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LO 18. Describe the possible impact of ACEs (adverse childhood experiences) on a child’s development. 

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LO 18. Describe the possible impact of ACEs (adverse childhood experiences) on a child’s development. 

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ACEs are Adverse Childhood Experiences.

Some examples of ACEs:
Maternal depression, emotional and sexual abuse, substance abuse, domestic violence, physical and emotional neglect, poverty, discrimination etc.

Consequences:
The more ACEs a child experiences, the more likely he/she is to suffer from poor health, low educational outcomes, and substance abuse later in life (and these effects can be passed on to further generations, leading to intergenerational harm and trauma.

The most sensitive period for the child's brain development is from conception to 2 years old.

Chronic stress (and examples of ACEs aforementioned) can actually lead to negative changes in the brain's architecture. For example, with prolonged, toxic stress, the neurone in the prefrontal cortex and hippocampus are damaged, leading to fewer neurone available to make meaningful circuit connections.

It is important to promote healthy relationships, and intervene ASAP when a child is facing toxic ACEs.

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LO 13 Outline the epidemiology (determinants, distribution, prevention and control) of meningococcal disease in South Africa. (Note: prevention and control includes the public health response to an outbreak of meningitis). Public Health readings 

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LO 13 Outline the epidemiology (determinants, distribution, prevention and control) of meningococcal disease in South Africa. (Note: prevention and control includes the public health response to an outbreak of meningitis). Public Health readings 

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Determinants:

Age (infants at high risk), immune status (HIV positive, asplenia), environmental factors (overcrowding), Serogroup

Distribution:

Late winter and early spring

Occurs sporadically in small clusters throughout the world

Mines, correctional and detention centres, academic institutions, displaced communities

Highest incidence in under 5’s

Serogroup B highest in Western Cape

Prevention:

Isolation

Surgical masks

Gloves worn

Handwashing

Eye protection

Needle disposal

Investigation of cases

Contact tracing

Pre exposure prophylaxis (vaccine)

Close surveillance

Control:

Isolation of patients for 24-48 hours.

Ceftriaxone/Cefotaxime

Notification

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 LO 14 Approaches a medical practitioner should adopt when dealing with notifiable diseases. 

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 LO 14 Approaches a medical practitioner should adopt when dealing with notifiable diseases. 

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Category 1 notifiable medical conditions that require immediate reporting by the most rapid means available upon diagnosis followed by a written or electronic notification to the Department of Health within 24 hours of diagnosis by health care providers, private health laboratories or public health laboratories

Category 2 notifiable medical conditions to be notified through a written or electronic notification to the Department of Health within seven (7) days of clinical or laboratory diagnosis by health care providers, private health laboratories or public health laboratories.

Category 3 notifiable medical conditions to be notified through a written or electronic notification to the Department of Health within 7 days of diagnosis by private and public health laboratories.

Category 4 notifiable medical conditions to be notified through a written or electronic notification to the Department of Health within 1 month of diagnosis by private and public health laboratories.

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LO 20. Explain the physiology of hearing from the external ear to the temporal lobe making reference to conduction and sensorineural deafness

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LO 20. Explain the physiology of hearing from the external ear to the temporal lobe making reference to conduction and sensorineural deafness

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In the human ear, a sound wave is transmitted through 4 separate mediums along the auditory system before a sound is perceived: in the outer ear, air; in the middle ear, mechanical; in the inner ear liquid and to the brain, neural.

Sound Transmission through the Outer Ear
Air transmitted sound waves are directed toward the delicate hearing mechanisms with the help of the outer ear, first by the pinna, which gently funnels sound waves into the ear canal, then by the external auditory canal.

Sound Transmission through the Middle Ear
When air movement strikes the tympanic membrane, the tympanic membrane moves. At this point, the energy generated through a sound wave is transferred from a medium of air to that which is solid in the middle ear. The ossicular chain of the middle ear connects to the tympanic membrane via the malleus, so that any motion of the eardrum sets the three ossicles into motion.

Sound Transmission through the Inner Ear
The ossicles transfer energy from a solid medium to the fluid medium of the inner ear via the stapes. The stapes is attached to the oval window. Movement of the oval window creates motion in the cochlear fluid and along the Basilar membrane. Motion along the basilar membrane excites frequency-specific areas of the Organ of Corti, which in turn stimulates a series of nerve endings.

Sound Transmission to the Brain
With the initiation of the nerve impulses, another change in medium occurs: from fluid to neural. Nerve impulses are relayed through the cranial nerve VIII  (Vestibulocochlear n.), through various nuclei along the auditory pathway to areas in the brain. It is in the temporal lobe of the brain that the neural impulses are interpreted.

A conductive deafness is a pathology related to an obstructed, or altered, transmission of sound to the tympanic membrane or through the ossicle chain of the middle ear. For example, damage to the pinna results in a failure of sound waves to be properly conducted to the auditory meatus.

Sensorineural hearing loss is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve. SNHL accounts for about 90% of reported hearing loss.

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LO 19. Describe the impact of communication barriers in healthcare and outline strategies for communicating with a deaf person. 

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LO 19. Describe the impact of communication barriers in healthcare and outline strategies for communicating with a deaf person. 

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Because of the communication barrier between deaf people and healthcare services, deaf people are unfortunate as this leads to an incorrect diagnosis, delayed diagnosis, improper treatment, and a poor standard of care towards them.
And this violates several rights; their right to health, right to information, to take part in decision making, right to give informed consent, to confidentiality, and to be treated with respect and dignity.
It is essential for professional interpreter services to be implemented for better provision of healthcare. This will improve their access to healthcare. But implementing this would be very costly, therefore language rights need to address.

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LO 1 (CHEMPATH) - Explain the glucose changes observed.

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LO 1 (CHEMPATH) - Explain the glucose changes observed.

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Glucose enters CSF via GLUT-1 transporters and the normal is 60-80% of plasma glucose
Infants < 6 months CSF glucose = serum glucose
If plasma glucose > 20 mmol/L, CSF glucose doesn’t rise further because transport system is saturated
CSF:plasma glucose ration decreases in the following (<0.6)
Bacterial meningitis
TB meningitis
Fungal meningitis
Hypoxia (anaerobic metabolism of glucose = less ATP/glucose)
Normal ratio in viral meningitis
Resource(s): CSF Chem Path Lecture by Dr van der Watt

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LO 17 Describe the impact of deafness on a child’s development (including language development). 

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LO 17 Describe the impact of deafness on a child’s development (including language development). 

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Language learning depends on a child's ability to pick up words they hear from people around them. Loss of hearing can delay language learning as children may not be able to hear words and sentences clearly, making it difficult for them to audibly learn a language.

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16. Outline the suggested recommendations for the use of the meningococcal vaccine in South Africa.

Although meningococcal disease (MD) incidence in South Africa is low, Neisseria meningitidis (NM) causes severe disease that is often life-threatening and can cause long-term disabilities. A quadrivalent protein-conjugated meningococcal vaccine (MCV4) is available, and provides protection against 75% of disease causing serogroups in South Africa.

Recommendations:  vaccination of persons at high risk of meningococcal disease is advised including those with complement
deficiency and asplenia; laboratory personnel from reference laboratories who work with NM; and travellers to Saudi Arabia.

The need for routine vaccine against meningococcal disease in South Africa is controversial given the current burden of disease.
However, due to the high morbidity/mortality of MD it is recommended that clinicians consider vaccination of healthy infants and children; HIV-infected persons with a CD4 count > 25%; students attending college /university /military academies; and miners.

Conclusion: Protein-conjugated meningococcal vaccine is preferable to the polysaccharide vaccine given the ability of the
protein-conjugated meningococcal vaccine to induce immune memory, allow for booster responses and eliminate carriage of the organism in the person vaccinated.

Although the incidence of meningococcal disease is currently
low in South Africa, the consequence of acquiring the disease can be devastating with high morbidity and mortality despite adequate treatment.

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15. Differentiate between the following types of cases: sporadic case, primary case, co-primary case and secondary case

Sporadic case
-A single case with no known history of close contact with another case

Primary case
-A case with no known close contact with another case

Co-primary case
-A close contact in whom disease develops within 24 hours of onset of illness in the primary case

Secondary case
-A close contact of a primary case who becomes ill more than 24 hours after onset of
illness in primary case

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Chem path LO5 Discuss the appearance of cerebrospinal fluid findings in early meningitis with regard to cell count. Say what meningitis this presentation can be confused with.

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Chem path LO5 Discuss the appearance of cerebrospinal fluid findings in early meningitis with regard to cell count. Say what meningitis this presentation can be confused with.

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Early: Clear CSF, polymorphonuclear cell dominant (neutrophils, basophils, eosinophils)

Later: Normal-raised protein
Normal glucose
Increased lymphocytes
Normal lactate
Clear CSF
Confused with ?

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Chem Path LO 3: Explain the ADA (adenosine deaminase) changes seen. Comment on specificity.

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Chem Path LO 3: Explain the ADA (adenosine deaminase) changes seen. Comment on specificity.

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ADA is an enzyme involved in purine metabolism. The function of the ADA is to eliminate a molecule called deoxyadenosine, which is generated when DNA is broken down, as it converts deoxyadenosine, which is toxic to lymphocytes, to another molecule called deoxyinosine, which is not harmful. ADA is abundant in T-lymphocytes, which increases in TB.

CSF ADA levels can be/are found to be elevated in TBM cases, with high specificity (89%) and sensitivity (92%). Useful diagnostic test in distinguishing TBM cases from non-TBM cases.

https://medlineplus.gov/genetics/gene/ada

https://pubmed.ncbi.nlm.nih.gov/28492211

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LO 12. . Outline and contrast the roles of antibiotic agents and steroids in the treatment of meningitis

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LO 12. . Outline and contrast the roles of antibiotic agents and steroids in the treatment of meningitis

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The most common causes of meningitis is bacterial infections therefore, antibiotics are indicated as a form of treatment. All antibiotics used in the treatment of acute meningitis, with the exception of those used in the treatment of tuberculous meningitis should be given intravenously. Use of the intrathecal route is unnecessary, since the drugs commonly used penetrate well into the CSF or do so when the meninges are inflamed.

The rationale for and selection of empiric antibiotic therapy for bacterial meningitis

- bacterial meningitis is a lethal condition which is a medical emergency requiring treatment immediately or as soon as medical contact takes place

- empiric antibiotic therapy is based on the clinical presentation

I.V therapy- when a drug is given Intravenously, it all enters the systemic circulation therefore has a systemic availability of 100%. The drug escapes the metabolism via the GIT & liver.

Treatment for meningeal tuberculosis

The principles of treating TB meningitis are the same as those of pulmonary TB.

- fortunately most anti-TB dugs penetrate the CSF well, the one exception being streptomycin

- Treatment starts with rifampicin, isoniazid, pyrazinamide and ethambutol for 2 months, continuing with rifampicin and isoniazid for a further 10 months

-in developing countries(eg. Botswana/SA), a regimen of isoniazid, pyrazinamide and streptomycin is a suitable alternative

-despite the relatively poor penetration of streptomycin into the CSF, it is generally given intramuscularly; intrathecal administration is not recommended

- corticosteroids are not usually required, but prednisolone may be used if there is spinal block, raised intracranial pressure, neurological signs or a high protein concentration in the CSF.

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LO 22. Revise the body's innate and adaptive immune response to bacterial infection 

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LO 22. Revise the body's innate and adaptive immune response to bacterial infection 

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Pathogen infections are recognized by the immune system, which consists of two types of responses:
- innate immune response
- antigen-specific adaptive immune response

The innate response is characterized by being the first line of defense that occurs rapidly in which leukocytes (neutrophils, monocytes, macrophages, eosinophils, mast cells, dendritic cells), etc., are involved. These cells recognize the pathogen-associated molecular patterns (PAMPs), which have been evolutionarily conserved by the diversity of microorganisms that infect humans.

Recognition of these pathogen-associated molecular patterns occurs through pattern recognition receptors such as Toll-like receptors (TLRs) and some other intracellular receptors such as nucleotide oligomerization domain (NOD), with the aim of amplifying the inflammation and activating the adaptive cellular immune response, through the antigenic presentation.

In an infection by extracellular bacteria, the host triggers a series of responses to combat the pathogen and prevent its spread. The main mechanism of the innate immune response to eradicate bacteria is activation of the complement system, phagocytosis, and inflammatory response. Both the alternative and the lectin pathways of the complement system participate in the bacteria opsonization and potentiate their phagocytosis. To perform the correct phagocytosis, activation of several surface receptors in phagocytes, including scavenger receptors, mannose, Fc, and mainly TLRs is required.

Activation of these receptors results in inflammation, by recruiting leukocytes to the site of infection. On the other hand, the humoral adaptive immune response is the main protective against extracellular bacteria. Its primary function is to block infection, through the release of antibodies that are directed against the antigens of the bacterial cell wall, as well as of the toxins secreted by certain extracellular bacteria. The effector mechanisms used by the antibodies include neutralization, opsonization, and classical complement pathway activation, which allow bacteria phagocytosis. In the case of neutralization, IgG, IgM, and IgA participate; while in the opsonization, the IgG participates; and in complement activation, the IgM and some subclasses of IgG participate.

Protein antigens from extracellular bacteria also activate the cellular adaptive immune response, which is mediated by CD4⁺ T cells. These CD4⁺ T cells produce cytokines that induce local inflammation, increase phagocytosis, as well as microbicidal activities of macrophages and neutrophils. The Th17 cells are also involved in recruiting monocytes and neutrophils, promoting local inflammation. Similarly, there is an induction of the Th1 immune response that contributes to the macrophages activation with ample phagocytic capacity and the production of the cytokines, such as IFN-γ.

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Discuss the different cell count changes associated with the various conditions listed.

Generally speaking, CSF will show an increase in neutrophils with a bacterial infection. An increase in lymphocytes with a viral or fungal infection. Sometimes an increase in eosinophils with a parasitic infection

Normal CSF: Normally, there are no RBCs in the cerebrospinal fluid, and there should be no more than five WBCs per cubic millimeter of CSF. If your fluid contains RBCs, this may indicate bleeding.

< 2 polymorphonucleocytes [PMN])
Normal cell counts do not rule out meningitis or any other pathology

Viral meningitis: initially abundance of neutrophils (polymorphonuclear cells) during the innate immune reaction, however, these cells are then replaced by lymphocytes as it is a viral infection.
10-1000 cells per uL

Bacterial meningitis-untreated: More WBCs compared to viral meningitis (100 to 1000 cells per cubic millimeter), polymorphonuclear cells predominate as they are the frontline cells when fighting off a bacterial infection

'' treated: Polymorphonuclear and WCC decreased due to treatment, lymphocytes, however, may predominate (as low as 1 WBC/µL)

TB meningitis: Abundance of both PMNCs as well as lymphocytes, however, lymphocytes predominate

Fungal meningitis: Lymphocytosis with occasional mononuclear increase

Brain abscess: elevated WBC (pus within the abscess is essentially composed of dead WBCs)

Subarachnoid haemorrhage: Intact RBCs visualised in CSF

Traumatic tap: RBCs in CSF

SAH or Traumatic Tap?
SAH often can be distinguished from traumatic LP by comparing the RBC counts of the first and last tubes of CSF. However, this is not always reliable, especially at higher numbers of RBCs.

A potentially more reliable method of differentiating SAH from a traumatic LP is to spin down the CSF and examine the supernatant fluid for the presence of xanthochromia, a pink or yellow discolouration of the CSF supernatant caused by the breakdown of RBCs and subsequent release of haem pigments. However, this method is sensitive and specific only when spectrophotometry (rather than the naked eye) is used to identify xanthochromia. If xanthochromia is present, a subarachnoid haemorrhage diagnosis is confirmed.

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LO 8. Describe the organisms causing brain abscesses in terms of pathogenesis and pathology 

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LO 8. Describe the organisms causing brain abscesses in terms of pathogenesis and pathology 

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They are often polymicrobial.

- Gram-positive cocci: Staphylococcus aureus, Streptococcus anginosus

- Gram-negative bacilli: Escherichia coli

- Mixed anaerobes

- Branching Gram-positive bacilli:
Nocardia (aerobic)
Actinomyces (anaerobic)

Brain abscesses develop in response to a parenchymal infection with pyogenic bacteria, beginning as a localized area of cerebritis and evolving into a suppurative lesion surrounded by a well-vascularized fibrotic capsule.

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LO 2 Discuss CSF production, flow and drainage/reabsorption, and its related structures.

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LO 2 Discuss CSF production, flow and drainage/reabsorption, and its related structures.

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CSF is produced by the choroid plexus made up of specialised ependymal cells in the floor of the lateral ventricles and roof of the 3rd and 4th ventricles. CSF flows from the lateral ventricles into the 3rd ventricle via the interventricular foramina, and from the 3rd ventricle into the 4th ventricle via the cerebral aqueduct. CSF leaves the 4th ventricle via median and lateral apertures into the subarachnoid space or the central canal canal. CSF in subarachnoid space is reabsorbed by arachnoid granulations into the superior sagittal sinus because pressure in the subarachnoid space is greater than the venous sinus pressure

Specialized ependymal cells are connected by tight junctions and surround capillaries. They secrete CSF into ventricles and remove waste products. CSF circulation is aided by cilia of the ependymal cells. 500 ml of CSF is produced per day.

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LO 5 Outline and explain the precautions to take before performing a lumbar puncture

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LO 5 Outline and explain the precautions to take before performing a lumbar puncture

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Lumbar puncture is contraindicated in the following:
Local infection of the skin
Raised inter-cranial pressure
Coagulopathy

Lumbar punctures are a sterile process and it is important to maintain sterility. Clean the area, use sterile gloves/ needles.

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Discuss the role of the support cells of the brain

Pericytes:
Cells of microvessels including capillaries, venules, and arterioles

Provide structural support and vasodynamic capacity to microvasculature

Role in structural stability of vessel wall

Endothelial cells associated with pericytes are more resistant to apoptosis than isolated endothelial cells- indicates role of pericytes in structural integrity and genesis of the BBB

Phagocytic activity

Astrocytes (foot processes):
Provide biochemical support for endothelial cells

Role in morphogenesis and organization of vessel wall

Factors released by astrocytes involved in postnatal maturation of BBB

Direct contact between endothelial cells and astrocytes necessary to generate BBB

Co-regulate function by the secretion of soluble cytokines

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Focal neurological signs
category 2 notifiable disease

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Meningitis- inflammation of meninges
Different aetiologies - viral, bacterial, etc.
Ceftriaxone- antibiotic. Treats meningitis and bacterial pneumonia
Meningitis is contagious
Chief symptoms- high fever, stiff neck. sever headache

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How meningitis is spread
Bacterial aetiologies of meningitis
Epidemiology of meningitis
Notifiable disease categories
Anatomy of meninges

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Subjective:
1 years old
irritable in last 24 hours
vomiting and not wanting to eat
Anathi is very quiet, makes no attempt to speak

Objective:
Pyrexial, drowsy,
bulging anterior fontanelle, neck stiffness
No focal neurological signs,
CT scan - no brain herniation
No significant abnormalities with CSF microscopy, tests, routine culture, and chest X-ray

Assessment:
meningitis

Plan:
referral to RXH
lumbar puncture
Ceftriaxone administered
Disease notification
prophylaxis for the family
Parent training for Ms Mkizhe

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LO 7. Describe the organisms causing meningitis in terms of the epidemiology, pathogenesis, and pathology.

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LO 7. Describe the organisms causing meningitis in terms of the epidemiology, pathogenesis, and pathology.

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Various causes, bacteria, viruses, fungi and parasites.

Bacteria:

1.       Streptococcus Pneumoniae

Gram positive coccus

• Forms pairs or “diplococci”

• Most common cause of bacterial meningitis in Cape Town

• But more often causes respiratory tract infections

• Nasopharyngeal colonisation → penetrate mucosal barrier →

bloodstream → central nervous system

2.       Listeria Monocytogenes

Gram positive bacilli

• Huge South African outbreak 2017-2018 due to contaminated polony.

Sporadic cases still prevalent

• Risk factors

• Neonate

• Pregnancy

• Older age

• HIV

• Immunocompromise

3.       Neisseria Meningitidis

Gram negative coccus

• Forms pairs or “diplococci”

• “Meningococcal meningitis”

• Rapidly progressive

• “Fine in the morning”, “Headache at lunch”, “Dead by dinner”

• Associated classically with haemorrhages

• Droplet spread then colonises upper respiratory tract

4.       Haemophilus influenza

Gram negative bacilli, or small gram-negative coccobacilli

• Type B causes invasive disease, may occur after an upper respiratory infection. The infection usually spreads from the lungs and airways to the blood, then to the brain area.

• Rare since introduction of vaccine, but used to be common in infants and children

• Definitive treatment: IV ceftriaxone for 10 days

5.       TB Meningitis

TBM”

• Mycobacterium tuberculosis

• Epidemiology

• HIV

• Clinical features

• Subacute, gradual onset meningitis

• Neurological fallout e.g., cranial nerve palsy.

6.       Neurosyphilis (Treponema Pallidum)

It invades the nervous system at any stage of infection and causes a wide range of symptoms.

Transmission is through a syphilitic sore, sores maybe found around the genitals.

It is considered a sexually transmitted infection.

Several distinct syndromes

• Meningitis

• Asymptomatic

• Symptomatic

• Meningovascular syphilis

• Late neurosyphilis

• General paresis

• Tabes dorsalis

Fungi:

1.       Cryptococcal meningitis:

·         Fungus/yeast

Risk factors

• HIV

• Immunocompromise

• Subacute picture

• Range of clinical findings

It is not spread through contact, but one is infected through the inhalation of soil particles contaminated by bird droppings. The fungi first infects the body and then the infection spreads to the central nervous system, resulting in cryptococcal meningitis.

2.       Locally invasive fungal infection.

Rhinocerebral fungal infection

• “Mucormycosis” or “zygomycosis”

• Highly destructive “flesh-eating” fungus

• Opportunistic fungal infection of oral cavity and sinuses

• Infection extends into the brain

• Risk factors

• Diabetes

• Immunocompromise

Parasites:

(Protozoa)

1.       Cerebral malaria

Usually, Plasmodium falciparum

• Severe form of malaria

• Decreased level of consciousness, agitation, confusion, seizures

• Resembles meningitis

• Complex pathogenesis:

• Sequestration of parasites in vasculature

• Release of inflammatory cytokines

• Increased serum lactate

• Hypoglycaemia

2.       Toxoplasmosis

Protozoan parasite

• “Toxoplasmosis”

• Latent infection in brain

• Reactivates in immunocompromised hosts

• HIV

• CNS manifestations

• Encephalitis

• Space-occupying mass lesion

3.       Naegleria fowleri

• “Primary amoebic encephalitis”

• Healthy people

• “Brain-eating” amoeba

• Acquired in warm freshwater

• Enters through cribriform plate along olfactory nerve

• Extremely rare

(Metazoa)

1.       Flat worms, e.g.

Taenia solium (cysticercosis)

• Pork tape worm

• Complex life cycle

• The adult parasite resides in the gut of the definitive host, humans

• The parasite ovum or egg is ingested by the intermediate host

• The parasite penetrates the gut and migrates to organs where it forms cysts

• Humans can be either the definitive host or the intermediate host

VIRUSES:

Acute and chronic

Acute:

·         Enteroviruses

o   Incubation period – 7-14 days

o   Primary replication

§  oropharyngeal and intestinal mucosa

o   Secondary replication

§  Lymphatic system – tonsils, Peyer's patches

§  Transient viraemia - various cell types according to virus type

Clinical presentations

·         Usually mild, may be non-specific

·         Myocarditis, GIT disturbance, respiratory infection, rash (hand, foot, and mouth disease)

·         CNS involvement - a minority of cases (for most enteroviruses)

o   Still the most common viral cause of aseptic meningitis

o   Degree of severity varies

o   Most enteroviral meningitis is self-limiting

o   <2 weeks of age: severe infection, permanent damage, outbreaks in neonatal units

·         Paramyxoviruses

o   Mumps

·         Aseptic meningitis

§  15% of mumps infections

o   Onset varies

§  1 week before the onset of parotitis

§  3 weeks afterwards

o   Symptoms subside 3-10 days later

o   Recovery is usually complete

o   Deafness: does not require meningitis first; ~1:20000 cases

·         Encephalitis

o   1 in 6000 mumps cases

o   Convulsions, abnormal movement, abnormal sensory perception, focal neurological signs

o   Outcome varies

o   Measles

•          Acute measles post-infectious encephalitis

•          Measles inclusion body encephalitis

•          Subacute sclerosing panencephalitis (SSPE)

•          1 in 1000-5000 cases of measles

•          Otherwise, healthy persons

•          15% of cases are fatal

•          20-40% of survivors are left with
permanent neurological damage

•          Patient usually still has a rash

•          Within 8 days of onset

•          Possible in the prodromal stage

•          Fever, headache, seizures, ataxia, and coma

•          Autoimmune reaction against the basic myelin protein

•          Immune-compromised patients

•          Children with leukaemia receiving radiation therapy

•          HIV: accelerated process

•          Incubation period - a few weeks to 6 months

•          Convulsions, usually myoclonic jerks

•          Mostly limited to one side

•          Hemiplegia and/or decreased consciousness

•          Death within a few months

·         Rubella

•          Togaviridae

→ Alphaviruses

→ Rubivirus → Rubella

•          Like alphaviruses, rubella can cause

–         Rash

–         Arthritis

–         Meningitis – rare, usually mild and benign

•          Rubella post-infectious encephalitis

–         1 in 5000-10000 cases

–         within a week after the rash onset

–         immune-mediated

–         ADEM / PIEM

·         Herpesviruses

o   Use retrograde spread via axons some use anterograde nerve uptake e.g. via olfactory.

o   Most common cause of sporadic viral encephalitis

§  2/3: Virus reactivation – usually HSV 1

§  1/3: Primary infection (neonates) – usually HSV 2

o   HSV 1 more severe than HSV 2

o   Affinity for the temporal lobes

§  temporal lobe seizures, speech disorders & personality changes

o   Medical emergency: start treatment immediately

§  Acyclovir

·         Arboviruses

o   Not a viral family: arthropod borne, has mammalian hosts

o   Vectors

§  Things, in this case organisms, that transmit a virus from natural host to the victim – usually refers to arthropod vectors

§  Mosquitos

·         Aedes

·         Culex

·         Anopheles

§  Ticks

·         Hyalomma

·         Rabies

o   Use retrograde spread via axons

o   Found in animals, e.g., dogs, jackal, bay-eared fox.

o   100% fatal (with a few exceptional exceptions)

o   Incubation – 2 weeks à months (years)

o   Onset – drowsy, confused, anxious, tense, restless, nightmares, insomnia, fever, local pain / tingling in site of infection

o   Later – lucid moments with delirium, hallucinations, terror

o   Furious/agitated rabies – brain stem, cranial nerves, limbic system, higher centres

o   Dumb/paralytic rabies – medulla, spinal cord, spinal nerves

o   Spasms – in response to stimuli

§  Water, also air, slamming doors, etc

o   Death – pneumothorax, asphyxiation, coma, apnoea

Chronic:

·         Measles

·         CMV

o   Uses Trojan horse- entry via a leukocyte.

o   HIV-associated + immunocompromised

o   Slow, progressive

o   Optic neuritis / retinitis

·         JC virus/PML

o   Progressive multifocal
leukoencephalopathy

o   JC virus: polyomavirus

§  70% of population infected – latency

o   Clinical picture

§  Limited to immunosuppressed people

§  Neurological syndrome with slow onset, rapid progression over weeks/months

§  Cognitive dysfunction, dementia, seizures, ataxia, aphasia, cranial nerve deficits, hemiparesis or quadriparesis, coma

o   Diagnosis

§  CT scan: single or multiple hypodense, none enhancing cerebral white matter lesions, may involve cerebellum and brain stem

§  CSF for PCR – useful if positive, low NPV

o   Treatment – HAART

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LO 10 List the typical organisms found in meningitis in the neonate and young children and reasons for the difference

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LO 10 List the typical organisms found in meningitis in the neonate and young children and reasons for the difference

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•Neonates: Escherichia coli, group B streptococci, listeria monocytogenes

•Infants and children (2-5 years):  haemophilus influenza (now decreased due to vaccine)
Neonates are breast fed and could get congenital infections from their mothers, as seen in Listeria monocytogenes. Furthermore, the Blood brain barrier of neonates is immature and thus, a greater amount of organisms can get into the brain, accounting for the difference between the two.

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CSF Interpretation

Collection of CSF

·       CSF is aspirated via lumbar puncture under strictly aseptic conditions

·       Approximately 10-12ml can be taken from an adult and <3ml from a neonate

·       Care must be taken not to contaminate the sample with blood

·       The fluid is collected into 3 (or 4) tubes via passive flow through the needle

·       The tubes should be labelled with a number, indicating the order in which they were collected:

1.     Glucose (0.5ml in a grey top with sodium fluoride, NaF) – blood glucose should be measured at the same time

2.     Chemistry (1ml in a plain tube) – used for protein, chloride, IgG

3.     Microbiology and haematology for cell count and culture

4.     Molecular and other reference labs

Condition | Appearance | Opening Pressure  | Cell Count and Cell Type | Glucose | Protein | Other chemistry tests e.g. Chloride; ADA; oligoclonal bands; etc. | Microbiology and Virology
Normal  | Clear   | 80-200mm water | <5 cells per μLNo RBCs or neutrophils | 50-70% of blood value (normal blood value: 4.1-5.9mmol/L), except in infants <6 months. Normal fasting CSF glucose: 2.2-3.9. CSF glucose lags behind plasma glucose by 30-90 minutes | 0.15-0.4g/L(<1% of plasma) | Lactate <2.1mmol/L Normal CSF chloride is slightly higher (116-127mmol/L) than serum chloride (114 mmol/L) LDH up to 40μL in adults and 70μL in infants  |
Viral meningitis | Clear  | Usually normal | Lymphocytosis (<100/μL)PMNs may predominate initially | Normal  | Normal to elevated | Normal lactate (<2.1mmol/L) | PCR
Tuberculous meningitis | May form coagulum on standing | Variable  | High mixed PMNL and lymphocyte cell count. Usually, predominance of lymphocytes | Low  | Mild to marked elevation | Low chloride (<110mmol/L)High CSF Adenosine deaminase (ADA) Lactate is elevated even if cultures are negative | Acid-Fast/ZN staining for Mycobacterium
Bacterial meningitis (untreated) | Turbid CSF | Elevated opening pressure | 100s to 1000s/μL Polymorphonuclear lymphocytes (PMNL) | Lower than 60% of blood value – very low | Protein levels >0.8g/L | High CSF lactate (>3.9mmol/L)Increased serum procalcitonin  | Gram-positive stainPositive blood culture
Bacterial meningitis (partially treated) | Turbid or clear, depending on stage of treatment- resembles aseptic meningitis | Elevated or normal  | PMN and white cell count decreasesLymphocytes may predominate  | Glucose normalizes after a few hours of treatment | Protein decreases over a few days |  | Latex agglutination may be required for common bacterial antigens or PCR
Fungal (Cryptococcal)Meningitis | Variable appearance | Variable  | Lymphocytosis Occasional mild mononuclear increase | Normal/low glucose | Raised protein  | Low chloride  | India Ink staining
Syphilis |   |   | Lymphocytosis  | Normal glucose | Raised protein | Normal chloride  | VRDL and RPR serologyOrganisms not seen
Brain abscess |   | Increased  | Elevated WBC count | Normal glucose | Raised protein |   |
Post seizure (infectious causes excluded) |  |   |  |  |  | Raised lactate |
Subarachnoid Haemorrhage | Xanthochromia: 2-4 hours after haemorrhage, RBCs lyse and release oxyhaemoglobin giving the CSF a pink to orange colour. RBCs in CSF longer than 4 hours cause yellow staining. By 12 hours, Hb is metabolized to bilirubin, giving it a yellow colour |   | Intact RBCs in the CSF | Low glucose  |  | Raised LDH |
Multiple Sclerosis |   |   |   |   | High CSF protein  | Elevated myelin basic protein (MBP)Oligoclonal bands IgG index is raisedCSF albumin/serum albumin >9  |
Traumatic tap (blood contamination into CSF) |   |   | RBCs in the CSF  |   |   | Fresh traumatic taps with intact RBCs do not dramatically increase LDH levels  |

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Anathi is a one-year-old who lives with her mother, Ms Mkhize, and their extended family of 8 people in a small two bedroomed brick house. Ms Mkhize brings Anathi to the clinic because she has been very irritable over the last 24 hours and has been vomiting and not wanting to eat. The doctor examines her and finds that she is pyrexial (40°C), drowsy and has neck stiffness and a bulging anterior fontanelle.

He refers Anathi to Red Cross Children’s Hospital (RXH) urgently as he suspects meningitis. While waiting for transport Anathi is given a dose of Ceftriaxone. Dr Smith, the casualty officer at RXH performs a lumbar puncture on Anathi as she has no focal neurological signs and after a CT brain scan shown no features of brain herniation. The cerebrospinal fluid (CSF) is sent for microscopy, biochemical tests and routine culture. Her chest X-ray shows no significant abnormalities. Anathi is admitted to hospital and intravenous Ceftriaxone treatment continued.

Dr Smith asks Anathi’s mother if she ever received a vaccination for meningitis, but she does not remember saying she has been stressed because she had recently divorced Anathi’s alcoholic father. After 72 hours the CSF has grown Haemophilus influenzae type B. Anathi is discharged after 10 days in hospital.

The doctor at RXH completes the required notification forms, as this is a category 2 notifiable disease. In order to classify Anathi’s case and in order to contain the disease, Dr Smith asks Ms Mkhize if there are any other close contacts that exhibited similar symptoms as Anathi in the past week or two. He informs Ms Mkhize that prophylaxis will be offered to the family. Ms Mkhize wonders how common this disease is and what could have been done to prevent it.

A month after being discharged from hospital, Ms Mkhize brings Anathi to the clinic again as she is concerned that he is very quiet and makes no attempt to speak despite the fact that, previously, she was speaking some words such as “mamma”. She is referred back to RXH where she is found to have sensorineural hearing loss by the audiologist. The audiologist recommends that Ms Mkhize commence with “parent training” to be taught how to communicate with Anathi and encourage her to sign and lip read which will support her development.

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LO 3 Discuss the structure and function of the blood-brain barrier (BBB).

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LO 3 Discuss the structure and function of the blood-brain barrier (BBB).

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BBB structures: Cerebral capillaries, meninges, choroid plexus.

Cerebral capillaries:

(pericytes may be involved, but their role is not yet known)

Astrocytes play NB role in BB: glial cells with foot processes in direct contact with endothelial cells, which generates BBB.

Factors released by astrocytes involved in postnatal maturation of BBB

Co-regulate function by the secretion of soluble cytokines

Meninges:

Blood vessel are found in the meninges, in the subarachnoid space, and extend into pia mater and into cerebrum.

Choroid plexus:

Blood-CSF barrier.

Where CSF is synthesised.

Fx:

Structural and functional barrier which impedes and regulates the influx of most compounds from blood to brain

Regulates passage of molecules in and out of brain to maintain environment of neurons; essential for normal CNS function.

Responsible for metabolic activities such as the metabolism of L-dopa to regulate its concentration in the brain.

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LO 1 Describe in detail the layers of the meninges which are affected by meningitis.

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LO 1 Describe in detail the layers of the meninges which are affected by meningitis.

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⇒ Coverings of the Central Nervous System:
o The CNS is supported by bone and membranous coverings
− The brain is located within the cranial cavity of the skull
− The spinal cord is located within the vertebral/spinal canal of the vertebral column
o Within the cranial cavity, the brain is surrounded and supported by 3 meninges
⇒ The Dura Mater:
o A thick, strong membrane
of dense irregular connective tissue that contains some collagen and elastic fibres – it ensheathes the brain like a loose-
fitting bag
o In some regions, the dura is tightly adherent to the interior surface of the skull (floor of cranial cavity, midline of cranial
roof), whereas in other areas, the two are separated by a narrow extradural space (frontoparietal area)
o It is comprised of 2 layers: (1) an endosteal layer lining the inner surface of the skull and covering the skull foramina and
(2) a meningeal layer continuous with the dura around the spinal cord
o The 2 layers of the dura mater normally closely adherent to one another, but become separated in certain locations to
enclose blood-filled spaces, the dural venous sinuses
o Dural folds: 2 large reflections of dura that extend into the cranial cavity and occupy the fissures between the major
components of the brain
− Falx cerebri:
• The falx cerebri it is the largest of the dural folds and helps to limit excessive movements of the brain
• It has an attached border that adheres to the inner surface of the skull and a free border that lies above the
corpus callosum;
• Anteriorly, the falx is attached to the bony ridge of the crista galli; posteriorly, it becomes continuous with the
tentorium cerebelli
− Tentorium cerebelli:
• A horizontal dural fold which extends inwards from the occipitotemporal region of the skull to lie in the
transverse cerebral fissure, between the posterior part of the cerebral hemispheres and the cerebellum
• It has a free border that encircles the midbrain, as the midbrain communicates between the posterior and middle
cranial fossae
• In the midline, the tentorium becomes continuous superiorly with the falx cerebri
− Diagphragma sellae:
• Forms roof over pituitary fossae (the depression in the body of the sphenoid bone that contains the pituitary
gland)
• In the centre of the diagphrama sellae is a opening for the stalk of the pituitary gkand
• Diagphramae sellae also forms roof of the cavernous sinus which lies on either side of the sphenoid bone
⇒ The Arachnoid Mater:
o A soft, translucent fibrous membrane that loosely envelopes the brain
o Separated from the dura by a narrow subdural space, through which veins pass en route to the dural venous sinuses
⇒ The Pia Mater:
o A microscopically thin, delicate and highly vascular membrane that is closely adherent to the surface of the brain,
following all its concavities and convexities
o Between the pia and arachnoid mater lies the subarachnoid space, which contains a filamentous network of connective
tissue strands (trabeculae) and is traversed by numerous arteries and veins; it also contains cerebrospinal fluid (CSF)

o The subarachnoid space is of greatly varying depth in different regions since the arachnoid mater fits loosely around the brain while the pia closely follows its surface contours
o Where significant depressions or fissures in the brain are spanned by the arachnoid mater, subarachnoid cisterns are formed – 2 of these are particularly large:
− The cisterna magna lies between the cerebellum and the dorsal surface of the medulla – CSF flows from the 4th ventricle into this cistern
− The inter-peduncular cistern is located at the base of the brain, where the arachnoid spans the space between the 2 temporal lobes – this cistern contains the optic chiasm; the cistern is deepest between the 2 cerebral peduncles of

Meningitis is an infectious disease of the central nervous system that causes inflammation of the meningeal membranes, involving all three layers surrounding the brain and spinal cord: dura mater, arachnoid, and pia mater. The arachnoid and pia mater become inflamed and opaque along with the first two layers of the cortex and the spinal cord.

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LO 11 - Describe the patterns and mechanisms of viral effects in the CNS: meningo/encephalitis, acute perivenous demyelination and SSPE.

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LO 11 - Describe the patterns and mechanisms of viral effects in the CNS: meningo/encephalitis, acute perivenous demyelination and SSPE.

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I have broken down the question into the following headings which I will discuss in details:

Viral infections in the CNS.

Mechanisms viral infections

Patterns/syndromes of viral infections in the CNS

Post-infection Syndrome:

Acute Perivenous demyelination

SSPE

Viral infections in the CNS.

Infections of the CNS by viruses is a very hard process for the virus. That is because the CNS has strong protective mechanisms to stop entry of viruses. The most popular mechanisms is the presence of the BLOOD BRAIN BARRIER. This makes it very hard for the virus to access the brain tissues and often times, the infection occurs if the barrier is compromised. However, other viruses have developed ways of getting into the brain without having to go through the BBB.

Mechanism of viral infections.
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Retrograde & Anterograde are the terms used to describe the direction of the movement of substances like neurotransmitters in the neurons. i.e. from the cell body to the axon terminal is anterograde & vice versa.  Viruses can infect the skin (e.g. HSV) or muscles (e.g. Polio) and eventually enter into the axon terminals of the neurons.

In sensory neurons which herpes usually infect, they will move by RETROGADE movement and go into the cell body located in the dorsal root ganglia. In most cases, during reactivation, the viruses can move back to the skin from the cell body, causing some vesicular rash on that area of the skin. BUT, rarely, it can move from the cell body towards the spinal cord or BRAIN by ANTEROGRADE movement and thus making its way to the spinal cord or the BRAIN if the nerve involved is the trigeminal nerve.

The principle is similar for other viruses that use this route and the diagram below depicts that (A,B,C)

Trojan horse is another fascinating mechanism and it is used by the popular virus called HIV to make its way into the BRAIN. The name comes from some story about how the Greeks used some disguise to make their way into some city and eventually destroy the people there. It is worth mentioning for the sake of understanding the mechanism. In this process, the virus infects the leukocytes like macrophages, hide in them and when they enter the brain by crossing the BBB, that’s how the virus also gains access to the CNS which kind of makes sense. This is possible since during an infections, the astrocytes secrete some cytokines to increase the permeability of BBB for some leukocytes to enter and launch an immune response. This means that some leukocytes like macrophages do have the ability to cross the BBB and in some cases, the virus would enter them and use them to gain access to the CNS.

Other mechanisms are self explanatory and I don’t want to make the LO text heavy.

The patterns or syndromes of viral infections in the CNS.
(Image)

Post-infection Syndromes:

These are auto-immune disorders that occur after a viral infection. Basically, the immune cells created against the virus attack your own tissues afterwards because they have similar characteristics with the viral epitopes.

Subacute Sclerosing Panencephalitis (SSPE) .

it is a progressive neurological disorder characterized by inflammation of the brain (encephalitis). The disease may develop due to reactivation of the measles virus or an inappropriate immune response to the measles virus.

SSPE usually develops 6 to 8 years after the original viral attack. It can sometimes take 20-30 years. Initial symptoms may include memory loss, irritability, seizures, involuntary muscle movements, and/or behavioral changes, leading to neurological deterioration. It is very rare but fatal.

Acute Perivenous Demyelination

Perivenous demyelination is the pathological hallmark of acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis (ADEM) is characterized by a brief but widespread attack of inflammation in the brain and spinal cord that damages myelin. It is thought to be autoimmune after MEASLES infection or very, very rarely, after MEASLES vaccination. It is basically due to the immune reaction(often T-cell mediated) developed against measles cross-reacting with the myelin sheath and often misdiagnosed as Multiple Sclerosis.

Both of these diseases seem to be post-viral syndromes of MEASLES infection.

*ADEM - Acute Disseminated Encephalomyelitis – eventually results in Acute Perivenous Demyelination.

* MIBE - measles inclusion body encephalitis – Associate with immune suppression

* SSPE occurs in later stages according to the time line.

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2. Chloride is normally higher in the CSF than serum to compensate for the low negative protein count in CSF (electroneutrality). Low CSF chloride count in TB meningitis occurs because of high protein count in CSF (compensates: proteins are negatively charged).