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A neurological disease characterised by increased muscle tone & spasms. Caused by CLOSTRIDIUM TETANI An anaerobic, motile, gram positive rod that forms oval, colourless, terminal spores tennis racket or drumstick shape.

1. Infectious but not contagious 2. Brought about by direct inoculation of material containing the causative agent 3. Always a serious disease fatal up to 60% of unimmunized persons, usually within 10 days of onset. When symptoms develop within 3 days, the prognosis is poor.

Lockjaw Tetanos a Greek word to strech First described by Hippocrates & Susruta

1. A common inhabitant of the soil especially if fertilized with manure 2. Anaerobic (does not grow in the presence of free oxygen), gram (+) bacillus with round terminal spore with slender body giving a drumstick appearance 3. The organism comes in 2 forms, spore forming and the vegetative form 4. Spores are extremely resistant to heat and ordinary antiseptics 5. Multiplies only at the site of the wound

2 Forms of Clostridium tetani

Slender, gram positive, nonencapsulated, motileanaerobic bacillus Susceptible to bactericidal effect of heat, chemical disinfectants and antibiotics Pathogenic form

2. Sporulated
Bulge at one end; drumstick appearance Highly resistant to disinfection by chemicals or heat

6. The organism releases 2 types of toxins: a. Tetanolysin Dissolves/destroys the red blood cells Results to anemia Thus, patient is pale-looking b. Tetanospasmin Causes muscle spasm Acts on MYONEURAL JUNCTION of the muscles and on the INTERNUNCIALFIBERS of the spinal cord and the brain. Results into multiple muscle spasms Inhibits the spastic muscle from sending transmissions to the brain, which would inhibit progression of spasms. Due to this, adjacent muscles will also undergo spasm similar to a chain reaction or a domino reaction.

In the wound, there would be an inflammatory response (6 cardinal signs of local inflammation):
a. b. c. d. e. Rubor redness Calor heat Tumor swelling Dolor pain Functio laesa loss of function

It is found worldwide in soil, in inanimate environment, in animal feces & occasionally human feces.

1. More in the tropics 2. Newborns whose method of delivery and umbilical cord care are not aseptic 3. Compound fracture 4. Following surgeries; any punctured wound; infected wounds; burns; tooth decay 5. Bites/scratches 6. Women are poorer risks than men, so are the very young and the very old

Occurs sporadically Affects unimmunized, partially immunized & fully immunized who fail to maintain adequate immunity with booster doses of vaccine. Although it is an entirely preventable disease by immunization , the burden of disease worldwide is great.

As reporting is inaccurate & incomplete, particularly in devoleping countries, W.H.O considers reported cases to be an underestimate & takes case/death estimates to assess the burden of disease. In 2002, the estimated deaths in all age groups 2,13,000 of which 1,80,000 were attributable to neonatal tetanus. More common in areas where soil is cultivated, in rural areas, in warm climates, during summer, among males.

1. Commonly 5-10 days but may vary from 2 days to several weeks or longer, depending on the extent, location, and character of the wound (3-21-28 days) 2. A short incubation period gives a bad prognosis 3. The longer the incubation period, the greater the probability of recovery

The shorter the incubation period, the poorer the prognosis. Shorter incubation period is 2-3 days. An incubation period of one month has a better prognosis than an incubation period of 2-3 days.

1. Animal and human feces (manure). The organisms are found in the intestinal wall of herbivorous animals, including man. 2. Soil and dust 3. Plaster of Paris, unsterile sutures, pins, rusty metals, scissors

1. Break in skin integrity through punctured wound that is contaminated by dust, soil, or animal excreta containing spores of Clostridum tetani. a. Rugged traumatic wounds and burns b. Umbilical cord stump in newborn especially for babies delivered at home with faulty cord dressing; babies delivered to mothers without Tetanus toxoid immunization c. Unrecognized wounds (cleaning of the ears with sharp materials) d. Dental extraction, circumcision, ear piercing

Range of injuries & accidents trivial pin prick, skin abrasion, puncture wounds, burns, human bites, animal bites & stings, unsterile surgery, IUD, bowel surgery, dental extractions, injections, unsterile division of umbilical cord, compound #, otitis media, ulcers, eye infections, gangrene NOT TRANSMITTED FROM PERSON TO PERSON

C. tetani enters body through a wound causes local infection and tissue necrosis in anaerobic conditions spores germinate (reproduce) toxins produced (TETANOSPASMIN & TETANOLYSIN) disseminated via blood and lymphatics acts at several sites:
1. Central nervous system 2. Spinal cord 3. Brain 4. Sympathetic nervous system

While reproducing, they also release toxins that enter the bloodstream and the lymphatics and eventually spread into the central nervous system, or absorbed by the motor nerve ending and passes up through the axon cylinder, to the anterior horn cells of the spinal cord. This stimulates contraction of the muscles supplied by the neurons to which the toxin diffuses.

Contamination of wounds with spores of C.tetani. Germination & toxin production in wounds with low oxidation reduction potential (devitalized tissues, active infection ) Tetanospasmin (neurotoxin) Tetanolysin (hemolysin)

Tetanospasmin (exotoxi) produced locally , released into bloodstream Binds to peripheral motor neuron terminals & nerve cells of ant.horn of spinal cord The toxin after entering axon , transported to nerve cell body in brain stem & spinal cord retrograde intraneuronal transport Toxin migrates across synapse presynaptic terminals- blocks the release of Glycine & GABA from vesicles.

The blocking of neurotransmitter release by Tetanospasmin involves cleavage of Synaptobrevin essential for proper fn of synaptic vesicle release apparatus With diminished inhibition resting firing rate of alpha motor neurons increases rigidity Lessened activity of reflexes which limit polysynaptic spread of impulses, agonists & antagonists recruited - spasms

Loss of inhibition of preganglionic sym neurons sympathetic hyperactivity

1. Clinical Observation - based entirely on clinical findings a. Assess patient physically b. Assess for the presence of lockjaw c. If lockjaw is positive, a logical question would be Do you have a wound? 2. Examine all cases with wound infection & muscle stiffness 3. Wound cultures in suspected cases, C. tetani can be isolated from wounds of pts without tetanus & frequently cannot be isolated from wounds of those with tetanus. If there is afresh wound, microorganisms are still present there. 4. Electromyograms continous discharge of motor units, shortening / absence of silent interval seen after AP. 5. Muscle enzymes raised


1. Spinal Cord a. Striated muscles Lockjaw b. Trigeminal nerves Trismus c. Facial nerves Risus Sardonicus d. Spinal nerves - Opisthotonus 2. Brain Respiratory Center Pharyngeal Spasm Abdominal Spasm General Rigidity (Tonic)

Traumatic Puerperal Otogenic Idiopathic Tetanus neonatorum Generalized Neonatal Local

Clinical Features
May begin from 2 days to several weeks after the injury USUALLY 1

Remember Shorter the incubation period More severe the attack Worse the prognosis

Clinical features
GENERALIZED TETANUS Most common Increased muscle tone & generalized spasms Median time of onset after injury 7 days Pt 1st notices increased tone in masseter ( Trismus, lock jaw ) Dysphagia Stiffness / pain in neck, shoulder, back muscles appear concurrently / or soon thereafter Rigid abd & stiff prox.limb muscles . Hands, feet spared.


Risus Sardonicus : Spasm of facial muscles ( frontalis & angle of mouth muscles ) producing grinning facies Opisthotonus : Painful spasms of neck, trunk and extremity. producing characteristic bowing and arching of back Some pts devolep paroxysmal, violent, painful, generalized muscle spasms cyanosis . Spasms occur repetitively & may be spontaneous /provoked by slightest stimulation. Constant threat during general spasm is reduced ventilation, apnea / laryngospasm.

Risus sardonicus

Mild ds ( muscle rigidity , no / few spasms ) Moderate ds (trismus, dysphagia, rigidity, spasm) Severe ds ( freq explosive paroxysms ) Autonomic dysfn complicates severe cases - labile htn, hyperpyrexia, profuse sweating, peripheral vasoconstriction, raised catecholamines.

Neonatal Tetanus
Usually fatal if untreated Children born to inadequately immunized mothers, after unsterile treatment of umbilical stump During first 2 weeks of life.

Poor feeding ,rigidity and spasms

Local Tetanus
Uncommon form Manifestations are restricted to muscles near the wound. Cramping and twisting in skeletal muscles surrounding the wound local rigidity

Prognosis excellent

Cephalic Tetanus
A rare form of local tetanus Follows head injury / ear infection Involves one / more facial cranial nerves Trismus and localised paralysis, usually facial nerve, often unilateral. Incubation period : few days Mortality : high

1. Clinical Observation - based entirely on clinical findings a. Assess patient physically b. Assess for the presence of lockjaw c. If lockjaw is positive, a logical question would be Do you have a wound? 2. Examine all cases with wound infection & muscle stiffness 3. Wound cultures in suspected cases, C. tetani can be isolated from wounds of pts without tetanus & frequently cannot be isolated from wounds of those with tetanus. If there is afresh wound, microorganisms are still present there. 4. Electromyograms continous discharge of motor units, shortening / absence of silent interval seen after AP. 5. Muscle enzymes raised

Serum Anti toxin levels >= 0.1 IU/ml protective & makes tetanus unlikely .

1. Prevention 1.1 Active Immunization with tetanus toxoid (TT) 6 weeks after birth (together with Diphtheria and Pertussis/DPT): 0.5 ml for 3 doses (4-8 weeks interval)

DPT Immunization for Pregnant Individuals Dose: 0.5 ml Route: Intramuscular Number of Doses given: a. Two (2) doses with three (3) booster doses or; b. Two (2) doses with booster dose given every pregnancy When given: a. 1st Dose: Anytime during second trimester of pregnancy b. 2nd Dose: With one (1) month interval c. Booster Dose: Given with successive pregnancy/ies

1. Prevention 1.2 Tetanus Toxoid for non-pregnant women 1st Dose (TT1) given anytime 0.5 ml IM 2nd Dose (TT2) after 1 month 3rd Dose (TT3) after 6 months 4th Dose (TT4) after 1 year 5th Dose (TT5) after another year Booster Dose given after 10 years

Succeeding doses of Tetanus Toxoid are given based on DATE OF LAST DOSE If a person is high-risk, give booster dose every five (5) years If a person is low risk, give booster dose every ten (10) years Effect of TT administration on the mother Slight soreness or heaviness on site of injection

1. Prevention 1.3 Antitoxin is used for the treatment of clinical tetanus and for passive immunization or prophylaxis in recently wounded individuals never previously immunized with tetanus toxoid

Prevention Active Immunization

For partially immunized, unimmunized and recovering from tetanus

It stimulates production of protective antitoxin 2 prep : combined vaccine : DPT monovalent vaccine : plain / formol toxoid tetanus vaccine , adsorbed

2. Control 2.1 Medical Aseptic technique 2.2 Concurrent Disinfection (all materials contaminated with secretions should be securely wrapped in paper and burned ASAP) and Terminal Disinfection (walls and furniture washed with soap and water, room thoroughly aired, mattress and pillows autoclaved or aired/sunned for 6-8 hours)


Wash wound with soap and running water Place antiseptic solution on wound Use thin dressing Band Aid Plastic Strips are allowable as they have air ventilation holes Do not use plaster Use only those types of plasters with air ventilation holes to introduce oxygen to the wound

3. Treatment 3.1 Medical Care objectives are: a. Neutralize the toxin top priority since the toxin is responsible for the S/Sx of the disease and the systemic infection (1) Give anti-tetanus serum (ATS) or tetanus anti-toxin (TAT) Comes from a horse serum Do SKIN TESTING first If (-) for skin test, inject TIG 0.01 ml in 0.09 ml NSS. Epinephrine or steroid is given to counteract prophylaxis (2) If (+) for skin testing, DO NOT GIVE the drug Resort to human serum tetanus immunoglobulin (TIG) a) Give skin test first: anti-tetanus serum (ATS) b) If skin test is negative, inject Tetanus Anti-Toxin (TAT) 0.01 ml in 0.09 ml NSS. Epinephrine or steroid is given to counteract prophylaxis.

In the Philippine setting, the horse serum is given despite a (+) skin test. This is done by giving fractional doses. Example: Initial administration of 0.01 of drug and 0.099 PNSS After 30 minutes, 0.05 of the drug and 0.95 of PNSS After another 30 minutes, another increase in the dose of the drug When administering tetanus horse serum, always have ready the following:
a. EPINEPHRINE b. CORTICOSTEROID These would be necessary to counteract any delayed reaction, which may cause hypersensitivity reactions leading to anaphylaxis and eventually the death of the patient.

NEUTRALIZE TOXIN : Inj. Human Tetanus Immunoglobulin (TIG) 3000 6000 units IM, usually in divided doses as volume is large. ANTIBIOTIC THERAPY : Although of unproven value , antibiotics adm to eradicate vegetative cells the source of toxin IV Penicillin 10 -12 million units daily for 10 days IV Metronidazole 500mg Q 6 hrly / 1gm Q 12 hrly Allergic to Penicillin : consider Clindamycin & Erythromycin

b. Kill the microorganism (1) Give IV Penicillin (drug of choice): antibiotic to kill the bacteria (eradicate vegetative cells) & is given 1 hour before meals or 2 hours after meals for bioavailability. If allergic to penicillin, consider Clindamycin & Erythromycin (2) On the fresh wound, do daily cleansing with the use of hydrogen peroxide. (3) Then apply antiseptic solution like Betadine or Povidone (4) Then cover wound with THIN DRESSING to allow air to circulate through the wound (5) It may also be good to expose the wound but avoid contact with flies.

c. Prevent and control spasms (1) Muscle relaxants Given during acute phase of tetanus; done via the IV route methocarbamol (Robaxin, Robaxisal), Lionesal (Baclofen), Eperison (Myonal) May be given per orem when the patient is on his way to recover (2) Sedatives Valium (diazepam); use IV push or IV drip Concept: I.V. drip regulation is titrated based on the frequency of the spasm The more frequent the spasm, the faster the rate of the titration. (3) Tranquilizers Thorazine

(4) Continued spasms : intubate & ventilate (5) Proceed with other supportive management a. For urinary retention, do catheterization b. For constipation, administer laxatives as ordered.

CONCEPT: Stimuli triggers spasms

Types of Stimuli: (1) Exteroceptive Stimuli Comes from outside environment of the patient Examples: bright light and noise Place the patient in dim and quiet environment (2) Interoceptive Stimuli Comes from inside or within the patient Examples: stress, pain, coughing, passage of flatus (3) Proprioceptive Stimuli There is participation of the patient and other people Examples: touching, turning, jarring the bed of the patient

3.2 Nursing Care done to prevent patient from having spasms a. Place the patient should be in a quiet, darkened/dimmed, wellventilated, and non-stimulating environment
CONCEPT: Patients are isolated so as not to be exposed to stimuli.

b. Practice Minimal/gentle handling of patient.

Touching and Turning is not contraindicated
However, do these as gently as possible Inform the patient before proceeding with any procedure

c. Practice Cluster Care

Do all nursing activities in one setting Proper scheduling of nursing care activities so as not to disturb patient often: daily cleansing bath with warm water, change position, oral hygiene Do other nursing care activities with vital signs taking

3.2 Nursing Care d. Liquid diet of 3,000-4,000 calories via tube feedings as indicated e. Prevent injury (1) Do not leave patient alone (2) Siderails of bed always raised (3) Padded tongue blades or metal spoon to guard against respiratory obstruction e. Proper wound care wash with flowing water, then rinse with antiseptic solution and cover with thin dressing

Treatment general measures

Goal is to eliminate the source of toxin, neutralize the unbound toxin & prevent muscle spasm & providing support - resp support Admit in a quiet room in ICU Continuous careful observation & cardiopulmonary monitoring Minimize stimulation Protect airway Explore wounds debridement

Management of autonomic dysfn

Labetalol Continuous infusion of esmolol Clonidine / verapamil

Additional measures
Pts recovering from tetanus should be actively immunized Hydration Nutrition Physiotherapy Prophylactic anticoagulation Bowel, bladder, back care Treatment of intercurrent infection

DPT (Diphtheria Pertussis Tetanus) Vaccine

When given: 1st Dose: 6 weeks after birth; 0.5 ml 2nd Dose: 10 weeks after birth; 0.5 ml 3rd Dose: 14 weeks after birth; 0.5 ml Number of Doses: three (3) Interval between Doses: Four (4) weeks Administration Site: Vastus lateralis muscle Route: Intramuscular


a. Expect fever to set in after administration of DPT vaccine Give paracetamol Apply warm compress for better drug absorption Immediately follow up with cold compress to avoid soreness b. If tenderness or swelling on site of injection is present: Do cold compress within twenty-four (24) hours Then do warm compress c. Observe for signs of convulsions within seven (7) days after DPT immunization This indicates that child has reaction with the pertussis component of the drug. Therefore, succeeding doses of DPT will NOT BE GIVEN Give ONLY the DT components If DPT is given again, this predisposes the child to neurologic disorders d. Observe if child cries uncontrollably


d. Observe if child cries uncontrollably This is an indication of development of neurologic disorders.

Monovalent vaccines
Purified tetanus toxoid ( adsorbed ) supplanted the palin toxoid higher & long lasting immunity response Primary course of immunization 2 doses Each 0.5 ml , injected into arm given at intervals of 1-2 months The longer the interval b/w two doses, better is the immune response 1st booster 1 yr after the initial 2 doses 2nd Booster : 5 yrs after the 1st booster ( optional ) Freq boosters to be avoided

Passive immunization
Temp protection human tetanus immunoglobulin /ATS Human Tetanus Hyperimmunoglobulin : 250-500 IU Does not cause serum sickness Longer passive protection compared to horse ATS( 30 days / 7 -10 days )

Passive immunization
ATS ( EQUINE ) : 1500 IU s/c after sensitivity testing 7 10 days High risk of serum sickness It stimulates formation of antibodies to it , hence a person who has once received ATS tends to rapidly eliminate subsequent doses.

Active & Passive Immunization

In non immunized persons 1500 IU of ATS / 250-500 units of Human Ig in one arm & 0.5 ml of adsorbed tetanus toxoid into other arm /gluteal region 6 wks later, 0.5 ml of tetanus toxoid 1 yr later , 0.5 ml of tetanus toxoid

Prevention of neonatal tetanus

Clean delivery practices 3 cleans : clean hands, clean delivery surface, clean cord care Tetanus toxoid protects both mother & child Unimmunized pregnant women : 2 doses tetanus toxoid 1st dose as early as possible during pregnancy 2nd dose at least a month later / 3 wks before delivery

Immunized pregnant women : a booster is sufficient No need of booster in every consecutive pregnancy

Prevention of tetanus after injury

All wounds should be thoroughly cleaned soon after injury Remove all foreign bodies, soil, dust, necrotic tissue A completed course of toxoid/booster < 5 yrs ago B- completed course of toxoid / booster >5 yrs ago & < 10 yrs ago C- completed course of toxoid / booster >10 yrs ago D- not completed course of toxoid / immunity status unknown

Wounds < 6hrs, clean, non penetrating & negligible tissue damage
Immunity Category A B C D Treatment Nothing more required Toxoid 1 dose Toxoid 1 dose Toxoid complete course

Other Wounds
Immunity Category A B C D Treatment Nothing more required Toxoid 1 dose Toxoid 1 dose + Human Tetanus Ig Toxoid complete course + Human Tetanus Ig


Meningitis is an inflammatory process of the leptomeninges and CSF

Space occupying lesions

CNS hemorrhage Brain tumours Brain abscess Metastatic tumours

1. acute pyogenic (bacterial) meningitis 2.acute aseptic (viral) meningitis 3.acute focal suppurative infection (brain abscess,subdural and extradural empyema) 4.chronic bacterial infection (tuberculosis).

Acute pyogenic bacterial meningitis

Most important Can be fatal if untreated Organisms: E.coli ---------- neonates Streptococci B ---------- neonantes H. influenzae-------------adolescents Neisseria meningitidis------------- young adults Streptococcus pneumonia--------- elderly

Clinical signs
Signs of infection (fever,malaise,rigor.) Signs of meningeal irritation: 1.headache 2.neck stiffness 3.photophobia 4.irritability C.S.F by lumbar puncture shows : a.cloudy purulent csf b.abundant neutrophils > 90,000/mm3 c.high protein level and d.reduced glucose level.

Grossly , pyogenic meningitis shows a thick layer of suppurative exudate covers the leptomeninges over the surface of the brain. Exudate in basal surface--- H.INFLUENZAE Exudate in covexity surface--- P.MENINGT Microscopically : neutrophils in the subarachnoid space

Antibiotic treatment------ full recovery Delayed or untreated cases--- can be fatal Healing by fibrosis cause obliteration of subarachenoid space--HYDROCEPHALUS Brain abscess Septic shock and skin rashes, why ?

Skin rashes
Is due to small skin bleed All parts of the body are affeced The rashes do not fade under pressure Pathogenesis: a. Septicemia b. wide spread endothelial damage c. activation of coagulation d. thrombosis and platelets aggregation e. reduction of platelets (cosumption ) f. BLEEDING rashes 2.adrenal hemorrhage Arenal hemorrhage is called Waterhouse-Friderichsen Syndrome.It cause acute adrenal insufficiency and is uaually fatal

Acute Aseptic (Viral ) Meningitis

Can follow any viral infection Less danger CSF shows : 1.lymphocytes 2. mild increase in protein 3. normal glucose level Viral meningitis is usually self-limiting and treated symptomatically.

Brain abscess
Causes : 1. complication of bacterial meningitis 2. bacterial endocarditis 3. pulmonary sepsis : peumoniaetc 4. other sepsis Brain abscess cause a space occupying lesion in the brain

Neisseria meningitidis


General Overview of Neisseria meningitidis

Encapsulated small, gram-negative diplococci Second most common cause (behind S. pneumoniae) of community-acquired meningitis in previously healthy adults; swift progression from good health to lifethreatening disease Pathogenicity: Pili-mediated, receptor-specific colonization of nonciliated cells of nasopharynx Antiphagocytic polysaccharide capsule allows systemic spread in absence of specific immunity Toxic effects mediated by hyperproduction of lipooligosaccharide Serogroups A, B, C, Y, W135 account for about 90% of all infections

Diseases Associated with Neisseria meningitidis

Following dissemination of virulent organisms from the nasopharynx:
Meningitis Septicemia (meningococcemia) with or without meningitis Meningoencephalitis Pneumonia Arthritis Urethritis

Neisseria meningitidis in Cerebrospinal Fluid

Epidemiology of Meningococcal Disease

Humans only natural hosts Person-to-person transmission by aerosolization of respiratory tract secretions in crowded conditions Close contact with infectious person (e.g., family members, day care centers, military barracks, prisons, and other institutional settings) Highest incidence in children younger than 5 years and particularly those younger than 1 year of age as passive maternal antibody declines and as infants immune system matures Commonly colonize nasopharynx of healthy individuals; highest oral and nasopharyngeal carriage rates in school-age children, young adults and lower socioeconomic groups

Age Distribution of Meningococcal Disease in USA

Lacking maternal antibody

Pathogenesis of Meningococcal Disease

Specific receptors (GD1 ganglioside) for bacterial fimbriae on nonciliated columnar epithelial cells in nasopharynx of host Organisms are internalized into phagocytic vacuoles, avoid intracellular killing in absence of humoral immunity and complement system (patients with late complement deficiencies are particularly at risk) Replicate intracellularly and migrate to subepithelial space where excess membrane fragments are released Hyperproduction of endotoxin (lipid A of LOS) and blebbing into surrounding environment (e.g., subepithelial spaces, bloodstream) mediates most clinical manifestations including diffuse vascular damage (e.g., endothelial damage, vasculitis (inflammation of vessel walls), thrombosis (clotting), disseminated intravascular coagulation (DIC)

Skin Lesions of Meningococcemia

NOTE: Petechiae have coalesced into hemorrhagic bullae.

Immunogenicity of Neisseria meningitidis

Following colonization of the nasopharynx, protective humoral immunity develops against the same or closely related organisms of the same serogroup, but not against other serogroups Bactericidal activity of the complement system is required for clearance of the organisms Cross-reactive protective immunity acquired with colonization by closely related antigenic strains and with normal flora of other genera (e.g., E. coli K1); progressive disease can occur in absence of serogroup-specific immunity

Laboratory Characterization of Neisseria meningitidis

Large numbers (e.g., >107cells/ml) of encapsulated, small, gram-negative diplococci (flattened along adjoining side) and polymorphonuclear leukocytes (PMNs) can be seen microscopically in cerebrospinal fluid (CSF) Transparent, non-pigmented nonhemolytic colonies on chocolate blood agar with enhanced growth in moist atmosphere with 5% CO2 Oxidase-positive Acid production from glucose and maltose but not from other sugars

Prevention and Treatment of Meningococcal Disease

Penicillin is drug of choice for treatment in adjunct with supportive therapy for meningeal symptoms Increasing MIC mediated by genetic alteration of target penicillin binding proteins is being monitored) Chloramphenicol or cephalosporins as alternatives Chemoprophylaxis of close contacts with rifampin or sulfadiazine (if susceptible) Polyvalent vaccine containing serogroups A, C, Y, and W135 is effective in people older than 2 years of age for immunoprophylaxis as an adjunct to chemoprophylaxis Serogroup B is only weakly immunogenic and protection must be acquired naturally from exposure to cross-reacting antigens


Encephalitis is an acute inflammatory process affecting the brain Viral infection is the most common and important cause, with over 100 viruses implicated worldwide Symptoms
Fever Headache Behavioral changes Altered level of consciousness Focal neurologic deficits Seizures

Incidence of 3.5-7.4 per 100,000 persons per year

Causes of Viral Encephalitis

Herpes viruses HSV-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, human herpes virus 6 Adenoviruses Influenza A Enteroviruses, poliovirus Measles, mumps, and rubella viruses Rabies Arboviruses examples: Japanese encephalitis; St. Louis encephalitis virus; West Nile encephalitis virus; Eastern, Western and Venzuelan equine encephalitis virus; tick borne encephalitis virus Bunyaviruses examples: La Crosse strain of California virus Reoviruses example: Colorado tick fever virus Arenaviruses example: lymphocytic choriomeningitis virus

What Is An Arbovirus?
Arboviruses = arthropod-borne viruses Arboviruses are maintained in nature through biological transmission between susceptible vertebrate hosts by blood-feeding arthropods Vertebrate infection occurs when the infected arthropod takes a blood meal

Major Arboviruses That Cause Encephalitis

Japanese encephalitis St. Louis encephalitis West Nile

Eastern equine encephalitis Western equine encephalitis

La Crosse encephalitis

West Nile Virus

West Nile Virus

Flavivirus Primary host wild birds Principal arthropod vector mosquitoes Geographic distribution - Africa, Middle East, Western Asia, Europe, Australia, North America, Central America

History of West Nile Virus

1937 - West Nile virus isolated from woman in Uganda 1950s First recorded epidemics in Israel (1951-1954, 1957) 1962 Epidemic in France 1974 Epidemic in South Africa. Largest ever West Nile epidemic. 1996 Romanian epidemic with features similar to those of the North American outbreak. 500 cases and 50 deaths. 1999 Russian outbreak. 40 deaths.

West Nile Virus: 1999 New York Outbreak

Crows dying in and around Queens in late summer 27 deaths among captive birds in the Queens and Bronx zoos Concomitant human infection of apparent encephalitis in the same area

Outbreak was first attributed to St. Louis encephalitis, but tissue samples from dead crows confirmed that it was West Nile virus
59 human cases requiring hospitalization, including 7 deaths

Spread of West Nile Virus in the US

2000 spread throughout New England and Mid-Atlantic regions.
18 new human cases reported

2001 spread throughout the entire eastern half of the US

64 cases reported, with NY, FL and NJ accounting for 60%

2002 spread westward across Great Plains into Western US. Reached California by Labor Day.
By end of 2002 cumulative human cases > 3900, with > 250 deaths

2003 US, Canada, Mexico

9,858 cases reported to CDC, including 262 deaths in 45 states and D.C.

West Nile Activity in the US Reports as of April 7, 2004

West Nile Activity in the US Counties Reporting Cases as of March 24, 2004

West Nile Virus 2004: BREAKING NEWS

April 13, 2004 Ohio may have first 2004 West Nile Case
79 year old man from Scioto County, OH was admitted April 1 with viral meningitis and encephalitis which rapidly progressed to coma over 2 days.
Initial IgM antibody titers were positive for West Nile virus and he complained of itching from insect bites upon admission

Has been treated with blood-pressure drugs to control over-response by the immune system to West Nile virus, causing brain inflammation.
Previously unresponsive and paralyzed. Can now open his eyes and shake his head in response to questions, but still cannot talk.

St. Louis Encephalitis

St. Louis Encephalitis

Flavivirus Most common mosquitotransmitted human pathogen in the US Leading cause of epidemic flaviviral encephalitis

History of St. Louis Encephalitis

1933 virus isolated during St. Louis and Kansas City, MO epidemic 1940s virus spread to Pacific Coast 1959-1971 virus spread to Southern Florida 1974-1977 last major epidemic. Over 2,500 cases in 35 states. 1990-1991 South Florida epidemic. 226 cases and 11 deaths. 1999 New Orleans outbreak. 20 reported cases.

St. Louis Encephalitis

Japanese Encephalitis

Japanese Encephalitis
Flavivirus related to St. Louis encephalitis Most important cause of arboviral encephalitis worldwide, with over 45,000 cases reported annually Transmitted by culex mosquito, which breeds in rice fields
Mosquitoes become infected by feeding on domestic pigs and wild birds infected with Japanese encephalitis virus. Infected mosquitoes transmit virus to humans and animals during the feeding process.

History of Japanese Encephalitis

1800s recognized in Japan 1924 Japan epidemic. 6125 cases, 3797 deaths 1935 virus isolated in brain of Japanese patient who died of encephalitis 1938 virus isolated from Culex mosquitoes in Japan 1948 Japan outbreak 1949 Korea outbreak 1966 China outbreak Today extremely prevalent in South East Asia. 30,000-50,000 cases reported each year.

Distribution of Japanese Encephalitis in Asia, 1970-1998

Eastern Equine Encephalitis

Eastern Equine Encephalitis

Togavirus Caused by a virus transmitted to humans and horses by the bite of an infected mosquito. 200 confirmed cases in the US 1964-present Average of 4 cases per year States with largest number of cases Florida, Georgia, Massachusetts, and New Jersey. Human cases occur relatively infrequently, largely because the primary transmission cycle takes place in swamp areas where populations tend to be limited.

History of Eastern Equine Encephalitis

1831 First recognized as a disease in horses. Over 75 horses died in 3 counties in Massachusetts. 1845-1912 epizootics in Northeast and Mid-Atlantic regions 1933 virus isolated from horse brains 1938 association of human disease with epizootics. 30 cases of fatal encephalitis in children living in same area as equine cases. 1947 largest recorded outbreak in Louisiana and Texas. 13,344 cases and 11,722 horse deaths

Western Equine Encephalitis

Western Equine Encephalitis

Togavirus Mosquito-borne 639 confirmed cases in the US since 1964 Important cause of encephalitis in horses and humans in North America, mainly in the Western parts of the US and Canada

History of Western Equine Encephalitis

Early 1900s epizootics of viral encephalitis in horses described in Argentina 1912 25,000 horses died in Central Plains of US 1930 San Joaquin Valley, CA outbreak. 6000 cases in horses. Virus isolated from horse brains 1938 virus isolated from brain of a child

La Crosse Encephalitis

La Crosse Encephalitis
Bunyavirus On average 75 cases per year reported to the CDC Most cases occur in children under 16 years old Zoonotic pathogen that cycles between the daytime biting treehole mosquito, and vertebrate amplifier hosts (chipmunk, tree squirrel) in deciduous forest habitats

Most cases occur in the upper Midwestern state, but recently cases have been reported in the MidAtlantic region and the Southeast
1963 isolated in La Crosse, WI from the brain of a child who died from encephalitis

Summary Confirmed and Probable Human Cases in the US

Virus Eastern Equine Years 1964-2000 Total cases 182 649 2,776 4,482 > 9,800

Western Equine 1964-2000 La Crosse St. Louis West Nile 1964-2000 1964-2000 1999-present

Molecular Biology of Viruses that can Cause Viral Encephalitis

Flaviviridae: West Nile Virus Togaviridae: Eastern and Western Encephalitis Bunyaviridae: La Crosse Virus


Japanese Encephalitis Virus St. Louis encephalitis virus West Nile Virus

Flavivirus: Virus Classification

Family Flaviviridae 3 Genera
Flavivirus, Pestivirus, Hepacivirus

Flavivirus - 12 Serogroups
Japanese encephalitis virus serogroup
Includes West Nile Virus (WNV), St. Louis Encephalitis, and others

Scanned images of West Nile virus isolated from brain tissue from a crow found in New York.

Viral Replication Cycle

Genome Structure

Viral Genome
Positive Strand RNA Genome 1 ORF Genome encodes single polyprotein which is subsequently cleaved
5 portion
3 structural proteins

3 portion
7 non-structural proteins

Genome also includes 5 and 3 noncoding regions which have functional importance

Secondary structure loops

3 Stem Loop of Plus Strand

Tertiary interactions of 3 non-coding region serve to stabilize and compact the 3 region of the genome and may also create binding sites for cellular and/or viral proteins Pseudoknots Formed by interactions between 3 stem loop and adjacent nucleotides
PK1 May be important for minus strand replication

Interacts with cellular proteins

P104, EF-1, and p84

Conserved Secondary and Tertiary Terminal RNA Structures in Minus Strand

Stem loop structures at 5 and 3 ends are conserved across flavivirus species suggesting a functional importance for these groups. Minus strand stem loops may play a role in facilitating the formation of replication complexes and in releasing newly synthesized minus strands from plus strands. In addition, its interaction with cellular proteins is important for replication.

Viral Proteins: Structural and NonStructural

Structural Proteins
Capsid (C), Membrane (M), Envelope (E)

The envelope - receptor binding

Dimers of E protein arrange their sheets in a head to tail formation which lie flat on top of the lipid bilayer. The distal portions of these proteins are anchored in the membrane

Non-Structural Multifunctional Proteins

NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5

Many functions of non-structural proteins have yet to be determined

Viral Non-Structural Proteins

NS1- may play a role in flavivirus RNA synthesis; it has been shown to be essential for negative strand synthesis NS2A, NS2B, NS4A, NS4B - may facilitate the assembly of viral replication complexes by an unknown mechanism NS3: Multifunctional Proteolytic function upon association with NS2B RNA triphosphatase function thought to be important for the synthesis of the 5 cap structure Helicase and NTPase activity Its activity may be upregulated through interaction with phosphorylated NS5 NS5
RNA dependent RNA polymerase Methyltransferase domain thought to be required for formation of the 5 cap

Model for Closed-Loop Complex Formation in Flaviviruses

Eastern Equine Encephalitis Virus Western Equine Encephalitis Virus Venezuelan Equine Encephalitis Virus

Family: Togaviridae
Genus: Alphavirus

49S Single Stranded Genome

~11700 Nucleotides

3 end: Five potential structural proteins

C, E3, E2, 6K, and E1

5 end: Unknown number of non-structural proteins probably involved in replication Genome has an opposite orientation from the Flaviviruses

Alphavirus Structure

Alphaviruses: Protein Function

E1and E2 glycoprotein heterodimers form trimers that appear as knobs on the surface of the virion
E1 transmembrane glycoprotein with 2 to 3 N-linked glycosylation sites E2 - glycoprotein with 1 to 2 N-linked glycosylation sites, contains short intracytoplasmic tail and hydrophobic stretch of amino acids that serves as the fusion peptide for viral entry

Capsid protein has a conserved N-terminal region which binds RNA and a Cterminal region which interacts with the cytoplasmic tail of E2 as well as capsid proteins E3 and 6K proteins are signal sequences for E2 and E1, respectively, and are largely cleaved off from the mature virion

Replication Cycle
Proposed Model: E1 glycoprotein interacts with proteins on the cell surface. E2 binds to cellular proteins and receptor-mediated endocytosis takes place.

In acidified endosomal compartment, glycoproteins fuse with membrane and the nucleocapsid is released. Virion RNA serves as mRNA, translation of non-structural proteins begins Structural proteins are transcribed as polyprotein E2 and E1 travel from ER to the Golgi At cellular membrane regions containing E1 and E2 heterodimers interact with nucleocapsids and viral particles bud from the cell surface

La Crosse Virus

La Crosse Virus

Genome - single strand of negative sense RNA Four structural proteins
Two external proteins Two associated with RNA to form nucleocapsid

Matrix proteins absent from Bunyaviruses, therefore capsid proteins and envelope glycoproteins directly interact prior to budding


Transmission Cycle is Key to Weaponization

Mosquito vector
Incidental infections

West Nile virus

Bird reservoir hosts

Incidental infections

Vector, Vector, Vector
In areas around NYC mosquitoes are extremely ubiquitous during the summer months

Mosquitoes are already virulent, further genetic engineering is unnecessary A fully effective cure is not available Diagnosis is difficult Widespread Panic would be generated as the outbreak progresses

The Iraq Connection

The US shipped various pathogens, including WNV, to Iraq in the 1980s In 1999 following the West Nile Virus outbreak in NYC there were fears that Iraqi bioterrorism was involved Investigations by the CDC and the CIA found no evidence of bioterrorism in the 1999 outbreak

WNV as a low-tech Bioweapon: Possible Connection to 1999 outbreak

Gather mosquitoes in an endemic area Incubate mosquitoes with a food source Put them to sleep Place mosquitoes in a matchbox Board plane to US Take bus from airport; Release mosquitoes from bus window Wait for outbreak
Source: Dr. Ilya Trakht

Clinical Considerations

Case Study
In August 2002, a 91 year old male from Northern Staten Island who presented initially with sudden onset of fever, left lower extremity weakness, inability to walk, and possibly some transient and mild AMS, was admitted to a Staten Island hospital. He was not considered to have aseptic meningitis or encephalitis and WN virus infection was not considered at that time. After being discharged, he was evaluated by a neurologist for persistent left leg weakness and inability to walk. In April 2003, the neurologist reported this case to the DOHMH as a possible polio case. Serological specimens were forwarded to the NYSDOH where they tested positive for WN virus.

Clinical Considerations

Patient History
Detailed history critical to determine the likely cause of encephalitis. Prodromal illness, recent vaccination, development of few days Acute Disseminated Encephalomyelitis (ADEM) . Biphasic onset: systemic illness then CNS disease Enterovirus encephalitis. Abrupt onset, rapid progression over few days HSE. Recent travel and the geographical context:
Africa Cerebral malaria Asia Japanese encephalitis High risk regions of Europe and USA Lyme disease

Recent animal bites Tick borne encephalitis or Rabies. Occupation

Forest worker, exposed to tick bites Medical personnel, possible exposure to infectious diseases.

History cont.
Japanese encephalitis is more common during the rainy season. Arbovirus infections are more frequent during summer and fall.

Predisposing factors:
Immunosuppression caused by disease and/or drug treatment. Organ transplant Opportunistic infections HIV CNS infections
HSV-2 encephalitis and Cytomegalovirus infection (CMV)

Drug ingestion and/or abuse Trauma

Initial Signs
Headache Malaise Anorexia Nausea and Vomiting Abdominal pain

Developing Signs
Altered LOC mild lethargy to deep coma. AMS confused, delirious, disoriented. Mental aberrations:
hallucinations agitation personality change behavioral disorders occasionally frank psychosis

Focal or general seizures in >50% severe cases. Severe focused neurologic deficits.

Neurologic Signs
Virtually every possible focal neurological disturbance has been reported. Most Common
Aphasia Ataxia Hemiparesis with hyperactive tendon reflexes Involuntary movements Cranial nerve deficits (ocular palsies, facial weakness)

Other Causes of Encephalopathy

Anoxic/Ischemic conditions Metabolic disorders Nutritional deficiency Toxic (Accidental & Intentional) Systemic infections Critical illness Malignant hypertension Mitochondrial cytopathy (Reyes and MELAS syndromes) Hashimotos encephalopathy Traumatic brain injury Epileptic (non-convulsive status) CJD (Mad Cow)

Differential Diagnosis
Distinguish Etiology
(1) Bacterial infection and other infectious conditions (2) Parameningeal infections or partially treated bacterial meningitis (3) Nonviral infectious meningitides where cultures may be negative (e.g., fungal, tuberculous, parasitic, or syphilitic disease) (5) Meningitis secondary to noninfectious inflammatory diseases

Can exclude subdural bleeds, tumor, and sinus thrombosis

Reserved for patients who are worsening, have an undiagnosed lesion after scan, or a poor response to acyclovir.

Clinical signs cannot distinguish different viral encephalitides

Differential Diagnosis cont.

Fever Headache AMS Focal Neurologic Signs Types of seizures Blood: Leukocytosis CSF: Pleocytosis EEG: Diffuse slowing MRI Encephalopathy Uncommon Uncommon Steady deterioration Uncommon Generalized Uncommon Uncommon Common Often normal Encephalitis Common Common May fluctuate Common Both Common Common +Focal Focal Abn.

Clinical Considerations



Clinical Considerations
Laboratory Diagnosis

Laboratory Diagnosis
Diagnosis is usually based on CSF
Normal glucose Absence of bacteria on culture. Viruses occasionally isolated directly from CSF
Less than half are identified

Polymerase Chain Reaction techniques

Detect specific viral DNA in CSF

NEW YORK STATE DEPARTMENT OF HEALTH (NYSDOH) Viral Encephalitis Letter of Agreement for

Physician Ordered Testing by Polymerase Chain Reaction (PCR)

NYSDOH's Wadsworth Center offers the following tests on CSF for viral encephalitis: PCR testing for a panel of viruses, including: herpes simplex, varicella zoster, cytomegalovirus, Epstein-Barr virus, enteroviruses, St. Louis encephalitis (SLE), eastern equine encephalitis (EEE), California encephalitis (including LaCrosse and Jamestown Canyon viruses), Powassan and West Nile (WN) viruses, and Enzyme-linked immunoassay (ELISA) for WN virus. If there is insufficient quantity of CSF (less than 1.0 ml) to conduct both ELISA and PCR for WN virus, please consider the following in determining which test is most appropriate for your patient: ELISA is more sensitive than PCR for WN viral testing and should be considered when there is stronger suspicion of WN virus than other viruses.

PCR is less sensitive for WN virus, but tests for a wide range of viruses. PCR should be considered if viruses other than WN virus are suspected.
Please note your testing priority below or on the viral encephalitis/meningitis case report form. If PCR testing is desired, the agreement below must be completed. Viral Encephalitis PCR Panel West Nile Virus ELISA Antibody Testing

Clinical Considerations
Disease Progression

Disease Progression
Worsening neurologic symptoms Vascular collapse and shock
May be due to adrenal insufficiency. Loss of tissue fluid may be equally important.

Homeostatic failure Decreased respiratory drive

Clinical Considerations

When HSE cannot be ruled out, Acyclovir must be started promptly (before the patient lapses into coma) and continued at least 10 days for maximal therapeutic benefit. Rocky Mountain spotted fever should also be considered, and empiric treatment with Doxycycline is indicated.

Suspected HSE Treatment Plan

Acyclovir is a synthetic purine nucleoside analogue with inhibitory activity against HSV-1 and HSV-2, varicella-zoster virus (VZV), EpsteinBarr virus (EBV) and cytomegalovirus (CMV)
In order of decreasing effectiveness

Highly selective

Acyclovir Action
Thymidine Kinase (TK) of uninfected cells does not use acyclovir as a substrate. TK encoded by HSV, VZV and EBV2 converts acyclovir into acyclovir monophosphate. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Acyclovir triphosphate interferes with Herpes simplex virus DNA polymerase and inhibits viral DNA replication. Acyclovir triphosphate incorporated into growing chains of DNA by viral DNA polymerase. When incorporation occurs, the DNA chain is terminated. Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by HSV-infected cells. Thus, acyclovir is much less toxic in vitro for normal uninfected cells because: 1) less is taken up; 2) less is converted to the active form.

Supportive Therapy
Fever, dehydration, electrolyte imbalances, and convulsions require treatment. For cerebral edema severe enough to produce herniation, controlled hyperventilation, mannitol, and dexamethasone.
Patients with cerebral edema must not be overhydrated. If these measures are used, monitoring ICP should be considered.

If there is evidence of ventricular enlargement, intracranial pressure may be monitored in conjunction with CSF drainage.
Outcome is usually poor. For infants with subdural effusion, repeated daily subdural taps through the sutures usually helps. No more than 20 mL/day of CSF should be removed from one side to prevent sudden shifts in intracranial contents. If the effusion persists after 3 to 4 weeks of taps, surgical exploration for possible excision of a subdural membrane is indicated.

Synthetic adrenocortical steroid Potent anti-inflammatory effects Dexamethasone injection is generally administered initially via IV then IM Side effects: convulsions; increased ICP after treatment; vertigo; headache; psychic disturbances

Clinical Considerations
Patient Prognosis

The mortality rate varies with etiology, and epidemics due to the same virus vary in severity in different years.
Bad: Eastern equine encephalitis virus infection, nearly 80% of survivors have severe neurological sequelae. Not so Bad: EBV, California encephalitis virus, and Venezuelan equine encephalitis virus, severe sequelae are unusual. Approximately 5 to 15% of children infected with LaCrosse virus have a residual seizure disorder, and 1% have persistent hemiparesis.

Permanent cerebral sequelae are more likely to occur in infants, but young children improve for a longer time than adults with similar infections.
Intellectual impairment, learning disabilities, hearing loss, and other lasting sequelae have been reported in some studies.

Prognosis w/ Treatment
Considerable variation in the incidence and severity of sequelae.
Hard to assess effects of treatment.

NIAID-CASG trials:
The incidence and severity of sequelae were directly related to the age of the patient and the level of consciousness at the time of initiation of therapy. Patients with severe neurological impairment (Glasgow coma score 6) at initiation of therapy either died or survived with severe sequelae. Young patients (<30 years) with good neurological function at initiation of therapy did substantially better (100% survival, 62% with no or mild sequelae) compared with their older counterparts (>30 years); (64% survival, 57% no or mild sequelae).

Recent studies using quantitative CSF PCR tests for HSV indicate that clinical outcome following treatment also correlates with the amount of HSV DNA present in CSF at the time of presentation.

Glasgow Coma Scale

Test Eye Opening To pain Response None 2 ____Score 1 To verbal stimuli 3 Spontaneously 4 Best None 1 Verbal Incomprehensible words 2 Response Inappropriate words 3 Disoriented conversation 4 Oriented conversation 5 Best None 1 Motor Abnormal extension 2 Response Abnormal flexion 3 Flexion withdrawal 4 Localizes pain 5 ______________Obeys commands _________6 _ Total score 3-15

Clinical Considerations

None for most Encephalitides JE
Appears to be 91% effective There is no JE-specific therapy other than supportive care Live-attenuated vaccine developed and tested in China
Appears to be safe and effective Chinese immunization programs involving millions of children

Vero cell-derived inactivated vaccines have been developed in China

2 millions doses are produced annually in China and Japan

Several other JE vaccines under development

Public Health Considerations

Endemic Prevention

Infection Control
CDCs Three Ways to Reduce your West Nile Virus Risk
Avoid mosquito bites Mosquito-proof your home Help your community

Avoid Mosquito Bites

Apply Insect Repellent Containing DEET Clothing Can Help Reduce Mosquito Bites
Cover up

Be Aware of Peak Mosquito Hours

Dusk to dawn are peak mosquito biting times for many species.

Mosquito-Proof Home
Drain Standing Water Install or Repair Screens

Community-Wide Efforts
Clean Up Breeding Grounds Ensure Safe Blood Supply Mosquito Control Programs


Blood Supply
NYC Policy Statement reflecting FDA policy: To reduce WN transmission through blood components. Blood donations will be screened for WN virus RNA using nucleic acid amplification tests (NAT). In the event of a NAT-reactive donation, blood centers will remove and quarantine all blood components associated with the donation and notify the state or local health department. In addition, blood testing centers have added screening questions to identify and exclude persons with fever and headache in the week prior to donation.

Mosquito Control Programs

NYC DOHMH Statement: We hope that spraying of adulticides will not be required this summer. However, if there is a threat of an outbreak of human illness and spraying is deemed necessary, targeted adult mosquito control measures (via ground or aerial spraying of pesticides) may be required.

Mosquito Control
But wait, theres more: Same Memo: Confirmed or suspected cases of pesticide poisoning must be reported to the New York State Department of Healths Pesticide Poisoning Registry at (800)-322-6850, and to the New York City Poison Control Center at (212)-764-7667.

Whats Being Sprayed

The adulticides used during the last three seasons in New York City is Sumithrin, a pyrethroid. Although pyrethroids are among the least toxic insecticides, they are nerve poisons, and act upon the sodium ion channels in nerve cell membranes. Inhaling pyrethroid insecticides can cause coughing, wheezing, shortness of breath, runny or stuffy nose, chest pain, or difficulty breathing. Skin contact can cause a rash, itching, or blisters. Sumithrin is not very toxic to mammals, but it is highly toxic to bees and fish.

Crop-Dusting NYC?
Aerosolized liquids sprayed over large areas of the city. Terrorism concern? New vector for urban area.

Public Health Considerations


Since 2000, the NYC DOHMH has conducted comprehensive arthropod-borne disease surveillance and control. In 2003, efforts will again focus on mosquito control through reduction of breeding sites and application of larvicides. In addition, comprehensive mosquito, avian and human data collected during the 2000-2002 seasons have allowed NYC DOHMH to develop more sensitive surveillance criteria for determining the level of WN viral activity in birds and mosquitoes that may indicate a significant risk for a human outbreak. These indicators will be monitored citywide to identify areas at risk for human transmission.

Standing Water Reporting

The Department of Health & Mental Hygiene is now accepting reports of standing water. However, we will not be able to visit and treat all reported nuisances. Therefore we are encouraging City residents and business owners to take immediate action to eliminate standing water on their property.

Dead-Bird Reporting
Online form

The Department of Health & Mental Hygiene is now accepting reports of dead birds. Only a sample of dead birds that meet specific criteria will be picked up and tested for the West Nile virus. However, your report of a dead bird is extremely important to us because dead bird reports may indicate the presence of West Nile virus. If you do not receive a call back from the Department of Health within two business days of making your report, please dispose of the bird.

Mosquito Testing
Five pools of mosquitoes collected in New York City have tested positive for West Nile (WN) virus. These include a pool of Culex salinarius, a human biting mosquito, collected on July 15, in the Willowbrook Park area of Staten Island, a pool of Culex restuans, primarily a bird-biting mosquito, collected from Brookville Park, Queens on July 17, a pool of Culex pipiens, a mosquito that bites both birds and humans, collected from the Hunts Point area of the Bronx on July 18, a pool of Culex species collected from Jamaica Bay, Queens on July 16, and a pool of Culex salinarius collected from Greenwood Cemetery, Brooklyn on July 21. These positive pools are the first evidence of West Nile (WN) virus in New York City in 2003

Disease Reporting
The New York City Department of Health and Mental Hygiene (NYC DOHMH) is again requesting that during the peak adult mosquito season, from June 1 October 31, 2003, all suspected cases of viral encephalitis (all ages) and viral meningitis (adults only) be reported immediately by telephone or facsimile and that appropriate laboratory specimens (cerebrospinal fluid and sera) be submitted promptly for testing for West Nile (WN) virus.


What is Poliomyelitis?
polio= gray matter Myelitis= inflammation of the spinal cord This disease result in the destruction of motor neurons caused by the poliovirus. Polio is causes by a virus that attacks the nerve cells of the brain & spinal cord although not all infections result in sever injuries and paralysis.

When was it reported?

Poliomyelitis was recorded in the late 1700s with the first epidemic in the late 1800s. The cases that were reported in 1979 where mild and self-limited and do not result in paralysis.

How is polio transmitted?

Poliovirus is transmitted through both oral and fical routes with implantation and replication occurring in either the orapgaryngeal and or in the intestine of mucosa. Polio cases are most infected for 710 days before and after clinical symptoms begin.

What are the symptoms?

Many include fever, pharyngitis, headache, anorexia, nausea, and vomiting. Illness may progress to aseptic meningitis and menigoencephalitis in 1% to 4% of patients. These patients develop a higher fever, myalia and sever headache with stiffness of the neck and back.

Polio in children

Can it cause paralyzes?

Paralytic disease occurs 0.1% to 1% of those who become infected with the polio virus. Paralysis of the respiratory muscles or from cardiac arrest if the neurons in the medulla oblongata are destroyed. Patients have some or full recovery from paralysis usually apparent with proximally 6 months Physical therapy is recommended for full recovery.

Bed rest with close monitoring of respiratory and cardiovascular functioning is essential during the acute stage of poliomyelitis along with fever control and pain relievers for muscle spasms. Mechanical ventilation, respiratory therapy may be needed depending of the severity of patients.

Polio vaccine first appeared to be licensed in the United States in 1955. Advantages: Ease to administration Good local mucosal immunity Disadvantage: Strict cold shipping & storage requirements Multiple doses required to achieve high humeral conservation rates against all virus types

Vaccine (continuation)
Babies are given 4 doses through out their infancy. Adolescents and adults should get vaccinated as well. Adolescents younger than 18 should receive the routine four doses. You should get it if you travel outside places where polio id still an epidemic

What is post polio syndrome?

This can affect between 25 to 50 serious of polio. they show symptoms of muscle and joint pain general fatigue and weakness.

Three indications of PPS Previous diagnoses of polio ( late affect of polio to people that got it like when they where 10 years old) Long interval following recovery( people usually live long but effect can occur during 30 to 35 years after the diagnoses) Gradual onset (weakness that tends to be perceptible until it interferes with daily activities)

Polio was one of the most dreaded child disease in the 20th century in the U.S. An epidemic in 1916 killed 6,000 people and left 27,000 more paralyzed. In 1950 parents would not let their children go to local swimming pools or movies because of the polio virus.

Polio fact
The march of dimes began in 1938 a fund-raising campaign for polio. People were asked to send one dime directly to the White House to help fight the disease. In the first 3 days the White House received 230,000 dimes. President Franklin D. Roosevelt, whose profile is now on the dimes was himself paralyzed by polio.


Rabies Virus
Belongs to the genus Lyssavius (lyssa: rage in Greek) Include members of the Rabdoviridae family: Rabies, Makola, Duvenhage Enveloped bullet-shaped virus 5 structural proteins SS RNA, non-segmented, non-polar 12,000 nucletides

Rabies Virus
Envelope contains G-protein spikes, which bind to cells Nucleocapsid core: Matrix (M) protein, viral nucleoprotein (N), viral RNA Transcriptase (L) protein, non-structural protein (NS)

Rabies/Vector transmission
Spill over: Rabid animals transmit rabies among same & other species Compartmentalisation Concept: specific virus variants within a genotype perpetuate among particular hosts in different geographic areas Localized viral evolution: geographic barriers Occasional: emergence of viral variants with extended host range

Rabies/Vector transmission
The dog is the most common cause of Rabies transmission worldwide, Cats 2nd In developed countries: dogs immunized, other species of wild animals are reservoirs Bats: always considered rabid In the past: < 10% of animal rabies in USA and Canada Variants of bat rabies virus has become the most common cause of rabies death

Rabies/Vector transmission
Australia: previously Rabies free Endemic in 1996 Mainly animal infection: any animal may get infected Animal to human transmission Rabies control requires knowledge of animal reservoir, geography of infection Some animal are more infectious than others A single animal species is the source of infection in a certain area

Rabies/Vector transmission
North America Maintained by wild carnivores mainly raccoons, skunks and different bat sp. Central USA, Canada: Striped skunk Mid-Atlantic, SE USA: Raccoon NY, Quebec, Ontario: Red Fox Northwest: Arctic fox Arizona: Gray Fox Texas: Gray fox
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies surveillance in animals/USA

> 92% wild animals, 7.4% domestic species Raccoons: 36.3% most common Skunks: 30.5% Bats: 17.2% Foxes: 6.4% Cats: 3.8% Dogs: 1.2%
Kerbs JW et al.2003.J Am Vet Med Assoc. 223(12):1736-48

Rabies surveillance in animals/USA Massachusetts and Rhode Island: Enzootic in raccoon rabies Rabid skunks cases are exceeding raccoon cases Texas: greatest number of rabid skunks, overall rabid cases All cases of rabies in humans: Bat variants of rabies virus
Kerbs JW et al.2003.J Am Vet Med Assoc. 223(12):1736-48

Distribution of rabies virus variants associated with specific hosts throughout USA
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

Rabies/Vector transmission

Caribbean: Mongoose Europe: Red fox Iran: Wolf Africa: Jackal

Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Global distribution of mammalian rabies reservoirs and vectors

Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

Raccoons are social animals Well adapted to living at high population densities (urban/suburban) Prefer forested habitat

Skunks are another major reservoir of rabies virus in the USA

Rabies in animals/USA
Skunks are solitary animals Lower densities than raccoons Prefer grassland, agricultural areas, interfaces Skunks and raccoons coexist in the same geographic areas Cross-species transmission between skunks & raccoons due to aberrant behavior of rabid animals
Guerra MA 2003. Emerg.Inf.Dis. 9(9): 1143-1150

A productive pathogenesis cycle of animal rabies: virus entry into peripheral nerves via a bite, movement to the central nervous system resulting in encephalitis, and transit to the salivary glands, mediating infection of another host. Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002

Foxes maintain rabies from Arctic areas to temperate and tropical latitudes

Gray fox: A surge of rabies cases among gray foxes in Texas in 2002

Arctic fox

The Jackal is an important candid reservoir of rabies in the old world

Mongoose and related species are important in parts of Africa, Asia & the Caribbean. Transported from Asia for snake control in sugarcane plantations.

Rabid wolves are associated with severe bites and human deaths Wolves may not serve as true rabies reservoirs

Hosts 6/7 lyssavirus genotypes Widespread throughout North America, Latin America Infection rates in bats varies (4% to > 15%) Humans encounter bats that are sick, incapacitated Different bat species vary in their human interaction

Primary reservoir for rabies in All continents.

At least 39 cases in USA Only 9 (23%) has hx. of bite 20 (51%): known or likely contact with bats Bite is most likely mode of transmission Bat rabies viruses vary in their virulence properties Minor lesions should not be ignored
Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002

IP: usually < 10 days May be one year Change in disposition, restlessness, fear Furious or dumb syndrome Death within 10d of symptoms Wild animals: similar symptoms, lack of fear of man
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies/Vector transmission

The Lancet Neurology Vol 1 June 2002

A rabid dog displaying the classic form of paralytic rabies, including cranial-nerve deficits and hypersalivation
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

Infected animal saliva inoculated by by bite or scratch Infected saliva: contact with mucous membrane, transdermal exposure Virus shed in the saliva during, before or after clinical symptoms Human-Human: few reported cases following corneal transplantation Aerosol transmission: caves containing bats, lab work accident
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Risk of acquisition:
bite 5-80% Scratch 0.1-1.0%

Lyssavirus genotype dependent Dog: Nicotinic acetylcholine receptor on muscle Bat: Unknown receptor on epidermis /dermis Skunks: rabies virus antigens and genome can persist for months in muscle: host clearance, treatment

Budding from the plasma membrane of muscle cells into unmyelinated nerve endings Retrograde axoplasmic flow to the CNS Virus replication in dorsal root ganglia (DRG) and anterior horn cells Immune response to virus in DRG: neuropathic pain (Bat>dog) Prophylaxis at this stage cannot prevent death

Direct access of virus to peripheral nerves Travel to CNS at rate of 8-20mm/day Neuromuscular junction is the major site of entry into neurons Receptors on nerves that are used by the virus: Nicotic acetylcholine, neural adhesion molecule (CD56), NGF (p75 neurotrophin) receptor Viral spread to other neural cells via G-protein

Rabies/Pathogenesis CNS infection

Virus reaches CNS: rapid dissemination Preferential localization in brain stem, thalamus, basal ganglia, spinal cord Clinical manifestations of rabies are not totally explained by host, viral strain, virus localization Development of paralytic rabies is more likely after bite by vampire bat Paralytic rabies may have genetic predisposition

Rabies/Pathogenesis CNS infection

Cellular immunity may accelerate clinical picture Production of cytokines, pro-inflammatory mediators and chemokines in the CNS Cytokines modify hippocampus, limbic system, hypothalamic-pituitary-adrenal axis, serotonin metabolism Activation of p75 TNF receptor: recruitment of T and B cells In addition; viral induced depletion of metabolic pools, cell death

Rabies/Pathogenesis CNS infection

Eventually, the virus spreads centrifugally from the CNS to the heart, skin, salivary and serous glands in the tangue All major organs may contain the virus (except blood) Organs from patients with unexplained neurologic disease may transmit rabies by transplantation
Hemachudha T., The Lancet Neurology Vol 1, June 2002

Rabies/clinical manifestations
Most cases are males < 15yr 4 phases of illness First phase: asymptomatic Virus IP: 10-90 days (4d-19yr)

Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies/clinical manifestations
Second (prodromal) phase 2-10d Viral invasion of CNS (limbic system, spinal cord, brain stem) Respiratory symptoms Gastrointestinal symptoms Behavioral & emotional symptoms Local pain itching, numbness (50%)
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies/clinical manifestations
Third phase: neurologic signs Widespread infection of the brain Furious:

Hyperactive form Aggressiveness, biting, yelling, hallucinating Triggered by sensory stimuli Hydrophobia: drinking liquids Aerophobia: air blown on face Violent diaphragmatic contractions Hyper-reflexia, cholinergic manifestations lacrimation, salivation, mydriasis, pyrexia

Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Non-Classical Rabies/clinical manifestations

Most commonly after Bat exposure Bat rabies is different from dog rabies Third phase: neurologic signs Paralytic form: 20% of patients Flaccid paralysis and paresis Mimics GBS, transverse myelitis Inflammation is more extensive and severe Spinal cord markedly involved
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Non-Classic Rabies/clinical manifestations

Neuropathic pain, radicular pain, objective sensory and motor deficits Choreiform movements of the bitten limb during prodromal phase Focal brain stem signs, myoclonus Hemiparesis, hemisensory loss, ataxia, vertigo, Horners syndrome Seizures, ataxia

Non-Classic Dog Rabies/clinical manifestations

Ocular myoclonus, hemichorea Nocturnal agitation Repeated spontaneous ejaculation (autonomic dysfunction) Paraparesis Facial & pulbar weakness Bilateral arm weakness Seizures, ataxia

Rabies/clinical manifestations
Both forms: Fever Nuchal rigidity Paresthesia Fasiculations Convulsions Hypersalivation Hyperventilation
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies/clinical manifestations
Fourth phase: Coma Extensive cortical virus spread Death usually in 7 days Respiratory arrest Myocarditis Supportive care: sedation and analgesia
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Inspiratory spasms Sinus tachycardia Supraventricular and ventricular arrhythmias Reduced ejection fraction in all cases
Viral invasion of sinus node A-V node Myocarditis

Main cause of death: Circulatory collapse Hematemesis: 30-60% of patients 6-12 hrs before death

Rare survivors Atypical presentations 1972: bat related, unsteady gait, dysarthria, hemiparesis 1976: dog bite, quadreparesis,myoclonus, cerebellar signs,frontal lobe signs 1977: Lab worker, aerosol exposure to highly concentrated fixed rabies virus 1992-1995: 4 Mexican children (3:dog, 1: vampire bat), received vaccine, no Ig

Rabies/clinical manifestations
Mortality depends on
Severity of injury: bleeding Location of the wound: face,head, neck, hand: short IP Virus conc. in saliva

Rabies mortality of untreated bite by rabid dog: 38-57% Rabid wolves: MR 80% Rabid bats: risk even with superficial wound (replication of virus in epidermis/dermis)

Frequently missed Lab tests are non diagnostic Hyponatremia: inadequate intake, SIADH hypernatremia,: rare CSF analysis normal in 1/3 of patients in the 1st wk of illness CSF: viral meningoencephalitis EEG and head CT may be normal early in illness

MRI: abnormal, ill defined, increase signal intensity on T-2 images Areas involved: brainstem, hippocampi, hypothalami, deep & subcortical white and grey matter Godalinium enhancement only in late stages
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Viral culture: skin biopsy of the hair follicles at nape of the neck Virus culture: saliva, CSF, urine, respiratory secretions Culture in mice or in mouse neuroblastoma cell line Sensitivity 50-94%, specificity 100%
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Diagnosis/Tissue studies
Brain tissue: culture, histology for Negri bodies: yield low Immunohistochemistry on tissue Brain tissue: Immunostain (higher yield)
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Rabies specific antibodies in serum or CSF (RFFIT) Serology positive in serum in 7 days of symptoms Serology positive in CSF in 13 days of symptoms Rabies vaccine does not cause positive CSF antibodies Molecular studies, monoclonal antibodies in epidemiologic studies
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Section of rabid human brain processed by the DFA test, showing widespread viral inclusions, staining apple-green in colour
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

A neuron from a formalin-fixed section of a brain from a patient with rabies, showing reddish-brown viral inclusions in the cytoplasm. Processed by immunohistochemistry.
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

Immunofluorescent viral inclusions in a peripheral nerve in a cryostat section from a patient with rabies, obtained via an antemortem nuchal skin biopsy.
Rupprecht CE, The Lancet Infectious Diseases Vol 2 June 2002

Rabies/Differential Diagnosis
Meningitis/Encephalitis: Japanese, eastern equine, West Nile V., enterovirus 71, Nipah V. Epilepsy Drug toxicity Acute hepatic porphyria, neuropsychiatric disturbances Substance abuse, acute serotonin syndrome

Rabies/Differential Diagnosis
Tetanus: reflex spasms but clear sensorium, spasms of axial muscles, opisthotonus Paralytic rabies: GBS, Inflammatory polyneuropathy Side effects of nerve tissue vaccines: Semple vaccine, mouse brain vaccine (paralytic symptoms), but no phobic spasms, no local symptoms, no mental status changes

Pre-exposure prophylaxis: vaccination of people in high risk groups: Veterinarians Animal handlers Certain lab workers Travel to areas where canine rabies is common
Hammond GW (Principles and Practice of Pediatric Infectious diseases)

Pre-exposure prophylaxis: vaccination: intramuscular, 1ml (3 doses): at 0, 7, 21-28 days Antibodies usually persist for 2 yrs Repeat titers q6-24 months depending on level of exposure Acceptable titer levels are 1:5 or 0.5 IU/ml (RIFFT)
Red Book 2003

Rabies/Prevention vaccine types

Human Diploid Cell Vaccine (HDCV) Rabies Vaccine adsorbed (RVA) Purified chicken embryo cell (PCEC)
Red Book 2003

Rabies/Post-exposure prophylaxis
Consult local health department Type of animal bite Unprovoked attack vs a bite during attempt to feed or handle the animal Immunized animals: minimal risk Prophylaxis to anyone bitten by
wild mammalian carnivores bats potentially infected domestic animals

Red Book 2003

Postexposure treatment recommendations of the Advisory Committee on Immunization Practices

Rabies/Post-exposure prophylaxis
Exposure other than bite rarely causes infection Prophylaxis to patients with open wound scratch mucous membrane contaminated by saliva or potentially infectious material from rabid animal
Red Book 2003

Rabies/Post-exposure prophylaxis
Prophylaxis to patients with bat exposure if bite or mucous membrane exposure cannot be reliably excluded Bat in a room with pt asleep Bat in a room with unattended child No prophylaxis if bat caught and promptly tested negative
Red Book 2003

Rabies/Post-exposure prophylaxis
Humans with rabies Prophylaxis to people with sig. exposure to a rabies pt. if

scratch bite mucous membrane exposure to saliva or infectious tissue

No prophylaxis if casual contact (touching) or exposure to non-infectious material (urine, stool)

Red Book 2003

Post-exposure wound care

Prevent virus in wound from reaching neural tissue Prompt and thorough cleaning: flush wound with soap and water Benzalkonium chloride not superior to soap Update tetanus immunization Treat secondary bacterial infection Do not suture wound if possible
Red Book 2003

Post-exposure immunoprophylaxis
Passive and active Start ASAP RIG and rabies vaccine Vaccine : one of the 3 types (5 doses), same dose for all ages 1.0 ml IM at 0, 3, 7, 14, 28 d Intradermal regimens:used in some countries, not USA Avoid gluteal injection: less antibody response than deltoid or AL thigh
Red Book 2003

Human RIG is Given at the same time with the vaccine (ASAP) Dose: 20 IU/kg As much as possible to infiltrate the wound Remainder is given IM RIG and vaccine are Give at different sites & in different syringes Purified equine RIG (outside USA): dose is 40 IU/kg, may need desensitization
Red Book 2003

Persons who received a 3-dose pre-exposure rabies vaccine Those with adequate antibody response after previous immunization: give 2 doses of vaccine at 0,3 days Those who received postexposure prophylaxis with rabies vaccine (>7 d)
Red Book 2003

Immunoprophylaxis/RIG contraindications

Rabies Vaccine Adverse effects Less common in children than adults Adults: local rxn. (15-25%) Mild systemic rxn. (10-20%) Neurologic illness resembling GBS Acute generalized transient neurologic syndrome: not causally related Immune-complex reactions with booster doses of HDCV: 6%
Red Book 2003

Handling of suspected rabid animal

Management depends on the species, the circumstances of the bite and local epidemiology of rabies Dog, cat, ferret with suspected rabies should be captured and observed for signs of illness x 10 days If ill: euthanatized, head removed and shipped for examination Species with unknown periods of viral shedding may still be euthanatized and tested even if immunized
Red Book 2003

Bats, skunks, raccoons, foxes, most other carnivores:

Regard as rabid unless geographic area is known to be free of rabies or until animal proven negative by lab testing Immediate immunization and RIG
Red Book 2003

Livestock, rodents, and lagomorphs (rabbits & hare):

Consult local health department Bites of squirrels, gerbils, hamsters, guinea pigs, rats, mice, other rodents, rabbits, hare almost never require anti-rabies treatment
Red Book 2003

Handling of suspected rabid animal

Wild animals with suspected rabies should be euthanatized at once and brain tested for rabies No treatment for rabies if animal brain tests negative by rapid test (fluorescent antibody testing)
Red Book 2003

Rabies prevention
Educating children to avoid contact with stray or wild animals Avoid trying to capture or provoke stray animals Avoid touching animal carcasses Secure garbage Chimneys, other entrances should be covered International travelers: avoid contact with stray dogs, consider rabies vaccine
Red Book 2003

Post Exposure Prophylaxis/WHO

Category I:
touching feeding potentially rabid animal licking intact skin

no treatment Category II:

nibbling on uncovered skin licks on broken skin minor scratches without bleeding

wound disinfection, vaccine only

Post Exposure Prophylaxis/WHO

Category III:
Single, multiple transdermal bites Contamination of scratches or MM with saliva

wound cleansing, rabies IG, vaccine Animal observation in developing countries is not practical: frequent bites, delayed lab testing Delay treatment only if:

Species unlikely to be infected Lab diagnosis in 48hr Dog >1yr old with current vaccination (observe for 10d)

Prophylaxis/Nerve tissue vaccines

Not licensed in USA, available worldwide Only available vaccines in some countries Nerve tissue from sheep, goats, suckling rodents, mouse brain Subcutaneously 7 daily doses, plus days 10,20 and 90

Rabies Vaccine nerve tissue vaccines

Inactivated vaccines Neuroparalytic reactions in 1:2000 to 1:8000 Discontinue if a neurologic reaction occurs Steroids for life-threatening reactions
Red Book 2003

Rabies Vaccine variations

Attempts to reduce the cost of PEP Reduced IM regimen (2-1-1): 2 doses on day 0, 1 dose (day 7), 1 dose (day 21) Intradermal regimens 8 site regimen: 8-0-4-0-1-1 (0.1ml doses): sites include both deltoids, lat thighs, lower quadrants of the abdomen, suprascapular areas 2 site regimen: 2-2-2-0-1-1 (each=20% of IM dose): deltoids

Rabies post-exposure vaccination schedules for the rabies-naive patient

Rupprecht CE et al, The Lancet Infectious Diseases Vol 2 June 2002