Autoimmune encephalitis: Epidemiology, pathophysiology and clinical spectrum (part 2).

Autoimmune encephalitis (AE) represents a growing number of severe autoimmune-inflammatory diseases affecting both the white and grey matter of the brain. In part 1 of this series we focused on the epidemiology, pathophysiology and clinical presentation of this condition, with two illustrative cases. In this part, we will introduce the clinical criteria for AE, particularly for the diagnosis of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, which were developed to facilitate immune treatment in suspected cases before antibody results are available. We subsequently discuss the work up, differential diagnosis and treatment options for patients with this disease.

TOR1A mutation-related isolated childhood-onset generalised dystonia in South Africa.

BACKGROUND: Childhood-onset generalised dystonia is commonly caused by TOR1A mutations and is known to respond well to pallidal deep-brain stimulation (DBS) surgery. The incidence and prevalence of monogenic dystonia in individuals from Africa and specifically of African ancestry are unknown, and no local cases of TOR1A mutation dystonia are found in the literature. OBJECTIVES: To describe our experience with the outcome of TOR1A mutation-positive patients with isolated generalised dystonia (IGD) of childhood onset who were treated with pallidal DBS. METHODS: All patients with TOR1A mutations from Steve Biko Academic Hospital and the Pretoria Neurology Institute in Pretoria, South Africa (SA), who underwent DBS for IGD of childhood onset were identified. We conducted a retrospective analysis of their demographics, clinical presentation and time to generalisation, genetic status and family history, and response to DBS treatment of the internal segment of the globus pallidus (GPi), utilising pre- and post-surgical scores of the United Dystonia Rating Scale (UDRS). RESULTS: Three patients, all of black African ancestry, were identified. The median age at onset was 12 years and the median time to surgery from dystonia generalisation was 3 years. Two children presented with cervical-onset dystonia. Two patients were related, representing the only two with a positive family history. All three patients had a positive outcome after surgery, with improvement of 67 - 90% on the UDRS recorded at last follow-up. CONCLUSIONS: TOR1A mutations are found in SA patients of black African ancestry, with age of onset and generalisation comparable to those described in international studies. However, onset with cervical dystonia was more common than previously reported. Response to GPi DBS was excellent in all patients.

Quantitative spectroscopy of single molecule interaction times.

Single molecule fluorescence tracking provides information at nanometer-scale and millisecond-temporal resolution about the dynamics and interaction of individual molecules in a biological environment. While the dynamic behavior of isolated molecules can be characterized well, the quantitative insight is more limited when interactions between two indistinguishable molecules occur. We address this aspect by developing a theoretical foundation for a spectroscopy of interaction times, i.e., the inference of interaction from imaging data. A non-trivial crossover between a power law to an exponential behavior of the distribution of the interaction times is highlighted, together with the dependence of the exponential term upon the microscopic reaction affinity. Our approach is validated with simulated and experimental datasets.

Agent-based modeling: Population limits and large timescales.

Modeling, simulation, and analysis of interacting agent systems is a broad field of research, with existing approaches reaching from informal descriptions of interaction dynamics to more formal, mathematical models. In this paper, we study agent-based models (ABMs) given as continuous-time stochastic processes and their pathwise approximation by ordinary and stochastic differential equations (SDEs) for medium to large populations. By means of an appropriately adapted transfer operator approach, we study the behavior of the ABM process on long time scales. We show that, under certain conditions, the transfer operator approach allows us to bridge the gap between the pathwise results for large populations on finite timescales, i.e., the SDE limit model, and approaches built to study dynamical behavior on long time scales like large deviation theory. The latter provides a rigorous analysis of rare events including the associated asymptotic rates on timescales that scale exponentially with the population size. We demonstrate that it is possible to reveal metastable structures and timescales of rare events of the ABM process by finite-length trajectories of the SDE process for large enough populations. This approach has the potential to drastically reduce computational effort for the analysis of ABMs.

Life-threatening Listeria meningitis: Need for revision of South African acute bacterial meningitis treatment guidelines.

BACKGROUND: The recent listeriosis outbreak in South Africa (SA) received widespread attention in the media. More than 1 000 laboratory-confirmed cases of listeriosis occurred during an 18-month period, with a case fatality rate of 28%. Acute bacterial meningitis due to listeriosis was extremely rare at Steve Biko Academic Hospital in Pretoria until 2017/18, when we saw two very sick adults with this condition during the listeriosis outbreak. OBJECTIVES: To describe the presentation, treatment and outcome of these patients to raise awareness of this potentially fatal but treatable infection that does not respond to empirical third-generation cephalosporins. CASE REPORTS: Case 1: A 60-year-old man collapsed at home after being discharged from hospital for treatment of Listeria meningitis. On readmission he had neck stiffness and a depressed level of consciousness with right-sided hemiparesis. A computed tomography (CT) scan of the brain showed possible subarachnoid haemorrhage, but on CT angio- and venograms, extensive thrombosis of the superior sagittal, right transverse and bilateral sigmoid sinuses extending into the right internal jugular vein was noted. Patient 2: A 55-year-old HIV-positive hypertensive man on highly active antiretroviral therapy and antihypertensives visited the emergency department complaining of a new-onset headache. He was discharged on pain medication, but was readmitted the next day with a depressed level of consciousness, neck stiffness, low-grade fever and generalised tonic-clonic convulsions. A lumbar puncture revealed active cerebrospinal fluid that was culture-positive for L. monocytogenes. The patients received ampicillin and gentamicin for 3 weeks; the cerebral venous thrombosis was treated with unfractionated heparin. In both cases, the course of the disease was complicated. The first patient remained confused and suffered from psychotic episodes for 5 weeks. He was finally discharged after 6 weeks in hospital and continued to improve to the extent that he was able to return to work. The second patient needed intubation and ventilation and was treated in the intensive care unit. He improved over the next week and was finally discharged home with no residual neurological sequelae. CONCLUSIONS: Our two cases demonstrate that the listeriosis outbreak should change the way we view bacterial meningitis in SA: according to the National Institute for Communicable Diseases, empirical treatment for meningitis should include ampicillin and gentamicin in all adult patients with features of meningitis. There may be a need for an updated meningitis treatment guideline in SA.

In silico cytotoxicity assessment on cultured rat intestinal cells deduced from cellular impedance measurements.

Early and reliable identification of chemical toxicity is of utmost importance. At the same time, reduction of animal testing is paramount. Therefore, methods that improve the interpretability and usability of in vitro assays are essential. xCELLigence's real-time cell analyzer (RTCA) provides a novel, fast and cost effective in vitro method to probe compound toxicity. We developed a simple mathematical framework for the qualitative and quantitative assessment of toxicity for RTCA measurements. Compound toxicity, in terms of its 50% inhibitory concentration IC50 on cell growth, and parameters related to cell turnover were estimated on cultured IEC-6 cells exposed to 10 chemicals at varying concentrations. Our method estimated IC50 values of 113.05, 7.16, 28.69 and 725.15 µM for the apparently toxic compounds 2-acetylamino-fluorene, aflatoxin B1, benzo-[a]-pyrene and chloramphenicol in the tested cell line, in agreement with literature knowledge. IC50 values of all apparent in vivo non-toxic compounds were estimated to be non-toxic by our method. Corresponding estimates from RTCA's in-built model gave false positive (toxicity) predictions in 5/10 cases. Taken together, our proposed method reduces false positive predictions and reliably identifies chemical toxicity based on impedance measurements. The source code for the developed method including instructions is available at https://git.zib.de/bzfgupta/toxfit/tree/master.

Cryptococcal meningitis in a tertiary hospital in Pretoria, mortality and risk factors - A retrospective cohort study.

Aim This retrospective cohort study analyzes the impact of possible risk factors on the survival chance of patients with cryptococcal meningitis. These factors include the patient's socio-economic background, age, gender, presenting symptoms, comorbidities, laboratory findings and, in particular, non-adherence versus adherence to therapy. Methods Data were collected from all adult patients admitted to Kalafong Hospital with laboratory confirmed cryptococcal meningitis over a period of 24 months. We analyzed the data by the presentation of descriptive summary statistics, logistic regression was used to assess factors which showed association between outcome of measure and factor. Furthermore, multivariable logistic regression analysis using all the factors that showed significant association in the cross tabulation was applied to determine which factors had an impact on the patients' mortality risk. Results A total of 87 patients were identified. All except one were HIV-positive, of which 55.2% were antiretroviral therapy naïve. A history of previous tuberculosis was given by 25 patients (28.7%) and 49 (56.3%) were on tuberculosis treatment at admission or started during their hospital stay. In-hospital mortality was 31%. Statistical analysis showed that antiretroviral therapy naïve patients had 9.9 (CI 95% 1.2-81.2, p < 0.0032) times greater odds of dying compared to those on antiretroviral therapy, with 17 from 48 patients (35.4%) dying compared with 1 out of 21 patients (4.8%) on treatment. Defaulters had 14.7 (CI 95% 1.6-131.6, p < 0.016) times greater odds of dying, with 9 from 18 patients dying (50%), compared to the non-defaulters. In addition, patients who presented with nausea and vomiting had a 6.3 (95% CI 1.7-23.1, p < 0.005) times greater odds of dying (18/47, 38.3%); this remained significant when adjusted for antiretroviral therapy naïve patients and defaulters. Conclusion Cryptococcal meningitis is still a common opportunistic infection in people living with HIV/AIDS resulting in hospitalization and a high mortality. Defaulting antiretroviral therapy and presentation with nausea and vomiting were associated with a significantly increased mortality risk.

Basedow paraplegia: A possible misnomer.

Thyrotoxic myopathy frequently occurs in clinical practice; however, the association of hyperthyroidism with a flaccid, areflexic paraplegia, so-called Basedow paraplegia, appears to represent a controversial and doubtful entity. An 18-year-old female with undiagnosed and untreated Graves' disease presented with acute onset of global weakness predominantly in the lower limbs, but also affecting the upper limbs. The weakness was accompanied by hypotonia and areflexia. Clinically, the patient had a goitre and signs of thyroid ocular disease. Laboratory testing confirmed the presence of hyperthyroidism, and thyroid-stimulating hormone receptor antibodies were positive. The cerebrospinal fluid protein level was raised. The electroneuronographic and needle examinations were compatible with a clear denervation process, such as acute motor axonal neuropathy, a variant of Guillain-Barre syndrome. Intravenous immunoglobulin therapy, carbimazole and propranolol were administered. The occurrence of hyperthyroidism with a flaccid, areflexic paraplegia appears to represent more of a fortuitous than a causative association. It is important to consider and treat other causes, such as acute idiopathic polyneuritis.

Unwinding of a skyrmion lattice by magnetic monopoles.

Skyrmion crystals are regular arrangements of magnetic whirls that exist in a wide range of chiral magnets. Because of their topology, they cannot be created or destroyed by smooth rearrangements of the direction of the local magnetization. Using magnetic force microscopy, we tracked the destruction of the skyrmion lattice on the surface of a bulk crystal of Fe(1-x)Co(x)Si (x = 0.5). Our study revealed that skyrmions vanish by a coalescence, forming elongated structures. Numerical simulations showed that changes of topology are controlled by singular magnetic point defects. They can be viewed as quantized magnetic monopoles and antimonopoles, which provide sources and sinks of one flux quantum of emergent magnetic flux, respectively.

AIDS-related progressive multifocal leukoencephalopathy (PML): a retrospective study from Pretoria, South Africa.

INTRODUCTION AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, results from lytic infection of predominantly oligodendrocytes. Following the HIV pandemic, the incidence of PML has risen sharply, but has rarely been reported in Africa. An increasing number of PML cases were seen recently in a tertiary South African hospital, and this study describes their clinical and radiological features. METHODS: Patients with positive cerebrospinal fluid (CSF) JC virus confirmed by real-time polymerase chain reaction (PCR) were retrospectively identified from January 2008 to June 2012. Adults seen at Neurology with PML were identified, and clinical features, laboratory findings and imaging studies were analysed. RESULTS: Of 121 specimens, 19 were positive; records of 17 patients were available (ages 27 - 64; CD4 counts 11 - 328 x106/µl); clinical manifestations included focal weakness (47%), impaired co-ordination (41%), and speech disturbances (12%), and CSF analysis showed high protein in 76%, and pleocytosis in 35%. Fifteen patients had CT brain scans, showing white matter involvement in 12; MRI studies in 13 patients showed typical PML lesions. CONCLUSION: This report is the first case series of patients with PML from a South African neurology unit, emphasising the fact that PML occurs commonly in South African patients with HIV infection.

Comparison of HTLV-associated myelopathy (HAM) in HIV-positive and HIV-negative patients at a tertiary South African hospital.

BACKGROUND: HTLV-1 associated myelopathy (HAM), or tropical spastic paraparesis, is caused by a retrovirus, the human T-cell lymphotropic virus (HTLV). Although patients with HAM and HIV infection have been described, to our knowledge no direct comparison has been made between patients who are HIV positive and suffering from HAM (HHAM) v. those who are HIV negative and suffering from HAM. AIM: We aimed to compare clinical and radiological findings in HIV-positive and -negative patients with HAM. METHODS: Adult patients who presented to the Neurology Unit at the Steve Biko Academic Hospital from May 2005 to June 2012 with a progressive myelopathy and HTLV seropositivity were retrospectively identified and their clinical and radiological data were collected and reviewed. RESULTS: 21 patients with HAM were identified, of whom 9 were HIV-positive and 11 HIV-negative. One patient, whose HIV status had not been established, was not included in the study. Although the trend did not reach statistical significance, co-infected patients tended to present at an earlier age (HHAM 6/9 (66%) <40 years old; HAM 2/11 (18%) <40 years old) and presented to hospital earlier (HHAM 6/9 (66%) < 3 years symptomatic; HAM 7/11 (63%) > 3 years symptomatic). Cord atrophy occurred in 7/8 dually infected patients and 8/10 HIV-negative patients. CONCLUSION: Although the study is limited by the small number of patients, co-infected patients tended to have a younger age of onset and to present to hospital sooner, and thoracic cord atrophy was very common.

Quantifying the impact of nevirapine-based prophylaxis strategies to prevent mother-to-child transmission of HIV-1: a combined pharmacokinetic, pharmacodynamic, and viral dynamic analysis to predict clinical outcomes.

Single-dose nevirapine (sd-NVP) and extended NVP prophylaxis are widely used in resource-constrained settings to prevent vertical HIV-1 transmission. We assessed the pharmacokinetics of sd-NVP in 62 HIV-1-positive pregnant Ugandan woman and their newborns who were receiving sd-NVP prophylaxis to prevent mother-to-child HIV-1 transmission. Based on these data, we developed a mathematical model system to quantify the impact of different sd-NVP regimens at delivery and of extended infant NVP prophylaxis (6, 14, 21, 26, 52, 78, and 102 weeks) on the 2-year risk of HIV-1 transmission and development of drug resistance in mothers and their breast-fed infants. Pharmacokinetic parameter estimates and model-predicted HIV-1 transmission rates were very consistent with other studies. Predicted 2-year HIV-1 transmission risks were 35.8% without prophylaxis, 31.6% for newborn sd-NVP, 19.1% for maternal sd-NVP, and 19.7% for maternal/newborn sd-NVP. Maternal sd-NVP reduced newborn infection predominately by transplacental exchange, providing protective NVP concentrations to the newborn at delivery, rather than by maternal viral load reduction. Drug resistance was frequently selected in HIV-1-positive mothers after maternal sd-NVP. Extended newborn NVP prophylaxis further decreased HIV-1 transmission risks, but an overall decline in cost-effectiveness for increasing durations of newborn prophylaxis was indicated. The total number of infections with resistant virus in newborns was not increased by extended newborn NVP prophylaxis. The developed mathematical modeling framework successfully predicted the risk of HIV-1 transmission and resistance development and can be adapted to other drugs/drug combinations to a priori assess their potential in reducing vertical HIV-1 transmission and resistance spread.

The rapid-acting properties of insulin aspart are preserved in elderly people with type 2 diabetes.

AIMS: Elderly type 2 diabetes patients may face increased risk of hypoglycaemic episodes because of unpredictable eating habits. The pharmacokinetics and pharmacodynamics of insulin aspart (IAsp) were studied in elderly patients to examine the potential for postprandial dosing. METHODS: Nineteen type 2 diabetes subjects, aged > or =65 years, were enrolled in this randomized, double-blind, crossover trial. Subjects received 0.3 U/kg IAsp or regular human insulin during a glucose clamp procedure. RESULTS: IAsp showed a faster onset of action with significantly higher values for area under the glucose infusion rate curves, AUC(GIR(0-120 min)) and AUC(GIR(0-300 min)) (p = 0.0001). Maximum metabolic activity was higher (4.4 vs. 3.8 mg/kg/min, p = 0.0039) and occurred earlier with IAsp (196 vs. 278 min, p < 0.0001). Late metabolic activity (AUC(GIR (300-600 min))) was significantly lower with IAsp (p = 0.0006). CONCLUSION: Clinical studies are required to confirm whether postprandial administration of IAsp is appropriate for elderly patients.

The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-alpha-stimulated host cells.

Hepatitis delta virus (HDV) RNA editing controls the formation of hepatitis-delta-antigen-S and -L and therefore indirectly regulates HDV replication. Editing is thought to be catalysed by the adenosine deaminase acting on RNA1 (ADAR1) of which two different forms exist, interferon (IFN)-alpha-inducible ADAR1-L and constitutively expressed ADAR1-S. ADAR1-L is hypothesized to be a part of the innate cellular immune system, responsible for deaminating adenosines in viral dsRNAs. We examined the influence of both forms on HDV RNA editing in IFN-alpha-stimulated and unstimulated hepatoma cells. For gene silencing, an antisense oligodeoxyribonucleotide against a common sequence of both forms of ADAR1 and another one specific for ADAR1-L alone were used. IFN-alpha treatment of host cells led to approximately twofold increase of RNA editing compared with unstimulated controls. If ADAR1-L expression was inhibited, this substantial increase in editing could no longer be observed. In unstimulated cells, ADAR1-L suppression had only minor effects on editing. Inhibition of both forms of ADAR1 simultaneously led to a substantial decrease of edited RNA independently of IFN-alpha-stimulation. In conclusion, the two forms of ADAR1 are responsible almost alone for HDV editing. In unstimulated cells, ADAR1-S is the main editing activity. The increase of edited RNA under IFN-alpha-stimulation is because of induction of ADAR1-L, showing for the first time that this IFN-inducible protein is involved in the base modification of replicating HDV RNA. Thus, induction of ADAR1-L may at least partially cause the antiviral effect of IFN-alpha in natural immune response to HDV as well as in case of therapeutic administration of IFN.

Managing water supply and sanitation services to developing communities: key success factors.

A number of key success factors in the management of organisations responsible for the provision of water supply and sanitation services to developing communities have been identified as critical to the sustained success of such organisations. These factors have to receive specific and sustained attention from management. They should form the focus of management attention in addition to the many other important factors requiring management input. The key success factors which are critical to ensure a sustained water supply and the provision of sanitation services to developing communities centre around two main areas, i.e. the credibility of the organisation with the community it serves and the creation of an organisation culture of focusing on service to the community, on income generation and on minimising of losses.

Clinical, cerebrospinal fluid and pathological findings and outcomes in HIV-positive and HIV-negative patients with tuberculous meningitis.

BACKGROUND: The early diagnosis of tuberculous (TB) meningitis remains difficult. In South Africa, the HIV epidemic has shifted the spectrum of meningitis towards chronic infections (mainly tuberculosis [TB] and cryptococcosis). This study aimed to analyze clinical, cerebrospinal fluid (CSF) and pathological findings and outcomes in TB meningitis to evaluate whether HIV infection significantly influences the characteristic findings. PATIENTS AND METHODS: 40 consecutive patients with TB meningitis presenting at the Pretoria Academic Hospital were evaluated clinically and chest X-rays (CXR), computerized tomography (CT) brain scans, CSF profiles, HIV and routine blood tests were analyzed. Postmortem examinations (PM) were performed in seven patients and outcomes were assessed after treatment. RESULTS: 20 patients were HIV-positive and 17 were negative (three not tested). History and clinical findings were similar in both groups. The mean Glasgow Coma Scale (GCS) value on admission was 13 in both groups, while CXR showed abnormalities consistent with TB in 9/17 with HIV and 7/15 without, with abnormal CT brain scans in 15/19 patients with HIV and 12/16 without. Dilated ventricles and infarcts occurred more commonly in HIV-positive patients. The CSF results showed similar results in both groups. PM in three HIV-positive patients showed weakly formed granulomas and extensive endarteritis and infarcts. Outcomes were similar in the two groups, but a low GCS value on admission was a better prognostic indicator than the CD4-count in HIV-positive patients. CONCLUSION: HIV infection does not significantly alter clinical and CSF findings in TB meningitis in South Africa, but ventricular dilatation and infarcts are more frequent in HIV-positive patients. The GCS gives a better indicator of prognosis than the CD4-count.

Significance of cerebrospinal fluid adenosine deaminase isoenzymes in tuberculous (TB) meningitis.

Adenosine deaminase (ADA) exists as two isoenzymes, ADA(1) and ADA(2). It appears that the ADA(2) isoenzyme originates mainly from monocytes and macrophages. In tuberculous pleural effusions most of the ADA activity consists of ADA(2). The aim of this prospective study was to analyse ADA isoenzymes in the CSF of patients with meningitis to investigate whether the expected rise of the ADA(2) isoenzyme would occur in tuberculous meningitis. ADA isoenzyme analysis was performed on the CSF of 15 patients with tuberculous and 11 patients with bacterial meningitis by an automated kinetic enzyme coupled assay in the presence and absence of a specific ADA inhibitor. The ratio of ADA(2)/ADA(Total) was > 0.8 in 14/15 patients with tuberculous meningitis. In bacterial meningitis the ratio was > or =0.8 in 10/11 patients. The ADA(2) isoenzyme is the major contributor to increased ADA activity in the CSF of patients with tuberculous meningitis, probably reflecting the monocyte-macrophage origin of the ADA.

The impact of HIV on meningitis as seen at a South African Academic Hospital (1994 to 1998).

BACKGROUND: The increase in HIV infections in South Africa is alarming. The aim of this prospective 4-year study was to evaluate the rising incidence of HIV-related admissions due to meningitis at the Pretoria Academic Hospital (PAH) adult neurology ward and to investigate the spectrum of meningitis during this time. PATIENTS AND METHODS: Adults with meningitis presenting at the PAH neurology ward from March 1994 through February 1998 were included. HIV antibody status was determined and patients were assigned to five categories: bacterial, tuberculous, viral and cryptococcal meningitis, as well as an uncertain category. RESULTS: Over the 4-year study period 141 patients with meningitis were seen. Of these, 44 were HIV-positive (31%), with TB meningitis occurring in 16 (36%), cryptococcal meningitis in 22 (50%) and acute bacterial meningitis in three (7%). In the first 2 years of the study, 14% of patients were HIV positive; this figure rose to 44% in the 3rd year, and 57% in the final year. The spectrum of meningitis also changed: bacterial meningitis remained relatively stable at about 25% of the total; TB meningitis almost doubled from 16% in the 1st year to 31% in the last year of the study; viral meningitis initially occurred in 8% of patients and later in 3% of cases, while cryptococcal meningitis showed the most significant increase from 6% of cases in 1994/5 to 31 and 26% respectively in the last 2 years of the study. CONCLUSION: Over a 4-year period the HIV epidemic was responsible for a marked shift in the spectrum of meningitis towards chronic infections such as TB and cryptococcal meningitis at the PAH.