Central Nervous System Infections

INTRODUCTION
* Central nervous system infections are usually: 1- Blood-borne invasion; most common (e.g. polioviruses or Neisseria meningitidis) 2- Invasion via peripheral nerves; less common (e.g. herpes simplex, varicella-zoster, rabies)

INTRODUCTION
1- Blood-borne invasion takes place across: - blood-brain barrier (encephalitis) - blood-cerebrospinal fluid (CSF) barrier (meningitis). * Microbes can traverse these barriers by: - Infecting the cells that comprise barrier.

INTRODUCTION
2-Invasion via peripheral nerves: * Herpes simplex virus (HSV) and varicella-zoster virus (VZV) present in skin or mucosal lesions travel up axons to reach the dorsal root ganglia. * Rabies virus, introduced into muscle tissues by: - bite of a rabid animal. - It enters peripheral nerves and travels to CNS, to reach the neurons.

Pathologic consequences of CNS infection

* In CNS; viruses infect neural cells, sometimes showing a marked preference. * Polio and rabies viruses invade neurons. CJD virus invades oligodendrocytes. * Spread of infection is direct from cell to cell along established nervous pathways. * Bacteria and protozoa induce brain abscesses.

Meningitis

Introduction
* Meningitis is one of the most terrifying disease. * It can be fatal in hours. * Early symptoms resemble self-limiting conditions (flu and colds).

Definition of Meningitis
* A general name for inflammation of: a) Meninges: Sheaths that cover brain and spinal cord b) Cerebrospinal fluid: Fluid that circulates in the spaces in and around brain and spinal cord * Meningitis can be caused by: infectious or non-infectious agents * Infectious agents include: bacteria, viruses, fungi, protozoa and rickettsia.

Causes of Meningitis

Bacterial Infections Viral Infections Fungal Infection Mycobacterium tuberculosis Trauma to head or spine

Causes of Meningitis (cont.)

Most common causes of meningitis are:
a) Bacterial infections (Septic meningitis) may result in death or brain damage. b) Viral infections (Aseptic meningitis) usually resolve without treatment.

Bacterial Meningitis (Septic Meningitis)

- Pneumococcal, Streptococcus pneumoniae (38%) - Meningococcal, Neisseria meningitidis (14%)

- Haemophilus influenzae (4%)

- Staphylococcal, Staphylococcus aureus (5%) - Tuberculous, Mycobacterium tuberculosis

Symptoms of meningitis
Adults and children

Babies
Neonates and the elderly often present atypically

Neisseria Meningitidis (Meningococci)

*Meningococcus: The causative organism of epidemic cerebrospinal meningitis. * Aerobic gram-negative diplococci. *13 serogroups based on polysaccharide capsule. *Most invasive disease caused by: serogroups A, B, C, Y, and W-135.

Pathogenesis Of Meningococcal
Meningitis
* Organism colonizes membranes of nasopharynx.

* Organism may reach blood stream producing meningococcemia, the symptoms may be like upper respiratory tract infection. * Meningococcemia may occur with or without meningitis. * Meningitis is the most common complication of meningococcemia.

Clinical Features Of Meningococcal Meningitis

* Transmission: respiratory droplets

* Incubation period: 3-4 days

* Clinical Features - Fever - Vomiting - Headache - Stiff neck - Hypotension, and rash

Meningococcal Disease Laboratory Diagnosis

Specimen: - Cerebrospinal fluid (CSF) . Fluid usually collected from arachnoid space. . A sterile needle is inserted between 4th and 5th lumbar vertebrae and the CSF is allowed to drip into a dry sterile container - Blood

CSF
Appearance Normal CSF Clear colorless Cells (WBCs) Protein Glucose Below 5x106/l 15-40mg% 45-72mg%

Pyogenic Bacterial Meningitis Viral Meningitis

Purulent/cloudy usually many pus cells

High

very low

Clear/slightly turbid

Raised lymphocytes Raised lymphocytes

Normal or usually increased High reduced

Tuberculosis Clear/slightly Meningitis turbid

Meningococcal Disease Laboratory Diagnosis

Bacterial culture on chocolate agar in 5-10% CO2 Gram stain: Gm ve diplococci intracellular in pus Blood culture: give positive results

Detection of meningococcal polysaccharide antigens in CSF

PCR test for detection of meningococcal DNA in blood or serum

Neisseria Meningitidis Management

* Penicillin G is drug of choice for patients

* Chloramphenicol and cephalosporins for: - persons allergic to penicillin or - strain is resistant to penicillin
* Chemoprophylaxis for contacts: - Rifampicin, orally twice daily for 2 days - Ciprofloxacin as a single oral dose

Vaccination For Meningitis

- A polyvalent vaccine from the capsular polysaccharide of groups A, C, Y and W-135 strains.

- The vaccine does not include group B polysaccharide.

Viral Meningitis (Aseptic meningitis)

Etiological Agents:
Enteroviruses, most common (Coxsackie and Echovirus) Adenovirus Arbovirus Measles virus Herpes Simplex virus Varicella Zoster virus

Modes of transmission:
Primarily from person to person Arthopod vectors for Arboviruses

Incubation Period:
Enteroviruses 3-6 days Arboviruses 2-15 days

Most patients recover completely on their own

Tetanus

Introduction
* Tetanus (Greek Word) Tetanos means to contract

* Tetanus is an acute, often fatal, disease caused by: An exotoxin produced by Clostridium tetani
* Toxins are produced with growth of bacteria. * Tetanospasmin toxin: - Estimated human lethal dose (2.5 ng/kg).

Clostridium tetani
* Clostridium tetani: - Anaerobic gram-positive bacilli - Spore-forming bacteria * It is characterized by: . Generalized rigidity . Convulsive spasms of skeletal muscles . Muscle stiffness of jaw and neck (lockjaw) * It is prevented by immunization with tetanus toxoid

Reservoir Of Cl. Tetani

* Spores of Cl. tetani are found in soils and animal feces. * Spores are very resistant to: - heat - radiation - chemicals - drying

* Spores can survive for a long time in environment (months or years)

Mode Of Transmission
Transmission by: contaminated wounds - Surgical wounds - Deep puncture wounds - Crush wounds - Burns - Dental infection - Animal bites

- Delivery or abortion

Pathogenesis Of Tetanus
At

wound, blood supply to tissues decreases.

Cl.

tetani spores germinate into active vegetative cell that grows and produces Tetanospasmin toxin

Pathogenesis (contd)
* Tetanospasmin is a lethal neurotoxin. * It Induces spastic paralysis by:

inhibiting release of inhibitory neurotransmitters

which lead to uncontrolled muscle contractions (spastic paralysis)

Clinical Picture of Tetanus

* Lock jaw:

Convulsive muscle contractions of the jaw

* Opisthotonos: Extension of lower extremities, flexion of upper extremities and arching of the back.

* Neck rigidity
* Death Heart or respiratory failure

Diagnosis of Tetanus
* Tetanus is suspected upon exposure to a bite or a wound. * Diagnosis depends on: Clinical findings and history. * Because Cl. tetani exhibits such sensitivity to O2 it is very difficult to recover and/or grow from clinical specimens.

Treatment of Tetanus
* Antitoxin is administered
* Muscle relaxants * Supportive therapy (ventilator)

* Cleansing of the wound

Prevention of Tetanus
* A highly effective vaccine is available. * Tetanus immunity is achieved using: - A formalized tetanus toxoid. - Toxoid is administered as part of DTP vaccine * Boosters every 10 yrs.

Botulism

Microbiology

Clostridium botulinum:
Large, anaerobic Gram-positive bacilli Spore-forming Rarely infects humans Produces potent neurotoxin - 7 types (A-G) - Types A, B, E are the most common

Botulism
* Cl. botulinum spores widespread in: - soil - contaminated vegetables - meat and fish * Canned or preserved foods (without adequate sterilization) - Spores survive and germinate in anaerobic environment - Formation of toxin

Pathogenesis

Botulinus toxin is ingested; absorbed from gut into blood.

It acts on peripheral nerve synapses by blocking release of acetylcholine.

It affects motor and autonomic nervous system. If the organism is ingested by infants, it multiplies in gut and produce toxin, causing infant botulism.

Clinical Features

Incubation: 12-72 hours Classic syndrome

Acute symmetric cranial nerve palsies - Blurry vision, ptosis, dysphasia Descending flaccid paralysis - Complete skeletal muscle paralysis - Respiratory failure Autonomic: urinary retention Normal mentation

Diagnosis
* Diagnosis of botulism is mainly clinical

* Laboratory confirmation
Specimens: Contaminated food Patient's serum ELISA

Treatment
* Supportive care:
- Mechanical ventilation

* Passive immunization (antitoxin) - Trivalent antitoxin (Types A, B and E toxins). Complications: - Serum sickness (9 %) - Anaphylaxis (2 %)

Rabies

Rabies Virus

Rabies is an acute infection of the CNS which is fatal. The main animals involved are dogs, foxes and bats.

Pathogenesis

It is transmitted by the bite of a rabid animal, usually a dog. Following inoculation, the virus replicates in the striated or connective tissue at the site of inoculation and enters the peripheral nerves through the neuromuscular junction. It then spreads from the peripheral nerves to the CNS. Terminally, there is widespread CNS involvement but few neurons infected with the virus show structural abnormalities.

Laboratory Diagnosis

Histopathology - Negri bodies are diagnostic of rabies. Rapid virus antigen detection - The Direct Fluorescent Antibody test (DFA) is commonly used in which corneal impressions or neck skin biopsy are taken. Virus cultivation - The most definitive means of diagnosis is by virus cultivation from saliva and infected tissue. Virus cultivation can be done using cell cultures or more commonly, the specimen is inoculated intra-cerebrally into infant mice. Serology - circulating antibodies appear slowly but they are usually present by the time of onset of clinical symptoms.

Negri Body in neuron cell (left) and Positive DFA test (right).

Management and Prevention

Pre-exposure prophylaxis - Inactivated rabies vaccine is given to persons at increased risk of rabies e.g. vets, animal handlers, laboratory workers etc. Post-exposure prophylaxis - In cases of animal bites, dogs and cats in a rabies endemic area should be held for 10 days for observation. If signs develop, they should be killed and their tissues examined.

Post-exposure Prophylaxis

Wound treatment - surgical debridement should be carried out. Passive immunization - human rabies immunoglobulin is given around the area of the wound and an i.m. dose to confer short term protection. Active immunization - The human diploid cell vaccine is usually administered into the deltoid region, and 5 doses are usually given. Combined treatment with rabies immunoglobulin and active immunization is much more effective than active immunization alone.

Rabies Vaccines

The vaccines which are available for humans are inactivated whole virus vaccines. Nervous Tissue Preparation Duck Embryo Vaccine Human Diploid Cell Vaccine (HDCV)

Control of Rabies

Canine rabies accounts for more than 99% of all human rabies. Control measures against canine rabies include;
Stray dog control. Vaccination of dogs. Quarantine of imported animals.