Patel, Vinod Bhagu.Rinaldi, Simon.Moodley , Anandan Angamuthu.Moodley, Kaminie.2026-04-292026-04-2920232023https://hdl.handle.net/10413/24368Doctoral Degree. University of KwaZulu-Natal, Durban.Background: Literature regarding the prevalence, clinical features, CSF changes, laboratory investigations, response to therapy, and pathophysiology of autoimmune disease in HIV-associated lower motor neuron syndromes is limited. The above topic is broad and for the purpose of this thesis, has been restricted to chronic immune mediated polyradiculoneuropathies (chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune nodopathies, pure motor lumbosacral polyradiculopathy (PM LSP)),motor neuron syndrome (MNS),and myasthenia gravis(MG) as these are the commonest HIV-immune mediated lower motor neuron syndromes seen at our neuromuscular unit. Neuropathies due to HIV vasculitis and diffuse infiltrative lymphocytosis (DILS) were excluded as they are rare. Muscle disorders forms part of planned prospective work. Objective: To describe the differences in clinical presentation, electro-diagnostic findings, cerebrospinal fluid (CSF) changes, radiology (where applicable), treatment outcomes and pathophysiology of disease in HIV-infected immune mediated polyradiculoneuropathies, MNS and MG and to compare the above to the HIV-uninfected category. Additionally, we tested for nodal/paranodal and ganglioside antibodies in patients with HIV-associated chronic immune mediated radiculoneuropathies and MNS and explored their pathogenetic potential. We also explored genetic and immune factors that are potentially implicated in CCPD in two siblings, one HIV infected. Nodal/paranodal antibodies have not previously been described in an HIV-infected cohort of patients or in the African population in general and similarly genetic testing for acquired demyelination, has not been performed in South Africa. Methods: An insight into the virology, epidemiology, clinical aspects and immunology of HIV is essential in understanding the complexities of immune mediated neurological conditions which occur in people living with HIV infection and is discussed in chapter 1. Chapter 1 also provides background literature of the various neurological syndromes in the HIV-uninfected population, equipping the reader with the necessary tools to understand the clinicopathological correlates in the context of HIV. Available worldwide literature is discussed and analysed in chapter 2, which is a scoping review of the above topic. A retrospective analysis of medical records of all patients meeting the diagnostic criteria for chronic immune mediated radiculoneuropathies (CIDP,DRG,PM LSP), MNS/D, and MG from our neuromuscular unit in Durban, Kwa-Zulu Natal (KZN) between 2003 and 2020 was performed (see individual manuscripts).Clinical, demographic, laboratory, electrophysiological and treatment outcome data were extracted and compared in the 2 arms of the study, namely the HIV-infected and HIV-uninfected cohorts. In addition, HIV-infected patients who met the inclusion criteria for chronic immune-mediated radiculo-neuropathies (IMRN) and MNS were prospectively screened for IgG antibodies directed against nodal (neurofascin (NF)186) and paranodal (NF155, contactin1 (CNTN1) and contactin-associated protein-1, (Caspr1) cell adhesion molecules, using a live, cell-based assay. This has not been previously done in South Africa and is therefore novel. Further testing was performed to determine pathogenicity of the antibodies using myelin co-culture screens and addition of complement. Other novel antibody detection methods included myelin co-culture screens, immunoprecipitation experiments and mass spectrometry. Whole exome sequencing for a potential novel mutation, and genetics for known inherited disorders such as CMT, mitochondrial disease and leukodystrophy was performed in the surviving sibling with CCPD. Results: Manuscript 1: A comparison of clinical, electro-diagnostic, laboratory and treatment outcome differences in a cohort of HIV-infected and HIV-uninfected patients with Myasthenia Gravis: One hundred and seventy-eight (178) patients fulfilled the clinical criteria for MG. Twenty-four (13.4%) were HIV-infected and 154 (86.5%) were HIV-uninfected. There were 116 (65%) females, median 45 years, (IQR 40-62), 90 (50.5%) black African, 66 (37%) Indian, 20 (11.2%) white and two (1.1%) of mixed ancestry. In the HIV-infected cohort, 20 (87%) had generalised MG, 12 (50%) bulbar and 14 (60.9%) respiratory onset MG, 12 (50%) presented with MG Foundation of America (MGFA) class 5 disease at diagnosis, 6 (25%) presented with MG crisis during the 5-year follow up. Thirteen (54%) of the HIV-infected group required rescue therapy using (plasma exchange or IV immunoglobulin) combined with pulse cyclophosphamide compared to 17 (11%) in the HIVuninfected cohort respectively. At five years, eight (33%) of the HIV-infected group remained refractory to treatment compared to 10 (6.5%) HIV-uninfected cohort respectively. No adverse events were documented in HIV-infected patients receiving combination rescue therapy (PLEX or IVIG combined with IV cyclophosphamide). In conclusion HIV-infected MG patients are more likely to require combination rescue therapy with PE/IVIG and IV cyclophosphamide compared to those who were HIV-uninfected. No side effects were documented in the HIV-infected group receiving the above therapy. Manuscript 2: A comparative study of HIV-infected and HIV un-infected patients with motor neuron syndrome: One hundred and thirty-six patients were included in the study, 101 (76%) were HIV-uninfected and 35 (26%) were HIV-infected. Ninety four percent of the HIV-infected cohort were under 50 years, median 41, IQR (33-45), p<0.001, had median ALS functional rating scale revised score (ALSFRSRS)of 28, IQR (24-30) and 40% of these patients on anti-retroviral therapy (ART) survived longer than 10 years. Ninety one percent of the HIV-uninfected cohort were over 50 years, median 66 years, IQR (57-74), p<0.001, had median ALSFRS-RS score of 44 (IQR 42-45) and 93% died within 5 years of their illness. Manuscript 3: A comparative study of HIV-infected and HIV un-infected patients with CIDP: Eighty-four patients were included in the study. Amongst HIV-infected patients 61% were female, median age was 37 years (IQR 30-42), 87.2% presented with a monophasic progressive illness, median CSF lymphocyte count was 5.75 (IQR 0-7.2), 86% were corticosteroid (CST) responsive and 76% were in remission within 6- 12 months requiring no further treatment. HIV- uninfected patients were predominantly male (64%), older (median age was 53years (IQR 29-66)), 53% had a relapsing remitting course, median CSF lymphocyte count was 0 (IQR 0-2), 22% were corticosteroid responsive, 95% required combination therapy and 33% were not in remission by 18 months followup. Manuscript 4: Motor lumbosacral radiculopathy in HIV-infected patients: Eleven black African patients met the inclusion criteria. There were 6 females. The median age was 29 years, interquartile range (IQR), 23-41 years, median duration of symptom progression was 6.5 IQR (3-7.5) months. The median CD4 count of 327 cells/μL, IQR (146-457). The CSF median polymorphocyte count was 0 cells/μL, IQR 0-2, lymphocyte count was 16 cells/μL IQR 1-18 cells/μL, glucose was 3.1 mmol/L, IQR 2.8-3.4 mmol/L and protein was 1.02g/dl, IQR 0.98-3.4 g/dl. All patients tested negative for nodal (neurofascin (NF)186) and paranodal (NF155, contactin1 (CNTN1) and contactin-associated protein, Caspr1) cell adhesion molecules, using a live, cell-based assay and ganglioside antibodies, using ELISA. All patients were treated with corticosteroid therapy. Ninety one percent (91%) recovered fully within 6 months of treatment, median time for recovery was 3.4 months, IQR (1.8- 5.6). There were no relapses during the 18-month follow up period. Manuscript 5 : Nodal-paranodal antibodies in HIV-immune mediated radiculo-neuropathies: Clinical phenotypes and relevance: Twenty-four HIV-infected patients with IMRN were included in the study, 15 met the EFNS/PNS clinical and diagnostic criteria for CIDP, 4 had ventral root radiculopathies (PM LSP) and 5 had dorsal root ganglionopathies (DRG). Five patients with CIDP had combined central and peripheral demyelination. Three patients (12.7 %) tested positive for Neurofascin IgG1 antibodies in the following categories: 1 patient with PM LSP was NF186 positive and 2 patients were NF155 positive with DRG and mixed sensory motor CIDP with optic neuritis respectively. Manuscript 6: Case report of CCPD in siblings: Despite the above cases being fully worked up, they remain cryptic as various immune and genetic tests performed in this study have been inconclusive. Conclusion The 1st study shows that MG patients present with more severe bulbo-respiratory signs requiring supportive care in ICU. The study also suggests that immunosuppressive drugs, including IV cyclophosphamide may be safe and efficacious in HIV-infected patients. In the 2nd study, HIVinfected MNS patients were younger, had more severe disease at presentation and survived longer if treated with ART with possible reversal of the disease process, compared to patients with MND which is likely neurodegenerative. The findings of the 3rd study are that HIV-infected CIDP patients were younger, female predominant, had a CSF lymphocytosis, displayed slowly progressive disease, were highly steroid responsive and went into remission within 6-12 months of CST initiation compared to HIV-uninfected patients. This may argue for a different disease pathogenesis in this cohort. In the 4th study HIV-infected patients with PM LSP, had a pure motor presentation and responded to CST with no relapses during the 18 month follow up period. This cohort tested negative for NF186 and GM1 antibodies which are usually implicated in pure motor syndromes. The 5th study highlights the fact that nodal-paranodal antibodies occur at a similar frequency in HIV-infected and HIV-uninfected IMRN. However, interpretation of results in the context of HIV infection, especially with IgG1 subtypes and low antibody titres is challenging as many antibodies occur as an epiphenomenon in HIV and may therefore be non-specific and non-pathogenetic. Pathogenicity was not established using myelin co-cultures or complement assays. The 6th manuscript describes a rare and cryptic entity of CCPD in siblings and serves as a platform for future genetic, epigenetic and immune studies. The above retrospective and prospective studies add valuable new background information to the medical literature as they describe our clinical experience in complex and rare HIV- related patientconditions where international experience in managing such patients is scant. In addition our work, provides a crude but invaluable direction for future clinical management and basic science research protocols.enNeuromuscular.CIDP.CCDP.Thesis