•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.

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

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.

• “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

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

• “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

1.       Flat worms, e.g. 

• 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

·         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

 

·         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

·         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

 

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. 

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  |  

 

 

 

Viral infections in the CNS.

Mechanisms viral infections 

Patterns/syndromes of viral infections in the CNS

Post-infection Syndrome: 

Acute Perivenous demyelination 

SSPE  

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.
(Images)
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.

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. 

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.  

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.

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. 

 

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