5955477/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5955477/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e In 2022, African nations accounted for a quarter of all reported tuberculosis (TB) cases worldwide. This case report examines the diagnosis, treatment, drug toxicity, and patient management of tuberculous meningitis (TBM) in low-income country settings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e A 34-year-old married Ethiopian woman, Gravida I and Para 0, presented to Private Hospital in Addis Ababa on May 5, 2022, with a two-day history of left-sided limb weakness, incontinence, fever, headache, vomiting, photophobia, and confusion. \u0026nbsp;She had no history of contact with known pulmonary TB patients. On physical examination, she appeared acutely ill and was disoriented to time, place, and person. Laboratory findings revealed persistently elevated lymphocytes, platelets, and erythrocyte sedimentation rate (ESR). Cerebrospinal fluid (CSF) analysis showed low glucose (0.3 g/L) and elevated protein, but no acid-fast bacilli (AFB) were detected. The chest X-ray was unremarkable, but brain MRI revealed ring-enhancing lesions in the basal and suprasellar cisterns, suggestive of tuberculous (TB) granuloma.\u003c/p\u003e\n\u003cp\u003eThe patient was treated with first-line anti-tuberculosis treatment (ATT) regimen with adjuvant steroids for eight weeks and pyridoxine throughout the full course of treatment. During follow-up visits, the patient initially showed improvements in neurological symptoms but experienced a recurrence and worsening of the initial signs and symptoms on the ninth month of follow-up. Her physical examination was suggestive of signs of Cushing’s Syndrome. And, the control MRI was suggestive of hydrocephalus due to paradoxical reactions requiring placement of a ventriculoperitoneal shunt (VPS). The patient died on April 26, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e This case presents the challenges of diagnosis and treatment of paradoxical reactions complicated by signs of Cushing’s Syndrome secondary to TBM. In resource-limited countries, investigating brain imaging was an ideal diagnostic tool to identify underlying brain lesions. \u0026nbsp;However, isolation of MTB is the only confirmatory diagnosis, and all the cytokines and other markers can only be supportive of prognostic biomarkers and cannot be confirmatory even if used in various combinations. The case managers denied the patient to receive high dose corticosteroid therapy during the continuation phase of her ATT.\u003c/p\u003e","manuscriptTitle":"Paradoxical reactions in tuberculous meningitis complicated with Signs of Cushing’s Syndrome. A case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-03 08:07:34","doi":"10.21203/rs.3.rs-5955477/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ec325ade-f486-47de-9c06-045b1e94dfee","owner":[],"postedDate":"October 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-22T11:23:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-03 08:07:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5955477","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5955477","identity":"rs-5955477","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}