Browsing by Author "Heckmann, Jeannine"

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    Distal sensory polyneuropathy in HIV/TB co-infection : the role of vitamin B6 and N-acetyltransferase 2 genetic variation
    (2012) Centner, Chad; Heckmann, Jeannine; Dandara, Collet
    Both human immunodeficiency virus (HIV) infection and tuberculosis (TB) are complicated by a painful distal sensory polyneuropathy (DSP) that may be due to virus-related HIV-DSP, antiretroviral toxic neuropathy (ATN) or isoniazid-induced peripheral neuropathy (INH-PN). In co-infection with and co-treatment for HIV/TB, DSP risk is increased. Factors driving this risk may be vitamin B6 deficiency and slow metabolism of INH mediated by N-acetyltransferase 2 (NAT2) acetylation, both known risk
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    Distal sensory polyneuropathy in South Africans infected with human immunodeficiency virus : a cross-sectional analysis of a community cohort
    (2009) Maritz, Jean; Heckmann, Jeannine; Owen, E P
    Introduction: Distal sensory polyneuropathy (DSP), the most common neurological complication of HIV infection, is related to either HIV or antiretroviral therapy (ART). Dideoxynucleoside reverse transcriptase inhibitors such as stavudine are widely used in resource-poor countries and often associated with neuropathy. The prevalence of DSP in developed countries range from 21% to 63%; little data is available from Africa. We aimed to estimate the prevalence of DSP in a South African community clinic-based population and to investigate associated risk factors. Methods: In a cross-sectional study, DSP status was determined in 598 HIV-infected adults using validated tools (Brief Peripheral Neuropathy Screen and a modified version of the Total Neuropathy Score) to categorize subjects. Symptomatic DSP required the presence of at least two neuropathic signs together with at least one symptom. Asymptomatic DSP required the presence of two neuropathic signs. Clinical, anthropometric, quality of life and laboratory evaluations were prospectively performed. Information about CD4 counts, antiretroviral therapy (ART) and questionnaires regarding previous tuberculosis (TB) and alcohol exposure was retrospectively collected Results: Approximately half (49%) of the study population were diagnosed with DSP (30% symptomatic DSP). In the ART-naïve group 37% had evidence of neuropathy (23% symptomatic) compared to 63% of the ART-exposed subjects (39% symptomatic). Overall, subjects with DSP were older (p<0.001) and had lower CD4 counts (p<0.001) compared to those without neuropathy. Previously treated TB infection (p<0.001) and ART use (p<0.001) showed strong associations with DSP. In multivariate analyses the odds (95% confidence interval) of developing DSP was independently associated with ART use (OR 1.7, 1.0-2.9), age (per 10 year increments) (OR 1.7, 1.4-2.2) and previously treated TB infection (OR 2.0, 1.3-3.0). Although stavudine significantly associated with DSP, the duration of exposure was similar irrespective of neuropathy status. Pain or paresthesia was reported by 69% of those with symptomatic DSP and rated as at least moderate to severe. ART-exposed subjects had a tendency towards lower pain scores compared to ART-naïves (p=0.032). Conclusions: DSP is a clinically significant problem in urban HIV-infected Africans. The findings of this study raise the possibility that with avoidance of stavudine-containing regimens in older subjects, especially those with a history of previously treated TB infection, the prevalence of DSP may be reduced.
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    Identifying the molecular basis for treatment resistance in a subset of myasthenia gravis patients of African ancestory
    (2013) Auret, Jennifer Mary; Heckmann, Jeannine; Prince, Sharon; Abrahams, Amaal
    Myasthenia gravis (MG) is an autoimmune disease in which pathogenic antibodies block, target or destroy the acetylcholine receptors of the muscle endplate resulting in failure of neuromuscular transmission and fatigable weakness. We have previously shown that a subpopulation of South African MG patients of African genetic ancestry develop a severe extraocular muscle (EOM) phenotype whilst receiving standard immunosuppressive drug therapies. This phenotype associates with a functional c.-198C>G SNP (C>G SNP) in the regulatory region of decay accelerating factor (DAF), a complement regulatory protein, which is essential for protection against complementmediated damage. MG patients are treated with prednisone as the first-line immunosuppressant and frequently, an additional steroid-sparing agent, such as azathioprine, cyclosporin A or methotrexate. We hypothesised that MG patients with the C>G SNP when treated with immunosuppressant drugs, may have lower DAF protein levels contributing to increased susceptibility to autologous complement-mediated damage at their EOMs. This study tests this by comparing the effect of prednisone, azathioprine, cyclosporine and methotrexate individually and prednisone in combination with each of these steroid-sparing agents on wild-type and C>G DAF protein (western blotting) and mRNA (quantitative real time PCR) levels and promoter activity (luciferase reporter assays). These experiments were performed in EBV transformed lymphoblastoid cell lines from control individuals with wild-type DAF and MG patients carrying the C>G SNP. As a more representative model for this study the experiments were repeated in mouse skeletal muscle cells because there was no available EOM cell line. In support of the hypothesis of this study, prednisone, cyclosporin A and azathioprine individually was shown to repress C>G DAF protein levels while having either no effect on wild-type DAF or slightly activating it. Importantly, methotrexate was the only drug that was able to increase C>G DAF lymphoblast protein expression and therefore holds promise as a potentially effective treatment for MG patients with the C>G SNP. Moreover, using a calcein assay, clinically relevant doses of prednisone in combination with MG patient sera was shown to significantly increase the susceptibility of C>G DAF lymphoblasts to cell lysis (82% C>G DAF lymphoblasts vs. 9% wild-type DAF lymphoblasts). These results suggest that MG patient sera contain factor(s) that together with prednisone may also be responsible for the susceptibility of the EOMs in these patients to injury. The results show that the levels of DAF protein and mRNA did not always match which suggests that the drugs tested may regulate the DAF protein at a posttranscriptional level. In a mouse skeletal muscle model, Daf (equivalent to human wild-type DAF) protein expression was consistently repressed by prednisone treatment but activated by cyclosporine A, azathioprine and methotrexate. Furthermore, co-treatment of prednisone with either of the steroid-sparing drugs showed that azathioprine, and low doses of cyclosporin A and methotrexate were able to overcome the repressive effect of prednisone-only treatment on Daf expression. These observations indicate that the regulation of Daf may be species and/or cell-type specific. Together the results from this thesis suggest that in EOMs, where DAF is already downregulated, compared to other muscles, our MG patients with the C>G SNP may have an increased susceptibility to complement-mediated damage when treated with prednisone, which further represses C>G DAF expression.
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    Molecular analysis of decay accelerating factor as a potential susceptibility factor to developing treatment resistant extraocular muscle involvement in Myasthenia Gravis
    (2009) Uwimpuhwe, Henriette; Heckmann, Jeannine; Ballo, Robea; Prince, Sharon
    Myasthenia gravis (MG) is an autoimmune disorder in which auto-antibodies directed at the acetylcholine receptors (AChR) of the neuromuscular junction (NMJ) block, alter or destroy their targets. The anti-AChR antibodies cause activation of the classical complement pathway leading to inflammatory injury at the NMJ. Decay Accelerating Factor (DAF), a member of complement regulatory proteins, prevents activation of autologous components of complement pathways. The absence of DAF, in knock-out mouse models, has been shown to significantly increase the susceptibility to experimental autoimmune MG. A previous study showed that a high proportion of South African MG patients of African genetic ancestry develop immunosuppressive therapyresistant extraocular muscle (EOM) dysfunction. We hypothesized that these patients have deficient DAF expression in their EOMs resulting in less protection from complement injury.
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    Molecular characterisation of virus in the brains of patients with measles inclusion body encephalitis (MIBE)
    (BioMed Central Ltd, 2013) Hardie, Diana; Albertyn, Christine; Heckmann, Jeannine; Smuts, Heidi
    BACKGROUND: During 2009/10 a major measles epidemic caused by genotype B3 occurred in South Africa. Measles inclusion body encephalitis (MIBE) was diagnosed in a number of highly immuno-compromised HIV patients. The diagnosis was based on typical clinical and MRI findings and positive measles virus PCR in brain or CSF.To characterize the brain virus, nucleoprotein, matrix, fusion and haemagglutinin genes from 4 cases was compared with virus from acutely infected patients. METHODS: cDNA was synthesized using random primers and viral genes were amplified by nested RT-PCR. PCR products were sequenced in the forward and reverse direction and a contig of each gene was created. Sequences were aligned with reference sequences from GenBank and other local sequences. RESULTS: Brain virus was very similar to the South African epidemic virus. Features characteristic of persistent measles virus in the brain were absent. Mutation frequency in brain virus was similar to epidemic virus and had the same substitution preference (U to C and C to U). The virus of 2 patients had the same L454W mutation in the fusion protein. CONCLUSION: The brain virus was very similar to the epidemic strain. The relatively few mutations probably reflect the short time from infection to brain disease in these highly immuno-compromised patients.
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    Neuropsychiatric symptoms in thymoma-associated and non-thymoma myasthenia gravis
    (2012) Freeman, Carla Patricia; Heckmann, Jeannine; Lewis, Ian Storm
    Myasthenia gravis (MG) is an acetylcholine receptor antibody- mediated disease targeting the neuromuscular junction resulting in fatigable muscle weakness. A number of reports have suggested a high prevalence of psychiatric symptoms amongst MG patients. Approximately 10% of MG subjects are found to have an associated thymoma and despite thymomectomy, the MG persists. The presence of thymoma may lead to other antibody-mediated neuropsychiatric manifestations including limbic encephalitis. We hypothesized that the prevalence of neuropsychiatric symptoms may be higher in MG subjects with thymoma-associated MG when compared with those who have non-thymoma MG. This study aims to compare the prevalence of neuropsychiatric symptoms in a South African population of non-thymoma MG and thymoma-associated MG.
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    Project title: The Morbidity associated with Painful Neuropathy in HIV-infected subjects Anti-Retroviral Therapies: An assessment of self-management stratergies
    (2010) Ismail, Dr M; Heckmann, Jeannine
    Objective: To establish the frequency of anti-retroviral treatment (ART)-related distal sensory polyneuropathy in a community-based clinic. To identify the self-management strategies these subjects are using to cope with their pain, and the possible impact on therapeutic management. Methods: A cross-sectional analysis was done of the patients attending the ART clinic at Woodstock Community Health Centre (CHC). During the three-month study period, 123 patients on anti-retroviral therapy were asked to answer the questionnaire and those who had painful feet, were then asked to complete questions about health- seeking behaviors. All participants were asked to complete questions about their health status and all were assessed with the Brief Peripheral Neuropathy Screen (BPNS). Based on the finding of the BPNS, subjects were divided into those with symptomatic distal sensory polyneuropathy (SDSP) and those without. SDSP was defined as the presence of any of the neuropathic symptoms in addition to one of the following; either reduced or absent ankle reflexes or abnormal vibration sense of 10 seconds at the great toes. Further data was obtained from patients by asking them to answer questions with regard to quality of life (QOL) as well depression. Results: Almost one third of patients were diagnosed with SDSP. Of those affected, 73% had significant pain ranging from moderate to severe intensity. Many of these patients were using self-management strategies, such as paracetamol (68%), while close to a third of patients were also using activities such as massaging feet, soaking or elevating feet. A significant proportion of patients with symptomatic neuropathy experienced a negative impact on the following QOL categories; mobility, usual activities, pain or discomfort and anxiety or depression. Further, those with SDSP were also more likely to be unemployed. Conclusions: Our results show that SDSP is a significant problem affecting patients' QOL and that those patients are not adequately treated for pain, hence seeking alternative management strategies. These strategies do not seem to adequately relieve pain and hence better pain management strategies need to be explored in primary care facilities.
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    A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis
    (BioMed Central Ltd, 2011) Heckmann, Jeannine; Rawoot, Amanullah; Bateman, Kathleen; Renison, Rudi; Badri, Motasim
    BACKGROUND:Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements. METHODS: The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG. RESULTS: Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019). CONCLUSIONS: This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems.TRIAL REGISTRATION:SANCTR:DOH-27-0411-2436
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    Subacute measles encephalitis: The neurological sequelae of the measles outbreak in South Africa
    (2014) Albertyn, Christine Herculine; Heckmann, Jeannine
    A measles outbreak occurred in South Africa between 2009 and 2011 with 18 699 confirmed cases. This highly contagious virus can affect the central nervous system in many ways. Early in the disease course there may be direct viral involvement as a primary measles encephalitis or indirectly as an inflammatory immune mediated demyelinating meningoencephalitis. Latent infections are rare and may manifest in two ways: years later as subacute sclerosing panencephalitis (SSPE) caused by viral persistence in a seemingly immunocompetent host or months later as subacute measles encephalitis (SME) in an immunocompromised host. SME is characterised by seizures, typically epilepsia partialis continua, and altered mental status and carries a high mortality. It is an elusive diagnosis and usually confirmed on brain biopsy. Patients and results: Eight patients were diagnosed with SME between July and October 2010 at our tertiary referral hospital. All patients were HIV positive, with a median CD4 lymphocyte count of 37 cells/µl (range 1 to 268). All patients had epilepsia partialis continua during the course of the illness and other common features included encephalopathy, visual loss, hearing loss, and generalised seizures. Strikingly, cerebrospinal fluid (CSF) examination was normal in all patients and computed 4 tomography (CT) Brain imaging was normal in all but one patient. Magnetic resonance imaging (MRI) Brain demonstrated superficial and deep grey matter abnormalities in the majority of patients with contiguous cortical spread over weeks documented in one patient. Electroencephalograms (EEGs) showed periodic epileptiform discharges in seven patients. Diagnosis was confirmed by brain biopsy in one patient, by post-mortem examination in three patients and by supportive laboratory findings (positive measles PCR and/or measles antibodies in urine or CSF) in the remainder. The outcome was fatal in seven of the cases with a median time to death of 3 weeks. Conclusion: South Africa has the greatest number of people living with HIV: 12.6% of the population (6·4 million people) are infected. This is the largest SME case series to date and is seen in the aftermath of a measles outbreak in South Africa. Immunocompromised patients are clearly susceptible and typically present with epilepsia partialis continua and rapid decline in neurological functioning and death ensuing within a month in the majority of cases. MRI T2-weighted signal changes in the cortical grey matter, are typical. In the absence of a brain biopsy, we propose the use of measles virus PCR in urine and CSF. The importance of herd immunity, by enforcing the national vaccination programme, is reiterated.