The Correlation between Hyponatremia and/or Danged

The Correlation between Hyponatremia and/or Deranged Cerebrospinal

Fluid Glucose Levels and the Severity of Childhood Tuberculous Meningitis

Dr Rashid Salih

Dissertation presented for the degree of Master of Philosophy in Paediatric Neurology in the

Faculty of Medicine and Health Sciences at Stellenbosch University

December 2021

Supervisors: Prof Regan Solomons

Prof Ronald van Toorn

i

Declaration

I, the undersigned, hereby declare that the work contained in this assignment is my original work

and that I have not previously submitted it, in its entirety or in part, at any university for a

degree.

I agree that the library may lend or copy this dissertation on request.

Date: December 2021

Copyright © 2021 Stellenbosch UniversityAll rights reserved

Stellenbosch University https://scholar.sun.ac.za

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Abstract Introduction: Hyponatremia and/or hypoglycorrhachia are commonly encountered biochemical derangements during the acute stage of childhood tuberculous meningitis (TBM). Few studies have explored the correlation of the abovementioned derangements in relation to the staging of the disease (severity), as well as being biomarkers for vascular ischemic events, hydrocephalus, and seizures. Objective: We aimed to identify the prevalence and the correlation between serum hyponatremia (mild, moderate and severe) and/or hypoglycorrhachia in relation to clinical TBM features such as stage of disease, seizures and stroke. Design: A retrospective hospital based observational cohort study. Results: The prevalence of hyponatremia was 344 out of 481 (71.5%) patients; 169 (49.1%) had mild hyponatremia, 146 (42.4%) moderate hyponatremia and 29 (8.4%) severe hyponatremia. Increasing severity of hyponatremia was associated with stroke (clinical persistent hemi or quadriparesis with or without radiological infarcts), signs of brainstem dysfunction, cranial nerve palsies and non-communicating hydrocephalus (all p<0.05). No association was identified in relation to the age of the child, duration of symptoms or basal meningeal enhancement on baseline CT imaging. The prevalence of hypoglycorrhachia was 72.9% (306 out of 420). Children with hypoglycorrhachia were more likely to exhibited longer symptom duration prior to admission (p=0.02); non-communicating hydrocephalus (p=0.05) as well as higher cerebrospinal cell counts and protein levels (both p <0.01). Conclusion: Hyponatremia and/or hypoglycorrhachia occur in more than two-thirds of children with TBM. Increasing severity of hyponatremia is predictive of TBM disease complications such as stroke and non-communicating hydrocephalus. CSF glucose depletion correlates with non-communicating hydrocephalus and increased CSF inflammation. Key words: Tuberculous meningitis, Hyponatremia, Hypoglycorrhachia, Hyperglycorrhachia


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Acknowledgement

I would like to express my gratitude to Professor Regan Solomons and Professor Ronald van

Toorn for their support, guidance, and insight throughout this research project. My gratitude to

the Department of Paediatrics and Child Health at Stellenbosch University and Tygerberg

Hospital for the opportunity to train as a post-graduate student and senior registrar in paediatric

neurology.


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Table of Contents

i. Declaration

ii. Abstract

iii. Acknowledgement

iv. Table of Contents

vi. List of Abbreviations

Chapter 1: Literature review ………………………………………………………………1

1.1 Epidemiology of TB and TBM ……………………………………………………….……1

1.2 Clinical profile of childhood TBM ………………………………………………..….…….1

1.3 Diagnosis of childhood TBM ……………………………………………………….……...2

1.4 Predictors of outcome in childhood TBM …………………………………………….……2

1.4.1 Hyponatremia in childhood TBM …………………………………...………………….….2

1.4.2 Disturbed glucose metabolism in childhood TBM ………………………………...……….3

Chapter 2: Study aim of the investigation …………………………………………………..…4

2.1. Research justification ………………………...………………………………………....….4

2.2. Research Hypothesis ……….………………………………………………………..……4

2.3. Research question ……….…………………………………………………………..….….4

2.4. Aim ………………………………………………………………………………..……….4

2.5. Objectives…………………………………………………………………………..………4

Chapter 3: Methodology ……………………………….………………………………..…….5

3.1. Study design………………………….……………………………………...………...……5

3.2. Study Site ………………………………………………………………………………..…5

3.3. Clinical care ………………………...…………………………………………….…..…….5

3.4. Study population, sampling, case definition ……………………………………….….…...6

3.5. Data collection ………...………………………………………………...………………….6

3.6. Data management..…………….……………………………………………………………6

3.7. Variables …………………………………………….…………………….…………….….6


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3.8. Statistics …………………………………………………………………………………….8

3.9. Ethics ……………………………………………………………………………………….8

Chapter 4: Results ………………………………………………………………………………9

Chapter 5: Discussion ……………………………………….………………………...……….10

Chapter 6: Strengths and limitations …………….…………...……………...……………….12

Chapter 7: Conclusion …………………...………………… ……………………………….13

References……………………………………………………………………………………….14

Appendices ………………………………………...……………………………………………17

List of tables…...…………………………………………………………………………………17

List of figures ……………………………………...……………………………….……...…….22

Letter of ethics approval …...……………………………………………...…………………….24


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Operational abbreviations: ADH: Antidiuretic hormone

ANP: Atrial natriuretic peptide

ATP: Adenosine triphosphate

BCG: Bacillus Calmette-Guerin

BMRC: British Medical Research Council

CSW: Cerebral salt wasting

CSF: Cerebrospinal fluid

CT: Computed tomography

ECM: Routine Health Information

GCP: Good Clinical Practice

GCS: Glasgow Coma Scale

HREC: Health Research Ethics Committee

MRI: Magnetic resonance imaging

NHLS: National Health Laboratory Service

SIADH: Syndrome of inappropriate antidiuretic hormone

TAH: Tygerberg Academic Hospital

TB: Tuberculosis

TBM: Tuberculous meningitis


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Chapter 1: Literature review

1.1 Epidemiology of TB and TBM According to the 2019 World Health Organization (WHO) Global Tuberculosis (TB) bulletin, an estimated 10.0 million people developed TB disease in 2018. Worldwide, TB is one of the top 10 causes of death and the leading cause from a single infectious agent (above HIV/AIDS). Millions of people continue to fall sick with TB each year. In 2018, TB caused an estimated 1.2 million deaths among HIV-negative people and there were an additional 251 000 deaths from TB among HIV-infected patients.1

Tuberculous meningitis (TBM) represents 1% of all cases of TB. Although this percentage is disproportionately small, it contributes to a significant proportion of TB-related morbidity and mortality.1 Young children, elderly patients and those with immunodeficiency, mostly HIV co-infection and cancer, are at increased risk of developing TBM, contributed to by malnutrition, anaemia, advanced immune suppression and frequent TB exposure.2,3,4 The peak age for TBM incidence is <5 years.5,6 A large South African retrospective study of children diagnosed with TBM found that 82% of children were < 5 years of age.7 In the Western Cape Province of South Africa, TBM is the most common as well as most devastating form of bacterial meningitis.8

1.2 Clinical profile of childhood TBM Tuberculous meningitis is typically a sub-acute disease, mostly with an insidious onset and non-specific symptoms, delaying early recognition and diagnosis. As a consequence, clinicians should therefore have a high index of diagnostic suspicion. A prominent clinical feature of TBM is the sub-acute duration of symptoms, typically >6 days.7,9,10 TBM may also present acutely, or conversely, have a chronic presentation with symptom duration ranging from 3 days to 6 months.11

A prodromal phase of one or more of low-grade fever, malaise, headache, dizziness, vomiting, poor feeding and growth faltering, cough, irritability, and/or personality changes can persist for several weeks, after which patients then develop more central nervous system (CNS) specific symptoms including neck stiffness, depressed level of consciousness, raised intracranial pressure, motor deficit and cranial neuropathies. When TBM is allowed to progress without treatment, coma will ensue. Seizures, in contrast to adults, are commonly seen in children with TBM, and can occur in up to half of paediatric cases. 7,10,12 A history of recent close contact with an adult source-case with TB is found in half of children (47%-53%), which is more frequent than when compared to adults.7,10,11

The signs and symptoms of stage І TBM are non-specific and relate more to primary infection than neurological disease, leading to missed diagnosis.13 The majority of patients present with late stage TBM, stage II or III, with very poor outcome.7,11

1.3 Diagnosis of childhood TBM


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The most valuable, but also sometimes confusing test in the diagnosis of TBM, is evaluation of cerebrospinal fluid (CSF) from lumbar puncture, which is incorporated in the uniform research case definition for TBM.14 Characteristic CSF findings of TBM include clear and colourless appearance, markedly increased protein (0.4 - 5.0 g/L), increased white cells (range 5-1000 cells/mm3) and a low glucose concentration (absolute value < 2.2 mmol/L and/or a CSF: plasma ratio <50%). Lymphocytic predominance usually occurs, but very early in the disease a neutrophil predominance can cause diagnostic confusion.7,15,16,17,18 Atypical CSF findings are common, including normal CSF protein, glucose, cell count and neutrophil predominance.8 It is self-explanatory that the diagnosis of TBM is based on the recognition of early non-specific symptoms and general illness and not by the classical signs of meningitis. The presenting clinical symptoms, unfortunately, do not distinguish TBM from other forms of meningitis, especially partially-treated bacterial meningitis, contributing to diagnostic and treatment delay.15,16

1.4 Predictors of outcome in childhood TBM Several studies have investigated predictors of poor outcome in children with TBM.7,19,20 A large retrospective cohort study of 554 TBM children at our institution reported that the following factors are significantly associated with a poor outcome: young age, HIV-co-infection, stage III TBM disease, convulsions, cranial nerve palsies, headache, raised intracranial pressure, brainstem dysfunction, motor deficits, as well as radiological evidence of hydrocephalus and cerebral infarction. Stage of disease, headache, convulsions, motor deficits, brainstem dysfunction and cerebral infarctions were independently associated with poor outcome by multivariable logistic regression analysis. The study did not explore the association between serum hyponatremia and outcome. Furthermore, there was not a significant association between abnormal CSF/blood glucose ratios (inclusive of ratios <60% and >80%).7

1.4.1 Hyponatremia in childhood TBM Hyponatremia has long been recognized as a serious potential metabolic consequence of TBM, occurring in 35-65% of children with the disease.21 It is independently associated with a poor outcome which has been attributed to either a more delayed presentation or increased severity of TBM disease.22 Two pathological conditions have been implicated in the development of hyponatremia in TBM, namely the syndrome of inappropriate antidiuretic hormone (SIADH) and cerebral salt wasting syndrome (CSWS). Antidiuretic hormone (ADH) has been shown to decrease cerebral arterial resistance, increase microvascular pressure, whilst decreasing CSF production.23 In CSWS, the increased atrial natriuretic peptide (ANP) levels may result in reduction of the intravascular volume which has the potential to induce cerebral ischemia.24,25 In clinical practice, the distinction between the two conditions can be challenging because the primary secretion of ADH or ANP will lead to secondary factors that may make identification of the causative factor impossible. It furthermore necessitates an accurate assessment of a patient’s intravascular volume which often proves difficult, especially in resource-constrained settings. Some clinicians argue that the distinction may be impossible and of little clinical relevance as the treatment of intracranial-related hyponatremia should be hypertonic saline in all cases. There is furthermore no evidence supportive of fluid restriction. In fact, it may actually be harmful in TBM, as it may potentially compromise cerebral blood flow and induce cerebrovascular thrombosis.


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Hyponatremia in TBM has been evaluated in only a few studies. Table 1 lists all the studies that investigated hyponatremia in TBM. Of clinical interest, are the 2 studies by Misra UK et al. that reported a higher prevalence of basal exudates, depressed level of consciousness (GCS) and CSWS-related stroke in hyponatremic TBM patients. 23,25 1.4.2 Disturbed glucose metabolism in childhood TBM Hypoglycorrhachia (abnormally low cerebrospinal fluid glucose concentration) has long been recognised as a predictor of central nervous system microbial infection, including TBM in children. The pathophysiology underlying CSF glucose depletion remains controversial. Hypoglycorrhachia is associated with higher degrees of CSF inflammation.26 However, uncertainty exists whether solely inflammation or mycobacterial load, or both, are responsible for CSF glucose depletion. Recently, a study by Baud et al. concluded that the main driver of hypoglycorrhachia appears to be a combination of microbial meningitis with moderate to high degrees of CSF inflammation, suggesting that the presence of microorganisms capable of catabolizing glucose is a determinant of hypoglycorrhachia in meningitis.27 An additional major factor responsible for hypoglycorrhachia in TBM patients is thought to be related to inhibition of the entry of glucose because of the alteration of membrane glucose transport and increased anaerobic glycolysis by neural tissue. 28

Cerebral tissue is known to be extremely vulnerable to ischemic injury because of its relatively high oxygen consumption and near-total dependence on aerobic glucose metabolism. Interruption of cerebral perfusion leads to metabolic substrate (glucose) depletion, as well as hypoxemia, which then rapidly results in functional impairment. In addition, reduced perfusion also impairs the clearance of potentially toxic substrates from neural tissue (neurotoxicity). If oxygen tension, blood flow, and glucose supply are not re-established to its normal range within 3-8 minutes, adenosine triphosphate (ATP) stores start depleting and irreversible neuronal injury commences in most cases. The elevated CSF lactate level that commonly accompanies a low CSF glucose level provides additional support for increased anaerobic metabolism contributing to these changes. 27

There are very few reports of CSF glucose concentrations after ischemic stroke in the published literature. These reports suggest an association with mild to moderate elevation of CSF glucose concentrations, but interpretation of such data is marred by a failure to include simultaneous data on serum glucose concentraion and /or CSF-to-serum ratios.


https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/glucose-transport

https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/glycolysis

https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/nerve-tissue

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Chapter 2: Aim of the investigation 2.1 Research justification Childhood TBM remains a devastating disease and a global threat, especially in a TB endemic area like the Western Cape Province of South Africa. The majority of children diagnosed with TBM are less than 5 years of age. To accurately prognosticate outcome in childhood TBM, identification of poor outcome predictors (severity determinants) is of critical importance. Previous studies have identified stage of disease, headache, convulsions, motor deficits, brainstem dysfunction and cerebral infarctions as valuable predictors of poor outcome. Few studies have explored the predictive value of biochemical derangements (hyponatremia and deranged glucose metabolism (hyper and hypoglycorrhachia), especially in relation to staging of the disease, as well as being biomarkers for vascular ischemic events, hydrocephalus, and seizures. 2.2 Research hypothesis Hyponatremia and hypo/and hyperglycorrhachia are predictive of the severity of TBM disease at onset of disease. 2.3 Research question Is there a correlation between low serum sodium, abnormally low or high CSF glucose and the severity of TBM disease in children? 2.4 Aim To describe the correlation between hyponatremia, hypo / hyperglycorrhachia, and the severity of tuberculous meningitis in children over the past 30 years at TBH, Cape Town, South Africa 2.5 Objectives 1. To describe the prevalence of mild, moderate and severe hyponatremia in TBM children. 2. To describe the prevalence of a deranged CSF glucose profile in children presenting with

TBM. 3. To investigate whether there is a correlation between hyponatremia and level of

consciousness (GCS) at onset of the TBM disease. 4. To investigate whether there is a correlation between hyponatremia and staging of TBM

disease at onset of the disease. 5. To investigate whether there is a correlation between hyponatremia and stroke (i.e.

radiological infarcts) at presentation in children with TBM 6. To investigate whether there is an association between hyponatremia and seizures at

presentation in children with TBM. 7. To investigate whether there is an association between abnormal CSF glucose profile (CSF

hyper- or hypoglycorrhachia) and stroke (i.e. radiological infarcts) at presentation in children with TBM.


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Chapter 3: Methodology 3.1 Study design A retrospective observational study investigating the correlation between hyponatremia, hypo/hyperglycorrhachia, and the severity of tuberculous meningitis in children diagnosed with definite and probable tuberculous meningitis, between 1985 and 2015, at Tygerberg Academic Hospital (TAH). 3.2 Study site Tygerberg Academic Hospital (TAH) is a tertiary teaching hospital situated in the Western Cape Province of South Africa. It is currently the largest hospital in the Western Cape, and the second-largest hospital in South Africa serving as the academic and teaching hospital for Stellenbosch University. It lies within the metropole of Cape Town serving mostly poor communities in its geographical drainage area with a population over 2.6 million people. Each year, more or less 16 000 babies and children receive inpatient medical care at TAH and more than 100 000 receive specialist medical care as outpatients. In 2019 more than 100 children with TBM were admitted to the children’s neurology inpatient ward. 3.3 Clinical care On admission, all children underwent general physical and neurological examination. In patients with suspected raised intracranial pressure, brain computed tomography (CT) was performed prior to lumbar puncture. CSF analysis included biochemistry and microbiology and Mycobacterium tuberculosis culture. All children with TBM were treated with isoniazid (20 mg/kg/day, maximum 400mg daily), rifampicin (20 mg/kg/day, maximum 600 mg daily), pyrazinamide (40 mg/kg/day maximum 2g daily) and ethionamide (20 mg/kg/day, maximum 750 mg daily) for 6 months. All drugs were administered as a single daily dose before breakfast. Drugs were administered by nasogastric tube to patients who were unable to swallow. Treatment was prolonged to 9 months in cases with HIV co-infection and/or isoniazid monoresistance. Corticosteroids (prednisone 2mg/kg/day, maximum 60 mg) were prescribed for the first 4 weeks of therapy in all children with TBM. Institutional practice is to perform a lumbar puncture in all children with suspected TBM, even those with signs of raised intracranial pressure (ICP). Air encephalography is then performed to determine whether the hydrocephalus is communicating or non-communicating. TBM cases with non-communicating hydrocephalus are treated by ventriculoperitoneal (VP) shunting or third ventriculostomy, while communicating hydrocephalus is managed medically with diuretics (50 mg/kg/day of acetazolamide and 1 mg/kg/day of furosemide). Children presenting with signs of impending herniation are referred for emergency VP shunting (lumbar puncture contra-indicated).


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3.4 Study Population, sampling and case definitions 3.4.1 Inclusion criteria: All children aged between 3 months and 13 years All children with definite and probable TBM Children with baseline serum sodium samples (serum sodium analysis only) Children with baseline CSF glucose samples (CSF glucose samples only) Children with baseline brain CT scan.

3.4.2 Exclusion criteria: Children aged less than 3 months and older than 13 years Non-tuberculous meningitis and possible TBM Children with insufficient or incomplete data.

3.4.3 Sample size is estimated at 470 children fulfilling inclusion criteria. The uniform research case definition for TBM by Marais et al. (Table 2) was used to classify patients into three categories i.e. possible, probable or definite TBM.14 3.4.4 Definite TBM is defined as patients with fulfilling one of 2 criteria: A) Symptoms and signs of meningitis including ≥1 of headache, irritability, vomiting, fever, meningism, convulsions, focal neurological deficit, altered level of consciousness and lethargy plus ≥1 of the following: acid-fast bacilli seen in the CSF; Mycobacterium tuberculosis cultured from the CSF; or a CSF positive commercial nucleic acid amplification test for Mycobacterium tuberculosis. B) Acid-fast bacilli seen in the context of histological changes consistent with tuberculosis in the brain or spinal cord with suggestive symptoms or signs and CSF changes, or visible meningitis (on autopsy). 3.4.5 Probable TBM is defined as symptoms and signs of meningitis including ≥1 of headache, irritability, vomiting, fever, meningism, convulsions, focal neurological deficit, altered level of consciousness and lethargy plus a total diagnostic score of 10 or more points (when cerebral imaging is not available) or 12 or more points (when cerebral imaging is available) plus exclusion of alternative diagnoses. At least 2 points should either come from CSF or cerebral imaging criteria. 3.4.6 Possible TBM is defined as symptoms and signs of meningitis including ≥1 of headache, irritability, vomiting, fever, meningism, convulsions, focal neurological deficit, altered level of consciousness and lethargy plus a total diagnostic score of 6–9 points (when cerebral imaging is not available) or 6–11 points (when cerebral imaging is available) plus exclusion of alternative diagnoses. Possible tuberculosis cannot be diagnosed or excluded without doing a lumbar puncture or cerebral imaging. Patients are defined as Not tuberculous meningitis when an alternative diagnosis is established, without a definitive diagnosis of tuberculous meningitis or other convincing signs of dual disease


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3.4.7 The refined British Medical Research Council (BMRC) criteria was used to classify TBM severity as follows: Stage I: Glasgow coma scale (GCS) of 15, without focal neurological deficit; Stage II a: GCS of 15 with focal neurological deficit; Stage II b GCS of 11-14 with or without focal neurological deficit and Stage III GCS < 11 with or without focal neurological deficit.29,30 3.4.8 Hyponatremia was defined as a serum sodium less than 135 mEq/L. Severity of hyponatremia was defined by the serum sodium level as follows: Mild hyponatremia: serum concentration between 130 and 134 mEq/L; moderate hyponatremia: serum concentration between 120 to 129 mEq/L; severe hyponatremia: serum concentration <120 mEq/L.22

3.4.9 Hypoglycorrhachia was defined as a CSF glucose level of either < 2.2 mmol or alternatively a level which is < 50% of the blood glucose level.14,26 3.4.10 Hyperglycorrhachia was defined as a CSF glucose level of either > 7.8 mmol or alternatively a level which is > 80% of the blood glucose level. 3.4.11 Cerebral infarction was defined as an area of hypodensity in one or more arterial territory on a non-contrast CT scan. 3.4.12 TBM-related stroke was defined as the persistence (after 4 weeks) of an acute onset hemi or quadriplegia with or without CT evidence of arterial ischemic infarction. 3.4.13 Brainstem dysfunction was defined as the presence of long tract signs and cranial nerve palsies 3.5 Data collection The data was obtained from 2 existing TBM databases including prospectively enrolled childhood tuberculous meningitis at Tygerberg Hospital between 1985 and 2015. 3.6 Data management All data was handled and managed according to Good Clinical Practice (GCP) requirements and ethical standards. Patients’ identifications will be anonymized by giving each patient a unique identification number. The data captured will be password protected and only accessible to the principal investigator and supervisors. Confidentiality will be maintained at all points of the study. 3.7 Variables which were collected included:

• Age at onset • Serum sodium • CSF glucose • Serum glucose • CSF: serum glucose ratio


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• Stroke (persistence of a hemiplegia/quadriplegia with or without CT infarction) • TBM stage • GCS • Seizures • Hydrocephalus • Tuberculoma • HIV status

3.8 Statistical analysis Numerical variables were summarized using means and standard deviations, when the data is normally distributed. Medians and interquartile ranges were used when data is not evenly distributed. The X2 was used to assess the differences between categorical variables. The one-way ANOVA was used to compare means. The level of significance was at set at p <0.05 (2-sided). Upon analysis of correlation between degree of serum hyponatremia/ aberrant CSF glucose and TBM severity, receiver operating characteristic (ROC) curves were constructed and area under the curve (AUC) determined. 3.9 Ethical considerations Data was prospectively collected of approximately 400 patient’s between1985-2015, (existing TBM database). Ethical approval was previously granted, HREC reference numbers N10/11/367 and N11/01/006), for data collected over the 30-year period. Informed consent was obtained from the parents/caregivers. Since this is a retrospective observational study of routinely collected data, therefore will be minimal risks to the parents, patients or medical personnel involved in the study and the rights and welfare of the subjects will not be affected in any way, therefore a waiver of consent will be requested. The protocol was approved by the Stellenbosch University Health Research Ethics Committee (SU HREC). Project ID: 15296 HREC Reference No: S20/05/112.


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Chapter 4: Results Four hundred and eighty-one children with TBM were included. The median age was 28 (14-48.0) months and 239 (49.7%) were males. The diagnosis of TBM was definite in 91 (18.9%) and probable in 390 (81.1%). TBM severity data was available in 454 children; stage I in 13 (2.9 %), stage IIa in 84 (18.5%), stage IIb in 124 (27.3%) and stage III in 233 (51.3%). HIV prevalence was 5.2% (12 out of 233 tested). The prevalence of hyponatremia was 344 out of 481 (71.5%) patients; comprising 169 (49.1%) with mild hyponatremia, 146 (42.4%) with moderate hyponatremia and 29 (8.4%) with severe hyponatremia. Ten patients had hypernatremia (serum sodium >145mmol/L). Table 2 illustrates the demographic, clinical, laboratory and radiologic parameters of TBM children with and without serum hyponatremia (varying degrees of severity). Predictors of hyponatremia Table 3 illustrates the comparison of demographic, clinical, laboratory and radiologic parameters of TBM patients with and without serum hyponatremia (varying degrees of severity). TBM children with severe hyponatremia had significantly higher frequency of stroke (clinically-persistent hemi- or quadriparesis with or without radiological arterial ischemic infarction) (p=0.01), brainstem dysfunction (p<0.01), cranial nerve palsies (p=0.04) and non-communicating hydrocephalus (p=0.03). Children with moderate hyponatremia similarly were more likely to exhibit signs of brainstem dysfunction (p=0.02). Children with mild hyponatremia had significantly higher frequency of hydrocephalus (p=0.01). Figure 1 illustrates the median Glasgow Coma Score (GCS) on admission in relation to the severity of the degree of serum hyponatremia, whilst Figure 2 illustrates the prevalence and proportion of stroke in relation to the severity of the hyponatremia. No correlation was identified in relation to the age of the child, symptoms (vomiting, fever, seizures, headache, weight loss), duration of symptoms, basal meningeal enhancement, presence of tuberculomas or cerebral infarction on CT imaging on admission. Predictors of hypoglycorrhachia Table 4 illustrates the demographic, clinical, laboratory and radiologic parameters of TBM patients with and without CSF hypoglycorrhachia. The prevalence of hypoglycorrhachia was 72.9% (306 out of 420). Table 5 illustrates the comparison of demographic, clinical, laboratory and radiologic parameters of TBM patients with and without hypoglycorrhachia. TBM children with hypoglycorrhachia were more likely to exhibit longer symptom duration (p=0.02) and non-communicating hydrocephalus (p=0.05). In addition, TBM children with hypoglycorrhachia had higher CSF cell counts and protein. (P<0.01). No correlation was identified in relation to the age of the child, symptoms (vomiting, fever, seizures, headache, and weight loss), basal meningeal enhancement, presence of tuberculomas or stroke (clinically-persistent hemi- or quadriparesis with or without radiological arterial ischemic infarction).


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Chapter 5: Discussion In the present study, more than two-thirds of TBM children exhibited hyponatremia which was above the upper prevalence range (35-65%) reported in previous literature studies. The severity of the hyponatremia does seem to be of clinical importance as TBM children with severe hyponatremia (less than 10%) were more likely to exhibit severe neurological stigmata such as signs of brainstem dysfunction, cranial nerve palsies, stroke and non-communicating hydrocephalus. In this context it is important to appreciate that the signs and symptoms of raised intracranial pressure (ICP) and brainstem dysfunction often overlap. Brainstem injury, for example, may mimic all the signs of raised ICP whilst both raised ICP and brainstem dysfunction can induce cranial neuropathies. Hyponatremia itself may contribute to raised ICP and poor outcome through worsening of cerebral edema. Two pathological conditions, namely the syndrome of inappropriate antidiuretic hormone (SIADH) and cerebral salt wasting (CSW), have been implicated in the development of hyponatremia in TBM. SIADH involves the continued secretion of ADH despite normal or increased plasma volume. The resultant impairment of water secretion and consequent water retention produces hyponatremia with concomitant low serum and high urine osmolality (the hallmarks of SIADH). Cerebral effects of SIADH include decreased cerebral arterial resistance, increased microvascular pressure, a reduced blood flow to the choroid plexus and decreased CSF production. Non-osmotic factors, in particular hypovolemia, also play a role in the release of ADH, therefore there may be more than one reason for increased ADH levels in the typical patient with meningitis. The underlying mechanism for CSW in TBM is thought to be related to increased release of natriuretic factors such as ANP and brain natriuretic peptide (BNP). It is characterized by increased urine sodium losses, in combination with extracellular fluid losses due to the accompanying renal water loss. Hyponatremia ensues if urine sodium losses are greater than water losses. In CSW, total body sodium is reduced, while in SIADH total body sodium is normal, i.e. the hyponatremia in SIADH is dilutional. The release of BNP occurs mainly from the ventricles, hypothalamus, sympathetic projections and the adrenal medulla and is thought to occur secondary to ventricular dilatation/distention. CSW is thought to be a protective mechanism in response to excessively raised ICP and vasospasm. Previously, SIADH was assumed to be the commonest cause of hyponatremia in TBM, however more recent studies report CSW as more common.40 The differentiation between the two conditions is important because the treatment of one may be detrimental to the other. Distinction between the 2 conditions is often difficult, especially in resource-constrained settings. This occurs because the primary secretion of ADH or BNP often leads to secondary factors that cloud


https://www.sciencedirect.com/topics/medicine-and-dentistry/vasopressin

https://www.sciencedirect.com/topics/medicine-and-dentistry/cerebral-salt-wasting

https://www.sciencedirect.com/topics/medicine-and-dentistry/hypovolemia

https://www.sciencedirect.com/topics/medicine-and-dentistry/patient-with-meningitis

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the identification of the causative factor. CSW may result in secondary compensatory secretion of ADH and SIADH which in turn can result in inhibition of aldosterone secretion. Therefore, the presence of ADH in the plasma, even in the setting of a ‘clinical picture’ of SIADH, does not appear to be enough to confirm the diagnosis. An accurate assessment of the patient’s intravascular volume is necessary; however, this is difficult. Some suggest that the distinction may be impossible, but perhaps is less important than previously thought and that the treatment for CNS-associated severe hyponatremia should be hypertonic saline in all cases. There is no evidence from the literature supportive of fluid restriction in TBM-associated hyponatremia; in fact, it may precipitate hypovolemia, which should be avoided at all costs.41 In CSW, fludrocortisone has been used in patients who are refractory to saline and oral salt treatment. In addition to arginine vasopressin peptide receptor antagonist (V2 receptor antagonists) found to be useful for the management of hyponatremia in SIADH.40 We postulate that the increased risk of stroke in the study TBM children with severe hyponatremia can be attributed to probable CSW induced volume contraction. This postulation is supported by a study from Misra who reported that hypovolemia due to cerebral salt wasting may contribute to stroke in TBM.25 Similarly, the correlation between severe hyponatremia and hydrocephalus can be explained by excessive BNP release secondary to ventricular distention. A reduction in CSF glucose level and a change in the CSF: serum glucose ratio is often used as one of the diagnostic indicators of meningitis. Glucose is mainly transported into the CSF by facilitation across the choroid plexus and the ventricular and subarachnoid capillary system while some of it is transported by simple diffusion. Current theories postulate that the pathogenesis of hypoglycorrhachia is multifactorial and includes inhibition of glucose entry into the subarachnoid spaces due to alterations in the blood brain barrier, increased rate of glucose transport across the arachnoid villi, increased glycolysis by leucocytes and bacteria and increased rate of metabolism in the brain and spinal cord. Of interest is that the study TBM children with hypoglycorrhachia exhibited higher CSF cell counts and protein; a finding that can be attributed to the higher degrees of CSF inflammation.26

Few studies have explored the clinical significance of hypoglycorrhachia in TBM children at onset of disease. In this study, TBM children with hypoglycorrhachia were more likely to exhibit longer symptom duration, as well as non-communicating hydrocephalus. The former can be explained by exposure to a longer period of inflammation, whilst the latter is postulated to be due to association with more severe inflammation, increasing the risk of obstruction of CSF flow.


https://www.sciencedirect.com/topics/medicine-and-dentistry/aldosterone-release

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Chapter 6: Strengths and limitations Strength: Study strengths include a very large sample size collected over a 30-year period and the fact that all the data was collected prospectively. The inclusion, exclusion and diagnostic criteria were well defined. The study findings may potentially provide valuable information regarding the significance of biochemical derangements in relation to the severity of TBM disease. Limitations: A study limitation was incomplete data relating to some laboratory parameters and the small HIV-related TBM sample size. HIV testing only became routinely available during the latter part of the study and in some of the children the HIV status was unknown. The etiology of the serum hyponatremia was not determined as urine osmolality and sodium were not routinely requested. We were thus unable to distinguish between CSWS and SIADH. Despite this, it is important to note that the management of serum hyponatremia secondary to intracranial causes is uniform irrespective of etiology. Computed tomography is often the only imaging modality that is readily available in resource-constrained TB endemic settings. Unfortunately, CT is less sensitive at detection of acute arterial ischemic lesions (compared to MRI) and this may have resulted in an underestimation of the number of strokes. Further limitations were that we were unable to localize the site of infarction or quantify the degree of basal enhancement on CT brain.


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Chapter 7: Conclusion Hyponatremia and/or hypoglycorrhachia occur in more than two-thirds of children with TBM. Increasing severity of hyponatremia is predictive of TBM disease complications such as stroke and non-communicating hydrocephalus. It is our opinion that the increased stroke risk in TBM children with severe hyponatremia can be attributed to CSW-induced volume contraction, whilst the correlation between severe hyponatremia and non-communicating hydrocephalus can be explained by excessive BNP release secondary to ventricular distention. TBM children with hypoglycorrhachia exhibited higher CSF cell counts and protein; a finding that can be attributed to the higher degrees of CSF inflammation.


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https://www.ncbi.nlm.nih.gov/pubmed/?term=Davis%20LE%5BAuthor%5D&cauthor=true&cauthor_uid=8414030

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41. van Toorn R, Solomons R: Update on the Diagnosis and Management of Tuberculous Meningitis in Children. Semin Pediatr Neurol 21:12-18.


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Appendices List of tables Table 1: All studies in the literature that investigated serum hyponatremia in TBM

No 1st Author, year Patients Hyponatremia No (%) Any association?

1. Inamdar et al., 201621 75 29 (39) 2. Misra UK et al., 201623 76 34(45) CSWS was related to the severity of TBM.

Hyponatremia was related to ↓GCS and basal exudates

3. Misra UK et al., 201825 81 34 (42) Stroke occurred in 40% of patients, 50% of whom had CSWS. Patients with CSWS had more frequent deep white matter infarcts which were in the internal border zone in 4%

4. Karandanis et al., 197631 11 8 (73) 5. Davis et al., 199332 54 43(79) 6. Shian et al., 199333 16 11(70) 7. Singh et al., 199434 20 13 (65) No effect on outcome after 72 hours 8. Narotam et al., 199435 24 15 (63) 9. Smith et al., 200036 20 12 (60) 10. Bussman et al., 200037 195 20 (10) 11. Anderson et al., 201038 104 51 (49) 12. Lee SA et al., 201839 47 37 (79)

CSWS- cerebral salt wasting syndrome, TBM- tuberculous meningitis, GCS- Glasgow coma scale


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Table 2: Clinical, laboratory and radiologic parameters of paediatric TBM with and without varying severity of serum hyponatraemia

* Includes patients with serum sodium >145mmol/L TBM= tuberculous meningitis, IQR= interquartile range, HIV=human immunodeficiency virus, GCS= Glasgow Coma Scale, ICP= intracranial pressure, CSF= cerebrospinal fluid

All patients (n=481)

n/N (%)*

Without hyponatermia

(n=127) n/N (%)

Mild hyponatremia (n=169) n/N (%)

Moderate hyponatremia

(n=146) n/N (%)

Severe hyponatremia

(n=29) n/N (%)

Male gender 239/481 (49.7) 57/127 (44.9) 82/169 (48.5) 80/146 (54.8) 15/29 (51.7) Age on admission in months median 28.0: IQR 14.0-48.0 23.0: IQR 12.0-48.0 30.0: IQR 16.0-49.0 29.0: IQR 16.0-49.0 28.0: IQR 24.0-44.5

Vomiting 223/421 (53.0) 55/112 (49.1) 78/148 (52.7) 70/129 (54.3) 14/25 (56.0) Fever 303/448 (67.6) 90/120 (75.0) 101/156 (64.7) 91/137 (66.4) 17/27 (63.0) Seizures 193/421 (45.8) 49/112 (43.8) 67/148 (45.3) 59/129 (45.7) 13/25 (52.0) Headache 107/421 (25.4) 28/112 (25.0) 40/148 (27.0) 34/129 (26.4) 5/25 (20.0) Symptom duration > 5 days 401/481 (83.4) 111/127 (87.4) 138/169 (81.7) 120/146 (82.2) 24/29 (82.8)

HIV status Infected 12/233 (5.2) 3/71 (4.2) 4/83 (4.8) 3/62 (4.8) 2/12 (16.7) GCS <15 357/454 (78.6) 90/119 (75.6) 125/160 (78.1) 109/139 (78.4) 24/27 (88.9)

TBM severity Stage I 13/454 (2.9) 7/119 (5.5) 4/160 (2.5) 2/139 (1.4) 0 Stage IIa 84/454(18.5) 21/119 (17.6) 32/160 (20.0) 28/139 (20.1) 3/27 (11.1) Stage IIb 124/454 (27.3) 37/119 (31.1) 44/160 (27.5) 36/139 (25.9) 6/27 (22.2) Stage III 233/454 (51.3) 54/119 (45.4) 80/160 (50.0) 73/139 (52.5) 18/27 (66.7) Hemiparesis 283/454 (62.3) 69/119 (58.0) 100/160 (62.5) 85/139 (61.2) 21/27 (77.8) Stroke (hemiparesis and/or radiologic infarction) 301/445 (67.6) 77/119 (64.7) 108/160 (67.5) 92/139 (66.2) 24/27 (88.9) Cranial nerve palsy 135/454 (29.7) 29/119 (24.4) 48/160 (30.0) 46/139 (33.1) 12/27 (44.4) Raised ICP symptoms 98/453 (21.6) 28/119 (23.5) 31/160 (19.4) 30/138 (21.7) 7/27 (25.9) Brainstem dysfunction 159/454 (35.0) 29/119 (24.4) 53/160 (33.1) 53/139 (38.1) 19/27 (70.4)

Serum sodium (mmol/L) median 132.0: IQR 127.0-135.0

CSF leucocytes 10-500 cells/L 402/454 (88.5) 107/119 (89.9) 146/160 (91.3) 121/139 (87.1) 23/27 (85.2) CSF lymphocyte predominance 373/454 (82.2) 101/119 (84.9) 131/160 (81.9) 115/139 (82.7) 22/27 (81.5) CSF protein concentration >1g/L) 334/449 (74.4) 85/116 (73.3) 109/159 (68.6) 114/138 (82.6) 19/27 (70.4) CSF glucose <2.2mmol/L 297/441 (67.3) 75/116 (64.7) 105/156 (67.3) 95/134 (70.9) 19/26 (73.1) Basal meningeal enhancement 360/435 (82.8) 97/114 (85.1) 120/154 (77.9) 113/132 (85.6) 21/26 (80.8) Tuberculoma(s) 60/435(13.8) 19/114 (16.7) 20/154 (13.0) 17/132 (12.9) 3/26 (11.5) Infarction 157/435 (36.1) 41/114 (36.0) 60/154 (39.0) 43/132 (32.6) 8/26 (30.8) Hydrocephalus 400/435 (92.0) 99/114 (86.8) 147/154 (95.5) 122/132 (92.4) 24/26 (92.3) Non-communicating hydrocephalus 116/494 (29.4) 25/97 (25.8) 40/145 (27.6) 43/122 (35.2) 8/23 (34.8) Death 34/378 (9.0) 5/97 (5.2) 13/133 (9.8) 13/117 (11.1) 3/23 (13.0)


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Table 3: Comparison of demographic, clinical, laboratory and radiologic parameters of TBM in patients with and without hyponatraemia

TBM= tuberculous meningitis, OR= odds ratio, CI= confidence interval, GCS= Glasgow Coma Scale, ICP= intracranial pressure, CSF= cerebrospinal fluid

Mild hyponatremia vs Normotraemia

Moderate hyponatremia vs Normotraemia

Severe hyponatremia vs Normotraemia

p-value OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) Definite TBM 0.25 1.43 (0.77-2.65) 0.14 1.60 (0.85-2.98) 0.87 0.91 (0.28-2.91)

Male Gender 0.50 1.17 (0.74-1.86) 0.10 1.49 (0.92-2.40) 0.51 1.32 (0.59-2.95) Mean age 0.07 0.05 0.16

Vomiting 0.57 1.16 (0.71-1.89) 0.42 1.23 (0.74-2.04) 0.53 1.32 (0.55-3.16) Fever 0.09 0.63 (0.37-1.07) 0.13 0.66 (0.38-1.14) 0.20 0.57 (0.23-1.37) Convulsions 0.81 1.06 (0.65-1.74) 0.76 1.08 (0.65-1.80) 0.45 1.39 (0.58-3.32) Symptom duration >5 days 0.13 0.60 (0.31-1.17) 0.18 0.62 (0.31-1.24) 0.44 0.65 (0.22-1.96) Weight faltering/loss 0.23 1.34 (0.83-2.17) 0.91 1.03 (0.63-1.70) 0.69 0.84 (0.36-1.99)

GCS <15 0.58 1.17 (0.67-2.05) 0.57 1.18 (0.66-2.11) 0.11 2.70 (0.76-9.58) Advanced TBM Stage (2b/3) 0.58 1.17 (0.67-2.05) 0.58 1.18 (0.66-2.11) 0.11 2.70 (0.76-9.58)

Hemiparesis 0.45 1.21 (0.74-1.96) 0.61 1.14 (0.69-1.88) 0.06 2.54 (0.95-6.74) Stroke (hemiparesis and/or radiologic infarction) 0.63 1.13 (0.69-1.87) 0.80 1.07 (0.64-1.79) 0.01 4.36 (1.24-15.35)

Cranial nerve palsy 0.30 1.33 (0.78-2.28) 0.12 1.54 (0.89-2.65) 0.04 2.48 (1.04-5.91) Raised ICP 0.40 0.78 (0.44-1.39) 0.73 0.90 (0.50-1.62) 0.79 1.14 (0.44-2.97) Brainstem dysfunction 0.11 1.54 (0.90-2.62) 0.02 1.91 (1.11-3.28) <0.01 7.37 (2.92-18.61)

CSF leucocytes 10-500 cells/L 0.71 1.17 (0.52-2.63) 0.47 0.75 (0.35-1.64) 0.48 0.65 (0.19-2.18) CSF lymphocyte predominance 0.51 0.81 (0.42-1.53) 0.64 0.85 (0.44-1.66) 0.66 0.78 (0.26-2.34) CSF protein >1g/L 0.40 0.80 (0.47-1.35) 0.07 1.73 (0.95-3.16) 0.76 0.87 (0.34-2.18) CSF glucose <2.2 mmol/L 0.65 1.13 (0.68-1.87) 0.29 1.33 (0.78-2.27) 0.41 1.48 (0.58-3.82) Basal meningeal enhancement 0.14 0.62 (0.33-1.17) 0.91 1.04 (0.51-2.12) 0.59 0.74 (0.24-2.22) Tuberculoma(s) 0.40 0.75 (0.38-1.47) 0.40 0.74 (0.36-1.50) 0.52 0.65 (0.18-2.39) Infarction 0.62 1.14 (0.69-1.88) 0.58 0.86 (0.51-1.46) 0.62 0.79 (0.32-1.98) Hydrocephalus 0.01 3.18 (1.25-8.09) 0.15 1.85 (0.80-4.29) 0.44 1.82 (0.39-8.49)

Non-communicating hydrocephalus 0.41 1.24 (0.74-2.08) 0.13 1.30 (1.57-2.82) 0.03 2.66 (1.09-6.44) Death 0.20 1.99 (0.69-5.79) 0.12 2.30 (0.79-6.70) 0.17 2.76 (0.61-12.50)


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Table 4: Demographic, clinical, laboratory and neuroimaging features in paediatric TBM with and without hypoglycorrhachia 1985-2015

TBM= tuberculous meningitis, IQR= interquartile range, TST= tuberculin skin test, GCS= Glasgow Coma Scale, , ICP= intracranial pressure, CSF= cerebrospinal fluid

Normal glycorrhacia (n=114) n/N (%)

Hypoglycorrhacia (n=306) n/N (%)

Definite TBM 21/114 (18.4) 60/306 (19.6) Probable TBM 93/114 (81.6) 246/306 (80.4)

Male Gender 60/114 (52.6) 153/306 (50.0) Age at admission in months median 29.0: IQR 14.5-63.5 27.0: IQR 15.0-47.0

Vomiting 46/100 (46.0) 146/267 (54.7) Fever 70/107 (65.4) 192/284 (67.6) Convulsions 47/100 (47.0) 122/267 (45.7) Headache 28/100 (29.0) 63/267 (23.6) Symptom duration >5 days 86/113 (76.1) 262/306 (85.6)

TST Positive 51/90 (56.7) 163/264 (61.7) HIV status Infected 6/58 (10.3) 3/129 (2.3) Nutrition Weight faltering/loss 41/107 (38.3) 133/285 (46.7)

GCS <15 86/114 (75.4) 236/300 (78.7) TBM Stage Stage I 6/114 (5.3) 6/300 (2.0) Stage IIa 22/114 (19.3) 58/300 (19.3) Stage IIb 29/114 (25.4) 91/300 (30.3) Stage III 57/114 (50.0) 145/300 (48.3)

Hemiparesis 58/107 (54.2) 182/287 (63.4) Stroke (hemiparesis and/or radiologic infarction) 66/107 (61.7) 200/287 (69.7)

Cranial nerve palsy 27/107 (25.2) 85/287 (29.6) Raised ICP 26/107 (24.3) 58/286 (20.3) Brainstem dysfunction 33/107 (30.8) 100/287 (34.8)

Serum sodium (mmol/L) median 132.0: IQR 127.5-136.0 131.0: IQR 127.0-135.0 CSF leucocytes 10-500 cells/L 90/107 (84.1) 270/287 (94.1) CSF lymphocyte predominance 88/107 (82.2) 238/287 (82.9) CSF protein concentration >1g/L) 73/107 (68.2) 242/287 (84.3) Basal meningeal enhancement 84/106 (79.2) 230/275 (83.6) Tuberculoma(s) 16/106 (15.1) 35/275 (12.7) Infarction 35/106 (33.0) 102/275 (37.1) Hydrocephalus 94/106 (88.7) 255/275 (92.7)

Non-communicating hydrocephalus 27/100 (27.0) 103/273 (37.7) Death 8/89 (9.0) 23/236 (9.7)


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Table 5: Comparison of demographic, clinical, laboratory and radiologic parameters in paediatric TBM with and without hypoglycorrhachia TBM= tuberculous meningitis, OR= odds ratio, CI= confidence interval, ICP= intracranial pressure, CSF= cerebrospinal fluid

p-value OR (95% CI)

Definite TBM 0.78 1.08 (0.62-1.87) Male 0.57 0.88 (0.57-1.36) Mean age 0.04 Vomiting 0.14 1.42 (0.89-2.27) Fever 0.62 1.13 (0.70-1.81) Convulsions 0.82 0.95 (0.60-1.50) Symptom duration >5 days 0.02 1.87 (1.09-3.20) Weight faltering/loss 0.14 1.41 (0.90-2.22) Advanced TBM Stage (2b/3) 0.48 1.20 (0.72-2.00) Hemiparesis 0.10 1.46 (0.93-2.30) Stroke (hemiparesis and/or radiologic infarction) 0.13 1.43 (0.90-2.27)

Cranial nerve palsy 0.39 1.25 (0.75-2.07) Raised ICP 0.39 0.79 (0.47-1.34) Brainstem dysfunction 0.46 1.20 (0.74-1.93) Mean serum sodium 0.89 CSF leucocytes 10-500 cells/L <0.01 3.00 (1.47-6.12) CSF lymphocyte predominance 0.87 1.05 (0.59-1.88) CSF protein >1g/L <0.01 2.51 (1.49-4.20) Basal meningeal enhancement 0.31 1.34 (0.76-2.36) Tuberculoma(s) 0.54 0.82 (0.43-1.55) Infarction 0.46 1.20 (0.75-1.92) Hydrocephalus 0.20 1.63 (0.77-3.46)

Non-communicating hydrocephalus 0.05 1.64 (0.99-2.71) Death 0.84 1.09 (0.47-5.54)


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List of Figures: Figure 1: Illustration of the median GCS on admission in relation the severity of the serum hyponatremia


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Figure 2: Illustrates the prevalence of stroke in relation to the severity of hyponatremia on admission in TBM children.


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Ethical Approval

Approval Notice New Application

03/11/2020 Project ID: 15296 HREC Reference No: S20/05/112 Project Title: The Correlation between Hyponatremia and/or Deranged Cerebrospinal Fluid Glucose Levels and the Severity of Childhood Tuberculous Meningitis Dear Dr Rashid Salih The New Application received on 30/10/2020 was reviewed and approved by members of Health Research Ethics Committee via expedited review procedures on 03/11/2020. Please note the following information about your approved research protocol: Protocol Approval Date: 03 November 2020 Protocol Expiry Date: 02 November 2021 Please remember to use your Project ID 15296 and Ethics Reference Number S20/05/112 on any documents or correspondence with the HREC concerning your research protocol. Please note that the HREC has the prerogative and authority to ask further questions, seek additional information, require further modifications, or monitor the conduct of your research and the consent process. After Ethical Review Translation of the informed consent document(s) to the language(s) applicable to your study participants should now be submitted to the HREC. Please note you can submit your progress report through the online ethics application process, available at: Links Application Form Direct Link and the application should be submitted to the HREC before the year has expired.


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Please see Forms and Instructions on our HREC website (www.sun.ac.za/healthresearchethics) for guidance on how to submit a progress report. The HREC will then consider the continuation of the project for a further year (if necessary). Annually a number of projects may be selected randomly for an external audit. Provincial and City of Cape Town Approval Please note that for research at a primary or secondary healthcare facility, permission must still be obtained from the relevant authorities (Western Cape Department of Health and/or City Health) to conduct the research as stated in the protocol. Please consult the Western Cape Government website for access to the online Health Research Approval Process, see: https://www.westerncape.gov.za/general-publication/health-research-approval-process. Research that will be conducted at any tertiary academic institution requires approval from the relevant hospital manager. Ethics approval is required BEFORE approval can be obtained from these health authorities. We wish you the best as you conduct your research. For standard HREC forms and instructions, please visit: Forms and Instructions on our HREC website https://applyethics.sun.ac.za/ProjectView/Index/15296 If you have any questions or need further assistance, please contact the HREC office at 021 938 9657. Yours sincerely, Mrs. Melody Shana Coordinator HREC1


http://www.sun.ac.za/healthresearchethics

https://www.westerncape.gov.za/general-publication/health-research-approval-process

Documents

The Correlation between Hyponatremia and/or Danged