Browsing by Author "Heckmann, Jeanine"

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    Open Access
    HIV-associated Neuropathy and Autonomic Dysfunction in South Africans on established ART impacts daily living
    (2020) Dudley, Meagan Taryn; Heckmann, Jeanine; Borkum, M; Basera, Wisdom
    Introduction A common complication of Human Immunodeficiency Virus (HIV) and anti-retroviral therapy (ART) is distal sensory polyneuropathy (DSP). Older age and previous TB are risk factors for DSP among HIVinfected Africans before and shortly after ART initiation. Little is known about autonomic dysfunction in Africans on long-term ART and the impact of DSP and autonomic impairment on their quality of life. Our aim was to describe the frequency, characteristics and functional consequences of DSP and autonomic dysfunction in a healthy HIV-infected community-based cohort after at least 5 years of ART. Methods HIV-infected South Africans on the government-sponsored ART program for at least 5 years were included in this cross-sectional analysis. Each consenting participant underwent a focussed neurological assessment using the Brief Peripheral Neuropathy Screen (BPNS) and a reduced version of the Total Neuropathy Score (rTNS). DSP was defined as the presence of at least 2 neuropathic signs in a distal and symmetrical distribution, and symptomatic DSP (SDSP) when accompanied by neuropathic symptoms. Heart rate variability and orthostatic hypotension were measured as described by the Ewing classic battery, and the Survey of Autonomic Symptoms (SAS) questionnaire assessed the presence and severity of autonomic symptoms. We used a modified version of the Lower Extremity Functional Scale (LEFS) to assess lower limb physical ability. Results The 67 participants had a median age of 41 years (interquartile range (IQR) 36-46) and 61 (91 %) were women. The median duration of ART was 7 years (IQR 6-10). DSP criteria were met in 54 (80.6%) and 24 (44.4%) had symptomatic DSP. Comparing participants with DSP to those without DSP, there was no difference in sex (P=0.39), age (P=0.79), current CD4 (P=0.69), viral suppression (P=0.34), ART duration (P=0.22) or previous tuberculosis (TB) (P=0.72) in those with DSP. Similar outcomes were obtained for SDSP. Abnormal autonomic tests were present in 60%. Those with SDSP had more severe autonomic symptoms than those with asymptomatic DSP (P=0.0008). We found that those with DSP and SDSP had significantly lower LEFS percentage scores than those without (P=0.039 and P=0.013 respectively). 5 Conclusion DSP remains a common complication of HIV in the modern era of ART and can lead to significant functional impairment. Autonomic dysfunction is prevalent in SDSP.
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    On the application and generation of subsensory electrical nerve stimulation for the improvement of vibration perception in patients with HIV-related sensory neuropathy
    (2019) Karpul, David; Breen, Paul; Van Schaik, Andre; Heckmann, Jeanine
    This work investigates the application of Subsensory Electrical Noise Stimulation (SENS) to improve symptoms of HIV-related peripheral sensory neuropathy (HIVPN). HIV-PN occurs in roughly half of the 5 million people in South Africa with HIV. The disease has been shown to reduce quality of life and increase the risk of secondary ailments. Currently there is no treatment available. Previously, SENS has shown promise to improve tactile sensitivity in healthy populations and elderly individuals with peripheral neuropathic desensitisation. This work first establishes if SENS can improve the peripheral sensitivity of patients with HIV-PN, and secondly addresses practical aspects of using SENS in a therapeutic context. The vibrotactile sensitivity deficits of participants with HIV-PN and a matched control cohort is documented and analysed. It is found that HIV-PN participants have reduced sensitivity at all tested vibration frequencies (25 Hz, 50 Hz and 128 Hz), but especially at low frequencies. The interaction with vibration frequency indicates that HIV-PN may interact differently with different types of peripheral mechanoreceptors. SENS is then applied at four different amplitudes in an attempt to improve perception thresholds of the three vibration frequencies. SENS was shown to generally have a beneficial effect on 50 Hz vibration sensitivity for low SENS amplitudes. It had no effect, or a detrimental effect, at high SENS amplitudes, and also for 25 Hz and 128 Hz vibration frequencies. This work is also the first to document measures of pain with interventions of this type. No clear effects of SENS on sensations of pain were observed, which is a vital outcome if the therapy is to be developed further, since neuropathic pain is a frequent symptom of HIV-PN. The application of SENS as a practical therapy requires the accurate measurement of the participant’s electrical perception threshold, and a wearable device to apply the electrical signal on an ongoing basis. Research into the stability of electrical perception thresholds specifically aimed at subthreshold signals that would improve tactile sensitivity is presented. It was found that these thresholds vary wildly and correlated very little with possible explanatory variables, which introduces a new challenge for the development of SENS in future research. Currently there are no devices available to apply SENS in non-laboratory settings or for continuous use. The electronic design of a stimulator for using SENS as a wearable intervention is presented and characterised. The circuit is an efficient, low-power voltage to current converter that generates high voltages (120 V peak to peak) from a small, low-voltage rechargeable battery. The design and testing of control and instrumentation circuitry, as well as the addition of various safety and interface features is also documented. The battery life of the circuit is tested to operate for up to 33 hours and the circuit is tested to operate as expected in vivo. The results of this work demonstrate the potential viability of SENS as a therapy for HIV-PN, reveals the variability of electrical perception thresholds, explores the measures of pain for SENS interventions, and provides a complete and thoroughly tested design and implementation of an unparalleled electronic stimulator for nonlaboratory environments. The conclusions of this work form both a strong theoretical and practical basis for future SENS intervention research.
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    Treatment-resistant ophthalmoplegia in myasthenia gravis: Clinical, molecular and functional studies of patient-derived orbital tissues
    (2023) Europa, Tarin; Heckmann, Jeanine; Nel Melissa
    Introduction: Myasthenia gravis (MG) is an immune-mediated disorder affecting the neuromuscular junction. Weakness of the extraocular muscles (EOMs) occurs frequently in MG and typically responds to immune therapies similarly to the non-ocular muscles. Susceptible individuals with the ophthalmoplegic subphenotype of MG (OP-MG), which occurs almost exclusively in acetylcholine receptor positive MG (AChR-MG), may manifest treatmentresistant extraocular muscle weakness despite the use of standard immune therapies. The pathogenetic mechanisms involved in the development of treatment-resistant ophthalmoplegia in MG are still unknown and no effective treatment currently exists. Aim: To investigate the molecular-genetic pathogenesis of the OP-MG subphenotype. Methods: Triangulation of data from clinical observations, review of MG muscle biopsy histopathology, gene expression studies in OP-MG patient-derived orbital muscles (AChR-MG) and bioenergetic studies in highly specialised perimysial ocular fibroblasts of these OP-MG cases was used to identify the underlying pathogenetic mechanisms of OP-MG and to verify previous hypotheses generated by next generation sequencing studies. Results: Myasthenic ophthalmoparesis may persist despite immune therapies in 40% of cases in the first year of immune treatment. Delay to diagnosis of MG and therefore initiation of treatment (>1 year) was an unfavourable prognostic factor for resolution of ophthalmoparesis and suggested that with prolonged weakness, pathological changes may occur at the level of the muscle. Review of the literature documenting histopathology in MG muscle biopsies showed that neurogenic atrophy and features of mitochondrial stress, which may be secondary consequences of functional denervation and reduced contractility, are frequently observed in MG muscle biopsies and the EOMs may be particularly susceptible, demonstrating features of fatty and fibrocellular replacement of myofibres. Gene expression studies performed in the orbital muscles of OP-MG and non-MG control cases supported the hypotheses of previous unbiased genomic studies showing that genes harbouring OP-MG associated gene variants may be involved in a dysregulated network of genes including genes in pathways involved in atrophy signalling, muscle contractility and mitochondrial homeostasis. Several genes were significantly downregulated in the OP-MG orbital muscles compared with controls. MicroRNAs which are biological regulators of gene expression, were hypothesized to be a potential pathogenetic mechanism causing downregulation of these genes in OP-MG orbital muscles and several microRNAs highly expressed in EOMs were associated with the significantly repressed genes in OP-MG orbital muscle using available data in public microRNA databases. Preliminary dynamic bioenergetic assays in perimysial ocular fibroblasts derived from the EOM myotendons of OP-MG and non-MG control cases suggested that regulation of mitochondrial homeostasis may be altered in the context of MG. Conclusion: Gene expression analyses in patient-derived orbital muscles support the hypotheses of previous genomic studies suggesting that pathogenetic mechanisms involving pathways relating to muscle atrophy, contractility and mitochondrial homeostasis may by triggered in the EOMs in the context of MG. Dysregulation of these pathways is likely to impact EOM regeneration in the context of MG-induced complement-mediated attack as well as contractility in this specialized muscle allotype with a high firing rate. These complex aberrant molecular-genetic interactions may contribute to persistent ophthalmoplegia despite adequate immune therapies in OP-MG cases.